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PubMed1982

Comparison of midazolam and flunitrazepam for night sedation. A randomised double-blind study.

In a double-blind randomized study midazolam 15 mg and flunitrazepam 2 mg caused a significantly better night's sleep than placebo. Midazolam had a moderate sedative effect the following morning but, in other respects studied, no residual effects were found. In contrast, flunitrazepam decreased both the degree of apprehension and excitement the following morning. Flunitrazepam also inhibited salivary secretion and caused less cardiovascular changes than placebo or midazolam. The dose of thiopentone needed for induction of anaesthesia was significantly lower in those given flunitrazepam. The results show that midazolam is a potent sedative agent with a short duration of action.

Adult↗
PubMed1983

Efficacy and tolerance: comparative studies with brotizolam and flunitrazepam.

Efficacy of and tolerance to 0.25 mg brotizolam and 2.0 mg flunitrazepam were compared over a period of 6 days in ambulatory patients complaining of sleep disturbance. The study was double-blind and randomised with a parallel group design. Both drugs improved sleep. More patients assessed sleep latency as shorter during the first night of ingestion with flunitrazepam than with brotizolam, but assessments were comparable over the next 5 days. The number of patients who considered that the frequency of nocturnal awakenings was less did not differ significantly between drugs. Tolerance to brotizolam (0.25 mg) was assessed more favourably than with flunitrazepam (2.0 mg). The study suggests that brotizolam (0.25 mg) is indicated for patients who have difficulty in falling asleep and staying asleep, and who must preserve their alertness during the early part of the next day. Flunitrazepam (2.0 mg) is equally effective, but at this dose there is a higher incidence of adverse effects.

Adult↗
PubMed1990

Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo.

1. The effects of zolpidem 20 mg, flunitrazepam 2 mg and placebo, administered at bed time, were studied in 12 healthy young male volunteers. 2. The assessments included, at awakening, subjective ratings of overnight sleep, cognitive function, psychomotor performance (digit symbol substitution, choice reaction time, flicker fusion threshold), subjective ratings of alertness, and plasma assay of residual drug concentration. Daytime sleep propensity during the day after dosing was evaluated with the multiple sleep latency test. 3. Compared with placebo, both active drugs improved subjective assessment of the ease of getting to sleep. At awakening, under flunitrazepam treatment, the reduction of performance, on memory and psychomotor tests, paralleled an increased subjective rating of sleepiness, but zolpidem treatment left subjects unimpaired compared with placebo. Similarly, daytime sleep propensity was enhanced throughout the following day under flunitrazepam treatment, but not under zolpidem treatment. Plasma assay for residual drug concentration at awakening found significant amounts of flunitrazepam and marginal amounts of zolpidem. 4. Results indicate that zolpidem 20 mg is devoid of residual effects in a range of tasks that were sensitive enough to demonstrate a prolonged wakefulness impairment following flunitrzepam 2 mg in healthy volunteers.

Administration, Oral↗
PubMed1991

Inter- and intraindividual variability in the concentration-effect (sedation) relationship of flunitrazepam.

1. The relationship between plasma flunitrazepam concentrations and the degree of sedation was evaluated in 20 healthy subjects receiving two single oral doses of 1 mg flunitrazepam on two different occasions (1 week apart). The degree of sedation was rated blindly during the two treatment sessions in parallel with blood sampling (48 h). 2. A strong correlation between the concentrations of flunitrazepam in plasma and the degree of sedation was found according to the sigmoid Emax model. The plasma drug concentration producing 50% of maximal effect (EC50) was found to be 7.0 and 6.5 ng ml-1 on the two occasions, respectively. The variability in EC50 between subjects was larger (C.V. 39%) than the variability within subjects (C.V. 27%). 3. The steepness of the concentration-response curve as reflected in the slope factor(s) showed a virtual 'all or none' response to flunitrazepam with s values ranging from 3 to 30 with a mean of about 14. 4. The results in young healthy subjects suggest that the present dosage recommendations for temporary insomnia (1-2 mg) may be inappropriate; the dose can probably be reduced to 0.5 mg in some patients to achieve moderate sedation.

