CLINICAL STUDIES OF INDUCTION AGENTS XLIII: FLUNITRAZEPAM

Br.J. Anaesth. (1976) 48, 551

CLINICAL STUDIES OF INDUCTION AGENTS XLIII: FLUNITRAZEPAM J. W.

DUNDEE, C. R. VARADARAJAN, J. H.

GASTON AND R.

S. J. CLARKE

SUMMARY

particularly when used as a premedicant (Vega, 1971; Wickstrom, 1973), in respect of its cardiovascular effects (Coleman et al., 1973; Clarke and Lyons, 1975) and its ability to produce amnesia (George and Dundee, 1976). Reports on its use as an i.v. anaesthetic agent are difficult to interpret. In some studies, other drugs have been given also (de Castro, 1972) or the reports are incomplete, inconclusive or based on a small number of observations (Ungerer and Erasmus, 1973; Villand, Carli and Klepping, 1973; Yoo, 1973). In general, they show a great similarity between the action of diazepam and flunitrazepam (de Olivera et al., 1973; Stovner, Endresen and Osterud, 1973). This paper reports a study designed to evaluate flunitrazepam as an i.v. induction agent. This was undertaken because of our previous experiences in DIAZEPAM FLUNITRAZEPAM similar studies of diazepam (Brown and Dundee, FIG. 1. Structural formulae of diazepam and flunitrazepam. 1968). It is not intended to discuss the relative merits of barbiturates and benzodiazepines as induction clear organic solution, made up to 1 mg/ml with a agents but, simply, to report our findings with supplied diluent. It has been widely used in anaes- flunitrazepam. thetic practice, particularly in continental Europe and METHOD South America, both as pre-anaesthetic medication, for induction of anaesthesia and as a mild sedative. The study was divided into three parts: Volunteers. After the nature of the study had been These early studies show that flunitrazepam has an explained, 50 female medical students in good general effect similar to that of an equivalent dose of diazepam, health received flunitrazepam 2-6 mg i.v. over a period of 1 min. Approximately equal numbers reJ. W. DUNDEE, M.D., PH.D., F.F.A.R.C.S., M.R.C.P.; C. R. ceived 2, 4 or 6 mg to allow us to assess the approxiVARADARAJAN, B.SC., M.B., F.F.A.R.C.S.; J. H. GASTON,* M.B., F.F.A.R.C.S.; R. S. J. CLARKE, M.D., PH.D., F.F.A.R.C.S.; mate sleep dose of the drug. Two minutes later the Department of Anaesthetics, The Queen's University of depth of sleep was graded according to the arbitrary Belfast, Northern Ireland. * Present address: Waveney Hospital, Ballymena, five-point scale described by Brown and Dundee (1968): awake, slightly drowsy, moderately drowsy, Northern Ireland. Flunitrazepam (Ro 5-4200) is a relatively new benzodiazepine, related to diazepam (fig. 1) and considered to be about 10 times as potent as the established compound. As in the case of diazepam, it is insoluble in water and is available for i.m. or i.v. injection in a

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Flunitrazepam (Ro 5-4200) has been studied as an induction agent in 220 volunteers or patients. It was assumed to be 10 times as potent as diazepam. The maximum soporific effect did not occur until 90-120 s after injection. There was great individual variation in response to flunitrazepam and some patients did not lose consciousness even after receiving 6 mg (approximately 0.1 mg/kg). Opiate premedication enhanced its action, but delayed recovery. There was a dose-related increase in minor respiratory upset with flunitrazepam in unpremedicated patients and a high frequency of arterial hypotension following large doses given to patients who had received opiate premedication. Venous sequelae were no more frequent than after comparable doses of diazepam. Flunitrazepam was not a very satisfactory drug for the induction of anaesthesia, and recovery was too prolonged for routine use.

