Dependencia y abstinencia de Zolpidem. Reporte de un caso de convulsiones generalizadas

El zolpidem es un agente hipnótico no benzodiacepínico utilizado con suma frecuencia en el tratamiento del insomnio e indicado para emplearlo en el corto plazo. No está indicado para el tratamiento crónico de los trastornos del sueño, pese a lo cual se evidencia en la práctica clínica que gran cantidad de pacientes lo reciben por arios. Si bien se ha descrito que presenta un mejor perfil de efectos adversos que las benzodiacepinas y que genera menos riesgo de dependencia y abstinencia que estas, existen sendos reportes de casos de dependencia y abstinencia de zolpidem. Se presenta el reporte de un caso de convulsiones tónico-clónicas generalizadas por abstinencia a dosis de 300 mg/día de Zolpidem y se realiza una breve revisión de la literatura.

Zolpidem is a non-benzodiazepine hypnotic agent used most frequently in the treatment of insomnia, indicated for short-term use. It is not indicated for the chronic treatment of sleep disorders, despite which there is evidence in clinical practice that a large number of patients receive it for years. Although it has been described that it presents a better profile of adverse effects than benzodiazepines and that it generates a lower risk of dependence and withdrawal than these, there are significant reports of cases of dependence and withdrawal from zolpidem. A report of a case of generalized tonic-clonic seizures due to with drawal at a dose of 300 mg per day of zolpidem is presented and a brief review of the literature is carried out.

Analysis of Forty-Two Psychoactive Substances in a Single Hair by Micro-Segmental Technique / 法医学杂志

OBJECTIVES@#To establish an LC-MS/MS method based on single hair micro-segmental technique, and verify the detection of 42 psychoactive substances in 0.4 mm hair segments.@*METHODS@#Each piece of single hair was cut into 0.4 mm segments and extracted by sonication and the segments were immersed in dithiothreitol-containing extraction medium. Mobile phase A was the aqueous solution containing 20 mmol/L ammonium acetate, 0.1% formic acid, and 5% acetonitrile. Mobile phase B was acetonitrile. An electrospray ionization source in positive ion mode was used for data acquisition in multiple reaction monitoring (MRM) mode.@*RESULTS@#The 42 psychoactive substances in hair had a good linear relationship within their respective linear ranges (r>0.99), the limits of detection were 0.2-10 pg/mm, the limits of quantification were 0.5-20 pg/mm, the intra-day and inter-day precisions were 1.5%-12.7%, the intra-day and inter-day accuracies were 86.5%-109.2%, the recovery rates were 68.1%-98.2%, and the matrix effects were 71.3%-111.7%. The method was applied to hair samples collected from one volunteer at 28 d after a single dose of zolpidem, with zolpidem detected in 5 hairs was 1.08-1.60 cm near the root tip, and the concentration range was 0.62-20.5 pg/mm.@*CONCLUSIONS@#The micro-segmental technique of single hair analysis can be applied to the investigation of drug-facilitated sexual assault cases.

Determination of zolpidem tartrate tablets after radiation by UHPLC / 药学实践杂志

Objective To establish a UHPLC method for the determination of zolpidem tartrate tablets after radiation, and to investigate the effect of different radiation doses on the content of zolpidem tartrate tablets. Methods Ultra high performance liquid chromatography was used. The content of zolpidem tartrate tablets irradiated by γ-ray was determined. Using C18 column, acetonitrile methanol-0.05 mol/L phosphoric acid solution (the pH value as 5.5 with triethylamine) (18∶26∶56) was used as the mobile phase. The flow rate was 0.7 ml/min, and the detection wavelength was 254 nm. Results The method validation showed good linearity in the concentration range of 5-80 μg/ml (r=0.999 6); The average recovery was 98.2%, RSD was 1.72%, and the repeatability was 0.87%. The contents of zolpidem tartrate were 105.1%, 106.4%, 102.7% and 105.4% under 0, 8, 25 and 80 kGy radiation. Conclusion UHPLC has accurate results with short analysis cycle in this study. It is suitable for the determination of zolpidem tartrate tablets after radiation. The content of zolpidem tartrate tablets remained basically unchanged after radiation.