Dose-Response Relationship, Drug↗
PubMed1982

Flunitrazepam as an induction agent in elderly, poor-risk patients.

Great interindividual variation was found in response to flunitrazepam when the latter was used as an induction agent for general anaesthesia in elderly, poor-risk patients. However, no significant changes in the pharmacokinetics of this nitrobenzodiazepine derivative were found, which suggests that there are pharmacodynamic alterations in response to the drug with advancing age. A sudden but transient drop in blood pressure was found in three out of 12 patients, even although flunitrazepam was given, i.v., in low 0.3-0.5 mg incremental doses. A marked amnesic effect was found. No analgesics were needed in the recovery room (2 h), supporting the evidence that flunitrazepam has an analgesic-sparing effect. Flunitrazepam resulted, in general, in smooth induction of anaesthesia, but a long time was needed for induction.

Age Factors↗
PubMed1985

Sublingual flunitrazepam for premedication.

The clinical effects of a standard 2 mg flunitrazepam tablet given sublingually for premedication were evaluated in a group of 50 patients undergoing otorhinolaryngologic surgery. A comparable group of 49 patients received 10 mg of diazepam orally. The degree of sedation and anxiety was assessed objectively and subjectively before induction of anaesthesia. Flunitrazepam produced better sedation judged by the observer as well as by the patients. There was less anxiety in the flunitrazepam group but this was not statistically significant. Side effects were few and patient acceptability high. Sublingual premedication using flunitrazepam could be a useful alternative to other forms of premedication.

Administration, Oral↗
PubMed1982

Comparison of the kinetics of [3H]diazepam and [3H]flunitrazepam binding to cortical synaptosomal membranes.

[3H]Diazepam and [3H]flunitrazepam ([3H]FNP) binding to washed and frozen synaptosomal membranes from rat cerebral cortex were compared. In Tris-citrate buffer, gamma-aminobutyric acid (GABA) and NaCl both increased [3H]diazepam binding more than [3H]FNP binding. GABA and pentobarbital both enhanced this effect of NaCl. Because of the extremely rapid dissociation of [3H]diazepam in the absence of NaCl and GABA, the Bmax (maximal binding capacity) was smaller by the filtration assay than by the centrifugation assay. [3H]FNP, which dissociates more slowly, had the same Bmax in both assays. [3H]Diazepam association had two components, and was faster than [3H]FNP association. [3H]Diazepam dissociation, which also had two components, was faster than that of [3H]FNP, and also had a greater fraction of rapidly dissociating species. [3H]FNP dissociation was similar when initiated by diazepam, flunitrazepam, clonazepam, or Ro15-1788, which is a benzodiazepine antagonist. [3H]Diazepam dissociation with Ro15-1788, flunitrazepam, or clonazepam was slower than with diazepam. GABA and NaCl, but not pentobarbital, increased the percentage of slowly dissociating species. This effect of NaCl was potentiated by GABA and pentobarbital. The results support the cyclic model of benzodiazepine receptors existing in two interconvertible conformations, and suggest that, distinct from their binding affinity, some ligands (like flunitrazepam) are better than others (like diazepam) in inducing the conversion of the receptor to the higher-affinity state.

Animals↗
PubMed1985

Effects of guanyl nucleotides on [3H]flunitrazepam binding to rat hippocampal synaptic membranes: equilibrium binding and dissociation kinetics.

