Behavioral effects of flunitrazepam: reinforcing and discriminative stimulus effects in rhesus monkeys and prevention of withdrawal signs in pentobarbital-dependent rats

Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABA(A) modulators. One group of monkeys (n=3) responded to receive injections of methohexital or saline (i.v.) while other groups (n=2-4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n=2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n=3-6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines.     

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.     

Hypnotic action of flunitrazepam in the rat: Does 5-HT mechanism play a role?

This study examined whether pharmacological manipulation of serotonergic (5-HT) systems would affect the hypnotic action of flunitrazepam in rats. Flunitrazepam, a potent hypnotic, was used alone or combined with parachlorophenylalanine (pCPA), an inhibitor of the synthesis of 5-HT, 8-OH-DPAT, a 5-HT_1A receptor agonist and fluvoxamine, an inhibitor of the reuptake of 5-HT. Flunitrazepam increased the amount of orthodox sleep, the latency of rapid eye movement (REM) sleep and decreased the amount of REM sleep. The drug pCPA decreased the total sleep time and the amount of orthodox and REM sleep. Administration of flunitrazepam to pCPA-pretreated rats induced orthodox sleep in an identical way to that found in the controls. The drug 8-OH-DPAT increased wakefulness and the latency of REM sleep. The association of flunitrazepam with 8-OH-DPAT abolished the increase in waking seen after 8-OH-DPAT alone. In contrast, the combined treatment with flunitrazepam and 8-OH-DPAT resulted in a lengthening of the latency of REM sleep significantly greater than that observed with the same dose of each drug alone. Fluvoxamine increased the latency and decreased the amount of REM sleep. The association of fluvoxamine with flunitrazepam induced a decrease in REM sleep, equal to the sum of the effects of the two drugs alone. Fluvoxamine did not modify the other effects of flunitrazepam. The present experiments demonstrate that the association of pCPA, 8-OH-DPAT and fluvoxamine, did not alter the hypnogenic effect of flunitrazepam. The possibility of an involvement of 5-HT mechanisms in the effect of flunitrazepam on the phasic events in sleep is questionable.     

Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate.

The abuse of methylenedioxymethamphetamine (MDMA), flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate (GHB) is discussed. Club drugs are chemical substances used recreationally in social settings. Use is increasingly frequent among young people, especially during all-night dance parties. All four agents have been classified as controlled substances. MDMA ("ecstasy") is available as a tablet, a capsule, and a powder; formulations may contain many adulterants. MDMA increases the release of neurotransmitters. The desired effects are euphoria, a feeling of intimacy, altered visual perception, enhanced libido, and increased energy. The most common adverse effects are agitation, anxiety, tachycardia, and hypertension. More serious adverse effects include arrhythmias, hyperthermia, and rhabdomyolysis. Flunitrazepam is a potent benzodiazepine. At higher doses, the drug can cause lack of muscle control and loss of consciousness. Other adverse effects are hypotension, dizziness, confusion, and occasional aggression. Ketamine is a dissociative anesthetic used primarily in veterinary practice. It may be injected, swallowed, snorted, or smoked. Like phencyclidine, ketamine interacts with the N-methyl-D-aspartate channel. Analgesic effects occur at lower doses and amnestic effects at higher doses. Cardiovascular and respiratory toxicity may occur, as well as confusion, hostility, and delirium. GHB, a naturally occurring fatty acid derivative of gamma-aminobutyric acid, was introduced as a dietary supplement. Increasing doses progressively produce amnesia, drowsiness, dizziness, euphoria, seizures, coma, and death. Flunitrazepam, ketamine, and GHB have been used to facilitate sexual assault. Supportive care is indicated for most cases of club drug intoxication. The increasing abuse of MDMA, flunitrazepam, ketamine hydrochloride, and GHB, particularly by young people in social settings such as clubs, should put health care professionals on guard to recognize and manage serious reactions.     

