Review Articles

Drugs 20: 353-374 (1980}

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Flunitrazepam: A Review of its Pharmacological

Properties and Therapautic Use

M A .K. M attila and H .M. Lami

Depertrnet'll of ANe slhesiology. Kuopio University Central Hospital. Kuopio

Summary Synopsis: Flunltrazepam l Is a betlrodlareplne derivative whose hypnotic effect predomi-

nates over the sedative. anxlolytic. muscle-relaxing and ant lconvulsatll effects characteristic of
betlzodlareplnes. T1rus , It is used as a night-time hypnotic and in anaestheslology; due to the
pronounced hypnotic effect II Is not appropriate as a daytime sedative. As a hypnotic for insom-
nia its effee/ ls usually characterised by a very fa st onset ofactton and quiet s/«p without In-
terruptions. On the morning after a hypnotic dose some residua l psychomotor impairment does
OC'Cur, which Is comparable to that with usual doses ofnitrazepam or flurazepam , but clinically
apparent 'hangover' occurs Inf requetllly .There is no pronounced cumu lative effect with chronic
use. /n anaestheslology it has proven to be useful as a hypnotic on the night bef ore operation, as
an oral, Itllram uS€ular or Intravenous premedication, in induction and as a supplement to other
anaes thetics. Its sedative and amnesic properties can also be benefi cial in intensive care
pattents . Much of the usefulness of flun ltrarepam In anaesthesia relates to Its sy nergistic effect
with other anaesthetics. to Its effective amnesic action and its acceptable effects on circulation
and respiration. Pussible drawbacks Include a somewhat unusual course of Induction (when
used for this purpose)and an often prolonged recovery. Allhough the safe dosage range Is wide
with flunltfQrepam . its effective application both as a hypnotic for insomnia and In anees -
theslology Is dependen.t upon use of the optimal dosage. and adequate knowledge of Its pnar-
macokinetlc properties.

Pharm(lcodynamic Studies .. Flunitrazepam. like other benzodiazepin es. has a selective

effect on GABA (gamma-aminobutyric-acid)..mediated sy naptic processes of the brain ,
Facilitation of the inhibitory effect of G ABAergic synaptic transmission especially affects the
limbic system. (The highly selective and saturable sy naptic inhibition of GA BA- mooiated ac-
tivities is accepted as the basis of the extraordinary safety range of benzodiazepines .l The dif-
fere nt affi nity of various benzodiazepines to specific benzodiazepine receptors correlates well
with the ir pharmacological and therapeutic potencies. The relative weight -for -weight potency
of flunitrazepam is high, on an average about 10 times as potent as diazepam ; howeve r, ther e
is wide variation in this potency coefftcient for differenl effects.
Flunitrazepam prod uces a dose- and time-dependenl amnesi c effect, which is more com-
plete and somewhat IOlli er than the amnesia after diazepam , but clearly less intense and
shorter than that produced by lorazepa m. This amnes ic effect is an important characteristic of

' Rohypoor (Hoffmann·La Roche).

Fluniuuepam: A RlMew ".

fluniuazcpa m 's USC in di fferen t anaesthesia lCChniqlJtS, as it prt"ients patients Ircm Mv in,
unpleasant Clperiences du ring different stages o r anaesthesia and operation.
The most typical featu re o r flunitrazepam o n the cardio vascular system is peripheral vaso-
dilatat ion . Th is is poss ibly d ue 10 its dirtCI relu ing effect o n the muscle fibres in the vascular
wall. A eecreese in cardiac output also occurs. wh ich is more pronounced in patients with
cardiovascular disease _This effect. together with a marked decrease in peripheral res istance .
resul ts in a sil nilica nt red uctio n o r syslo lic blood pressu re. The pri mary phenom enon may be
lim ited to th is per ipheral vasod ilatation, with a seconda ry decrease in veno us return. Th is
emphasises the imponana: or no rmal blood volume and active fluid in rusio n when Ilu-
nitrazepam is used intravenously.
Flunitrazepam has a depressive influ ence o n respiration, eve n in small intraveno us doses ,
and this effect is augmented by simulta neously administered analgesi cs or hypnoti cs. In occa-
sional extreme CL'iCS there may be need fer respiratory assistance. The effect o n respiration
results in a significant decrease in arterial oxygen tension ; Ibis may be corrected by incr easing
olygen conce ntration in the inspired ai r.

