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PubMed1978

Comparative evaluation of hypnotic efficacy of flunitrazepam in psychiatric in-patients.

Flunitrazepam in 2-mg and 4-mg doses was compared with flurazepam 30 mg and nitrazepam 10 mg for hypnotic efficacy in a double-blind, multiple cross-over trial involving 41 psychiatric in-patients. In the vast majority of comparisons involving a number of sleep parameters differences did not reach significance level. Flunitrazepam 4 mg tended to produce the shortest latency time and the longest duration of sleep but also the most side-effects. Nitrazepam 10 mg appeared to have a slight advantage over the other drugs in terms of patient preference. For severe sleep disturbance flunitrazepam 2 mg tended to be the most satisfactory drug in terms of efficacy and paucity of side-effects.

Adult↗
PubMed1981

Triazolam (Halcion) versus flunitrazepam (Rohypnol) against midwinter insomnia in Northern Norway.

In a double-blind, cross-over trial, triazolam (0.25 mg) was tested against flunitrazepam (1 mg) in the typical midwinter insomnia which is often seen among otherwise healthy people in Northern Norway. Each drug was given for five nights, in random order, with a five-night placebo period between the active drugs (providing for a single blind comparison with placebo). A total of 2 outpatients started the trial; 19 completed. There were highly significant differences between each active drug and placebo on the subjectively scored variables sleep latency, duration of sleep, and total evaluation of sleep, and also significant differences for feeling in the morning, number of awakenings, and quality of sleep; all differences were in favour of the active drugs. Generally, the sleep variables were rated on the same level in the placebo period as they were for the last five nights prior to the trial. There were no significant differences between triazolam and flunitrazepam on any variable. However, eight patients stated a preference for triazolam and eight for flunitrazepam. These two groups of patients did not differ significantly with regard to sex, age, previous use of hypnotics, or severity of insomnia. Only three patients complained about side effects. Notably, the feeling of being alert and refreshed in the morning was significantly superior in the active drug periods as against the placebo period. It is concluded that both active drugs were highly effective, with a minimum of side effects, in this type of insomnia and with the relatively low dosage used.

Adolescent↗
PubMed1983

Effect of midazolam, flunitrazepam, and placebo against midwinter insomnia in northern Norway.

Forty-three outpatients with "midwinter insomnia" (an early type insomnia commonly seen north of the Polar Circle when the sun stays below the horizon) were randomly allocated to one of three treatment groups, receiving either 15 mg midazolam, 1 mg flunitrazepam, or placebo, for 5 nights, double blind, after 3 nights without drug. In all three groups, this was followed by 5 nights on placebo (single blind). Several subjective sleep variables were recorded every morning, some variables also at noon. Placebo had practically no effect on any sleep variable, whereas both active drugs markedly improved sleep with regard to the following variables: sleep latency, number of awakenings, total duration of sleep, quality of sleep, total evaluation of sleep, and feelings of drowsiness in the morning and at noon. In the withdrawal period, patients who had received active drug showed a deterioration of sleep on most variables, but not beyond the baseline level. A true "rebound insomnia" could thus not be demonstrated. There was no significant difference in any of the variables between midazolam and flunitrazepam treatment. Side effects were reported by very few patients. Midazolam seems to be as effective as flunitrazepam in this type of insomnia, in spite of its much shorter biological half-life.

Adolescent↗
PubMed1984

Benzodiazepine inhibition of flunitrazepam receptor binding, adenosine uptake, and pentylenetetrazol-induced seizures in mice.

The potencies of seven benzodiazepines (BDZs) were established by three tests: inhibition of [3H]flunitrazepam receptor binding, inhibition of [3H]adenosine uptake, and prevention of pentylenetetrazol-induced seizures in mice. There is a high correlation between the potency for inhibition of [3H]flunitrazepam receptor binding and the antipentylenetetrazol potencies of benzodiazepines (r = 0.941; p less than 0.01). The antipentylenetetrazol potencies of benzodiazepines correlate well with their ability to inhibit [3H]adenosine uptake (r = 0.860; p less than 0.05 and greater than 0.01). However, there is no significant correlation between the potency for the inhibition of [3H]flunitrazepam receptor binding and the potency for inhibition of [3H]adenosine uptake (r = 0.751; p greater than 0.05). In addition, there is a marked difference in BDZ potency as measured by these two tests in vitro. The ratios of the Ki values (Ki2/Ki1) range from 98 for BDZ I to 64615 for clonazepam. The data presented indicate that antipentylenetetrazol activity of benzodiazepines results from an interaction between BDZ and nanomolar affinity BDZ receptors.

