Summary
Synopsis: Flunitrazepam1 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. Asa 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 ofnitrazepam 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.
Pharmacodynamic Studies: Flunitrazepam, like other benzodiazepines, has a selective effect on GABA (gamma-aminobutyric-acid)-mediated synaptic processes of the brain. Facilitation of the inhibitory effect of GABAergic synaptic transmission especially affects the limbic system. (The highly selective and saturable synaptic inhibition of GABA-mediated activities is accepted as the basis of the extraordinary safety range of benzodiazepines.) The different affinity of various benzodiazepines to specific benzodiazepine receptors correlates well with their pharmacological and therapeutic potencies. The relative weight-for-weight potency of flunitrazepam is high, on an average about 10 times as potent as diazepam; however, there is wide variation in this potency coefficient for different effects.
Flunitrazepam produces a dose- and time-dependent amnesic effect, which is more complete and somewhat longer than the amnesia after diazepam, but clearly less intense and shorter than that produced by lorazepam. This amnesic effect is an important characteristic of flunitrazepam’s use in different anaesthesia techniques, as it prevents patients from having unpleasant experiences during different stages of anaesthesia and operation.
The most typical feature of flunitrazepam on the cardiovascular system is peripheral vasodilatation. This is possibly due to its direct relaxing effect on the muscle fibres in the vascular wall. A decrease in cardiac output also occurs, which is more pronounced in patients with cardiovascular disease. This effect, together with a marked decrease in peripheral resistance, results in a significant reduction of systolic blood pressure. The primary phenomenon may be limited to this peripheral vasodilatation, with a secondary decrease in venous return. This emphasises the importance of normal blood volume and active fluid infusion when flunitrazepam is used intravenously.
Flunitrazepam has a depressive influence on respiration, even in small intravenous doses, and this effect is augmented by simultaneously administered analgesics or hypnotics. In occasional extreme cases there may be need for respiratory assistance. The effect on respiration results in a significant decrease in arterial oxygen tension; this may be corrected by increasing oxygen concentration in the inspired air.
Pharmacokinetic Studies: Knowledge of the pharmacokinetic behaviour of flunitrazepam is extremely important for optimum practical use of this drug, especially in anaesthesiology. Flunitrazepam is almost completely (80 to 90%) absorbed from the gastrointestinal tract, but the bioavailability of suppositories is only 50 %. After intramuscular injection the absorption corresponds with absorption via the oral route, thus differing profitably from diazepam which is erratically absorbed from intramuscular sites. Flunitrazepam is 80% bound to plasma proteins. Its pharmacokinetic behaviour can be illustrated with a 3-compartment model, which has important clinical implications. Rapid redistribution from the central (plasma) compartment to tissue compartments explains the discrepancy between the half-life of the drug and the duration of its clinical effects. Thus, the overall elimination half-life is about 20 hours, which is much longer than the duration of clinical effects. There is fairly good correlation between the clinical effects and the logarithm of the plasma concentration.
Metabolism of flunitrazepam is nearly complete. There are several metabolites, but the most important are the 7-amino, the 1-desmethyl, and the 3-hydroxy derivatives. Some of the metabolites are active and may have an important influence on clinical effects. Excretion is via the urine, and thus renal insufficiency results in accumulation of the metabolites. In patients with normal renal function there is no progressive accumulation of metabolites with a daily dose of 2mg flunitrazepam. Metabolism and elimination are age-dependent, and the dose must be reduced in elderly patients.
Therapeutic Trials: Flunitrazepam has been studied in 2 areas of use — as a night hypnotic and in different applications in anaesthesiology.
The hypnotic effects of flunitrazepam have been studied in both ‘normal’ people and in insomniacs. In a dose of 2mg flunitrazepam is an effective and fast sleep-inducing drug with a sufficient duration of action to maintain quiet sleep until morning. In double-blind trials it was significantly better than a placebo, barbiturates or nitrazepam. Flunitrazepam causes a significant latency in the appearance of the first REM (rapid eye movement) period, and decreases the number of REM periods during the night, but not the duration of individual REM periods. There is a marked shift of REM periods to the last two-thirds of the night. These effects on sleep patterns are probably less ’unphysiological’ than the effects of barbiturates. The data concerning residual effects of flunitrazepam in the morning are somewhat divergent. Some authors claim that there is no morning-after hangover, but others have demonstrated impaired psychomotor skills the next morning. There may be residual anxiolysis on the following day, which can be desirable or undesirable depending on the patient’s daily activity and requirements.