fharmaC'Qkin~tI~ $ t"din: Know ledge o r th e pha rmaco kine tjc beha viour o r flun itru epam
is extremel y important jc r optimum practical. use o r thi s drug, c:specially in arwsthes iology.
Fluniuazepam is al most oomp lele1y (&010 90 % ) a bsorbed fro m the gastrointestinal tract. bu t
the biof,vaila bility or su ppositories is on ly 50% . A rter inuam uscular injecti o n the abso rption
corresponds with a bsorption via the o ral route , thus di fferina profi tably rrom diazepa m
which is erratically absorbed rrcm int ramuscula r sites. Fluni uazepam is &0 % bound 10
plasma pro teins. hs phar macokinetic be:havlour can be illustrated with a 3-companment
model, .... hich has important clinical imp licatio ns. Rapid redistribution Ircm the a: ntral
(plasma) oompa nment to tissue oompa,nments explains the discrepanq between the IWr·Jire
o r the dro l and the d uration o r its clinical effects . Thus, the overal l dimination hair-lire is
about 20 hou rs, .... hich is much longer than the d uration or clinica.l effects. There is rairly
good a melation betw een the clinica1 effects and the logarithm or the plasma conce ntration.
Meabolism o r flunitrazeplm is nearl y comp1ete. There are several metabolites. but the
most important are the 7-amino . the l-desmet hyl, and the 3-hydro lY der ivatives . Some o r the
metabolites are acu ve and may have an important innuence on dinica l effects . Elcr etion is
...io the urine, and thus renal ins ufficiency resu lts in accum ulation o r the metaboli tes. In
patie nts ....ith norma.l renal runction there is no progressi ve accu mulatio n o r metabolites w ith
a da ily dose o r 2ml fluniuazepam . Metabolism and d iminatio n are age-dependent. and the
dose must be reduced in dderly pat ients .

TherQPC'Uf/~ Trials: Flu nitrazepam has been studied in 2 areas or use - as a night hypno-
tic and in di fferent applicat ions in an eesthesiclcgy.
The hypnotic effects o r Ilunit razepa m have been studied in both 'no rmal' people and in in-
so mn iacs. In a dose o r 2mg Ilunitrazepam is an effective and fast sleep-induci ng drug with a
sufficient d ura tio n or actio n 10 mai nta in quiet sleep until morning. In double-blind trials it
was signifKantly better than a placebo , barbitu rates o r nitraupam. Flunitrazepam causes a
signi fICant latenc y in the appea rance o r the first REM {rapid eye movement} period, and
decreases the number o r REM period s during the nilbt, bUI not Ibe duratio n or individ ual
REM periods. There is a marked sh ift o r REM periods 10 the 1asl: two-Ib irds or ee night.
These effects on sleep pat terns are proba bly less 'unphysioloaicar than the effects o r bubilur·
altS . 1ne da ti oonceming residual effects o r flunitrazcpam in the morni ng are some what
di ver genL Some autbors clai m that theft is no mornina-aftef hangover. but others have
de monstrated impaired psychomotor skills the nell morning. The re lNy be residual amio-
lysis o n the rollow ing day, wh ich can be desinble o r undesirable depending on the patient's
daily acti vity &nd requ irements .
Flunitrazcpam 2mg a ppears to be sui table for usc as a pre medication o n the night ee rcre
anacstlJesia. On operation day the effect can be inc:reased by another 2mg given o rally o r in-
 '55

uamuscu larl.y . The patient ....i11 be sltc;ly and am:~y minimised until anaesthesia. Anaes-
thesia induction ma y be pcf"formed with intravenous flunitrazepam. The dose is dependent o n
age and pb ys.iw status and the usc of otbcr uaesthetics. but 0.02 to O.03ma/kg is most fre-
que ntly used . In so me resistant patien ts &naeSlbesia cannot be induced w ith n unitrazepam.
Typically, such patients an: add iacd to sedatives, especially benzodiazepines, or alcohol. In
sud! cases the effect o f n un itraz.epam ma y be polentiated with qcnts such as fentanyl and
nitrous Olide or th iope nto ne. Indeed , flunitrazepa m sho ws typ ical synergis m with n itrous e x-
ide, analg~ and kel.lmine. Synergism with muscle reluanlS is less ob vious. The course of
anaesthesia wilh nunitrazepam is usually quiet and even. Depending on the dose of
flunitrazepam , a nd use of o ther anaesthetics, the reco very ma y be eithe r relative ly fast Of
prolonged. T yp ically, during recov ery the patient will fall aslee p wh en he is free from pa in or
is undisturbed. Th e a m nes ic properties o f nunitrazepam ha ve been w idely a pplied in supple -
mentation of other general or local anacsth csias using incremental doses of fiunitrazepam .
Properly titrated doses improv e different stages and different types of anaesth esia . Postopera -
tive nausea and vomiting are reduced by Ilunitrazepam. In intensive care, its amnesic and
hypnotic effects and synergism with analgesics can be applied to impr ove the patient's
tolerance of unpleasan t the rapeutic procedu res.