Flunitrazepam (Ro 5-4200) and sleep cycle in insomniac patients

The action of flunitrazepam (Ro 5-4200), a benzodiazepine derivative, was assessed on the sleep cycle of insomniac patients by means of all-night reeordings. Baseline placebo nights were compared with the drug (2–8 mg p.o.) and with the placebo post-drug nights.Flunitrazepam induced a shift to faster frequencies of the EEG and a disappearance of sleep stages 3 and 4 while stage 2 was increased. In 10 out of 12 studied insomniacs the compound was effective in inducing and maintaining sleep (decrease in NREM sleep latency, wake time and number of wakes) throughout the drug administration period. Both NREM and REM sleep were increased, the latter most likely in relation to a blockade of processes precluding NREM emergence.The hypnotic action of flunitrazepam was still present during the first withdrawal night, pointing out to a carry over effect.Supported by a grant from Hoffman-La Roche.     

Flunitrazepam and triazolam: a comparison of behavioral effects and abuse liability

The performance, observer-rated, and participant-rated effects of orally administered placebo, and two benzodiazepines, flunitrazepam (2, 4 and 8 mg/70 kg) and triazolam (0.25, 0.5 and 1 mg/70 kg), were compared in 14 sedative drug abusers using a double-blind crossover design. Both flunitrazepam and triazolam produced dose-related decrements in memory and psychomotor/cognitive performance, and increases in many participant- and observer-rated measures. Effects of flunitrazepam had an earlier onset and a longer duration than those of triazolam. Although there was evidence that the flunitrazepam doses selected for study were somewhat higher overall relative to the selected triazolam doses, analysis of the participant-rated measures collected 24 h after drug administration (next-day) suggests that flunitrazepam may have a greater abuse liability than triazolam when abuse liability is assessed 24 h after drug administration. The highest flunitrazepam dose produced effects that were significantly greater than those of the highest triazolam dose on next-day ratings of good effects, take again, and worth; all tested flunitrazepam doses produced effects greater than any triazolam dose on next-day ratings of liking and take again. The highest flunitrazepam dose, but no triazolam dose, significantly increased the maximum dollar value at which participants chose drug over money in a Drug versus Money Choice Procedure.     

Effects of zolpidem and flunitrazepam on nocturnal sleep of women subjectively complaining of insomnia

Eighteen non-pregnant woman complaining about insomnia were polysomnographically investigated for 3 nights with weekly intervals. They received placebo, 2 mg flunitrazepam or 10 mg zolpidem according to a cross-over double blind design. The patients were selected by general practitioners on the basis of subjective complaints. Zolpidem is a recently introduced short-acting imidazopyridine hypnotic, binding to a subunit of the benzodiazepine 1 receptor. Flunitrazepam is a well-known hypnotic, binding to both the benzodiazepine 1 and 2 receptor subtypes. Objective recording did not substantiate the subjective complaint of insomnia. Sleep patterns during placebo differed only little from that expected from age matched healthy persons. Both flunitrazepam and zolpidem significantly shortened sleep onset (5 min of continuous sleep beginning with NREM 1 sleep). The sleep composition following flunitrazepam was characterized by an increase in NREM 2, a prolongation of the time to REM sleep, a reduction of REM sleep and an increase in NREM 3–4 sleep during the first 2 h of sleep. The sleep composition following zolpidem resembled more that seen in persons without sleep complaints. However, as compared to placebo, there was a decrease of the time spent awake during sleep and an increase in NREM 3–4 during the first 2 of sleep.     

Benzodiazepines in Miami-Dade County, Florida driving under the influence (DUI) cases (1995-1998) with emphasis on Rohypnol: GC-MS confirmation, patterns of use, psychomotor impairment, and results of Florida legislation.

Benzodiazepines are central nervous system depressant drugs often detected in biological samples from driving under the influence (DUI) offenders. They are associated with marked psychomotor impairment and represent up to 20% of all Miami-Dade County, Florida DUI urine samples analyzed in our laboratory annually. Flunitrazepam emerged in the mid-1990s as an illegal drug in the U.S. that was predominantly abused recreationally and associated with sexual assaults. Immunoassays for benzodiazepines do not discriminate between different benzodiazepines, and certain metabolites, such as 7-aminoflunitrazepam, react poorly with immunoassay reagents. A simple and sensitive method for the detection and quantitation of major benzodiazepines and metabolites by gas chromatography with mass selective detection is presented. This method was used to confirm benzodiazepines in general and flunitrazepam in particular. Data collected over a three-and-a-half-year period are summarized. Whereas flunitrazepam was present in up to 10% of DUI cases in 1995 and 1996 and had fast become the most frequently encountered benzodiazepine in Miami-Dade County DUI-related urine samples, a dramatic drop in case numbers followed the legal reclassification of the drug as a Schedule I substance in Florida in February 1997. Flunitrazepam was often used alone or in combination with cannabis and cocaine. A recent rise in clonazepam cases coincides with the decrease in flunitrazepam confirmation and may indicate a new trend in the abuse of benzodiazepines in South Florida.     