Flunitrazepam 2mg appears to be suitable for use as a premedication on the night before anaesthesia. On operation day the effect can be increased by another 2mg given orally or intramuscularly. The patient will be sleepy and anxiety minimised until anaesthesia. Anaesthesia induction may be performed with intravenous flunitrazepam. The dose is dependent on age and physical status and the use of other anaesthetics, but 0.02 to 0.03mg/kg is most frequently used. In some resistant patients anaesthesia cannot be induced with flunitrazepam. Typically, such patients are addicted to sedatives, especially benzodiazepines, or alcohol. In such cases the effect of flunitrazepam may be potentiated with agents such as fentanyl and nitrous oxide or thiopentone. Indeed, flunitrazepam shows typical synergism with nitrous oxide, analgesics and ketamine. Synergism with muscle relaxants is less obvious. The course of anaesthesia with flunitrazepam is usually quiet and even. Depending on the dose of flunitrazepam, and use of other anaesthetics, the recovery may be either relatively fast or prolonged. Typically, during recovery the patient will fall asleep when he is free from pain or is undisturbed. The amnesic properties of flunitrazepam have been widely applied in supplementation of other general or local anaesthesias using incremental doses of flunitrazepam. Properly titrated doses improve different stages and different types of anaesthesia. Postoperative nausea and vomiting are reduced by flunitrazepam. In intensive care, its amnesic and hypnotic effects and synergism with analgesics can be applied to improve the patient’s tolerance of unpleasant therapeutic procedures.
Side Effects: The only common side effect of flunitrazepam when used as a hypnotic is a possible residual effect on the morning following the night of drug intake. The use of flunitrazepam in anaesthesia results in prolongation of recovery, this effect being highly dose-dependent. However, when patients are kept under proper postoperative observation the long standing anxiolytic, sedative and synergistic effect with analgesics may be advantageous. In some cases disturbing cough or hiccup may occur at induction. During injection of flunitrazepam the patient often experiences pain along the injection vein. However, significantly fewer long term venous sequelae occur than with intravenous diazepam (with propyleneglycol as solvent). No allergic reactions have been reported with flunitrazepam.
Dosage and Administration: Flunitrazepam is relatively contraindicated in patients with myasthenia gravis. Its use during early pregnancy and in Caesarean section, as a part of general anaesthesia, is unsettled. Doses of 0.02mg/kg or more should be avoided in outpatients, because of possible long lasting disturbances in coordination.
The usual dose of flunitrazepam as a sleep-inducing agent is 2mg orally. In older patients 1 mg may be more suitable. As a premedication 2mg orally on the night before operation, and then 2mg orally or 1.5 to 2 mg intramuscularly for adult patients 2 to 3 hours prior to anaesthesia is recommended. The usual induction dose is 0.02 to 0.03mg/kg. As a supplement 0.005 to 0.01 mg/kg is usually sufficient. These doses should be reduced in patients with cardiovascular disease and in older patients.
Similar content being viewed by others
References
Amrein, R.: Zur Pharmacokinetik und zum Metabolismus von Flunitrazepam; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer(Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen — Klinische Anwendung, pp.8–24 (Springer Verlag; Berlin, Heidelberg, New York 197
Amrein, R.; Cano, J.P.; Hartmann, D.; Ziegler, W.H. and Dubois, R.: Clinical and psychometric effects of flunitrazepam observed during the day in relation to pharmacokinetic data; in Priest, Pletscher and Ward (Eds) Sleep Research, pp.83–98 (MTP Press Limited, Lancaster 1979).