The effects of guanyl nucleotides on the binding of [3H]flunitrazepam to rat hippocampal synaptic membranes were studied. In equilibrium binding studies, gamma-amino-n-butyric acid (GABA) increased and GTP decreased the binding affinity of [3H]flunitrazepam; GTP also caused a decrease in binding capacity. The effect, however, is variable. In studies of the dissociation kinetics of [3H]flunitrazepam using diazepam and the antagonist Ro 15-1788 as the displacers, there was evidence of two dissociation rate constants. GTP increased both the fast- and slow-dissociation rate constants and increased the ratio of the slow-dissociation binding state. The effect of GTP was mimicked by its nonhydrolyzable analogue 5'-guanylylimidodiphosphate but not by ATP and occurred when diazepam, but not when Ro 15-1788, was used as the displacer. GABA antagonized the effect of GTP on the dissociation of [3H]flunitrazepam. The nature of the benzodiazepine receptor, its actions, and the possible role of cyclic AMP as a second messenger are discussed.

Adenosine Triphosphate↗
PubMed1978

A controlled long-term study of flunitrazepam, nitrazepam and placebo, with special regard to withdrawal effects.

The hypnotic effect of flunitrazepam (Ro 5-4200), nitrazepam and a placebo was studied in 117 outpatients using hypnotics for at least 3 months prior to the study. They obtained various neurotropic drugs and this and other treatments were unchanged throughout the trial period of 13 weeks. This consisted of 3 weeks on the previously used hypnotic, 3 weeks on a test drug (during the first of these a doubling of the dose was permitted if the initial dose of 1 mg flunitrazepam, 5 mg nitrazepam or one tablet of placebo was not satisfactory) and 4 weeks' observation after a request to stop medication with the test drug. The effects were evaluated every week by self-ratings. Also noted were: the frequency of dose increase after 1 week of the test period, number of drop-outs in the test period, and failure in the attempt to stop taking the test drug. A "psychological concentration test" was done, as was a follow-up interview. The self-ratings had a good reliability and showed that more patients experienced shorter sleep induction, longer sleep time, better sleep quality and a subjective feeling of having had a better rest with flunitrazepam than with either nitrazepam or placebo. There were no differences between the nitrazepam and the placebo groups. Tiredness was the most common side effect and appeared in the same frequency in all groups. The number of patients who increased the dose after 1 week's medication, as well as the number of drop-outs, was significantly higher in the nitrazepam and placebo groups than in the flunitrazepam group. There was no difference in the ability to discontinue the medication between the test groups or between groups having previously used different hypnotics. The "psychological concentration test" did not reveal any differences between groups. It was concluded that withdrawal of a hypnotic in chronic users was not facilitated by the use of a placebo. This was interpreted as due to a strong psychological dependence upon the hypnotics and their lack of pharmacological effects during long-term treatment.

Adult↗
PubMed1986

Pharmaco-EEG, behavioural methods and blood levels in the comparison of temazepam and flunitrazepam.

In a double-blind placebo-controlled cross-over study, the blood levels and pharmacodynamic properties of temazepam were compared with flunitrazepam using quantitative pharmaco-EEG and psychometric methods in ten healthy volunteers. Computer-assisted spectral analysis of the EEG after three doses of temazepam (10 mg, 20 mg and 40 mg) compared with placebo showed statistically significant changes in brain function. These changes were also seen after the administration of the reference drug (flunitrazepam 2 mg) and are typical of anxiolytic sedatives. Psychometric and psychophysiological tests demonstrated significant alterations at the behavioural level, especially after higher doses of temazepam and 2 mg flunitrazepam, as expected. However, low doses or low blood levels of temazepam induced an improvement of performance in certain variables. Dose-efficacy calculations identified 2 mg flunitrazepam and 40 mg temazepam as the most CNS-effective, followed by 20 mg and 10 mg temazepam, while the least changes occurred after placebo. Time-efficacy calculations showed marked inter-drug differences. The pharmacodynamics of both drugs parallel their respective pharmacokinetics. Regression and correlation analyses between blood levels and EEG or psychometric changes revealed that beta activity and the centroid of the EEG were positively correlated with plasma levels, while alpha activity, psychometric variables and skin conductance were negatively correlated. Psychometric variables started to deteriorate above a blood level of approximately 250 ng/ml, while below this level an improvement was seen. Such (sedative) blood levels were only reached after doses higher than 10 mg temazepam. Our findings indicate that 10 mg temazepam has tranquilizing properties, while 20 mg and 40 mg doses exert, in addition, sedative sleep-inducing effects.