Cognitive and balance dysfunctions due to the use of zolpidem in the elderly: a systematic review / Alterações cognitivas e de equilíbrio devido ao uso de zolpidem em idosos: uma revisão sistemática

ABSTRACT. Zolpidem is one of the most widely prescribed hypnotic (non-benzodiazepine) agents for sleep disorder. Recently, an increase in the demand for this drug has been observed, mainly in the elderly population. Objective: This study aims to analyze the acute effect of zolpidem on cognitive and balance dysfunctions in the elderly population. Methods: A study was conducted by two independent researchers in four virtual scientific information bases and included randomized controlled trials. The studies evaluated elderly patients using zolpidem. Cognitive and balance dysfunctions were analyzed. Results: Six articles were included. The mean age of the participants in the studies was 69 years. The following zolpidem dosages were evaluated: 5, 6.25, 10, and 12.5 mg. Comparing zolpidem and placebo, relating to the cognitive dysfunctions, there is no statistically significant difference between the groups. However, in relation to balance dysfunctions, there is a statistically significant difference between the intervention and the comparison, favoring placebo. Conclusions: Zolpidem, even in usual doses (5 mg and 10 mg), has shown to increase the risk for balance dysfunctions. However, this does not occur in relation to cognitive changes.

RESUMO. Zolpidem é um dos agentes hipnóticos (não benzodiazepínicos) mais prescritos para o manejo dos distúrbios do sono. Recentemente, observou-se um aumento na demanda por esse medicamento, principalmente pela população idosa. Objetivo: Este estudo visa analisar o efeito agudo do zolpidem em relação às alterações cognitivas e de equilíbrio na população idosa. Métodos: Uma busca em quatro bases de informação científica virtual foi feita por dois pesquisadores independentes e incluiu ensaios clínicos randomizados. Os estudos avaliaram o uso de zolpidem em pacientes idosos. Alterações cognitivas e de equilíbrio foram analisadas. Resultados: Seis artigos foram incluídos. A média de idade entre os estudos foi de 69 anos. As seguintes posologias foram analisadas: 5; 6,25; 10; e 12,5 mg. Em relação às alterações cognitivas, comparando-se zolpidem com placebo, não há diferença estatisticamente significativa entre os grupos. Entretanto, no desfecho alterações de equilíbrio, há diferença estatisticamente significativa entre intervenção e comparação, a favor do placebo. Conclusões: Zolpidem, mesmo em doses usuais (5 e 10 mg), mostrou aumentar o risco para alterações de equilíbrio, entretanto, isso não ocorre em relação às alterações cognitivas.

Treatment with zolpidem after ethanol administration potentiates the expression of ethanol-induced behavioral sensitization in mice

Contradictory findings suggest that the behavioral and abuse-related effects of ethanol are mediated by its action at α1 subunit-containing GABAA (α1GABAA) receptors. In the present study, we investigated the effects of a sub-chronic post-ethanol administration treatment with zolpidem, an α1-preferring positive allosteric modulator at GABAA receptors, on the subsequent expression of ethanol-induced behavioral sensitization in mice. Animals received ethanol (1.8 g/kg, ip) or saline treatments every other day for 15 days (8 treatment sessions) and were subsequently treated with zolpidem (0.5 mg/kg, ip) or vehicle 4 times on alternate days. At the end of the treatment phase, animals were challenged with saline or ethanol on separate days for the evaluation of the expression of conditioned locomotion and behavioral sensitization. Eight-day treatment with ethanol did not lead to the development of ethanol-induced behavioral sensitization. Animals treated with ethanol and subsequently administered vehicle showed similar locomotion frequencies during the last ethanol challenge compared to the control group receiving ethanol for the first time. Animals treated with ethanol and subsequently administered zolpidem expressed behavioral sensitization to ethanol during the ethanol challenge. The present study adds to the literature by providing further evidence of a role of α1GABAA receptors on the behavioral effects of ethanol. Because of the current highly prevalent co-abuse of ethanol and benzodiazepine drugs in humans, the use of zolpidem and other α1GABAA receptor ligands during ethanol withdrawal should be monitored carefully.

