Zolpidem Dependence Research Articles

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

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.

Table of Contents

AbstractLandmark Study Examines Medications for Schizophrenia TreatmentFolate Deficiency in Schizophrenia — Is Supplementation Warranted?Possible Interaction Among Quetiapine, Doxepin and PantoprazoleBottom LineAmantadine for Olanzapine‐Induced Weight GainAntipsychotics and Obesity: A Behavioral Treatment ApproachCATIE Study — Editorial Examines Treatment ChoicesSales of Adderall XR in Canada to ResumeZolpidem Dependence May Be Treatable with Flumazenil InfusionExtended‐Release Sleep AidRisperdal M‐Tab Labeling Change

Dependence on zolpidem: two case reports of detoxification with flumazenil infusion

Zolpidem is a hypnotic drug that is chemically distinct from benzodiazepines (BDZ). It has been suggested that it acts selectively on gamma-aminobutyric acid receptors. However, recent evidence has shown that the behavioural effects of zolpidem are generally similar to those of BDZs. Flumazenil is usually considered to be a BDZ antagonist. Nonetheless, in chronic BDZ users, it acts as a partial, bland agonist. We describe two cases of zolpidem dependence that were detoxified by the use of flumazenil infusion. BDZ dependence is usually treated with tapering of the medication. As an alternative, abrupt discontinuation of the medication and rapid detoxification using flumazenil has been used. Flumazenil may represent an alternative to detoxification treatment by employing a tapering approach, or by replacement therapy with BDZs with a long half-life, particularly where patients are hard to treat or have low compliance to treatment.

High-Dose Zolpidem Dependence in a Patient with Chronic Facial Pain

High-Dose Zolpidem Dependence in a Patient with Chronic Facial Pain

Abnormal auditory N400 in a case of zolpidem dependence, during a working memory test

Zolpidem is a GABA (A) agonist, which is indicated for the short-term management of insomnia. Recent research provide evidence suggesting that zolpidem produces spatial working memory (WM) deficits and dependence; however, the underlying mechanisms of these effects are unknown. Since the auditory N400 component of event-related potentials (ERPS) is considered as an index of memory use of context processing, the present study focused on N400 waveform of ERPs elicited during a WM task in a case suffering from zolpidem dependence. The patterns of N400 waveform of this case were compared to the patterns obtained from healthy controls. This comparison revealed that zolpidem dependence is accompanied by reduced amplitudes located at posterior brain areas and diffuse prolongation of N400. These findings may indicate that zolpidem dependence manifests alterations with regard to the memory use of context processing, involving or affecting a wide-ranging network of the brain's structures.

Three Cases of Zolpidem Dependence Treated with Fluoxetine: The Serotonin Hypothesis

Zolpidem is an Imidazopyridine hypnotic that is believed to act selectively at al subunit-containing gamma-aminobutyric acid type A (GABAA) receptors and thus to have minimal abuse and dependence potential. We present three cases of Zolpidem abuse and dependence in which the drug was used not for sedation but for stimulation and anxiolysis. All of the patients were treated with fluoxetine (a selective serotonin reuptake inhibitor) and managed to discontinue the abuse and remain abstinent from the drug. The efficacy of this kind of medication on the abuse of a GABAergic agonist, in this case dependence on zolpidem, leads to a serotonergic and GABAergic system interaction hypothesis.

Dependence on zolpidem: a case report

We report the case of a patient with a history of zolpidem dependence. The patient, after a stressful life event, started using zolpidem. She rapidly developed tolerance and dependence, taking 50–100 mg, and sometimes up to 300 mg, of zolpidem daily. Also, our patient suffered episodes of altered consciousness, accompanied by visual hallucinations.

A warning regarding the potential of zolpidem dependence

A warning regarding the potential of zolpidem dependence