Administration, Oral↗
PubMed1999

Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior.

OBJECTIVE: The authors examined the efficacy of intramuscular flunitrazepam compared with intramuscular haloperidol for the immediate control of agitated or aggressive behavior in acutely psychotic patients. METHOD: Twenty-eight actively psychotic inpatients, aged 20-60 years, who were under treatment with neuroleptic agents were selected for the study. Each was randomly assigned on a double-blind basis to receive either 5 mg i.m. of haloperidol (N=13) or 1 mg i.m. of flunitrazepam (N=15) during an aggressive event. Verbal and physical aggression was measured over time with the Overt Aggression Scale. Patients were also rated with the Brief Psychiatric Rating Scale and the Clinical Global Impression scale. RESULTS: Both flunitrazepam and haloperidol exhibited acute antiaggressive activity. This beneficial effect, as assessed by the Overt Aggression Scale, was obtained within 30 minutes. CONCLUSIONS: Intramuscular flunitrazepam may serve as a convenient, rapid, safe, and effective adjunct to neuroleptics in reducing aggressive behavior in emergency psychiatric settings.

Acute Disease↗
PubMed1989

The effects of nitrazepam and flunitrazepam on oxygen desaturation during sleep in patients with stable hypoxemic nonhypercapnic COPD.

Serious respiratory depression has been described in COPD patients receiving hypnotics during acute exacerbations. There are few studies quantifying the effects of hypnotics on oxygenation during sleep in patients with stable hypoxemic COPD. In this study, the effects of single therapeutic doses of nitrazepam and flunitrazepam on SaO2, apneas during sleep and other sleep variables were measured in 14 COPD patients. All patients used theophylline. Sleep-induced decrease in mean SaO2 was 1.3 percent after placebo, 1.4 percent after nitrazepam and 1.9 percent after flunitrazepam (no significant differences). Sleep apneas were not more common or longer after nitrazepam or flunitrazepam, but sleep quality seemed to improve. It is concluded that oxygenation during sleep in these nonobese patients with stable hypoxemic nonhypercapnic COPD, all on maintenance theophylline therapy, was affected very little by single therapeutic doses of nitrazepam or flunitrazepam.

Aged↗
PubMedDate not supplied

[Impacts of the new flunitrazepam regulations on the consumption of hypnotics].

The frequent misuse of flunitrazepam has led the French drug agency (AFSSAPS [Agence française de sécurité sanitaire des produits de santé]) to subject this agent to the regulatory regime for drugs known to produce dependency; this drug may now be prescribed for no more than 14 days, is available only on an "ordonnance sécurisée" (prescribing and dispensing subject to stupefacient regulations), and pharmacists must dispense no more than 7 days' supply. We identified, in a French medical-care database, 738 patients who had received at least one flunitrazepam prescription in January 2001, and monitored the hypnotics delivered to this cohort over a period of 8 months. Sixty-nine percent of the patients had replaced flunitrazepam by another hypnotic without any further change. The most surprising result of our survey was the discovery that nearly half of the selected patients stopped using hypnotics during the review period. Although many hypotheses can be offered to account for this phenomenon, it seems that many consumers halted their consumption of flunitrazepam as a result of the new regulatory regime.

Adult↗
PubMed1992

[Premedication in retrobulbar anesthesia. A blood gas analysis comparison of sublingual flunitrazepam and intravenous midazolam].