Amrein, R.; Cano, J.P. and Hugin, W.: Pharmakokinetische und pharmakodynamische Befunde nach einmaliger untravenöser, intramusculärer und oraler Application von Rohypnol; in Hügin, Hossli und Gemperle (Eds) Bisherige Erfahrungen mit ‘Rohypnol’, pp.39–56 (Editiones ‘Roche’, Basle 1976).
Benke, A.; Balogh, A. and Reich-Hilscher, B.: Der Einfluss von Flunitrazepam (Rohypnol) auf die Atmung. Wiener klinische Wochenschrift 87: 656–658 (1975).
Bergmann, H.: Anwendung und Dosierung von Flunitrazepam im Rahmen der Allgemeinanästhesie; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli and Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen — Klinische Anwendung, pp. 130–147 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Bixler, E.O.; Kales, A.; Soldates, C.R. and Kales, J.D.: Flunitrazepam, an investigational hypnotic drug: sleep laboratory evaluations. Journal of Clinical Pharmacology 17: 569–578 (1977).
Bond, A.J. and Lader, M.H.: Residual effects of flunitrazepam. British Journal of Clinical Pharmacology 2: 143–150 (1975).
Breimer, D.D.: Clinical pharmacokinetic and biopharmaceutical aspects of hypnotic drug therapy; in Priest, Pletscher and Ward (Eds) Sleep Research, pp.63–81 (MTP Press Limited, Lancaster 1979).
Brown, S.S. and Dundee, J.W.: Clinical studies of induction agents XXV: Diazepam. British Journal of Anaesthesia 40: 108–112 (1968).
Cano, J.P.; Soliva, M.; Hartmann, D.; Ziegler, W.H. and Amrein, R.: Bioavailability of various galenic formulations of flunitrazepam. Arzneimittel-Forschung 27: 2383–2388 (1977).
de Castro, J.: L’utilisation en anesthesiologie du Ro 5-4200. Premieres observations cliniques. Ars Medici 8: 1233–1268 (1972a).
de Castro, J.: A tar-Analgesia with Ro 5-4200, pancuronium and ketamine. Congresso Mundial de Anesthesiogia, Kyoto, Japan 1972. Actas del Congreso, pp. 18–23 (1972b).
Clarke, R.S.J. and Lyons, S.M.: Diazepam and flunitrazepam as induction agents for cardiac surgical operations. Acta Anaesthesiologica Scandinavica 21: 282–292 (1977).
Coleman, A.J.; Downing, J.W.; Moyes, D.G. and O’Brien, A.: Acute cardiovascular effects of Ro 5-4200: A new anaesthetic induction agent. South African Medical. Journal 47: 382–384 (1973).
Cullen, DJ.: Interpretation of blood-pressure measurements in anesthesia. Anesthesiology 40: 6–12 (1974).
Deacock, A.R. de C.: New agents in anaesthesia. British Journal of Hospital Medicine 13: 419–430 (1975).
Doenicke, A. and Lorenz, W.: Histaminliberierung durch Flunitrazepam; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli and Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen — Klinische Anwendung, pp.62–66 (Springer Verlag; Berlin, Heidelberg, New York, 1978).
Doenicke, A.; Suttmann, H. and Sohler, W.: Der Einfluss von Flunitrazepam und Lormetazepam auf die Blutgase; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp.93–98 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Dundee, J.W.: Amnesie action of benzodiazepines: Diazepam, flunitrazepam and lorazepam. Excerpta Medica International Congress Series 387, 110 (1976).
Dundee, J.W.; Gamble, J.A.S. and Assaf, R.A.E.: Plasmadiazepam levels following intramuscular injection by nurses and doctors. Lancet 2: 1461 (1974).
Dundee, J.W.; Varadarajan, C.R.; Gaston, J.H. and Clarke, R.S.J.: Clinical studies of induction agents. XLIII: Flunitrazepam. British Journal of Anaesthesia 48: 551–555 (1976).
Dölp, R. and Heyden, M.: Anwendung und Diserung von Flunitrazepam im Bereich der Prämedication. Teil I.; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp.99–103 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Editorial: On being aware. British Journal of Anaesthesia 51: 711–712(1979).