The Drug Safety and Rational Use of Zolpidem Tartrate / 中国药学杂志

OBJECTIVE: To givesafety recommendations for the dose, time of administration, and precautions for zolpidem tartrate. METHODS: Search relevant websites and databases, the pharmaceutical characteristics, clinical application, adverse reactions, drug interactions and rational use of zolpidem tartrate were reviewed. RESULT:S In order to ensure the safety of medication for patients, it is recommended that women and the elderly aged 65 years and above should use the minimum effective dose of 5 mg•d-1. Short-term use, the course of medication should not exceed 4 weeks. Insomnia patients can choose to treat as needed (intermittent, not every night). Follow the prescribed course of treatment and dosage in strict accordance with the doctor's advice. CONCLUSIONS: Zolpidem tartrate can treat various types of insomnia with definite curative effect and mild adverse reactions.Clinicians and pharmacists should pay attention to the safety risks of zolpidem and inform patients of the contraindications and precautions.

Paradoxical Motor and Cognitive Function Recovery in Response to Zolpidem in a Patient with Hypoxic-ischemic Brain Injury: A Case Report

We report an extremely rare case of a patient with hypoxic-ischemic brain injury who recovered consciousness and motor and cognitive functions due to paradoxical response after zolpidem administration. A 32-year-old woman who had attempted suicide by hanging was admitted. The patient had stabilized in a state of drowsy mentality, quadriparesis, dysphagia, and impaired cognition. Brain magnetic resonance imaging was suggestive of hypoxic ischemic brain injury and unilateral infarction in the right posterior cerebral artery territory. Due to sleep disturbance, zolpidem was administered, and paradoxically consciousness level and function returned to near-normal during the duration of the drug-effect. In addition to previous reports, our case characteristically showed remarkable motor and cognitive function recovery, not only consciousness level. The drug-effect time was gradually decreased after 18 months and absent after 3 years. We have reviewed related literature and discussed possible neuropharmacological and neurobiological mechanism.

Comorbid Zolpidem Dependence and Over-the-Counter Compound Analgesic Abuse

Zolpidem is a commonly prescribed hypnotic used to treat insomnia. However, its potential for abuse and dependence has recently become controversial. Although over-the-counter (OTC) medications are widely used, their abuse potential has not received much research attention. We report a case of comorbid zolpidem and OTC compound analgesic abuse. OTC analgesics may serve as gateway drugs, and physicians must be cautious about this issue, especially when prescribing hypnotics or benzodiazepines.

Effects of zolpidem on sleep parameters in patients with cirrhosis and sleep disturbances: A randomized, placebo-controlled trial

BACKGROUND/AIMS: The aim of this study was to study the efficacy and safety of zolpidem for sleep disturbances in patients with cirrhosis. METHODS: Fifty-two Child-Turcotte-Pugh (CTP) class A or B cirrhotics with Pittsburgh Sleep Quality Index >5 were randomized to either zolpidem 5 mg daily (n=26) or placebo (n=26) for 4 weeks. RESULTS: The therapy of 4 weeks was completed by 23 patients receiving zolpidem (3 stopped treatment due to excessive daytime drowsiness) and 24 receiving placebo (2 refused to continue the study). In the zolpidem group, after 4 weeks of therapy, there was significant increase in total sleep time (TST) and sleep efficiency compared to baseline and improvement in polysomnographic parameters of sleep initiation and maintenance (i.e., decrease in sleep latency time, decrease in wake time, and decreases in number of arousals and periodic limbs movements per hour of sleep), without any significant change in sleep architecture. CONCLUSIONS: Four weeks of 5 mg daily zolpidem in CTP class A or B cirrhosis patients with insomnia led to significant increases in TST and sleep efficiency and improvement in polysomnographic parameters of sleep initiation and maintenance without any significant change in sleep architecture.