Adenosine↗
PubMed1999

Zinc and flunitrazepam modulation of GABA-mediated currents in rat suprachiasmatic neurons.

The suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for generating circadian rhythms in mammals, and GABA is the predominant neurotransmitter in the SCN. Properties of gamma-aminobutyric acid-A (GABAA) responses in SCN neurons were examined in acutely prepared hypothalamic slices from 3- to 8-wk-old rats with the use of whole cell voltage-clamp techniques. Zn2+ reduced the amplitude of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in a concentration-dependent manner ranging from a reduction of control amplitude to 88% at 10 microM to 27% at 1,000 microM. Zn2+ reduced IPSC amplitude to a similar degree in the presence of tetrodotoxin and also significantly reduced the amplitude of currents evoked by application of exogenous GABA (100 microM, pressure applied). Zn2+ increased the frequency of IPSCs at lower concentrations and decreased it at higher ones. Flunitrazepam (100 nM) usually failed to potentiate the amplitude of sIPSCs, but prolonged sIPSC kinetics. Two exponential components were normally resolved in the sIPSC decay constants, and flunitrazepam significantly increased those two components. Thus flunitrazepam increased the duration of sIPSCs and potentiated the amplitude of currents evoked by pressure application of GABA. Zn2+ and benzodiazepine each modulated the effect of GABA in nearly all cells, suggesting that most SCN neurons have a similar GABAA receptor subunit composition in this respect. Zn2+ also affected sIPSC frequency, which suggests that Zn2+ increased neuronal firing rate at lower concentrations. These results begin to define the cellular roles that these GABAA receptor modulators might play in circadian regulation.

Animals↗
PubMed1982

Automated electron-capture gas chromatographic analysis of flunitrazepam in plasma.

Nanogram quantities of flunitrazepam and its major metabolite, desmethylflunitrazepam, can be reliably quantitated in human plasma using electron-capture gas-liquid chromatography. After addition of methylnitrazepam as the internal standard, plasma samples are extracted with an organic solvent (benzene:isoamyl alcohol). The organic extract is separated, evaporated to dryness, reconstituted, and injected onto the chromatograph using an automatic sampling system which allows up to 100 analyses/24 h. The sensitivity limits are 0.5 ng/ml for flunitrazepam and 1-2 ng/ml for desmethylflunitrazepam. Use of the method is illustrated in a study of the pharmacokinetic properties of flunitrazepam following a single 1.0-mg intravenous dose.

Adult↗
PubMed1983

A comparative study of zopiclone and flunitrazepam in insomniacs seen by general practitioners.

A double-blind crossover trial was conducted in 42 outpatients of either sex in order to obtain information on the properties of 7.5 mg of zopiclone in a general practice setting compared with 2 mg of flunitrazepam. Each patient went through two periods of treatment, each period lasting 10 days. A comparison of the effect of the drugs showed a significant difference with regard to effectiveness and sleep latency favoring flunitrazepam. When patient's preferences were analyzed there was a highly significant difference favoring flunitrazepam both for effectiveness and tolerance. The side effects from both drugs were generally mild.

Adolescent↗
PubMed1975

EEG sleep studies of insomniacs under flunitrazepam treatment.

This study investigates the effect of flunitrazepam, a new benzodiazepine, on the sleep of insomniac patients under chronic treatment. Polygraphic recordings have shown that this drug decreases not only the activity of the wakefulness system, but also the activity of the synchronizing system of slow-wave sleep. The subjective feeling of improved and sounder sleep seems to be related to a decrease of wakefulness pressure as well as to a decrease of body motoricity, but not with the modification of sleep stages themselves. Flunitrazepam appears to possess some regulatory properties on REM sleep, since this stage is enhanced in patients with an initial low amount of REM sleep and decreased in those having a higher initial REM sleep. Flunitrazepam possesses potent and useful hypnogenic properties in man but does not induce physiological sleep.

Adult↗
PubMed1998

Use and abuse of flunitrazepam.

Flunitrazepam is not available in the US, and it is presently illegal to import it. Flunitrazepam has no therapeutic advantage over benzodiazepines presently marketed in the US. Its quick onset of sedation, amnesic properties, and additive effects with alcohol have led to its reputation as a party drug, club drug, or date rape drug. Several measures have been undertaken to curb its illicit use. It is unclear whether flunitrazepam poses a greater public health risk than other benzodiazepines.

Anti-Anxiety Agents↗
PubMed1996

The effect of triazolam and flunitrazepam--two benzodiazepines with different half-lives--on breathing during sleep.