Eisele, V.; Weinreich, A. and Bartle, S.: Perioperative awareness and recall. Anesthesia and Analgesia, Current Researches 55: 513–518 (1976).
Freuchen, I.; Ostergaard, J.; Kühl, J.B. and Mikkelsen, B.O.: Reduction of psychotomimetic side effects of Ketalar® (ketamine) by Rohypnol® (Flunitrazepam). A randomized, double blind trial. Acta Anaesthesiologica Scandinavica 20: 97–103 (1976a).
Freuchen, I.; Ostergaard, J. and Mikkelsen, B.O.: Flunitrazepam (Rohypnol®) compared with enibomal (Narcodorm®) as an anaesthetic induction agent: a controlled clinical trial. Current Therapeutic Research 20: 36–44 (1976b).
Freuchen, I.; Ostergaard, J. and Mikkelsen, B.O.: Flunitrazepam (Rohypnol®) compared with nitrazepam (Mogadon®) and aprobarbital as evening premedication prior to anaesthesia: a controlled clinical trial. Current Therapeutic Research 23: 90–93 (1978).
George, K.A. and Dundee, J.W.: Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man. British Journal of Clinical Pharmacology 4: 45–50 (1977).
Haefely, W.E.: Synaptic pharmacology of barbiturates and benzodiazepines. Agents and Actions 7/3: 353–359 (1977).
Haldemann, G.; Hossli, G. und Schaer, H.: Die Anaesthesie mit Rohypnol (flunitrazepam) und Fentanyl beim geriatrischen Patienten. Anaesthesist 26: 168–171 (1977).
Hartelius, H.; Larsson, A.-K.; Lepp, M.; Malm, U.; Arvidson, A. and Dahlström, H.: A controlled long-term study of flunitrazepam, nitrazepam and placebo, with special regard to withdrawal effects. Acta Psychiatrica Scandinavica 58: 1–15 (1978).
Heermann, J. und Candas, H.: Prolongierte Amnesie nach ‘Rohypnol’ i.v. vor der Lokalanästhesie bei; Ansprechbarkeit während der Operation. Laryngologie, Rhinologie, Otologie 56: 273–276(1977).
Hegarty, J.E. and Dundee, J.W.: Sequelae after the intravenous injection of three benzodiazepines — diazepam, lorazepam and flunitrazepam. British Medical Journal 2: 1384–1385 (1977).
Hegarty, J.E. and Dundee, J.W.: Local sequelae following the i.v. injection of three benzodiazepines. British Journal of Anaesthesia 50: 78–79 (1978).
Heinzl, H. and Hossli, G.: Anwendung und Dosierung von Flunitrazepam im Bereich der Prämedication. Teil II.; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli and Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp. 104–107 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Heipertz, W.; Vontin, H.; Schoer, R. und Junger, H.: Die Amnesie nach den Benzodiazepinen Flunitrazepam und Lorazepam.; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp. 163–168 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Herrero, F.J.: Prüfung des Präparates Ro 5-4200 als Schlafmittel in der Geriatrie. Revista Espanola Gerontologia 8: 415–422 (1973).
Hillestad, L.; Hansen, T.; Melson, H. and Drivenes, A.: Diazepam metabolism in normal man. I. Serum concentrations and clinical effects after intravenous, intramuscular and oral administration. Clinical Pharmacology and Therapeutics 16: 479–484 (1974).
Jovanovic, U.J.: Vigilanzverlauf und Schlafqualitäten unter Einwirkung von Flunitrazepam; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp.25–53 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Kanto, J.; Aaltonen, L. and Kangas, L.: Placental transfer and breast milk levels of flunitrazepam. Current Medical Researches 26: 539–546 (1979a).
Kanto, J.; Kangas, L. and Mansikka, M.: Flunitrazepam versus placebo premedication for minor surgery. Acta Anaesthesiologica Scandinavica 23: 561–566 (1979b).
Kapp, W.: Zur Pharmakologie von Flunitrazepam; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp. 1–7 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Knoche, E.; Taub, E. und Dick, W.: Möglichkeiten der medikamentösen Beeinflussung von unerwünschten Nebenwirkungen und Aufwachreaktionen nach Ketamin-Anaesthesie. Anaesthesist 27: 302–308 (1978).