Evaluation of the effect of different routes of administrating flumazenil against hypnosis / 药学实践杂志

Objective To study the effect of flumazenil on hypnotic mice induced by diazepam and zolpidem ,and to eval-uate the possibility of flumazenil oral administration .Methods First ,Kunming mice were injected intraperitoneally with nor-mal saline and sodium pentobarbital (S + W) ,diazepam and pentobarbital sodium (D + W) ,zolpidem and pentobarbital sodi-um (Z + W) .The hypnotic effect of diazepam and zolpidem on prolonging the sleep time of pentobarbital sodium would be ver-ified by (D + W) group and (Z + W) group .Then the mice were injected intraperitoneally with flumazenil .The sleep time was used as the evaluation index to evaluate the effect of flumazenil against hypnosis . Finally , the oral administration of flumazenil was observed against hypnosis ,which was evaluated by using sleep time as an index .Results Compared with the control group (S+W) ,the diazepam group (D+W) and the zolpidem group (Z+W) significantly prolonged the sleep time in-duced by pentobarbital sodium (P<0 .001 ,P<0 .05);After Intraperitoneal injection of flumazenil ,compared with the diazepam group (D+W) and the zolpidem group (Z+W) ,the sleep time of the diazepam group [F(ip)+D+W] and the zolpidem group [F(ip)+Z+W] were significantly shorter (P<0 .001 ,P<0 .05);After oral administration of flumazenil ,the sleep time of the diazepam group [F(ig)+ D+ W] and the zolpidem group [F(ig)+ Z+ W] were also significantly shorter (P< 0 .001 ,P<0.05) .Conclusion Flumazenil ,whether intraperitoneal injection or intragastric administration ,could antagonize the hypnotic effect of diazepam and zolpidem .It was proved that oral administration of flumazenil had the same effect compared with intrap-eritoneal injection of flumazenil ,which provided the possibility of preparation of oral administration of flumazenil .

Transient Global Amnesia Developed after Zolpidem Intake

We report two patients who complained of transient anterograde amnesia and repetitive questioning, that developed after taking zolpidem and lasted for several hours. The clinical manifestations of these patients fulfill the clinical criteria for transient global amnesia (TGA). The typical clinical manifestation of TGA following the consumption of zolpidem suggests a possible relationship associated with its drug mechanism.

In vitro and in vivo evaluation of nano-based films for buccal delivery of zolpidem

Abstract Insomnia is becoming increasingly prevalent in the world general population. Therapies used by patients include over-the-counter therapies, herbal and dietary supplements, and pharmacological or nonpharmacological treatments. Among these, zolpidem is a pharmacological treatment popularly used for insomnia. Zolpidem is well tolerated and especially efficacious for initiation of sleep, and therefore is effective for the treatment of sleep-onset insomnia. The purpose of the present study was to design and evaluate zolpidem nanoparticle-impregnated buccal films to prolong the duration of its action. Zolpidem nanospheres were prepared by double emulsion solvent evaporation and then loaded into buccoadhesive films (Z1-Z4) comprised of different concentrations of HPMC K100, Eudragit® RL 100, and carbopol 974P. The prepared films were characterized for physicomechanical properties, mucoadhesion, percent hydration, in vitro drug release, ex vivo permeation, and in vivo studies. In vitro drug release was found to depend upon film composition. Ex vivo studies showed that film Z4 had the highest flux. In vivo studies revealed that administration of zolpidem nanosphere-impregnated film enhanced absorption of the drug (p < 0.0001), with a higher peak plasma concentration (52.54 ± 8.22 ng/mL) and area under the curve from time 0 to α (236.00 ± 39.51 ng.h/mL) than oral administration. The increase in time taken to reach the maximum drug concentration (1.5 h) further signifies the potential of these films to provide prolonged drug release. Given these promising results, we concluded that these buccal films could be an alternative route for effective zolpidem delivery.

Study on Simultaneous Determination Method of Zolpidem,Dexzopiclone and Zaleplon in Human Plasma by UPLC-MS/MS / 中国药房