Benzodiazepines for sedation may decrease the PaO2, the arterial O2 saturation (SaO2), and the CO2 response more in the elderly than in the young. The purpose of this study was to assess changes in blood gases due to i.v. midazolam or sublingual flunitrazepam given as premedication in elderly patients for unilateral cataract surgery. METHODS. Fifty patients over 65 years of age with treated arterial hypertension and other co-existing diseases (ASA III-IV) were randomly assigned to have: (1) i.v. midazolam titrated until they became drowsy (17 patients; 2.85 +/- 0.84 mg [mean +/- SD]); (2) sublingual flunitrazepam (16 patients; 0.005 mg/kg); or (3) no sedation (17 patients; controls). On entering the operating theatre, the radial artery was cannulated and the first blood gas analysis was obtained. The premedication was then given. At 5, 10, 20, and 30 min after premedication, before and 10 min after retrobulbar block, before operation, 5 and 15 min after the beginning of the operation, 10 and 20 min after administration of 500 mg acetazolamide i.v. during the operation, and 10 and 20 min after the operation additional arterial blood samples were analysed (a total of 15 measuring points). Pulse oximetry, invasive blood pressure, and ECG were continuously monitored. All patients received oxygen 3 l/min during the operation by nasal cannula. Differences between the three groups were analysed by Student's t-test or U-test and a P value < 0.05 was considered significant. RESULTS. The patient demography, including duration of anaesthesia and operation, was similar in the three groups (Table 1). No significant differences were seen in heart rate, mean arterial pressure, PaO2, pulse-oximetric oxygen saturation (SpO2), base excess, or serum bicarbonate levels. The PaCO2 increased in patients after midazolam (P < 0.01) and flunitrazepam (P < 0.05) until the beginning of the operation compared with the control group (Fig. 3); 20 min after the operation there was still a significant difference between the midazolam group and the controls. SaO2 was significantly (P < 0.05) lower in the midazolam group 10 and 20 min after administration of premedication compared with the control group, but was within physiological limits (Fig. 5). Despite titration, 2 patients had severe respiratory insufficiency 3 min after midazolam: the SpO2 decreased below 85% and the paO2 below 55 mmHg. The paCO2 was higher (P < 0.05) in the midazolam group 10 min after acetazolamide compared with the controls. CONCLUSIONS. The results of the study show the potential hazards of i.v. midazolam in the elderly. If sedation is required for cataract surgery under local anaesthesia, we recommend sublingual flunitrazepam or the use of benzodiazepines with lower hypnogenic effects in the elderly. A thorough preoperative discussion of anaesthesia and the operation might be an adequate substitute for any premedication in high-risk patients; the best blood gas analysis results were obtained in the control group.

Administration, Sublingual↗
PubMed1990

[Antagonism of flunitrazepam and fentanyl by flumazenil, naloxone or nalbuphine].

The new benzodiazepine antagonist flumazenil represents another approach to the ever-present problem of recurring respiratory depression after anesthesia with flunitrazepam and fentanyl. Objective and subjective side effects of flumazenil were studied in comparison with the opiate antagonists naloxone and nalbuphine. METHODS. One hundred fifty surgical patients, ASA I or II, aged 18-65 years were studied. After premedication with atropine 0.5 mg and flunitrazepam 0.5 mg anesthesia was induced with flunitrazepam 0.5 mg, fentanyl 0.1 mg and etomidate 10 mg and maintained with N2O/O2 2:1 and additional increments of 0.1 mg fentanyl as required. Relaxation for intubation and surgery was obtained with non depolarizing muscle relaxants. After the operation the patients were extubated and then flumazenil 0.4 mg, naloxone 0.05 mg, or nalbuphine 20 mg was given i.v. (randomized and double-blind). In 15 patients blood pressure and heart rate were monitored. In all patients postoperative pain was assessed by the time interval between administration of the antagonist and need for the first analgesic medication. On the 1st postoperative day recall of postoperative events and of pictures shown 5, 30, 60, 120, and 240 min after administration of the antagonist was tested. The patients were interviewed a second time for side effects on day 3-6 after the operation. RESULTS. The three antagonists produced no significant effects on arterial pressure and heart rate. There were no differences between the antagonists in the incidence of postoperative nausea and/or vomiting or postoperative pain. After flumazenil, a significant transient increase in vigilance and better recall of postoperative events was noted within 5 and 30 min after administration of the drug. CONCLUSION. On the basis of the objective clinical findings, there is no reason to prefer either benzodiazepine or opiate antagonists after flunitrazepam and fentanyl. However, postoperative amnesia can be reduced by flumazenil if this is desirable.