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TABLE I. Numbers of subjects in the various series related to the initial dose of flunitrazepam

Initial dose Study

Subjects

Premedication

2

3

4

6

Total

Induction only

Volunteers Patients

Nil Various opiates

12 7

3

19 43

19 7

50 60

Patients Patients

Nil Pethidine 75 mg

10 20 20

10

20 20

10 20

50 60

49

13

102

56

220

Full anaesthesia Total

2 to 6 mg. The depth of sleep was noted 2 min after injection and the induction characteristics were recorded as described previously. In these patients anaesthesia was maintained with gaseous or volatile anaesthetics according to requirements, combined with neuromuscular blockade. No further observations were made, except for notes about the state of the veins. Venous sequelae. The injections were given into the largest visible arm vein and the needle was removed at the end of the injection. No other drugs were injected through this needle and no tourniquet was applied. On the 2nd and 3rd days after operation the veins were inspected and the occurrence of phlebitis, thrombosis or thrombophlebitis noted as described by Hewitt and his colleagues (1966). The findings with respect to venous sequelae were compared with data from similar patients who had been anaesthetized with diazepam. RESULTS

Table I shows the number of patients in the various studies. In presenting the findings, the induction data from comparable series are pooled. The recovery data are related to the total dose of flunitrazepam given and are limited to those patients who did not receive a volatile supplement. The onset of sleep with flunitrazepam resembles that with diazepam. Assessed on clinical criteria, this drug reached the maximum depressant effect in 6090 s. Figure 2 shows the degree of drowsiness occurring in 2 min, related to the dose of drug given to the volunteers and in those patients who did not receive opiate premedication. The results in the two series are very similar. Figure 3 gives comparable data for the two series of patients who received opiate premedication. Although sleep was induced in a greater proportion of patients with any given dose of flunitrazepam in combination with opiate premedication, the difference between the opiate and non-

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very drowsy, and asleep. The occurrence of excitatory effects (tremor, hypertonus or involuntary muscle movement), respiratory upset (cough, hiccup, laryngospasm) or obvious respiratory depression (sufficiently severe to require manual assistance) was also recorded. Arterial pressure was measured by auscultation and the heart rate was counted at 1-min intervals for the first 10 min following injection. On the basis of this study, the relative potency of flunitrazepam in relation to diazepam and the approximate anaesthetic dose were established. Patients detailed study. One hundred and ten fit women undergoing minor gynaecological operations and who were not regularly taking any sedatives or tranquillizers were studied. Their ages ranged from 16 to 65 yr and their weights from 43 to 75 kg. Fifty of these patients did not receive premedication and the remainder received pethidine 75 mg and atropine 0.6 mg. The initial doses again ranged from 2 to 6 mg as shown in table I. These were injected over 1 min and the depth of sleep was assessed as stated above. Anaesthesia was continued with 75% nitrous oxide in oxygen with further doses of flunitrazepam or volatile agents as required. The induction characteristics were noted as in the volunteers and anaesthesia was graded according to the scheme described by Dundee and Riding (1960) and Dundee, Moore and Nicholl (1962). Grades 1 and la were regarded as "acceptable". The patients were seen at 1 and 6 h after operation and the depth of sleep was again graded according to the scheme of Brown and Dundee (1968); at this time the incidence of vomiting and nausea was noted. Induction study. Sixty patients undergoing more major operations (age range 14-68 yr, weight range 52-77 kg) were premedicated with one of several opiate analgesics plus atropine, although they had received no other sedative for 24 h. The patients received initial doses of flunitrazepam ranging from

553

FLUNITRAZEPAM

TABLE I I . Percentage frequency of induction complications

• PATIENTS » VOLUNTEERS

Pre-anaesthetic medication

<» SLIGHT w

MODERATE

g

MARKED

Opiate

Nil

A3 *.•*•:; - •• v vS/« • •

ASLEEP

DOSE (mg/kg)

2-3 32

4 39

6 29

2 4 30 . 63

6 27

Excitatory effects Respiratory upset Arterial systolic hypotension ( > 20 mm Hg)