OBJECTIVE:To develop a method for rapid,accurate and simultaneous determination of dexzopiclone,zolpidam and zaleplon in human plasma. METHODS:After the plasma sample was processed by liquid-liquid extraction,UPLC-MS/MS was established to detect plasma sample with carbamazepine as internal standard. The separation was performed on a Waters ACQUITY UPLC HSS T3 column with mobile phase composed of 0.1% ammonium solution-acetonitrile (gradient elution) at flow rate of 0.2 ml/min. The column temperature was set at 40 ℃,and sample size was 5 μl. The detection was performed by multiple reaction monitoring (MRM) via electrospray ionization (ESI) source in positive mode. The mass transition ion-pairs were as follows:m/z 308.2→263.1(zolpidem),m/z 389.3→245.0(dexzopiclone),m/z 306.2→236.1(zaleplon),m/z 237.3→151.2(internal standard). RE-SULTS:The linear range of zolpidem,dexzopiclone and zaleplon were 0.02-20.00,0.50-20.00,0.02-20.00 ng/ml,respectively (r=0.990 1,0.996 8,0.991 7). LLOQ of them were 0.02,0.50,0.02 ng/ml,and detection limit were 0.01,0.20,0.01 ng/ml. RS-Ds of intra-day and inter-day were all lower than 15% ;extraction recovery were 88.9% -106.5% ;matrix effect were 94.8%-106.3%. CONCLUSIONS:The method is simple,rapid,sensitive and specific,and it can be used for simultaneous deter-mination of zaleplon,zolpidem and dexzopiclone in human plasma.

Determination of Trace Platinum in Zolpidem Tartrate by GFAAS / 中国药房

OBJECTIVE:To establish a method for determination of trace platinum in zolpidem tartrate. METHODS:Graphite furnace atomic absorption spectrometry(GFAAS)was adopted for direct determination after dissolving sample in 1% Hydrochloric acid solution. Horizontal platform graphite tube was performed with detection wavelength of 244.79 nm,slit width of 0.2 nm and current intensity of hollow cathode lamp of 6 mA. The mode of background correction was zeeman effect,the peak height was used as measurement pattern,and the injection volume was 20 μl. RESULTS:The linear range of platinum was 0-100 ng/ml(r=0.999 0);RSDs of precision and reproducibility tests were no more than 2.0%;recovery was 97.78%-103.07%(RSD=1.6%,n=9);the detection limit was 1.48 ng/ml. CONCLUSIONS:This method is simple and rapid with good precision and accuracy,and can be applied for the determination of trace platinum in zolpidem tartrate.

Zolpidem-Induced Arousal by Paradoxical GABAergic Stimulation: A Case Report With F-18 Flumazenil Positron Emission Tomography and Single Photon Emission Computed Tomography Study

Zolpidem is a non-benzodiazepine drug that has selectivity for the gamma-aminobutyric acid (GABA) receptors. We experienced paradoxical effect of zolpidem in a 48-year-old male patient with hypoxic-ischemic brain injury after cardiac arrest. The patient was in stupor and could not communicate. His Glasgow Coma Scale (GCS) was E2M4V2 and Rancho Los Amigos (RLA) was grade III to IV. Zolpidem was prescribed to induce sedation but paradoxically, he became alert (GCS 15, RLA VII) and was able to communicate. The arousal lasted for 2 hours repeatedly following each administration of the medication. While he was alert, electroencephalogram showed the reversal of slow wave into beta range fast activity and F-18 flumazenil positron emission tomography (PET) showed increased GABAergic receptor activity in both frontoparietotemporal cortices. Single photon emission computed tomography (SPECT) also showed increased cerebral perfusion and reversal of cerebellar diaschisis.

Content Determination of Zolpidem Tartrate in Microsamples of Rat Plasma by HPLC-fluorescence Method / 中国药房

OBJECTIVE:To establish a method for the content determination of zolpidem tartrate in microsamples of rat plas-ma. METHODS:Rats were given zolpidem tartrate solution 3 mg/kg intragastrically,and 0.2 ml blood sample were collected and isolated. 50 μl plasma was precipitated by methanol,and the supernatant was determined by HPLC-fluorescence combined with ex-ternal method. Agilent HC-C18 column was used with mobile phase consisted of 0.03 mol/L KH2PO4 solution(containing 0.2% tri-ethylamine)-methanol (33∶67,V/V) at flow rate of 1.0 ml/min. The excitation and emission wavelengths were 254 nm and 390 nm,respectively. The sample size was 20 μl. RESULTS:The linear ranges of zolpidem tartrate in plasma was 2-200 μg/L(r=0.999 7),and the limit of quantification was 2 μg/L. The method recoveries of zolpidem were (96.96 ± 1.35)%-(105.0 ± 5.36)%(RSD=2.20%-4.88%,n=5),and extraction recoveries were (79.72 ± 0.01)%-(80.77 ± 0.02)%(RSD=1.34%-3.90%,n=5). The intra-day and inter-day RSDs were 1.40%-5.10% and 3.22%-9.25%(n=5),respectively. CONCLUSIONS:The method is simple,sensitive and suitable for the content determination of zolpidem tartrate in microsamples of plasma.