We performed a double-blind single-dose placebo/hypnotics crossover study randomized within groups to test the potential problems that a group of normal subjects, including subjects who snore, may face using hypnotic medications. Two benzodiazepine hypnotics--triazolam, 0.25 mg, and flunitrazepam, 2 mg tablets--were considered. Subjects were monitored with nocturnal polysomnography, including esophageal pressure (Pes) monitoring as a measure of respiratory efforts, and were given daytime performance tests. Results were analyzed for the total nocturnal sleep period and also by thirds of the night in consideration of the different half-lives of the studied drugs. Three specific respiratory variables were evaluated: mean breathing frequency for selected unit of time, "Delta Pes" (esophageal pressure at peak end-expiration minus Pes at peak end-inspiration) expressed in cm H2O, and the ratio of Delta Pes/Delta TI (inspiratory time), taken as an index of respiratory drive calculated for each respiratory cycle. There was no significant increase in either the respiratory disturbance index or the oxygen desaturation index (number of drops in arterial oxygen saturation of 4% or more per hour of sleep, as measured by pulse oximetry). There was a significant increase in mean breathing frequency with flunitrazepam compared with placebo, as well as a significantly larger percentage of time during sleep with Delta Pes above 10 cm H2O (taken as a cutoff point for normal respiratory effort) with both triazolam and flunitrazepam compared with placebo. These respiratory changes, even if significant, were minor but may become a liability in association with specific abnormalities.

Adult↗
PubMed1980

Flunitrazepam: a review of its pharmacological properties and therapeutic use.

Flunitrazepam is a benzodiazepine derivative whose hypnotic effect predominates over the sedative, anxiolytic, muscle-relaxing and anticonvulsant effects characteristic of benzodiazepines. Thus, it is used as a night-time hypnotic and in anaesthesiology: due to the pronounced hypnotic effect it is not appropriate as a daytime sedative. As a hypnotic for insomnia its effect is usually characterised by a very fast onset of action and quiet sleep without interruptions. On the morning after a hypnotic dose some residual psychomotor impairment does occur, which is comparable to that with usual doses of nitrazepam or flurazepam, but clinically apparent 'hangover' occurs infrequently. There is no pronounced cumulative effect with chronic use. In anaesthesiology it has proven to be useful as a hypnotic on the night before operation, as an oral, intramuscular or intravenous premedication, in induction and as a supplement to other anaesthetics. Its sedative and amnesic properties can also be beneficial in intensive care patients. Much of the usefulness of flunitrazepam in anaesthesia relates to its synergistic effect with other anaesthetics, to its effective amnesic action and its acceptable effects on circulation and respiration. Possible drawbacks include a somewhat unusual course of induction (when used for this purpose) and an often prolonged recovery. Although the safe dosage range is wide with flunitrazepam, its effective application both as a hypnotic for insomnia and in anaesthesiology is dependent upon use of the optimal dosage, and adequate knowledge of its pharmacokinetic properties.

Anesthesia↗
PubMed1999

Simple and rapid color screening tests for flunitrazepam (Rohypnol).

Three new color/screening tests for flunitrazepam (Rohypnol) are reported. The two-step tests are simple, sensitive, highly specific, and effective for both cut and uncut flunitrazepam and standard over-the-counter preparations of flunitrazepam (i.e., Rohypnol tablets).

Anti-Anxiety Agents↗
PubMed2000

Analysis of biofluids for flunitrazepam and metabolites by electrospray liquid chromatography/mass spectrometry.

A rapid and sensitive liquid chromatography/electrospray ionization mass spectrometry (LC/MS) procedure has been developed for the analysis of biofluids containing flunitrazepam and its metabolites. Specimens were spiked with deuterated analogs of the analytes. Urine specimens were enzymatically hydrolyzed and blood specimens were untreated. Extractions were carried out using CleanScreen DAU SPE cartridges. The drugs were separated on a C18 column using a methanol-water-ammonium hydroxide (60:40: 0.03 v/v) mobile phase. After determination of base peaks using full scan mass spectrometry, the mass spectrometry method was optimized to operate in selected-ion monitoring (SIM) mode for the base peak of each analyte. Positive findings were confirmed by LC/MS/MS using the same mobile phase and column. This analytical procedure allows for the detection of low levels of flunitrazepam and metabolites in biofluids. It is useful for ascertaining the role of flunitrazepam in cases of drug-facilitated sexual assault.

Anti-Anxiety Agents↗
PubMed2001

Flunitrazepam metabolism by cytochrome P450S 2C19 and 3A4.