Korttila, K.: Amnesic action and residual effects of benzodiazepines used for intravenous sedation; in Priest, Pletscher and Ward (Eds) Sleep Research, pp. 123–133 (M P Press Limited Lancaster 1979).
Korttila, K. and Linnoila, M.: Skills related to driving after intravenous diazepam, flunitrazepam or droperidol. British Journal of Anaesthesia 46: 961–969 (1974).
Korttila, K. and Linnoila, M.: Amnesic action and skills related to driving after intravenous flunitrazepam. Acta Anaesthesiologica Scandinavica 20: 160–168 (1976).
Korttila, K.; Saarnivaara, L.; Tarkkanen, J.; Himberg, J.-J. and Hytönen, M.: Comparison of diazepam and flunitrazepam for sedation during local anaesthesia for bronchoscopy. British Journal of Anaesthesia 50: 281–287 (1978a).
Korttila, K.; Saarnivaara, L.; Tarkkanen, J.; Himberg, J.-J. and Hytönen, M.: Effect of age on amnesia and sedation induced by flunitrazepam during local anaesthesia for bronchoscopy. British Journal of Anaesthesia 50: 1211–1218 (1978b).
Korttila, K.; Sothman, A. and Andersson, P.: Polyethylene glycol as a solvent for diazepam: Bioavailability and clinical effects after intramuscular administration, comparison of oral, intramuscular and rectal administration, and precipitation from intravenous solutions. Acta Pharmacologica et Toxicologica 39: 104–117 (1976).
Kugler, J.; Doenicke, A.; Suttmann, H.; Laub, M.; Späth, M. und Wöller, L.: Einfluss von Flunitrazepam auf Verhalten und Psyche; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp.54–61 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Kurka, P.: Klinische Erfahrungen mit Ro 5-4200 in der Anaesthesie. Anaesthesist 23: 375–381 (1974).
Kurka, P.: Klinische Erfahrungen mit Flunitrazepamkombinationsnarkosen; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische G rundlagen-Klinische Anwendung, pp. 169–178 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Lader, M.: Correlation of plasma concentrations of benzodiazepines with clinical effects; in Priest, Pletscher and Ward (Eds) Sleep Research, pp.99–108 (M P Press Limited Lancaster 1979).
Lindgren, L.; Saarnivaara, L. and Himberg, J.-J.: Comparison of i.m. pethidine, diazepam and flunitrazepam as premedicants in children undergoing otolaryngological surgery. British Journal of Anaesthesia 51: 321–327 (1979).
List, W.F.: Monitoring of myocardial function with systolic time intervals. Acta anaesthesiologica Belgica 29: 271–285 (1978).
Marti, W.K.; Gumpenberger, H.; Lucas, M. and Vega, J.F.: Evaluation of Ro5-4200 as a principal narcotic agent in 1117 anesthesias for major surgery. Excerpta Medica International Congress Series 330: 184 (1974).
Mattila, M.A.K.; Larni, H.M.; Nummi, S.E. and Pekkola, P.O.: Effect of diazepam on emergence from ketamine anaesthesia. A double-blind study. Anaesthesist 28: 20–23 (1979a).
Mattila, M.A.K.; Martikainen, P. and Säilä, K.: Flunitrazepam compared with althesin as an induction agent in balanced anaesthesia. British Journal of Anaesthesia 49: 1041–1046 (1977).
Mattila, M.A.K.; Ruoppi, M.; Korhonen, M.; Larni, H.M.; Valtonen, L. and Heikkinen, H.: Prevention of diazepam-induced thrombophlebitis with cremophor as a solvent. British Journal of Anaesthesia 51: 891–894 (1979b).
Mattila, M.A.K.; Säilä, K.; Kokko, T. and Kärkkäinen, T.: Comparison of diazepam and tlunitrazepam as adjuncts to general anaesthesia in preventing arousal following surgical stimuli. British Journal of Anaesthesia 51: 329–337 (1979c).