Sid~ CjJ«I, : The only common side e ffect of nunitruep;am when used as a hypnotic is a '
possible residual effect on the morning following the night of drug intake. The use of
nunitrazepam in anaesthesia results in prolongation of recovery , this effect being highly e cse-
depende nt. How ever, when patients are kept under prope r postoperative obseTvatio n the kmg
standi ng alUioI.ytic, sohtive and syner gistic effect with analgesics may be advantageous. In
some cases disl: urbina cough or hia:up may occur at indloM:lion. During injection of
nunitruepa m the patient often experiences pain along the injection vein . However, si&nifi-
cantly fewer long ter m venous sequelae occur than with intraveoous diazepam (with pro-
pyleneglywl as sol vent!. No allergic reactions have bceD repo rud with nunitrazcpam.

DoSQ~ and AdministraliOff: Flunitrazepam is relatively contnindicated in patients with

myasth enia aravis. Its use du ring early pregnancy and in Caesarean section, as a pan of
aeocra.l l naesthesia. is unsettled . Doses of O.0 2mg/ q or more sho uld be avoided in ou tpa-
tems, because of poss ible long lasting disturbances in coord ination.
The usual dose of nuniuazepam as I sleep-inducing agent is 2mg orally . In older patients
I mg may be more suitable. As a premedica tion 2ma ora lly on the night before operatio n, and
then 2ma orally or I.S to 2mg intramuscularly for adu lt patients 2 to l hou rs prior to anaes-
thesia is recommended. The usual induct ion dose: is 0.02 10 O.Ol mg/ kg. As a supplement
0.005 to 0.0 1ma /ka is usually sufficient. Th ese doses should be reduced in patients with car-
diovascular disease end in older patients.

I . Pharmacodynamic St udies 1. 1 Effect on Brain Function

Flunimzepam, 5 (o-fluorophenyl).I ,l-dihydro-l - Benzodiazepincs have a rather selective effect on