Adult↗
PubMed1990

[Mid-latency auditory evoked potentials during induction of intravenous anesthesia using midazolam, diazepam and flunitrazepam].

Since intraoperative awareness is not infrequently observed under balanced anaesthetic regimens employing benzodiazepines for suppression of consciousness, we studied the effect of intravenous induction of general anaesthesia using the benzodiazepines midazolam, diazepam and flunitrazepam on mid-latency auditory evoked potentials and auditory evoked neuronal 30-40 Hz oscillation. Following informed consent in 30 patients scheduled for minor gynaecological procedures, anaesthesia was induced with midazolam (0.2-0.3 mg/kg b.w. i.v., group I n = 10), diazepam (0.3-0,4 mg/kg b.w., i.v., group II n = 10) or flunitrazepam (0.03-0.04 mg/kg b.w., i.v., group III n = 10). Auditory evoked potentials were recorded before, during and after induction of general anaesthesia on vertex (positive) and mastoides on both sides (negative). Auditory clicks were presented binaurally at 70 dBnHL with a frequency of 9.3 Hz. Using the electrodiagnostic system Pathfinder I (Nicolet), 1000 successive stimuli were averaged over a 100 ms poststimulus period and analysed off-line. Latencies of the peak V, Na, Pa were measured. By means of Fast-Fourier transformation-analysis corresponding power spectra were calculated to analyse energy portions of the AEP frequency components. In the awake state AEP showed an oscillatory component between 20 and 100 ms poststimulus latency. Corresponding power spectra indicated a predominant 30-40 Hz frequency. After induction of general anaesthesia using midazolam, diazepam and flunitrazepam, there was no increase in latencies of the peaks V, Na, Pa, but only a small decrease in amplitudes Na/Pa without statistical significance. The auditory evoked mid-latency neuronal oscillation persisted under induction of general anaesthesia with midazolam, diazepam, flunitrazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1977

[Flunitrazepam, trazodone and sulpiride in the treatment of recovery reactions after ketamine anesthesia].

The authors studied the effects of flunitrazepam, trazodone and sulpiride on recovery reactions following ketamine anaesthesia, in male patients aged between 15 and 25 years, following minor orthopaedic surgery. Only flunitrazepam and trazodone proved to be effective, whilst sulpiride was quite useless in the prevention of recovery reactions. The authors nevertheless feel that trazodone is preferable to flunitrazepam since it reduces all recovery reactions and, in particular, because it reduces the agitation induced by ketamine, rendering the pseudo-hallucinations pleasant, and because it is free of the hypnotic component of flunitrazepam, often inconstant and sometimes responsible for the patient swallowing his tongue.

Adolescent↗
PubMed1975

The effect of diazepam, flunitrazepam and droperidol with an analgesic on blood pressure and heart rate in man.

The effects of i.v. diazepam (0.3 mg/kg), droperidol (5 mg) and a new benzodiazepine, 5-(a-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one (flunitrazepam, Ro 5-4200) (0.03 mg/kg) on blood pressure and heart rate was studied in 62 healthy volunteer students. Observations were made after each drug alone, after diazepam and flunitrazepam each combined with pethidine (1 mg/kg), and after droperidol combined with fentanyl (0.2 mg). The doses of the benzodiazepines were halved in those subjects given pethidine but the dose of droperidol was the same with and without fentanyl. The blood pressure was measured by auscultation and the heart rate by counting the radial pulse. The systolic and diastolic blood pressure was regularly decreased by not more than 20 and 11 mmHg, respectively. Changes in the heart rate were slight. Flunitrazepam did not have greater effects than diazepam or droperidol through the combination of flunitrazepam and pethidine seemed to induce a greater fall in systolic blood pressure than did the combination of diazepam and pethidine. None of the changes observed was clinically significant.

Adult↗