Abuse liability of flunitrazepam among methadone-maintained patients

Abuse liability and acute subjective and psychomotor effects of flunitrazepam were assessed in ten methadone-maintained males with history of benzodiazepine and alcohol use, who voluntarily participated in a double-blind, controlled, cross-over, randomized clinical trial. There were six experimental sessions in which a single oral dose of flunitrazepam 1, 2, and 4 mg; triazolam 0.5 and 0.75 mg; and placebo was given. Evaluations included physiological measures; psychomotor performance tasks (simple reaction time, Digit Symbol Substitution Test, balance task, Maddox-wing device); and self-administered subjective effects questionnaires [Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), a series of visual analog scales (VAS)]. All drugs but flunitrazepam 1 mg caused an impairment of psychomotor tasks. Effects were more evident with the highest doses of both drugs. Only flunitrazepam 4 mg produced a significant decrease in balance time. Triazolam 0.75 mg induced increases in sedation measured by ARCI-PCAG, depression in POMS, and VAS-drowsiness scores. Flunitrazepam 4 mg caused euphoria-related effects as measured by increases in ARCI-MBG and “high” scores in the VAS. Our findings of flunitrazepam-induced euphoria in methadone-maintained subjects together with epidemiological evidence of flunitrazepam abuse by opioid dependents, suggest that it may be included in the group of benzodiazepines with a relatively high abuse potential. Received: 13 February 1998/Final version: 1 May 1998     

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     

Regional distribution of benzodiazepine binding sites in the human newborn and infant hypothalamus. A quantitative autoradiographic study

Using in vitro quantitative autoradiography and [3H]flunitrazepam we examined the rostrocaudal distribution of benzodiazepine binding sites in the human neonate/infant hypothalamus. The autoradiographic analysis shows the presence of a heterogeneous distribution throughout the rostrocaudal extent of this brain structure. High [3H]flunitrazepam binding corresponds primarily to the diagonal band of Broca and the preoptic region. The labelling in the preoptic region showed a rostrocaudal increase, contrasting in that with the other hypothalamic structures. Intermediate densities were present in the septohypothalamic, suprachiasmatic, periventricular and paraventricular nuclei as well as in the mammillary complex. Low binding was observed in the other hypothalamic structures. The benzodiazepine binding sites analyzed belong mostly to type II receptors. In an attempt to unravel possible differences related to age, we compared the autoradiographic distribution in three postnatal age ranges. The topographical distribution of these binding sites was almost identical in each period analyzed. We found, however, that benzodiazepine binding is generally low in the neonatal period and a tendency in increasing densities is observed during development. Taken together, these results provide evidence for a large distribution of benzodiazepine binding sites in neonate/infant hypothalamus, suggesting their implication in the development of this brain structure and the maintenance of its various functions.     

THIP and isoguvacine are partial agonists of GABA-stimulated benzodiazepine receptor binding

The effects of THIP and isoguvacine on 3H-flunitrazepam binding to washed membranes prepared from the cerebral cortex of adult rats have been examined. THIP, which has only minimal stimulatory effects on benzodiazepine (BZ) receptor binding, has been found to inhibit the stimulation induced by small concentrations (2 microM) of exogenous GABA. While isoguvacine stimulates BZ receptor binding, although to a smaller extent than GABA, it also antagonizes the stimulation of BZ receptor binding induced by GABA. Thus THIP and isoguvacine exhibit the properties of a partial agonist of GABA-stimulated BZ receptor binding.     

Benzodiazepine binding sites: Localization and characterization in the limbic system of the rat brain

The distribution of benzodiazepine binding sites was analysed in limbic structures of rat brain by quantitative radioautography of brain sections incubated with 3H-flunitrazepam (3H-FLU). Quantitative estimation of the binding parameters was made in each range of postero-anterior sections taken. Distribution of 3H-FLU binding sites was found to be rather homogeneous in most of the structures examined but there were regional differences which resulted from variations in the densities of sites rather than in their affinities. A particular distribution pattern of 3H-FLU binding sites was observed in the cingulate cortex contrasting with the homogeneous postero-anterior distribution measured in other cortical areas in the same slices. A significantly greater density of sites was found in the anterior part of the structure as compared to the posterior part. This difference, which corresponds to a change in the density of sites without alteration of their apparent affinity and occurs at a precise anatomical level, is discussed with reference to the anatomical organization of this brain structure and to its possible functional implications.     