methyl-1-nitro-2-H-I ,4-benzodiazepin-2-one (fig. l], GA BA (pmma-aminobutyric-aQd).mediated synap-
has a nitro-group and a fluorine atom in the molecule, tic precesses lHaddy, 1977). facilitating the release
both of which increase the hypnotic effeas of or effects of GABA. There are specific receptors for
benzodiazepines. benzodiazepines in the brain (Mohler et aI., t 918;
 Flunilfuepam; A Review
0,"
Fig. , . Chemical structure of flu...tre zepem.
Mohler and Okada, 1979), to which various
benzodiazepines have different affinities. These
affinities correlate with the pharmacological and
therapeutic potencies of the drugs . It is assumed
(Moh ler and Okada. 1979) that the brain also con-
tains a physiological ligand to these benzodiazepine
receptors. This could be nicotinamide, with
physiological benzodiazepine-like actions (Mohler et
al., 1979). The specific action and extremely wide
therapeutic range of benzodiazepines may be based on
a highly selective and saturable action on GABAergic
synaptic inhibition (Haefely, 1977). The effect of
benzodiazepines is dependent on the level of activity
of the GA BAergic synapse, which may explain some
surpr ising exceptional reactions to benzodiazepines.
for example in geriatric patients and small children.
Such effects of benzodiazepines have been reviewed
by Tallman et al. (1980).
/ ./ ./ Narcotic-like Effects
The sleep-inducing effect of benzodiazepines is
probably not dependent on their direct effect on the
sleep mechanism; rather, they work indirectly by
removal of anxiety and emotional stress (Haefely,
1977). In this way they differ from drugs directly
'56
affecting the sleep mechanism, such as barbiturates.
Fiun itrazepam's high potency as a hypnotic is
chemically related to its nitro-group and fluorine
atom , which are both known to potentiate the hypno-
tic properties of a benzodiazepine {Kapp. 1978;
Stovner et al., 1973).
As is the case with benzodiazepines in general,
flunitrazepam has no analgesic effects per se. Thus, it
is impossible to achieve an anaesthetic state with
flunitrazepam alone; the patient or experimental
anima l will react vigorously to any painful stimuli.
However, flunitrazepam does have a significant po-
tentiating effect on analgesics (e.g. Bergmann . 1978).
and especially on nitrous oxide (Stumpf et al., 1975).
/ ./ .2 Amnesic Ef(ect
In addition to sedative or hypnotic effects,
benzodiazepines can also show amnesic action. Its
degree and duration are pharmacodynamically dose-
related and different for various benzodiazepine
derivatives (Heipertz et al., 1978). Kugler et al. (1978)
assume that the amnesic effect is a consequenceof the
change in the peptide chain formation of certain
neurons. In anaesthesiology an am nesic property is
considered advantageous. It is beneficial for the
patient undergoing unpleasant procedures, such as
bronchoscopy (Korttila et aI., 1978a,b) and other
operations under local anaesthesia (Tolksdorf et al.,
I979a). and should be more widely employed in some
intensive care situations (Pasch and Rugheimer,
1978). An amnesic effect can be achieved without in-
fluence on the level of consciousness (Korttila and
Linnoila, 1976). During general anaesthesia the am-
nesic effect has an important role in preventing
perioperative awareness (Mattila et al., I979c). The
usual barbiturate-analgesic-relaxant-nitrous oxide se-
quence contains inadequate protection against ex-
periences and awareness during operation (e.g.
Editorial, 1979; Mattila et al., 1979c). Thus . because
thiopentone has no comparable amnesic properties
(e.g. Stovner et aI., 1973), there is an urgent need for
routine supplementation of anaesthesia with inhala-
tion anaesthetics or with benzodiazepines (Mattila et
al., 1979c). The amnesic effect of such agents is rei-
 Flun;\razepam: A Review
ated to serum concentration of the drug (Richardson
and Manford, 1979), and its duration can be con-
trolled by timing and administering the dosage ac-
cording to individual needs. Often amnesia also
covers the immediate postoperative period, which is
advantageous for hospitalised patients with major
surgery, but disadvantageous for outpatients un-
dergoing very short procedures. However, ad-
ministration of flunitrazepam to outpatients is not
strictly contraindicated. if the dose is selected
carefully and precautions for postanaesthetic 'street-
fitness' are fulfilled (Korttila et al., 1978a.b).
There is no retrograde amnesia after Iluni-
trazepam (McKay et al ., 1978), but only anterograde
amnesia starting from the time of the intravenous in-
jection or after adequate absorption of the oral or in-
tramuscular dose. The degree and duration of am-
nesia have been investigated by interviewing patients
on details of pre- or postanaesthetic procedures. A
more standardised investigation procedure is to show
different pictures during the effect of the drug. or
even cause painful stimuli (Korttila and Linnoila,
1976) to the patient, and determi ne remembrance
afterward. Thus, flunitrazepam has a definite amnesic
effect both after oral and parenteral administration
(Richardson and Manford, 1979). An oral dose of