6 22 16

0 16 25

3 22 17

0 3 10

0 0 30

2 3 12

TABLE III. Condition of patients at 1 h and 6h after operation related to total dose {4 mg or 6 mg) of flunitrazepam. There were 20 patients in each series Premedication Nil < +£ • Condition of patient DOSE (mg/kg)

FIG. 3. Degree of drowsiness 2 min after various doses of flunitrazepam in patients premedicated with an opiate.

opiate groups is not striking and there were still a few patients in the former group who did not fall asleep even after flunitrazepam 0.1 mg/kg. Figure 4 is an alternative presentation of the effects of opiate premedication on the soporific effects of flunitrazepam. Again, data from comparable series were pooled. The potentiating effect of narcotic premedication is much more obvious particularly with doses of 2 and 4 mg of flunitrazepam. Table II shows the incidence of induction complications related to the initial dose of flunitrazepam. NON-OPIATE

6040200

VERY

DROWSY

FIG. 4. Percentage frequency of patients who were asleep M or very drowsy a 2 min after injection of 2, 4 and 6 mg of flunitrazepam with opiate and non-opiate premedication.

Opiate

Flunitrazepam 4mg

Nil

Opiate

Flunitrazepam 6mg

1 h after operation Asleep Marked drowsiness Moderate drowsiness Slight drowsiness Awake

3 5 9 2 1

4 8 6 1 1

1 13 2 4 0

10 6 2 1 1

6 h after operation Moderate drowsiness Slight drowsiness Awake

0 4 16

3 9 8

2 4 14

0 12 8

Muscle movements occurred rarely during induction but respiratory complications (cough and hiccup) occurred in about 20% of the patients who did not receive opiate premedication, their incidence being significantly higher (x2 = 37, d.f. = 1; P< 0.0005) than in the opiate group. Marked respiratory depression was noted in only five of the 220 patients and it was always transient. A slight degree of arterial hypotension was found in about 16% of the patients who received flunitrazepam but this was transient also and did not cause any concern, being reversed with the onset of surgical stimulation. Except for the occurrence of hypotension in patients premedicated with opiates, there was no obvious dose-incidence relationship for any of these complications of induction. Prolonged drowsiness following surgery was not infrequent after flunitrazepam. The condition of the patients in the early postoperative period is analysed in table III. There were only 80 observations, since those patients who received volatile anaesthetic

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FIG. 2. Degree of drowsiness 2 min after various doses of flunitrazepam in patients (•) and volunteers (o).

Initial dose (mg) Number of subjects

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554

TABLE IV. Total number of cases and percentage frequency of venous complications observed on 2nd or 3rd day after operation using diazepam or flunitrazepam. (Phlebitis: discoloration of vessel and local pain; thrombosis: painless cord-like hardening of vessel; thrombophlebitis: painful cord-like hardening of vessel

Total dose (mg) Diazepam

10

20 30

Flunitrazepam

2-3 4 5-6 2-6

Thrombophlebitis

phlebitis

Thrombosis

69 43 45 157

9

5

9 7

9 8

5 7

5 5 3

60 58 26 144

12 12 15 13

7 4 8 6

5 2 4 3

2

supplements were excluded. Nevertheless this showed advantages in relation to the well-established the prolonged action of this induction agent. diazepam. Venous sequelae. Table IV shows the incidence of venous sequelae attributed to flunitrazepam compared TABLE V. Percentage frequency of acceptable and unacceptable with those following diazepam. The overall com- induction with different doses of flunitrazepam and different premedication plication rate (21% for flunitrazepam and 18% for diazepam) is very similar for the two drugs and the Dose troublesome complications of thrombophlebitis ocAcceptable Unacceptable Premedication curred in only 3 % of patients of either drug group. Nil DISCUSSION