McKay, A.C.; Dundee, J.W. and George, K.A.: The amnesic effect of orally administered benzodiazepines. British Journal of Anaesthesia 50: 1080–1081 (1978).
Milewski, P. und Dick, W.: Anwendung und Dosierung von Flunitrazepam in Kombination mit Analgetika; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp. 148–162 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Möhler, H. and Okada, T.: The benzodiazepine receptor in human brain; in Priest, Pletscher and Ward (Eds) Sleep Research, pp.3-12 (M P Press Limited Lancaster 1979).
Möhler, H.; Okada, T.; Ulrich, J. and Heitz, Ph.: Biochemical identification of the site of action of benzodiazepines in human brain by 3H-diazepam binding. Life Sciences 22: 985–996 (1978).
Monti, J.M. and Altier, H.: Flunitrazepam (Ro 5-4200) and sleep cycle in normal subjects. Psychopharmacologia 32: 323–349 (1973).
Monti, J.M.; Altier, H.; Pradro, M. and Gil, J.L.: The actions of flunitrazepam (Rohypnol®) on heart and respiratory rates and skin potential fluctuations during the sleep cycle in normal volunteers and neurotic patients with insomnia. Psychopharmacologia 43: 187–190 (1975).
Niessner, G.: Narkoseeinleitung mit Flunitrazepam in der Unfallchirurgie. Wiener Medizinische Wochenschrift 125: 350–351 (1975).
Pasch, Th. and Bugsch, L.A.: Beeinflussung der glatten Muskulatur kleiner Arterien durch Analgetika, Droperidol, Diazepam und Flunitrazepam. Anaesthesist 28: 283–289 (1979).
Pasch, Th. und Rügheimer, E.. Anwendung und Dosierung von Flunitrazepam in der Intensivmedizin; in Ahnefeld et al. (Eds) Rohypnol (Flunitrazepam) Pharmkologische Grundlagen-Klinische Anwendung, pp. 184–191 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Pearce, C: A clinical trial of Ro 5-4200 (Flunitrazepam) used to supplement spinal anaesthesia in elderly patients. British Journal of Anaesthesia 46: 877–880 (1974).
Powell, W.F. and Comer, W.H.: Controlled comparison of lorazepam and pentobarbital as hypnotics for presurgical patients. Anesthesia and Analgesia... Current researches 52: 267–271(1973).
Radakovic, D.: Bericht über den klinischen Einsatz von Flunitrazepam (’Rohypnol’) bei 4000 Patienten; in Hügin, Hossli und Gemperle (Eds) Bisherige Erfahrungen mit ‘Rohypnol’ (Flunitrazepam) in der Anästhesiologie und Intensivtherapie, pp. 141 -148 (Editiones ‘Roche’ Basle 1976).
Richardson, F.J. and Manford, M.L.M.: Comparison of flunitrazepam and diazepam for oral premedication in older children. British Journal of Anaesthesia 51: 313–319 (1979).
Rizzi, R.; Butera, G.; Lion, P. and Pesarin, F.: Flunitrazepam, a new benzodiazepine compound in general anaesthesia. Clinical and statistical considerations on the first thousand cases. Anaesthesia, Resuscitation and Intensive Therapy 3: 339–356 (1975).
Roily, G.; Lamote, P. and Cosaert, P.: Hemodynamic studies of flunitrazepam or Ro 5-4200 injection in man. Acta anaesthesiologica Belgica 25: 359–370 (1974).
Schmitz, J.E.; Lotz, P.; Bock, A.; Fisseler, A. und Ahnefeld, F.W.: Auswikungen des Flunitrazepam auf die Atmung; in Ahnefeld, Bergmann, Burri, Dick, Halma gyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp.67–81 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Schulte-Steinberg, O.: Anwendung und Dosierung von Flunitrazepam in Kombination mit der Regional-anästhesie; in Ahnefeld et al. (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp. 179–181 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Seitz, W.; Hempelman, G. und Piepenbrock, S.: Zur kardiovaskulären Wirkung von Flunitrazepam (Rohypnol®, Ro 5-4200). Anaesthesist 26: 249–256 (1977).
de Silva, J.A.F. and Bekersky, I.: Determination of clonazepam and flunitrazepam in blood by electron-capture gas-liquid chromatography. Journal of Chromatography 99: 447–460 (1974).