0.5mg caused amnesia in 30 % of cases, and Img in
65 % . which corresponds to the effect of 20mg
diazepam orally (McKay et al., I97S). Intravenous
flunitrazepam gives a dose- and time-dependent am-
nesia. the intensity and duration of which was
demonstrated by Tcl ksdorf et aI. (1979a) in patients
with flunitrazepam supplementation for local anaes-
thesia. An intravenous dose of OAmg caused 'good'
amnesia for 3596 of patients compared with S096
after O.8mg intravenously. These figures were ob-
served at 15 minutes after drug injection; the effect
had clearly declined at 30 minutes.
Korttila et at. (1978a) demonstrated that amnesia
was evident earlier and its duration increased with
age. These authors found that to cover the unpleasant
procedures of bronchoscopy with a 5 to 15 minute
amnesic 'shadow', in addition to local anaesthesia in-
travenous flunitr azepam 0.02mg / kg was needed for
'57
patients less than 40 years of age. 0.015mg/kg for
patients between 40 and 60 years and 0.01mg/kg for
patients more than 60 years. This provides amnesia
for SO 96 of patients for the time of bronchoscopy,
and allows patients to be discharged from the hospital
after 2 hours.
There is general agreement that in comparable
doses flunitrazepam is a better amnesic agent than
diazepam (Dundee, 1976; George and Dundee. 1977;
Korttila and Linnoila, 1974, 1976; Kortt ila et al.•
1975a,b; Lindgren et aI.• 1979: Mattila et al.• 1979c;
McKay et aI.• 1975: Richardson and Manford, 1979).
The amnesic effect is more reliable with Ilunitra -
zepam and of longer duration, the difference being
clearest with small doses IKornne and linnoila,
1974).
1.2 Cardiovascular Effects
J.1./ Effect on Cardiac Output
Rolly et al. (974) measured cardiac output in
'relatively healthy' patients with impedance car-
diography during induction with intravenous fluni-
trazepam 0.03mg/ kg. For 3 minutes after induction
cardiac output decreased by an average of II 96, and
stroke volume by 15 96 . The corresponding figures
for thiopentone in a similar investigation were 15 96
and 27 96 . respectively. and the authors thus sug-
gested that flunitrazepam is less cardiodepressant
than thiopentone. Coleman et al . (J 973) measured
cardiac output with the indocyanide dilution method
in healthy patients during flunitrazepam induction
(dose 2 to 3mg). Cardiac output was maintained at
the control level. but the heart rate increased signifi-
cantly by 2096. Tarnow et aI. 0 97S. 1979) used a
thermod ilution method to measure cardiac output in
patients with severecoronary artery disease under an-
aesthesia for aorto-corcnary bypass surgery. They
compared intravenous flunitrazepam 0.015mg/kg to
diazepam 0.15mg/kg. The cardiac index decreased
slightly in both the diazepam and flunitrazepam
groups, but the decrease was augmented to a signifi-
cant level after giving fentanyl. List (197S) applied the
measurement of systolic time intervals in comparing
 Fltmllra,epam : A Review
the effects of induction agents on heart function.
Using this method the relation of the pre-ejection
phase (PEP) to the left ventricular ejection time
(LVET) is illustrative of myocardial effects. After
Jmg of flunitrazepam intravenously at induction,
PEP! LVET increased by 7 % compared with the in-
crease of 27 % with thiopentone] to 5mg /kg, in-
dicating that thiopentone is significantly more
negatively inotropic than flunitrazepam (p <0.0 I). It
thus appears that the cardiodepressant effect of fluni-
trazepam is relatively small, even in patients with car-
diac disease. The effect is obviously indirect, via a
marked peripheral vasodilatation (e.g. Ungerer and
Erasm us, 1973 ; section 1.2.2) and decreased venous
return . However, despite its moderate cardiovascular
effects, in patients with cardiac disease the usual in-
travenous induction dose of flunitrazepam (0.02 to
O.O]mg / kg) may need to be reduced to 0.005 to
O.Olmg /kg (Tarnow et al., 1978).
/ .2.2 Effect on Peripheral Resistance
In isolated segments of the rat tail artery , Pasch
and Bugsch (1979) demonst rated marked relaxation
of the vascular smooth muscle produced by fluni-
trazepam after an induced constriction with
noradrenaline. This experimental finding is very im-
portant considering the cardiovascular effects of flu-
nitrazepam (vide infra).
After flunitrazepam administration, marked vaso-
dilatation with a decrease in the peripheral resistance
is an integral finding in several investigations (Cole-
man et al., 1973; Haldemann et aj., 1977; Kurka .
1974; Milewski and Dick, 1978; Seitz et al., 1977;
Tarnow et al., 1979; Ungerer and Erasmus, 1973).
This is also clearly seen in clinical practice with Iluni-
trazepam anaesthesia in the form of warm periphery.
This peripheral vasodilatation may be the primary
cardiovascular phenomenon, and the decrease in car-
diac output, decrease in systolic and diastolic blood
pressures and increase in heart rate, secondary
phenomena. Coleman et al. (197]) observed a signifi-
cant Ip <0.005) decrease in peripheral resistance in
patients with normal circulation. In the investigation