This study confirms that flunitrazepam is a slowacting induction agent which is very similar in action to diazepam (Stovner, Endresen and Osterud, 1973). There is a wide variability of action of both drugs, particularly in unpremedicated subjects. Despite this variability, our clinical findings support the view that flunitrazepam is about 10 times as potent as diazepam. When one considers variability of action combined with a relatively high incidence of respiratory problems in unpremedicated patients, flunitrazepam is not a very satisfactory drug for routine induction of anaesthesia. This is illustrated further in table V, which is based on the induction grades. Even with opiate premedication, anaesthesia was not of an acceptable standard in one patient out of every six. When one considers also the delay in recovery, it is not recommended that flunitrazepam should be used as a routine induction agent. It is probably in the field of light sedation that flunitrazepam may find a place in anaesthesia. Our studies show it to have an amnesic action comparable to diazepam (George and Dundee, 1976). Further studies are needed to assess its advantages and dis-

Opiate

2-3 4 6

40 54 82

60 46 18

2 4 6

86 85 85

14 15 15

ACKNOWLEDGEMENTS

We wish to thank our gynaecological and surgical colleagues of the Musgrave Park Hospital, Belfast, for their cooperation in this study. We are grateful to Dr L. Arenillas of Roche Products Ltd, for supplies of flunitrazepam. REFERENCES

Brown, S. S., and Dundee, J. W. (1968). Clinical studies of induction agents. XXV: Diazepam. Br. J. Anaesth., 40, 108. Clarke, R. S. J., and Lyons, S. M. (1975). Premedication for different types of surgery and anaesthesia. Paper read at 12th Congr. Scand. Soc. Anaesthesiol., Oulu, Finland, July 7-12, 1975. Coleman, A. J., Downing, J. W., Moyes, D. G., and O'Brien, A. (1973). Acute cardiovascular effects of Ro 5-4200 a new anaesthetic induction agent. S. Afr. Med. J., 47, 382. de Castro, J. (1972). The use of ketamine and Ro 5-4200: 1/100 in subvigil intravenous anaesthesia. Ars Medici, 27, 1286.

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10-30

Total cases

FLUNITRAZEPAM

555

ETUDES CLINIQUES SUR LES AGENTS D'INDUCTION. XLIII: FLUNITRAZEPAM RESUME

Le flunitrazepam (Ro 5-4200) a ete etudie en tant qu'agent d'induction sur 220 volontaires ou malades. On le supposait 10 fois plus puissant que le diazepam. L'effet soporifique maximum ne s'est produit que de 90 a 120 s apres la piqure. On a constate de grandes variations dans les reactions au flunitrazepam suivant les individus, et certains malades n'ont pas perdu conscience, meme apres l'administration de 6 mg (environ 0,1 mg/kg). L'administration prealable de medicaments opiaces renforcait son action, mais retardait la reprise de conscience. L'absorption de flunitrazepam a fait apparaitre chez les malades non traites auparavant aux medicaments opiaces une augmentation des troubles respiratoires mineurs, en fonction de la dose appliquee, ainsi qu'une hypotension arterielle tres frequente

a la suite de fortes doses administrees a des malades ayant ete traites au prealable avec des medicaments opiaces. Les sequelles d'ordre veineux ne se sont pas montrees plus frequentes qu'apres l'application de doses comparables de diazepam. Le flunitrazepam n'a pas donne de resultats tres satisfaisants en tant qu'anesthesique, et la reprise de conscience etait trop prolongee pour faire de ce medicament un usage courant. KLINISCHE ERGEBNISSE BEI EINLEITUNGSMITTELN. XLIII: FLUNITRAZEPAM ZUSAMMENFASSUNG

