The Clinical and Forensic Toxicology of Z-drugs

The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the management of insomnia. Increasing reports of adverse events including bizarre behavior and falls in the elderly have prompted calls for caution and regulation. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. Z-drugs exert their effects through increased γ-aminobutyric acid (GABA) transmission at the same GABA-type A receptor as benzodiazepines. Their pharmacokinetics approach those of the ideal hypnotic with rapid onset within 30 min and short half-life (1–7 h). Zopiclone with the longest duration of action has the greatest residual effect, similar to short-acting benzodiazepines. Neuropsychiatric adverse events have been reported with zolpidem including hallucinations, amnesia, and parasomnia. Poisoning with Z-drugs involves predominantly sedation and coma with supportive management being adequate in the majority. Flumazenil has been reported to reverse sedation from all three Z-drugs. Deaths from Z-drugs are rare and more likely to occur with polydrug overdose. Z-drugs can be detected in blood, urine, oral fluid, and postmortem specimens, predominantly with liquid chromatography–mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Zaleplon with its ultra-short half-life has been detected in few clinical or forensic cases possibly due to assay unavailability, low frequency of use, and short window of detection. Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.     

Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey

AIM: To show that the nonbenzodiazepine hypnotic zolpidem has a higher abuse potential than previously documented. METHOD: An official enquiry was carried out by the Nantes Centre for Evaluation and Information on Pharmacodependence (CEIP). The authors made a review of literature and analysed French data corresponding to the drug's postmarketing period collected by the CEIP network from 1993 to 2002. RESULTS: The literature review yielded mixed results concerning the behavioural effects of zolpidem. Data from the CEIP and the 53 literature case reports highlight significant dependence and abuse potential of zolpidem. CONCLUSIONS: This study adds to the growing evidence that zolpidem has the potential for abuse and dependence. As a consequence, the French drug monograph has been modified by the French Health Authorities.     

New directions in the treatment of insomnia

Sleep-related complaints are common in the general population. Prevalence rates are significantly higher among women and the older age groups. In addition, a substantial number of those experiencing insomnia state that the complaint is chronic. The management of chronic primary insomnia combines nonpharmacological measures and pharmacotherapy. In patients with chronic secondary insomnia, hypnotic medication may be beneficial as an adjunct to treatment of the primary disorder. Presently available hypnotic drugs include the benzodiazepines and the nonbenzodiazepine derivatives zopiclone, eszopiclone, zolpidem and zaleplon. The finding that the sedative/hypnotic effect of benzodiazepine and nonbenzodiazepine compounds is mediated through GABA_A receptors containing the α₁ subunit presents new possibilities for designing more effective and safe hypnotic drugs. Imidazopyridinone, imidazolyl-methyl-imidazole, ring-fused-imidazole, imidazolyl-methyl-pyridazine, imidazolyl-methyl-pyrimidine, imidazolyl-methyl-pyridine, imidazolyl-methyl-pyrazine, aryl acid pyrimidinyl-methyl-amide and pyridazinyl-methyl-amide, and pyrrolo-pyridine carboxylic acid amide derivatives have been reviewed that could be particularly useful in treating primary insomnia and secondary insomnia as an adjunct to treatment of the primary disorder. A range of tachykinin antagonists, including pyperidyl-carboxamide, C-aryl-piperidine, diazabicycle-piperidine, cyclic amine and N-benzyl-phenyl-heterocyclyl-propionamide derivatives, are being developed for insomnia treatment. However, there is little evidence to suggest that they will be a valid alternative for the management of insomnia.     

Role of drug testing as an early warning programme: the experience of the Republic of Korea

Drug testing plays an important role in the provision of information to health authorities on trends in drug abuse. In the Republic of Korea, the testing of urine and postmortem specimens has been used as part of a programme to monitor and control the abuse of non-controlled drugs, i.e., substances that were not originally included in the lists of controlled substances in that country. Zipeprol, dextromethorphan, carisoprodol and nalbuphine are examples of such drugs, which are widely used as medicines. Increasing levels of abuse of these drugs, including abuse that resulted in fatalities, were confirmed in the Republic of Korea by the results of drug testing. Based on the accumulated data from postmortem specimens, the health authorities in the Republic of Korea subsequently introduced controls on these drugs. A significant drop in fatalities related to the abuse of these non-controlled drugs underlined the importance of timely action for improving community health. In the context of drug testing, the analysis of non-controlled and new drugs always presents a scientific challenge, because specific analytical methods for testing for those drugs are not available. In the Republic of Korea, as part of the drug abuse warning programme, it was necessary to establish methods for the detection and quantification in biological fluids of all four non-controlled drugs and their metabolites in order to monitor the trends in drug abuse. The present paper puts forward epidemiological and clinical data on abuse and fatalities associated with zipeprol, dextromethorphan, carisoprodol and nalbuphine, as well as details of the analytical methods developed.     