The effects of substituting zopiclone in withdrawal from chronic use of benzodiazepine hypnotics

Twenty-four volunteers (19 women and five men) with insomnia and a history of chronic use of benzodiazepine hypnotics participated in a randomized, double blind, controlled clinical trial. The study was designed to assess the effects of substituting zopiclone (ZOP) – as an hypnotic – among chronic users of flunitrazepam (FLU), and to compare the subsequent withdrawal of ZOP with placebo controlled withdrawal of FLU. During the 5 weeks of a withdrawal protocol, sleep and physiological parameters were assessed by polysomnographic measures for 11 nights and by nightly actigraphic recordings for weeks 1, 3, and 5. Subjective effects of the withdrawal process were evaluated with daily sleep diaries, and with various weekly self-report symptom checklists. Paired t-tests performed on differences in objective sleep parameters between baseline and the last weeks of the withdrawal program showed a significant decrease in sleep quality within the FLU group, but not in the ZOP group. Subjective sleep diaries consistently reflected the objectively measured changes in sleep throughout the withdrawal program, indicating significant changes in sleep parameters only in the FLU group. The results obtained from the self report inventories aimed at assessing withdrawal symptoms, however, revealed no differences between the baseline week and the termination week of the program in any of the groups. After completing the pharmacological withdrawal, all subjects received a short-term cognitive behavioral intervention focused on improving their coping strategies with symptoms of insomnia; they were evaluated immediately after concluding the intervention, and at 3 and 12 month follow-ups. Received: 19 December 1997/Final version: 11 May 1998     

Quality control in therapeutic drug monitoring

Quality control of routine drug assays, like most immunoassays, should mainly be the responsibility of each individual laboratory: intra-laboratory quality control. External quality assessment should direct its efforts in particular to non-routine methods and to new assays. However, it may sometimes also be very useful to have laboratory results of routine assays studied in external programmes, since vague requests or difficult interpretations of drug concentrations need discussion outside the individual laboratory.     

Acute reversal of flunitrazepam effects by Ro 15-1788 and Ro 15-3505: inverse agonism,tolerance, and rebound

A phase 1 double blind crossover comparison of a new benzodiazepine antagonist (Ro 15-3505) with Ro 15-1788 and placebo, in the reversal of sedative and psychophysiological effects of single IV doses of flunitrazepam (2 mg), was carried out in 12 normal volunteers. The antagonists were equally effective, leading to full reversal of all effects with a potency ratio of approximately 2.5 mg Ro 15-1788 for 1 mg Ro 15-3505. Inverse agonism, in the form of unpleasant feelings and symptoms, was reported by all subjects following Ro 15-3505 but none after Ro 15-1788. Adaptational phenomena such as acute tolerance and rebound of sedative effects of flunitrazepam were also detected and their potential implications are discussed.     

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.     

Modulation of human risky decision making by flunitrazepam

Rationale GABA-modulating drugs produce disinhibitory effects that increase the probability of risk-taking behavior. Previous reports suggest that the misuse of the benzodiazepine flunitrazepam is associated with several forms of harmful risky behavior, including theft, violence, and intoxication-related auto accidents. Objectives The present study examined the dose–response relationships between acute flunitrazepam administration and human decision making under conditions of risk. The analyses also examined flunitrazepam-mediated changes in decision-making processes using a computational modeling approach, the expectancy valence model (EVM). Materials and methods Using a laboratory measure of risky decision making designed to address acute drug effects, 12 adults were administered placebo, 0.5, 1.0, and 2.0 mg/70 kg flunitrazepam in a within-subject, repeated measures counterbalanced design. Flunitrazepam was compounded and doses were administered in an 8-oz liquid solution. Primary data analyses examined subjective effects, response rates, distribution of choices between the risky and nonrisky option, and personality correlates related to peak drug effects. Individual-subject data were submitted to a computational modeling analysis (EVM) that provided parameter estimates corresponding to components of valence; updating expectancies about alternatives (learning/memory); and consistency between choices and expected outcomes (sensitivity to learned outcomes). Results Flunitrazepam produced dose-related changes in subjective effects and response rates, and increased selection of the risky response option. High doses significantly changed decision-making processes related to the learning/memory and consistency parameters. Conclusions At sufficiently high doses, flunitrazepam can engender increases in risky decision making. Globally, these changes appear similar to previous effects we have observed after acute administration of alcohol and alprazolam. As suggested by the EVM outcomes, the mechanisms underlying the changes in risky decision making are more similar to alprazolam than alcohol.