Bei 220 Voluntarprobanden wurde Flunitrazepam (Ro 54200) als Induktionsmittel angewandt. Es wurde als zehnmal so stark wie Diazepam angenommen. Der Maximalschlafpunkt fand erst 90-120 Sekunden nach der Injektion start. Es ergaben sich grosse individuelle Schwankungen, was die Ansprechbarkeit auf das Praeparat anbelangte; so verloren einige Patienten auch nach Abgabe von 6 mg (0,1 mg/kg) noch nicht das Bewusstsein. Obwohl die Verabreichung von Opiaten die Wirkung verstarkte, verzogerte dies das Erwachen. Es zeigte sich ein dosisbedingter Anstieg von oberen Atmungsorganinfekten, wenn Flunitrazepam unvorbehandelten Patienten gegeben wurde, sowohl wie auch ein ofteres Auftreten von arterieller Hypotonie nach Verabreichung hoher Dosierungen, als Nachfolge bei Patienten, die Opiatvorbehandlung erhalten hatten. Venenstorungen zeigten sich nicht haufiger als nach Gabe von vergleichbaren Dosierungen von Diazepam. Flunitrazepam ergab sich nicht als sehr giinstiges Mittel zwecks Narkoseeinleitung und das Erwachen war zu verzogert, urn routinemassig verwendet zu werden. ESTUDIOS CLINICOS DE AGENTES DE INDUCCION. XLIII: FLUNITRAZEPAM SUMARIO

Flunitrazepam (Ro 5-4200) ha sido estudiado como un agente de induccion con 220 voluntaries o pacientes. Se supuso que era 10 veces tan potente como el diazepam. El maximo efecto soporfero no se produjo hasta 90-120 s. tras la inyeccion. Hubo gran variation individual en la respuesta al flunitrazepam y algunos pacientes no perdieron la consciencia incluso tras recibir 6 mg (approximadamente 0,1 mg/kg). La premedicacion con opiaceos estimulo su accidn, pero demoro la vuelta en si. Hubo un aumento de alteraciones respiratorias menores, relacionado con la dosis, usando flunitrazepam en pacientes no premedicados y una elevada frecuencia de hipotension arterial tras grandes dosis dadas a pacientes que habian recibido la premedicacion opiacea. Las secuelas venosas no fueron mas frecuentes que tras dosis comparables de diazepam. Flunitrazepam no fue un farmaco muy satisfactorio para la induccion de anestesia, y el restablecimiento fue demasiado prolongado para usarlo rutinariamente.

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de Oliveira, A. A. M., Duarte, D. F., Gesser, N.3 and Linhares, S. (1973). Ro 5-4200—Emprego em inducao anestesica. Rev. Bras. Anestesiol., 23, 72. Dundee, J. W., Moore, J., and Nicholl, R. M. (1962). Studies of drugs given before anaesthesia. II: A method for the assessment of their influence on the course of anaesthesia. Br. J. Anaesth., 34, 523. Riding, J. E. (1960). A comparison of Inactin and thiopentone as intravenous anaesthetics. Br. J. Anaesth., 32, 206. George, K. A., and Dundee, J. W. (1976). Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man (benzodiazepine amnesia). Br. J. Clin. Pharm., (in press). Hewitt, J. C , Hamilton, R. C , O'Donnell, J. F., and Dundee, J. W. (1966). Clinical studies of induction agents. XIV: A comparative study of venous complications following thiopentone, methohexitone and propanidid. Br. J. Anaesth., 38, 115. Stovner, J., Endresen, R., and Osterud, A. (1973). Intravenous anaesthesia with a new benzodiazepine Ro 5-4200. Acta Anaesthesiol. Scand., 17, 163. Ungerer, M. J., and Erasmus, F. R. (1973). Evaluation of a new benzodiazepine, flunitrazepam (Ro 5-4200), as an anaesthetic induction agent. S1. Afr. Med.J., \1, 787. Vega, D. E. (1971). Induction of anaesthetic sleep by means of a new benzodiazepine derivative. Rev. Urug. Anestesiol., 5, 41. Villand, J., Carli, H., and Klepping, C. L. (1973). Emergency oesophageal and gastric fibroscopy in 102 cases of upper gastrointestinal haemorrhaging. Rev. Fr. Gastroenterol., 87, 77. Wickstrom, E. (1973). Flunitrazepam (Ro 5-4200): a new hypnotic. Tidsskr. Nor. Laegeforen, 93, 1494. Yoo, M. C. (1973). The effect of flunitrazepam upon respiration and circulation in man. J. Kor. Soc. Anaesth., 1,1.