Metabolism of benzodiazepine and non-benzodiazepine anxiolytic-hypnotic drugs: an analytical point of view

A review with 132 references. Several kinds of anxiolytic and hypnotic drugs are currently available on the market. Although BZDs are surely the most frequently prescribed among them, several chemically unrelated compounds have been commercialised, which can provide similar or even higher efficacy and tolerability. These drugs can prove useful for patients who are non-responder or intolerant to benzodiazepine treatment, thus giving broader therapeutic options to the clinician. The most important studies on the metabolic characteristics of several non-benzodiazepine anxiolytics and hypnotics are reported and briefly discussed in this review; moreover, the analytical methods related to these studies are also described and commented upon and their characteristics are highlighted. Finally, an update is included on recent (2007-2010) metabolism and pharmacokinetic studies on benzodiazepines. A monograph is included for each of the following drugs: zolpidem, zaleplon, zopiclone, ramelteon, buspirone and tandospirone; updates are included for the following benzodiazepines: alprazolam, bromazepam, diazepam, flunitrazepam, lorazepam, midazolam, oxazepam and triazolam.     

Conditioned taste aversion and place preference with buspirone and gepirone

The effects of the nonbenzodiazepine anxiolytics buspirone and gepirone were compared to diazepam at 1, 3, and 10 mg/kg using the conditioned taste aversion (CTA) paradigm. Buspirone and gepirone produced stronger CTA than diazepam (3 and 10 mg/kg) across repeated conditioning trials, indicating that these nonbenzodiazepine anxiolytics may have stronger aversive properties than diazepam. The effects of buspirone and gepirone (1 and 3 mg/kg) were also assessed using the conditioned place preference (CPP) paradigm. Both buspirone (1 and 3 mg/kg) and gepirone (3 mg/kg only) produced CPP, indicating that these drugs may have rewarding properties, and that buspirone is more potent than gepirone in producing CPP. These findings demonstrate that buspirone and gepirone have affective properties similar to abused drugs, and may therefore have abuse potential. It was also demonstrated that buspirone (3 mg/kg), but not gepirone (3 mg/kg), increased dopamine (DA) synthesis in the nucleus accumbens, a mesolimbic brain area thought to be involved in drug reward.     

Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans

The present study examined the acute behavioral effects and abuse potential of three drugs commonly used to treat sleep disorders, trazodone, zolpidem and triazolam, and placebo in ten male volunteers with histories of alcohol and drug abuse. Trazodone (100, 200 and 300 mg), a triazolopyridine antidepressant, was included because antidepressants are being used more frequently to treat sleep disorders, but it is unclear whether they have a distinct behavioral pharmacologic profile relative to benzodiazepine hypnotics. Zolpidem (15, 30 and 45 mg), an imidazopyridine hypnotic, was tested because it is the most commonly prescribed hypnotic and purportedly has a unique benzodiazepine-receptor binding profile. Triazolam (0.25, 0.5 and 0.75 mg), a triazolobenzodiazepine hypnotic, was included as the standard component because previous laboratory studies have demonstrated that it has at least some abuse potential. Trazodone, zolpidem and triazolam generally produced comparable dose-related increases in scores on the PCAG scale of the ARCI, which suggests the doses tested were equivalent on some behavioral dimension. The effects of trazodone on subject-rated items thought to measure abuse potential (e.g., subject ratings of Willing to Take Again) were less than those observed with triazolam. Zolpidem and triazolam produced comparable effects on these measures. The highest dose of zolpidem, but not triazolam, increased ratings of Like Drug, Happy, Good Effects, Friendly, Elated, Carefree and Bad Effects. Triazolam and zolpidem produced dose-dependent impairment on all of the performance tasks. Trazodone impaired performance on some, but not all, of these tasks. Consistent with the pharmacokinetics of these compounds, the time-action functions of trazodone, zolpidem and triazolam were similar on these measures. These data suggest that trazodone has less abuse potential than triazolam, and may be a viable alternative to benzodiazepine hypnotics in individuals with histories of alcohol or drug abuse. By contrast, despite its unique neuropharmacological profile, the acute behavioral effects and abuse potential of zolpidem are comparable to those of triazolam. Received: 20 June 1998 / Final version: 4 November 1998     

Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia

Zolpidem is an imidazopyridine agent that is indicated for the short term (< or = 4 weeks) treatment of insomnia (recommended dosage 10 mg/day in adults and 5 or 10 mg/day in the elderly or patients with hepatic impairment). Data have shown that the hypnotic efficacy of zolpidem is generally comparable to that of the benzodiazepines flunitrazepam, flurazepam, nitrazepam, temazepam and triazolam as well as nonbenzodiazepine hypnotic agents such as zopiclone and trazodone in the treatment of elderly and adult patients with insomnia. The comparative efficacy of a recently available nonbenzodiazepine hypnotic zaleplon and zolpidem has yet to be established. There was no evidence of tolerance developing to the hypnotic effects of zolpidem in a number of studies of up to 6 months' duration. However, tolerance has been described in a few patients taking the drug at high dosages for periods of up to several years. Zolpidem is well tolerated in patients with insomnia and the most common adverse events are generally nausea, dizziness and drowsiness. Although zolpidem produced some psychomotor and memory impairment over the first few hours after administration, it had few next-day effects (including effects on daytime well-being and morning coordination). In this respect, it was comparable or superior to flunitrazepam and flurazepam and comparable to other benzodiazepines in patients with insomnia. Zolpidem appears to have a low potential for abuse. Conclusions: Zolpidem is effective and well tolerated in patients with insomnia, including the elderly. Studies have shown that zolpidem generally has similar efficacy to other hypnotics including benzodiazepines and zopiclone. Zolpidem appears to have minimal next-day effects on cognition and psychomotor performance when administered at bedtime. In addition, there is little evidence of tolerance to the hypnotic effects of zolpidem, or rebound insomnia or withdrawal symptoms after discontinuation of the drug when it is given as recommended (10 mg/day for < 1 month) or over longer periods.     

非苯二氮类镇静催眠药埃佐匹克隆

埃佐匹克隆(Lunesta TM)为新型非苯二氮类镇静催眠药,是佐匹克隆的(S)-异构体。临床研究表明其耐受性良好,无明显反跳性失眠。已被FDA批准用于治疗成人失眠。现对其作用机制、药效学、药动学及临床评价做一介绍。     

Activity-based reporter assays for the screening of abused substances in biological matrices

Abstract

The (ab)use of designer drugs and steroid hormones has gained popularity due to the lower chance of getting caught, as routine drug or doping tests may miss these (novel) compounds. Current analytical approaches mostly make use of targeted, structure-based techniques, such as immunoassays or mass spectrometry (MS)-based methods. However, these approaches have limitations, including a lack of cross-reactivity and the need for prior knowledge of molecular identity. This has initiated considerable interest in the so-called “untargeted” screening strategies to detect these compounds. The use of “untargeted” MS-based screening methods (e.g. gas chromatography MS and especially high-resolution MS) has gained considerable interest to detect and identify novel compounds. However, due to their expensive and time-consuming character, very sophisticated analytical methods are not ideal as a first-line screening method and are not routinely implemented in most laboratories. Given the above, it is clear that there lies potential in novel “untargeted” screening approaches, which are less expensive, more high-throughput-amenable and more routinely applicable. Activity-based assays, capable of monitoring the biological activity of an abused substance in a biological matrix, have been proposed as an alternative. These biological assays do not require knowledge about a compound’s structure and could be used as a first-line screening tool to identify potentially positive samples. In this review, we focus on activity-based reporter bioassays for the detection of steroids and drugs of abuse in biological matrices. As for drugs of abuse, only bioassays for detecting cannabinoid or opioid activity in biological matrices are available, only (synthetic) cannabinoid receptor agonists and opioids are discussed.     

Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA2 and pKB analyses from behavioral studies

This review aims at providing a critical assessment of the effects of the most widely used benzodiazepine (flurazepam, flunitrazepam, temazepam, triazolam) and non-benzodiazepine (zopiclone and zolpidem) hypnotic drugs, based on the recording of polysomnographic variables. In the light of newly acquired neurophysiological data on the microstructure of sleep, this paper reconsiders the problem of insomnia and the current ideas on polysomnography and hypnotic drugs.     

Testing the abuse liability of anxiolytic and hypnotic drugs in humans.

This paper represents a comprehensive review of laboratory studies investigating the abuse liability of anxiolytic and hypnotic drugs in humans. The subjective effects of these drugs, most of which are either barbiturates or benzodiazepines, have been measured using various self-report questionnaires and their reinforcing effects have been studied using self-administration and choice procedures. Studies using both subjective and reinforcing effects reveal orderly relations between the two main chemical classes of anxiolytic/hypnotics (e.g. barbiturates are associated with higher abuse liability than benzodiazepines), between different doses of the drugs (e.g. higher doses are usually associated with higher abuse liability) and among different compounds within a class. The subjective and reinforcing effects of barbiturates and benzodiazepines depend critically upon the subject populations that are tested and it is argued that individuals with histories of drug abuse provide a more sensitive indicator of abuse liability than healthy volunteers. Several principles of abuse liability testing are discussed, including the selection of an appropriate subject population, the use of blind drug administration procedures, the comparison of a test compound to an appropriate standard, the inclusion of a placebo and a wide range of doses of the test drug and the use of multiple measures of likelihood of abuse.     