Stovner, J.; Edresen, R. and Osterud, A.: Intravenous anaesthesia with a new benzodiazepine Ro 5-4200. Acta Anaesthesiologica Scandinavica 17: 163–169 (1973).
Stumpf, Ch.; Gogolák, G.; Huck, S. und Andics, A.: Wirkung zentral dämpfender Pharmaka auf die Stickoxydul-Narkose. Anaesthesist 24: 264–268 (1975).
Tallman, J.F.; Paul, S.M.; Skolnick, P. and Gallager, D.W.: Receptors for the age of anxiety: Pharmacology of the benzodiazepines. Science 207: 274–281 (1980).
Tarnow, J.; Hess, W.; Schmidt, D. and Eberlein, H.J.: Wirkung von Flunitrazepam und diazepam auf den Kreislauf koronarchirurgischer Patienten bei der Narkoseeinleitung und während der extrakorporealen Zirkulation; in Ahnefeld, Bergmann, Burri, Dick, Halmágyi, Hossli und Rügheimer (Eds) Rohypnol (Flunitrazepam) Pharmakologische Grundlagen-Klinische Anwendung, pp. 119–129 (Springer Verlag; Berlin, Heidelberg, New York 1978).
Tarnow, J.; Hess, W.; Schmidt, D. und Eberlein, H.J.: Narkoseeinleitung bei Patienten mit koronarer Herzkrankheit: Flunitrazepam, Diazepam, Ketamin, Fentanyl. Eine hämo-dynamische Untersuchung. Anaesthesist 28: 9–19 (1979).
Tolksdorf, W.; Berlin, J.; Betchke, U.; Striebel, J.P., Westphe, K.T.P. and Lutz, H.: Rohypnol® (Flunitrazepam) als Sedativum bei Leitungsanästhesien unter besonderer Berücksichtigung der amnestischen Wirkung. Praktische Anästhesie 14: 59–70 (1979a).
Tolksdorf, W., Rohowsky, R.; Klose, R. and Lutz, H.: Beeinflussung der postoperativen Lungenfunktion durch Sedation mit Diazepam und Flunitrazepam während Leitungsanästhesien beim alten Patienten. Praktische Anästhesie 14: 52–58 (1979b).
Ungerer, M.J. and Erasmus, F.R.: Evaluation of a new benzodiazepine, flunitrazepam (Ro 5-4200) as an anaesthetic induction agent. South African Medical Journal 47: 787–790 (1973).
Vega, D.E.: Inducciön del sueno anestético con un nuevo derivado benzodiazepinico. Revista Uruguaya de Anesthesiologia 5: 41–44(1971).
Wendt, G.: Schicksal des Hypnotikums Flunitrazepam im menschlichen Organismus; in Hügin, Hossli und Gemperle (Eds) Bischerige Erfahrungen mit ‘Rohypnol’ (Flunitrazepam) in der Anästhesiologie und Intensivtherapie, pp.27-38 (Editiones ‘Roche’ Basle 1976).
Wickström, E.: Flunitrazepam (Ro 5-4200) et nytt hypnoticum. Tidskrift för den Norske Laegeforening 93: 1494–1499 (1973).
Wickström, E.: Double-blind study of flunitrazepam (Ro 5-4200) and Mandrax. Anaesthesist 23: 90–92 (1974).
Wickström, E.: Comparative studies with hypnotics; in Priest, Pletscher and Ward (Eds) Sleep Research, pp. 155–169 (MTP Press Limited Lancaster 1979).
Author information
Authors and Affiliations
Additional information
‘Rohypnol’ (Hoffmann-La Roche).
Rights and permissions
About this article
Cite this article
Mattila, M.A.K., Larni, H.M. Flunitrazepam: A Review of its Pharmacological Properties and Therapeutic Use. Drugs 20, 353–374 (1980). https://doi.org/10.2165/00003495-198020050-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-198020050-00002