Rapid method for the solid-phase extraction and GC-MS analysis of flunitrazepam and its major metabolites in urine

Recently, flunitrazepam (Rohypnol) has become an increasingly popular drug of abuse among young adults, who take it for its euphoric effects. In other cases, the drug has been used by rapists for its sedative and hypnotic effects that can induce a catatonialike trance and memory loss in potential victims; as a result, it has been nicknamed the "date-rape drug". For these reasons, the Drug Enforcement Administration recently considered adding the drug (a.k.a. "Roofies") to the same category as heroin and LSD. A selective and sensitive technique has been developed for extracting, detecting, and identifying flunitrazepam and its two major metabolites (7-aminoflunitrazepam and N-desmethylflunitrazepam) in human urine. Using a solid-phase extraction cartridge containing a "mixed-mode" bonded silica gel (Bond Elut Certify), flunitrazepam and its metabolites were selectively isolated from other urine components and quantitated and identified by gas chromatography-tandem mass spectrometry with a benchtop ion mass spectrometer. The extraction method is rapid, reproducible, and precise, and it has a broad linear working range. The overall extraction efficiency was found to be more than 90% for the parent drug as well as the two major metabolites.     

A comparison of the acute behavioral effects of flunitrazepam and triazolam in healthy volunteers

Flunitrazepam is an hypnotic benzodiazepine marketed in different European countries. Epidemiological studies have shown that it is frequently abused by opioid addicts. In a survey, liking scores for flunitrazepam in methadone maintenance patients were higher than ratings for other benzodiazepines. A double-blind, placebo controlled, crossover clinical trial was conducted to assess the acute behavioral effects of flunitrazepam (0.05 and 2 mg) and triazolam (0.25 and 0.50 mg) in healthy male volunteers. Drug effects on physiological measures, psychomotor performance, and subjective rating scales, including specific questionnaires to evaluate abuse liability (e.g., ARCI or liking scores), were assessed before and 6 h after drug administration. Flunitrazepam 2 mg produced the most intense disruptive effects on all the performance tasks, triazolam 0.50 impaired performance except balance. All study drugs at all doses produced sedation symptoms in all or part of the subjective effects questionnaires. Only flunitrazepam 2 mg induced significative increases in some of the scales (liking, good effects, high) that could be related to a possible abuse potential. The results seem to indicate that flunitrazepam, when administered to healthy subjects, produces some pleasurable subjective feelings, that could indicate a higher abuse liability of this drug as compared with other benzodiazepines.Presented in part at the 54th Annual Scientific Meeting of the College on Problems of Drug Dependence, Toronto, 1993     

Benzodiazepine self-administration in humans and laboratory animals – implications for problems of long-term use and abuse

 Drug reinforcement may represent the primary behavioral-pharmacological mechanism underlying two types of problematic use of benzodiazepines – recreational abuse by polydrug abusers and inappropriate chronic use by patients. High dose polydrug abuse for the purpose of getting high is readily recognized as a significant social problem. Inappropriate chronic benzodiazepine use is more subtle but relatively common: for anxiolytics, 36% of past-year users (3% of the adult population in the US) report using these drugs for 4 consecutive months or longer. The risks of such long-term use are much better documented than the benefits. This paper provides a current review of various problems that have been identified with the long-term use and the recreational abuse of benzodiazepines, including memory impairment, risk of accidents, falls and hip fractures in the elderly, a withdrawal syndrome, brain damage, overuse in the elderly, overuse by chronic pain patients, overuse by alcoholics and recreational abuse among alcoholics and polydrug abusers. A comprehensive review of the literature on benzodiazepine reinforcing effects in humans and laboratory animals is also provided. Drug self-administration studies in humans and laboratory animals provide models of both types of problematic benzodiazepine use. Recreational abuse of benzodiazepines has been modeled in human research with polydrug abusers and in laboratory animal studies, which show that the reinforcing effect of benzodiazepines is intermediate relative to other sedative compounds and is increased in subjects with histories of previous sedative drug self-administration. The problem of inappropriate long-term use of benzodiazepines by people without histories of drug abuse has been partially modeled in human studies showing that benzodiazepines function as reinforcers in subjects with anxiety, insomnia, and histories of moderate alcohol consumption, and in preclinical studies showing stable, low-rate benzodiazepine self-injection with concurrent physical dependence under conditions of continuous availability. Both human and animal research suggests that the drug history and current behavioral context may be important in the establishment of benzodiazepines as reinforcers. Limited human and animal research provides little support for the common belief that physical dependence enhances benzodiazepine reinforcement. Received: 25 October 1996 / Final version: 19 May 1997     

