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Cited by 34Pharmacogenetics and Drug MetabolismPharmacovigilance and Adverse Drug ReactionsPoisoning and overdose treatments

Zolpidem abuse, dependence and withdrawal syndrome: sex as susceptibility factor for adverse effects

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Cubała, Wiesław J., Landowski, Jerzy, Wichowicz, Hubert M.·2008·British Journal of Clinical Pharmacology
DOI 10.1111/j.1365-2125.2007.03028.xPMC PMC2291248
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Abstract

We read with interest the British Journal of Clinical Pharmacology's Spring 2007 special issue, addressing the issue of adverse drug reactions (ADR), suggesting how reactions can be prevented or minimized, generating hypotheses for further study, and proposing ways forward for future research. The issue tackled the susceptibility factors for ADR associated with age, polypharmacy, ethnic factors and the problems associated with prenatal exposure to drugs. However, our impression was that it left unaddressed the important issue of a patient's sex as a susceptibility factor for ADRs. Patient's sex influences both pharmacodynamics and pharmacokinetics, seemingly related to the endocrine factors that are the most prominent in drugs metabolized via CYP3A4, probably due to the action of sex hormones. The lower plasma concentrations of free testosterone, for example, may contribute to lower CYP3A activity, and exposure to testosterone activates the biotransformation of a number of CYP3A substrates [1]. Sex as a susceptibility factor for adverse effects seems to be well illustrated by cases of zolpidem abuse, dependence and withdrawal syndrome. As zolpidem dependence and withdrawal syndrome have been seen in subjects taking 160–2000 mg d−1[2, 3], the pharmacodynamics is of vital interest. A number of such cases have been described [4] and the core hypothesis on the phenomena described in those case reports is that zolpidem at high doses might lose its selectivity on GABA-A receptor and exhibit the same pharmacological effects as classical benzodiazepines [2]. Zolpidem metabolism is mediated by human cytochromes P450 (CYP), with a dominant role of CYP3A4 and a contributory role of CYP2C9, 1A2, 2D6 and 2C19 in decreasing order of importance, but not of 2A6, 2E1 or 2C8 [1, 5]. Thus the pharmacokinetic interactions may occur in patients receiving a number of concomitant treatments, including analgesics, antiarrythmics, antibiotics, antiepileptics, antihistamines, antineoplasm, antiparkinsonian drugs, antiprogestorone agents, antirejection drugs, β-blockers, calcium-channel blockers, HMG-CoA reductase inhibitors, non-nulceoside reverse transcriptase inhibitors, protease inhibitors, proton pump inhibitors, steroids and triptans [6]. In vitro studies have indicated that the rate of transformation of zolpidem to its major hydroxylate metabolite in human liver microsomes is increased by an average of 70% by coincubation with equimolar amounts of testosterone [1]. Also, in the presence of renal insufficiency and/or hepatic impairment, plasma protein binding of zolpidem is decreased [7, 8]. However, most zolpidem-related disorders involve women. This may be associated with the fact that insomnia is more prevalent in women (1.5 : 1 female : male ratio). On the other hand, women achieve up to 50% higher zolpidem plasma concentrations [9] and sex-related differences in zolpidem clearance are significant [1, 10]. In contrast, zolpidem clearance is higher and half-life shorter in women using oral contraceptives, which may contribute to the observed increased incidence of ADRs in women [7]. Thus, in many cases pharmacokinetics and pharmacodynamics contribute to the ADRs observed with zolpidem. However, sex should also be considered as a susceptibility factor for zolpidem ADRs and consideration of a patient's sex can significantly improve zolpidem pharmacotherapy with regard to efficacy and safety.

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  • The US Food and Drug Administration revised zolpidem dosing recommendations in 2013, halving the prescribed doses for women.

    “Reflecting these concerns, the US Food and Drug Administration (FDA) revised zolpidem dosing recommendations in 2013, halving the prescribed doses for women.”

    From Z-drug abuse and dependence: Clinical guideline of the Brazilian Academy of Neurology for diagnosis and management (2025) · cites this paper as [48]

    The Abstract discusses higher zolpidem plasma concentrations in women and the importance of considering sex in prescribing. It does not address an FDA dosing revision or a halving of doses for women; searches for the 2013 recommendation and dose reduction found no such passage in our copy. (LLM, conf=0.78)

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Authors
Cubała, W. J., Landowski, J., & Wichowicz, H. M.
Affiliations
Gdańsk Medical University (PL)
Corresponding author
Cubała, Wiesław J.
ORCID
Venue
British Journal of Clinical Pharmacology
Publisher
Wiley
Published
2007-09-15
Volume
65
Issue
3
Pages
444-445
ISSN
  • 0306-5251 (ISSN-L)
  • 1365-2125
DOI
10.1111/j.1365-2125.2007.03028.x
PMC
PMC2291248
OpenAlex
W2032506978
Cited by
34
References
9
Citations by year
2025: 2 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 2 · 2014: 4 · 2013: 2 · 2012: 2
FWCI
2.75
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • British Journal of Clinical Pharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
Keywords
drug abuse, drug addiction, withdrawal syndrome, sex differences, adverse drug reactions, CYP3A4, sex hormones, testosterone, GABAA receptor, benzodiazepine-like effects, pharmacokinetic interactions, pharmacodynamics, hypnotics, patient information leaflets
MeSH terms
Zolpidem, Female, Humans, Male, Pyridines, Sex Characteristics, Substance Withdrawal Syndrome, Substance-Related Disorders

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