of Tarnow et al. (J 979) the decrease in peripheral
358
resistance was 15 % with Ilunitrazepam: in contrast
diazepam did not decrease the peripheral resistance.
Diazepam was also ineffective in reversing nor-
adrenalin-induced constriction in the rat tail artery
experiments of Pasch and Bugsch (1979).
This specific effect of Ilunu razepam directly on the
vascular diameter includes important practical con-
clusions: vasodilatation is an advantageous effect in
decreasing the afterload of the heart, since vasodilata-
tion means pooling of the blood to peripheral vessels
and a decreased venous return. If the relative hy-
povolaemia due to this dilatation is not compensated
with an active fluid infusion, it will result in a
decreased cardiac output. Blood pressure measure-
ments have to be interpreted against this background,
and a moderate decrease in blood pressure during flu-
nitrazepam administration accepted as a logical conse-
quence of decreased peripheral resistance.
'Balanced' anaesthesia techniques with f1u nitraze-
pam induction naturally result in more complicated
effects on the cardiovascular system, as is illustrated
in the work of Tarnow et al. (979), where fentanyl,
suxamethonium and endotracheal intubation potenti-
ated the cardiovascular effects of f1unitrazepam.
/ .2.3 Effect on Blood Pressure
As would be expected, most clinical investigations
are limited to indirect blood pressure and pulse rate
measurements as a criterion for circulatory effects of
Ilunh razepam. Different authors have consistently
reported a decrease in arterial blood pressure with flu-
nitrazepam (Clarke and Lyons, 1977; Coleman et al.,
1973; Freuchen et al., 1976; Kurka, 1974; Seitz et
al., 1977; Stovner et al., 1973). However, to correctly
interpret these findings (Cullen, 1974), the vason-
latory effect of flunitrazepam must be kept in mind,
as demonstrated by the findings of Tarnow et al.
(1979). They observed a decrease of 25 % for fluni-
trazepam in the direct measurement of mean arterial
pressure, but in interpreting the significance of these
figures the approximately 15% decrease in peripheral
resistance which occurs with flunitrazepam must be
remembered. Thus, in compar ison with other induc-
tion agents, especially with diazepam(which does not
 Flunilta l6p am : A Review
alter peripheral resistance) and thiopentone, blood
pressure measurement data are not directly compar-
able, because there is a fundamental difference in the
primary reason for the change in blood pressure.
A marked fall (p <0.05) in central venous
pressure occurs during induction with nun itrazepam
(Coleman et al., 1973). This is a logical consequence
of the peripheral vasodilatation.
Stovner et al. (1973) reported an interesting find-
ing after comparing changes in blood pressure be-
tween a group receiving Ilunitrazepam and 100 %
oxygen during induction, and a group which received
III the dose of flunitrazepam and inhaled 67 %
nitrous oxide in oxygen. There were no differences
between the groups and the decrease in blood pressure
observed was considered to be a consequence of sleep
induction. Freuchen et al. (J 976b) reported an ob-
vious inhibition of blood pressure increase secondary
to ketamine induction when Ilunitrazepam was given
concomitantly.
J.2. 4 Effect on Pulmonary Circulation
Changes in pulmonary circulation remain obscure
in most clinical trials with new anaesthetics. Such
specialised data require some invasive investigations,
in which patients and doses used often do not corres-
pond with normal situations. In patients with coron-
ary artery disease there was a decrease in pulmonary
artery pressure from 18.2mm Hg to 14.6mm Hg
(mean values of 8 patients) in a group receiving
0.0 15mg /kg of flunitrazepam intravenously, without
a decrease in a diazepam (0. I 5mg /kg) group (Tarnow
et aI., 1978). The pulmona ry capillary wedge pressure
also fell from 9.5 to 5.9mm Hg in the flunitrazepam
group, compared with from 8.3 to 6.7mm Hg in the
diazepam group. As with the effect on cardiac output,
these effects may be secondary to decreased venous
return in the flunitrazepam group.
1.3 Respiratory Effects
Because of depressive effects on respiration,
flunitrazepam as an intravenous injection should be
359
given under conditions of careful respiratory control
and readiness for respiratory assistance.
J.3 .J Effects on Respiratory Frequency
and Minute Volume
Benke et aI. (J 975 ) have reported that fluni-
trazepam produces a typical hypoventilation-hyper-
ventilation pattern for about 15 minutes, before
'quiet' respiratory rhythm re-occurs. Schmitz et al.
(] 978) reported an increase in respiratory frequency,
which was associated with a marked decrease in
minute volume. Th is effect occurred with a dose of
0.5mg intravenously, and was accentuated with I mg.
Respiratory effects are seen only after intravenous ad-
ministration, and the injection rate is an important
factor, rapid administration producing more pro-
nounced effects. Thus, Bergmann (J 978) reported a
short apnoea period following rapid intravenous in-
jection of 2mg Ilunitrazepam.
Freuchen et al. (1976) compared slow intravenous
