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Clinically Important Drug Interactions with Zopiclone, Zolpidem and Zaleplon

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Abstract

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted.

Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H2 receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs.

Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this. Another explanation may be a difference in CYP metabolism. While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation.

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Acknowledgements

The authors were supported by the following grants from the National Institutes of Health, US Department of Health and Human Services: MH-58435, DA-13209, DA-13834, DK-58496, DA-05258, RR-00054. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave, Boston, Massachusetts, 02111, USA

    Leah M. Hesse, Lisa L. von Moltke &  David J. Greenblatt

  2. The Division of Clinical Pharmacology, Tufts-New England Medical Center, Boston, Massachusetts, USA

    Leah M. Hesse, Lisa L. von Moltke &  David J. Greenblatt

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  1. Leah M. Hesse
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  2. Lisa L. von Moltke
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  3. David J. Greenblatt
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Correspondence to David J. Greenblatt.

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Hesse, L.M., von Moltke, L.L. & Greenblatt, D.J. Clinically Important Drug Interactions with Zopiclone, Zolpidem and Zaleplon. CNS Drugs 17, 513–532 (2003). https://doi.org/10.2165/00023210-200317070-00004

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