Use of alternative specimens: drugs of abuse in saliva and doping agents in hair

It is generally accepted that chemical testing of biologic fluids is the most objective means of diagnosis of drug use. The presence of a drug analyte in a biologic specimen can be used to document exposure. The standard for drug testing in toxicology is an immunoassay screen conducted on a urine sample, followed by confirmation by gas chromatography with mass spectrometric detection. In recent years, remarkable advances in sensitive analytic techniques have enabled the analysis of drugs in unconventional biologic specimens such as saliva or hair. The aim of this review is to document the current status of drugs of abuse testing in saliva and some doping agents in hair. The influence on drug concentration of the procedure of saliva sampling is described. Screening procedures along with specific methods are reviewed for the determination of amphetamines, cannabis, cocaine, and opiates in saliva. Before an extensive review on the detection of anabolics, corticosteroids, and beta-adrenergic stimulants in hair, the place of this specimen in doping control is discussed, with a focus on the potential problems of this new technology.     

Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis

OBJECTIVES: To compare the clinical effectiveness of zaleplon, zolpidem or zopiclone (Z-drugs) with either benzodiazepines licensed and approved for use in the UK for the short-term management of insomnia (diazepam, loprazolam, lorazepam, lormetazepam, nitrazepam, temazepam) or with each other. METHODS: MEDLINE, EMBASE, PsycINFO, Science Citation Index/Web of Science were searched from 1966 to March 2003 and The Cochrane Library, reference lists of included studies and a number of psychopharmacology journals. Randomized controlled trials comparing either benzodiazepines with the Z-drugs or any two of the Z-drugs in patients with insomnia were included. Outcome measures included: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness. RESULTS AND CONCLUSIONS: Twenty four eligible studies were identified with a total study population of 3,909 (17 studies comparing a Z-drug with a benzodiazepine and 7 comparing a Z-drug). Insufficient or inappropriately reported data meant that meta-analysis was possible only for a small number of outcomes. There are few clear, consistent differences between the drugs. Some evidence suggests that zaleplon gives shorter sleep latency but shorter duration of sleep than zolpidem, reflecting the pharmacological profiles of the drugs.     

Workplace testing of drugs of abuse and psychotropic drugs

In France, workplace testing of drugs of abuse and psychotropic drugs is rarely performed; meanwhile it is a major public health problem. Furthermore, France is the European country that has been associated with the highest increase of the use of drugs of abuse, particularly cannabis. So workplace biological screening of drugs of abuse and of psychotropic drugs exposure is of major concern. New analytical techniques have been developed during the last years. The authors will consider analytical screening of drugs of abuse and particularly the comparison of analytical techniques applied to urine and saliva. The advantages and the disadvantages of these two matrices will be considered. Urinary and blood quantification will be reviewed, but also the interest of hair testing to explore chronic exposure. The research of psychotropic drugs in biological fluids is also a part of this paper. New analytical trends are promising and complete analysis of these substances will be soon routinely possible in blood using a single spot test.     

Correlates of Dependence and Beliefs About the Use of Hypnotics Among Zolpidem and Zopiclone Users

Background: Zolpidem and zopiclone are the two most commonly prescribed Z-drugs approved to treat insomnia. Objectives: To examine the demographic and clinical correlates of dependence and beliefs about hypnotic use among long-term zolpidem and zopiclone users in psychiatric treatment for insomnia. Methods: A total of 392 psychiatric outpatients who received zolpidem or zopiclone treatment for at least 3 months for insomnia were studied. Participants’ severity of hypnotic dependence and beliefs about the use of hypnotics to treat sleep problems were assessed. The correlation of dependence and beliefs about zolpidem and zopiclone treatment with demographic characteristics, hypnotic-using behaviors, co-use of addictive substances, and depressive symptoms were analyzed using multiple regression analysis models. Results: Zolpidem users reported more severe dependence and a lower level of necessity regarding the use of hypnotics than zopiclone users did. High equivalent doses of hypnotics and long duration of use were significantly associated with severe dependence and a low level of necessity. Severe depressive symptoms were signiciantly associated with severe dependence, a low level of necessity, and a low level of concern. Educational level was also associated with the levels of concern and necessity. Conclusions/Importance: There were differences in the level of dependence and belief about hypnotic use between zolpidem and zopiclone users. The correlates of dependence and belief identified in this study can serve as the basis for prevention and intervention programs.