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Zolpidem

A Review of Its Use in the Management of Insomnia

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Summary

Abstract

Zolpidem (Ambien®, Stilnox®, Myslee®), an imidazopyridine, is a nonbenzodiazepine hypnotic indicated for the short-term treatment of insomnia.

Zolpidem improves sleep in patients with insomnia. Its overall tolerability is favourable when administered according to the manufacturer’s prescribing information, with a low propensity to cause clinical residual effects, withdrawal, dependence or tolerance. In addition, most evidence suggests that the drug is associated with minimal rebound insomnia. In the only clinical trials that investigated the use of a hypnosedative drug in an ‘as-needed’ regimen, zolpidem produced a global improvement in sleep. Thus, zolpidem continues to be a useful therapeutic option in the pharmacological treatment of patients with insomnia.

Pharmacological Properties

Zolpidem, an imidazopyridine, is a GABAa agonist, with selective binding affinity for the benzodiazepine ω1 receptor. In general, zolpidem does not alter sleep architecture.

There were no significant next-day (i.e. >8 hours post-dose) clinical residual effects of zolpidem versus placebo in patients with insomnia in trials that used psychomotor or memory tests. In addition, differences in next-day effects on psychomotor function in patients with insomnia significantly favoured zolpidem 10mg versus zopiclone 7.5mg, flurazepam 30mg or flunitrazepam 1mg recipients.

Although psychomotor function was generally significantly impaired with zolpidem versus placebo ≤7 hours post-dose (i.e. during the night) in healthy volunteers (including some aged 64–79 years), these effects were absent the next day (from about 8 hours post-dose). There was generally no significant memory impairment with zolpidem relative to placebo, from about 8 hours post-dose. However, in one trial, anterograde amnesia was reported in zolpidem or triazolam recipients, but not zaleplon recipients. Some, but not all, studies found a significant effect of zolpidem on memory during the night (≤7 hours post-dose). However, the impairment was less severe than that with zopiclone.

Zolpidem 10mg is absorbed rapidly; the mean time to maximum plasma concentration is 1.4 hours (with a single dose), and the absolute oral bioavailability of the drug is ≈70%.

The drug is almost entirely protein bound in the plasma (92%). Although zolpidem is metabolised extensively, all three metabolites are inactive. Elimination is also rapid, with a mean terminal elimination half-life of 2.1 hours for a single dose of zolpidem 10mg.

Dosage adjustment is recommended for patients with hepatic impairment and in the elderly, since the mean maximum plasma concentration and area under the plasma concentration-time curve are increased in these patient groups. Dosage adjustment of zolpidem may also be required when coadministered with CNS-depressant drugs as these agents may enhance the CNS effects of any hypnosedative drug, including zolpidem.

Therapeutic Efficacy

Zolpidem is an effective hypnotic when used in a continuous regimen in adult and elderly patients with insomnia in trials of up to 5 weeks’ duration, and in trials of up to 12 weeks’ duration in adult patients with insomnia when used in ‘as-needed’ or intermittent regimens. Zolpidem 10 mg/day was at least as effective as trazodone 50 mg/day, was not inferior to zopiclone 7.5 mg/day and had broadly similar efficacy to doxylamine 15 mg/day, triazolam 0.25 or 0.5 mg/day, flunitrazepam 1 mg/day, or nitrazepam 5 mg/day (in trials in adult patients). Similarly, the efficacy of zolpidem 5 mg/day was not significantly different from that of triazolam 0.125 or 0.25 mg/day, or temazepam 15 mg/day in trials in elderly patients but was superior to zaleplon 5 mg/day for total sleep time.

Zolpidem 10 mg/day is effective when used on an ‘as-needed’ basis in patients with insomnia according to global efficacy ratings, although results across studies for sleep parameters are mixed. In three placebo-controlled trials of 4–12 weeks’ active treatment duration in patients with primary insomnia, subjective global ratings of efficacy were better in zolpidem than in placebo recipients. Total sleep time was improved versus placebo in two of these trials. In general, there was no significant difference between treatment groups for most other sleep parameters, and where differences were observed these were not consistent across studies. A placebo effect was evident in one trial. The equivalence of the intermittent and continuous zolpidem administration regimens was not established in two 2-week trials in patients with insomnia. In two noncomparative 3-week trials in a primary care setting, a total of >4000 patients with insomnia took zolpidem 10 mg/day ‘asneeded’. About 80% or 90% of patients experienced an improvement according to the Clinical Global Impression–Improvement scale in each trial.

Tolerance is unlikely with continuous or intermittent use of zolpidem.

Tolerability

Zolpidem is generally well tolerated, including in elderly patients. Serious adverse events are rare. The nature of adverse events with zolpidem was broadly similar to that of nonbenzodiazepines (e.g. zopiclone) and benzodiazepines (e.g. triazolam, nitrazepam).

Next-day residual effects evident from post-sleep efficacy assessments were not significantly different with zolpidem from those observed in doxylamine, trazodone, nitrazepam or triazolam recipients.

In comparative trials in patients with insomnia, which assessed rebound insomnia as a primary endpoint, zolpidem recipients did not experience significant rebound insomnia, unlike triazolam recipients. The incidence of rebound insomnia with zolpidem was similar to that with temazepam, less frequent than with zopiclone and more frequent than that with placebo. In other studies that included an evaluation of rebound insomnia, most found no evidence for this withdrawal reaction in patients with insomnia.

There are case reports of abuse, dependence or withdrawal syndrome, but in the majority of these cases, the recommended dose of zolpidem was exceeded and most patients had a history of substance abuse and/or a psychiatric disorder.

On the basis of available evidence, the tolerability profile of zolpidem 10 mg/ day used ‘as needed’ appears broadly similar to that of continuous use of the drug. There is a low potential for rebound insomnia with ‘as-needed’ use, according to data from two placebo-controlled trials. Dependence is not likely to occur, since ‘as-needed’ use was generally not associated with drug-seeking behaviour.

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Notes

  1. Also registered as Niotal®, Nitrest®, Somnil®, Somno®, Stilnoct®, Supedal®. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Tracy Swainston Harrison & Gillian M. Keating

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  1. Tracy Swainston Harrison
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  2. Gillian M. Keating
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Correspondence to Tracy Swainston Harrison.

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Various sections of the manuscript reviewed by: S. Ancoli-Israel, Department of Psychiatry, University of California, San Diego, California, USA; D.J. Nutt, Department of Community Based Medicine, University of Bristol, Bristol, UK; M.L. Perlis, Psychiatry M&D Psychology, University of Rochester, Rochester, New York, USA; D.J. Riemann, Department of Psychiatry and Psychotherapy, University Hospital Freiburg, Freiburg, Germany; M.B. Scharf, Department of Psychiatry, Wright State University School of Medicine, Dayton, Ohio, USA; R. Silvestri, Dipartimento di Neuroscienze, Scienze Psichiatriche ed Anestesiologiche, Università Degli Studi Di Messina, Messina, Italy; J.C. Verster, Department of Psychopharmacology, University of Utrecht, Utrecht, The Netherlands.

Data Selection Sources: Medical literature published in any language since 1980 on zolpidem, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). 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 search terms were ‘zolpidem’. EMBASE search terms were ‘zolpidem’. AdisBase search terms were ‘zolpidem’. Searches were last updated 2 December 2004.

Selection: Studies in patients with insomnia who received zolpidem. 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: Zolpidem, insomnia, nonbenzodiazepine, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Harrison, T.S., Keating, G.M. Zolpidem. CNS Drugs 19, 65–89 (2005). https://doi.org/10.2165/00023210-200519010-00008

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