Residual effects of zopiclone and benzodiazepine hypnotics on psychomotor performance related to car driving

A double-blind, randomized, cross-over study was carried out in 10 normal healthy volunteers to investigate the residual effects of 7.5 mg zopiclone, 1 mg lormetazepam, 0.25 mg triazolam, 1 mg flunitrazepam and placebo. Tests of psychomotor performance and analogues of car driving ability were administered the morning following night-time medication. Changes with respect to placebo in an information-processing task one hour after taking the medications confirmed the hypnotic efficacy of zopiclone, triazolam and flunitrazepam. Flunitrazepam also produced a significant depression of the Critical Flicker Fusion Threshold (CFF) and increased subjective ratings of sedation one hour after nocturnal dosing. Flunitrazepam impaired the reaction time on the information-processing test the morning following doses of 1 mg.     

Abuse Liability of Barbiturates and Other Sedative-Hypnotics

The principal action of the sedative-hypnotic drugs, of whom the barbiturates are the most widely known and utilized, is to produce drowsiness and promote sleep. At one time these were also the only drugs available to calm seriously anxious or disturbed people. Unfortunately, in addition to their clinical applications these drugs mainfest a very high abuse potential. Experienced drug abusers report feelings of well-being and euphoria while under the influence of these drugs. Self-administration experiments conducted in animals have shown that the the barbiturates are potent reinforcing agents. In controlled studies in humans, former drug abusers express a preference for barbiturates over benzodiazepines and will "work" to receive barbiturates. Long term consumption of the sedative-hypnotics, particularly barbiturates, leads to dependence characterized by a severe, potentially life-threatening abstinence syndrome following the abrupt withdrawl of the drug. Withdrawl manifestations include delirium and grand mal seizures. Because of the high abuse potential of these drugs, their manufacture and distribution has been greatly curtailed, and for most clinical applications they have been largely replaced by drugs, e.g., the benzodiazepines, which appear to have much less abuse liability.     

An abuse liability comparison of flunitrazepam and triazolam in sedative drug abusers

The present double-blind, placebo-controlled study compared the acute effects of oral administration of the benzodiazepine hypnotics flunitrazepam (6 mg/70 kg) and triazolam (1 and 2 mg/70 kg) on measures relevant to abuse liability as well as on psychomotor performance and observer- and participant-rated measures of drug effects in nine sedative drug abusers. Analysis of participant-rated measures collected 24 h after drug administration (next-day; assessing the overall effects of the drug received 24 h earlier) indicated that flunitrazepam, but neither triazolam dose, produced significant increases relative to placebo in next-day ratings of drug liking, the amount of money the drug would be worth on the street, and the amount of money the participant would be willing to pay for the drug on the street. Importantly, these abuse liability differences between flunitrazepam and triazolam were present at a dose of flunitrazepam (6 mg/70 kg) that produced overall drug effects that were comparable to, or significantly less than, those of a high triazolam dose (2 mg/70 kg). Consistent with results of a previous study in our laboratory, these results suggest that flunitrazepam may have a greater abuse liability than triazolam, and that this abuse liability difference emerges on measures taken 24 h after drug administration but not on same-day measures.     

Highly sensitive micro-plate enzyme immunoassay screening and NCI-GC-MS confirmation of flunitrazepam and its major metabolite 7-aminoflunitrazepam in hair.