We have identified CYP2C19 and CYP3A4 as the principal cytochrome P450s involved in the metabolism of flunitrazepam to its major metabolites desmethylflunitrazepam and 3-hydroxyflunitrazepam. Human CYP2C19 and CYP3A4 mediated the formation of desmethylflunitrazepam with Km values of 11.1 and 108 microM, respectively, and 3-hydroxyflunitrazepam with Km values of 642 and 34.0 microM, respectively. In human liver microsomes (n = 4) formation of both metabolites followed biphasic kinetics. Desmethylflunitrazepam formation was inhibited 31% by S-mephenytoin and 78% by ketoconazole, suggesting involvement of both CYP2C19 and CYP3A4. Formation of 3-hydroxyflunitrazepam was also significantly inhibited by ketoconazole (94%) and S-mephenytoin (18%). In support of these chemical inhibition data, antibodies directed against CYP2C19 and CYP3A4 selectively inhibited formation of desmethylflunitrazepam by 26 and 45%, respectively, while anti-CYP3A4 antibodies reduced 3-hydroxyflunitrazepam formation by 80%. Our data also suggest that CYP1A2, -2B6, -2C8, -2C9, -2D6, and -2E1 are not involved in either of these metabolic pathways. We estimate that the relative contributions of CYP2C19 and CYP3A4 to the formation of desmethylflunitrazepam in vivo are 63 and 37%, respectively, at therapeutic flunitrazepam concentrations (0.03 microM). We conclude that the polymorphic enzyme CYP2C19 importantly mediates flunitrazepam demethylation, which may alter the efficacy and safety of the drug, while CYP3A4 catalyzes the formation of 3-hydroxyflunitrazepam.

Anti-Anxiety Agents↗
PubMed1977

Premedication with flunitrazepam in gastro-intestinal endoscopy.

Administration of 2 mg flunitrazepam (Rohypnol; Roche) to patients before gastro-intestinal endoscopy caused significantly less anxiety and achieved significantly greater sedation than diazepam (Vallium; Roche). No differences were found between any of the trial groups with respect to ease of intubation, tolerance of the procedure, gastric peristalsis, and the state of the pylorus. Memory of the procedure was significantly less vivid in the groups who received 2 mg flunitrazepam, than in the other groups. The patients who received 2 mg flunitrazepam showed a significantly greater willingness to undergo a repeat procedure, both when asked immediately after the procedure, and when asked on the next visit. Pulse rate increased in all groups during the procedure. No change in respiratory rate or in systolic and diastolic blood pressure occurred in any group.

Anti-Anxiety Agents↗
PubMed1990

Double blind comparison of zolpidem 20 mg versus flunitrazepam 2 mg in insomniac in-patients.

The efficacy of zolpidem 20 mg was compared to that of flunitrazepam 2 mg. Forty-two insomniac female in-patients between 30 and 65 years of age were included in a double blind, parallel group trial and were randomly allocated to the two treatments. Study duration was 9 days with 2 days of placebo run-in, 5 days of active medication and 2 days of placebo withdrawal. Sleep latency, sleep duration, number of awakenings and time spent asleep during the night were given an ordinal score; condition in the morning was evaluated by Visual Analogue Scales and the psychomotor performance was evaluated by the tests: night-day for anterograde amnesia, digit span for verbal recall and Grünberger's fine motor function test. There was no significant difference between zolpidem and flunitrazepam for any of the variables; the drugs were significantly better than placebo baseline for all the sleep efficacy variables. The results of this study indicate that zolpidem is as effective as flunitrazepam in inducing and maintaining sleep but it does not induce a sense of weakness in the morning and does not impair memory.

Adult↗
PubMed1989

Effects of flunitrazepam on memory and their reversal by two antagonists.

The amnestic effects of flunitrazepam (2 mg intravenously) were studied in normal volunteers with emphasis on their relationship to sleep and their reversal by two specific benzodiazepine receptor antagonists (Ro 15-1788 and Ro 15-3505). The test battery was based on available clinical tests to assess various aspects of encoding and recall. The results suggest that flunitrazepam impairs acquisition of new information by interfering with encoding, and that these effects are clearly independent of sleep. Flunitrazepam effects on memory were fully reversed by both antagonists, as were the subjective and objective signs of sedation. This speaks against the hypothesis of different receptors for sedative and amnestic effects. Ro 15-3505 had shorter lasting effects than Ro 15-1788 and interfered with some tests; this is discussed in relation to its inverse agonistic effects.

Adult↗
PubMedDate not supplied

[Flunitrazepam and memory (author's transl)].

This work is based on the observation of memory troubles before sleep in patients with sleep problems treated with flunitrazepam. Eight subjects are tested in two sessions, flunitrazepam and placebo, in double blind, with memory tests given the evening after medication and controlled the next morning. One additional test is controlling vigilance. The results show that memory is significantly disturbed by flunitrazepam, both for direct and delayed memory, the next day. On the contrary, recognition is not altered, neither vigilance.

Adult↗