injections of enibomal (narcobarbital, 250mg) with
Ilunitrazepam (2mg) and reported that the reduction
of minute volume was equal for both drugs, but the
respiratory rate after enibomal was significantly
lower than after Ilunitrazepam.
J.3.2 Effect on Arterial Oxygen
Tension
A significant fall in arter ial oxygen tension after
induction with flunitrazepam seems to be a uniform
finding in investigations on its respiratory effects
(Benke et al., 1975; Clarke and Lyons, 1977;
Doenicke et al ., 1978; Niessner, 1975; Tarnow et al.,
1978). The decrease is evident with a O.5mg intraven-
ous dose, and is accentuated with increased dosage.
The low arter ial oxygen tension can be easily cor-
rected with an increased oxygen concentrat ion in the
inspiratory air , and is thus secondary to a decreased
minute volume (Qarke and Lyons, 1977; Niessner,
1975). Tarnow et al. ( 978) found a significantly
greater decrease in oxygen tension with 0.0 15mg/kg
intravenous flunitrazepam than with 0.15mg/ kg
diazepam.
 F..,nitrazepam: A Review
J.3.3 Effect on Carbon Dioxide Equilibrium
After intravenous flunitrazepam admini stration, a
parallel increase in carbon dioxide pressu re was ob-
served , along with the decrease in oxygen tension , as
a result of decreased alveolar ventilation (Benke et al.,
1975 ; Schmitz et aI., 1978).
J.3.4 Effect on Upper Airways
From a purely practical point of view it is impor-
tant to know the effects of intravenous flunitrazepam
on the patency of the upper airways. After intrav en-
ous injection relaxation of the jaw can result in a
closure of airways followed by cough and cyanosis
(Rizzi et al., 197 5). However , patients can easily be
ventilated with a bag and mask , and they tolerate a
pharyngeal airway and also endot racheal intubation
IRada kovic, 1976), sometimes with intr avenous
doses as low as 0.5mg and while still conscious .
Laryngeal and pharyngeal reflexes are obtunded and
the rima glottidis is widely open. When using
flunitrazepam together with analgesics these pheno-
mena are potentiated (Rizzi et aI., 1975).
2. Pharmacokinetic S tudie s
2. 1 Absorption
Flunitrazepam is absorbed from the gastrointes-
tinal tract rapidly and nearly completely (80 to 90% ;
Cano et al., 1977 ). The bioavailability in suppos itory
form is about 50 % . Plasma concentrations after oral
and int ramuscular administration are nearly identi·
cal. When injected intramuscularly flunitrazepam is
abso rbed reliably and rapidly. This is an obvious ad-
vantage when compared with intramuscular di-
azepam which is absorbed erraticall y (Hillestad et aj .,
1974): The present authors have found that the time
to onset after intram uscular injection can furt her be
shortened by giving the injection in small increments
in different places, or injecting the drug along the nee-
dle canal during slow withdrawal of the needle in-
stead of the usual depotinjection in one limited place.
This technique of intramuscular injection appears to
shorten the latency of onset of action , and results in a
higher initial plasma concentration, in a more potent
effect. and in a reduction of the dose needed, thus also
reducing the residual effects. After usual intramuscu-
lar injection, effective plasma concentrations are ob-
served in 10 to 20 minutes, but the concentration will
contin ue to increase until about 90 minutes after in-
jection , or oral administration (Amrein, 1978). In
practice these absorption characteristics of Ilunitraze -
pam mean short sleep induction and applicability as
an intramuscular premedica tion.
2.2 Distribution
The pharmacokinetics of flunitrazepam are illus-
trated by a 3-compartment distribution model;
knowledge of the distribution pattern of the drug be-
tween these compartments facilitates understanding
of the discrepancies between the duration of clinical
effects and the elimination of the drug (Breimer ,
1979). The distribution kinetics of a single intraven-
ous dose are the easiest to comprehend (fig. 2). Im-
mediately after injection the concentration in plasma
(the central compartment> is corr espondingly high.
However , very fast distrib ution to body tissue occurs ,
rapid ly to a second compart ment and slowly into a
third 'deep' compartment. As a resu lt there is a very
steep decline in plasma concent ration (fig. 3); during
the first hour after intravenous admini stration 213 of
the injected flun itrazepam is distributed from the
plasma into body tissues (Am rein , 1978). 9 hour s
after intravenous injection the central compart ment
contains about 12 % , the second compart ment about
18 % and the deep compartment 40 % of the injected
dose, wh ile 30 % has been eliminated. At 24 hours
after injection 6 % of the original dose is in the central
compartment, 9 % in the second compartment and
30% in the third, 55 % having been eliminated.
These seemingly theoretical figures provide important
clinical information. The degree of sedation produced
is fairly closely corre lated with the logar ith m of the
plasma concentration (A mrein et al., 1979). Thu s, the
obse rvable clinical effect disappears long before the