Efficacy observation of zolpidem in improvement of sleep quality of patients received methadone maintenance treatment / 中国基层医药

Objective To explore the efficacy of zolpidem in improvement of sleep quality of patients received methadone maintenance treatment (MMT).Methods 80 cases of MMT with insomnia were randomly divided into the study group (administered with zolpidem)and the control group (administered with placebo), 40 cases in each group.Pittsburgh sleep quality index (PSQI)and treatment emergent symptoms scale (TESS)were assessed before treatment and at the weekend of 4th,8th after treatment.Results The scores of PSQI in the study group were much lower than those in the control group (t =-2.517,P =0.014;t =-3.611,P =0.000),while the effective rate in the study group was significantly higher than that in the control group (χ2 =4.949,P =0.026). Conclusion Zolpidem could improve the sleep quality of patients with MMT.

Acute Kidney Injury due to Rbadomyolysis Complicated with Zolpidem Overdose / 대한내과학회지

Zolpidem (Stilnox®, Handok, Seoul, Korea) is a hypnotic imidazopyridine that is often used to treat insomnia because it has less abuse and addiction potential than benzodiazepines. Its side effects include headache, dizziness, and nausea, but these are mild. Zolpidem intoxication rarely has severe complications. Here, we report a case of acute kidney injury due to rhabdomyolysis related to zolpidem. A 51-year-old man was admitted with drowsy mentality after taking an overdose of zolpidem in a suicide attempt. Laboratory findings showed a blood urea nitrogen of 59.9 mg/dL, serum creatinine of 5.8 mg/dL, and creatine phosphokinase of 16,210 IU/L. Acute kidney injury associated with rhabdomyolysis complicating zolpidem intoxication was diagnosed. The patient was managed with hemodialysis and recovered completely in terms of renal function and muscle enzyme levels.

Zolpidem Induced Sleep-related Eating and Complex Behaviors in a Patient with Obstructive Sleep Apnea and Restless Legs Syndrome

Zolpidem-induced sleep-related complex behaviors (SRCB) with anterograde amnesia have been reported. We describe herein a case in which the development of zolpidem-induced sleep-related eating disorder (SRED) and SRCB was strongly suspected. A 71-year-old Korean male was admitted to the Department of Psychiatry due to his repetitive SRED and SRCB with anterograde amnesia, which he reported as having occurred since taking zolpidem. The patient also had restless legs syndrome (RLS) and obstructive sleep apnea (OSA). His baseline serum iron level was low at admission. Zolpidem discontinuation resulted in the immediate disappearance of his SRED, but did not affect his RLS symptoms. These symptoms rapidly improved after adding a single i.v. iron injection once daily, and so he was discharged to day-clinic treatment. These findings indicate that zolpidem can induce SRCB. Although the pathophysiology of zolpidem-induced SRED and other SRCB remains unclear, clinicians should carefully monitor for the potential induction of complex behaviors associated with zolpidem in patients with comorbid RLS or OSA.

An unusual presentation of visual hallucinations with zolpidem: a case report.

Zolpidem is a hypnotic drug with rapid -onset and short duration of action. It is popularly used for the induction and maintenance of sleep in adults suffering from insomnia. It supersedes benzodiazepines with better tolerability and has fewer side effects such as less residual sedation and the potential for rebound insomnia and dependence is also less. Adverse neuropsychiatric reactions such as visual hallucinations, amnesia, sleepwalking and nocturnal eating are known to occur with zolpidem. Literature suggests higher incidence of visual hallucinations with zolpidem when used along with selective serotonin reuptake inhibitors. Furthermore, visual hallucinations are one of the causes for drug withdrawal. We are reporting a case of zolpidem induced visual hallucinations when used alone and also which disappeared with proper assurance to the patient in subsequent use.