Flunitrazepam (Rohypnol) is a benzodiazepine used in the treatment of insomnia as a sedative hypnotic and as preanesthetic medication in European countries and Mexico. Although it has no medicinal purpose in the United States, the occurrence of its abuse is increasing. Sexual abuse of both men and women while under the influence of so-called "date-rape" drugs has been the focus of many investigations. Reported date-rape drugs include flunitrazepam (FN), clonazepam, diazepam, oxazepam, gamma-hydroxybutyrate, and many others. FN has been banned in the United States because of its alleged use in such situations. Unfortunately, the detection of FN or its metabolites 7-aminoflunitrazepam (7-AFN) and desmethylflunitrazepam in a single specimen such as urine or blood is difficult in criminal situations because of the likelihood of single-dose ingestion and the length of time since the alleged incident. Hair provides a solution to the second of these problems in that drugs tend to incorporate into hair and remain there for longer periods of time than either urine or blood. There are various techniques for the detection of FN in plasma, blood, and urine, but little work has been done with hair. Hair collection is a virtually noninvasive procedure that can supply information on drug use for several months preceding collection. The objective of this paper was to determine if a commercially available micro-plate enzyme immunoassay system was sufficiently sensitive for the routine screening of 7-AFN in hair by the development of extraction procedures and optimization of the immunoassay kit. Further, this study used the same solid-phase extraction to isolate FN and its major metabolite, 7-AFN, and gas chromatography-mass spectrometry with negative ion chemical ionization for confirmation. Two seven-point standard curves were established ranging from 0.5 pg/mg to 100 pg/mg for 7-AFN and 2.5 pg/mg to 200 pg/mg for FN with respective deuterated internal standards. A replicate analysis of controls was performed to establish inter- and intraday variabilities. Two suicide cases along with one alleged date-rape case and one case of an emergency room patient whose blood screened positive for benzodiazepines were analyzed. All the hair specimens screened positive for benzodiazepines using micro-plate enzyme immunoassay. Two cases, including the date-rape case, were negative for FN and 7-AFN, and two postmortem hair samples were confirmed positive for FN and its metabolite.     

Efficacy and side effects of flunitrazepam and pentobarbital in severely insomniac patients

One hundred thirty-seven current or prospective recipients of hypnotics were screened to obtain a sample of 12 severely insomniac patients for a study concerning efficacy and side effects of 2 mg flunitrazepam and 100 mg pentobarbital as hypnotics. During the baseline period, these 12 subjects showed wide intraindividual variability of sleep and performance. This variability was not reduced by the hypnotics, which on the average did not adversely affect performance. Flunitrazepam, but not pentobarbital, slightly reduced sleep latency. Neither hypnotic prolonged sleep duration or reduced the number of wakings. The generalizability of the results to the population of recipients of hypnotics is discussed.     

Intravenous drug abusers with antisocial personality disorder: increased HIV risk behavior

Intravenous drug abuse is strongly associated with HIV transmission and with having a diagnosis of Antisocial Personality Disorder (ASPD). While the co-occurrence of intravenous drug abuse and ASPD is related to poor drug abuse treatment outcome, little is known about the contribution of ASPD to the intravenous drug abusers (IVDAs) level of HIV risk. The present study related the diagnosis of ASPD with specific drug use behaviors associated with high risk of HIV transmission. Subjects (N = 100) were intravenous drug abusers who volunteered for an HIV risk assessment study. Subjects with ASPD reported significantly higher rates of injection-equipment sharing and shared with significantly more people than IVDAs without ASPD.     

上海地区药物滥用流行病学回顾性调查

目的·· :了解上海地区药物滥用流行病学情况 ,为药物滥用防治工作提供科学依据。方法·· :对1992年 -2000年上海地区收治的23730例自愿和强制戒毒者病案资料进行回顾性调查分析。结果··:上海地区吸毒群体除具有青年男性、未婚、初中文化程度、无业闲散人员占多数等特征外 ,近年来呈现以下流行特征 :(1)吸毒人数呈逐年上升趋势 ;(2)18a以下青少年吸毒人数上升速度明显 ;(3)女性吸毒人数急剧增加 ;(4)多药滥用严重 ,毒品种类呈多样化 ;(5)吸毒引发的犯罪呈上升趋势 ;(6)吸毒者中合并躯体疾病比例逐年增高。结论·· :上海地区药物滥用趋势严重 ,给社会、家庭、个人造成很大危害。加强毒品危害和知识的宣传教育 ,特别是对青少年和高危人群的教育刻不容缓 ,提高戒毒质量 ,降低毒品危害也应提到议事日程予以关注。