i ..
i"
L ,L--L..L..J-'----'--L_=_ • case according to W ickstr om (1979). During daily
i ..
~
i"
. reached on the fifth day, when the total content of
, •
L, '---------=----'---'-----'----'--'---'--
"
.
t
M
J "'---;-------'-;-'--'-0'--'-;,'-
• "
F"I.2. Rellll Ml .mounts 01 flUllltr . tep.m I 'll> of do_) in
the 3com~"m&Ilt •. aocl reIlI tive , moun" me labohsed, . fl ef
inlfllVeoou. injection (A mrein, 19781.
'pure' elimination phase of the drug is reached
(Breimer, 1979>, as a result of distribution of the drug
out of the plasma into body tissues; the elimination
half-life is not an appropriate parameter on which to
base judgements of the drug's expected duration of
effects. The pattern aftcr a single oral or intram uscu-
lar dose differs from that presented above in that
distri bution to the second compartment occurs
simultaneously with absorp tion , and the high con-
centration peak typK:a1 for an intravenous dose is flat·
tened. Otherwise the distribution is similar.
"The concentrations and contents of nunitrazepam
in these 3 compart ments can be calculated when the
volumes of the compartments and the intermediate:
'61
distribu tion coefftcients are kno wn. It appears that
the central and second compart ments are about equal
in volume, but tbat the third compartment is 4 times
larger (Cano et al.• 1977). On the basis of this type of
distr ibution. we could expect in theory that fluni-
trazepam should be unsuitable for long term use as a
night hypnotic due to accumu lation . Th is is not the
adm inistration of 2mg flunitrazepam a steady-state is
nunitrazepam in the body is twice that following the
original dose. However , most of the drug is in the 'in-
ert' th ird compart ment.
A very interesting detail in the distr ibution pattern
is the observation of Kanto et aJ. (1979a) that con-
centrations of flunitrazepam in umbilical blood are
less than expected. and relatively less than those after
diazepam. These findings may have considerable
practical importance, as there is a real need for a good
hypnotic and amnesic: agent as a part of general anaes-
th esia for Caesarean section (Editorial. 1979).
2.3 Metabolism
A unitraz.epam is metabolised th rough several
pathways (fig. 4); only. small amount is excreted as
unchanged drug (We ndt, 1976). Th e principal meta-
bolites are the r-amino, the 3-hydroxy and the
desmethyl derivative. At least one of these com -
pounds (the r-annno metabolite) has anaesthet ic ac-
tivity in animal studies (Korttila and Linnoila, 1976.
Amrein, 1978),
2.4 Excretion
Aunitrazepam is excreted in the form of several
different metabolites th rough the kidneys, only 10 %
being excreted in faeces. Elimination is slow. with an
elimination half-life of about 20 hours (Amrein.
1978). Th is long half-life is not reflected in a long
duration of clinical effect (Breimer, 1979). as a result
of distribution of the drug into body tissues <see sec-
tion 2.2).
 FlI rotra.z8Qllm: A Rev;ew 36'

2 m, l ...

.."
+

- - Compart t 1
- - _ Comp8rt t2
•• • ••• •• Com~rtmerl1 3

••
30

" , •,
,, ,,
I

"
I

, ,, ,,
" m, 2 p.o. 2 m, I.m. I
+ ,, , H.... y •• dat ion
Of .1•••
"""'"."",,,,,,,,,,,,,,,,'" ",... """"""""",,,,,,,,," """""1."""",,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
,
,
r
. -" " --" .

- 10 - . -, -4 _2 0 2 4 , • 10 12 ~ l' " 20 22
Tme lhoutll

FIf1 . 3. Tl'Mloretical concentrations of f1.."trazepam in the 3 compartments al ler Ofll premedocauon t2mg l on the n;gtrt before
surgery. r.tramuscular premedicalion (2mg l on lhe morning of surgery and intraYIIr"Il)ld induction t2mgllAmrein. 1918~

In severe kidney disease th ere is an accumulat ion
of metabolites (at least one of wh ich is act ive) after
daily use of nunitrazepam , but no accumulation of
nunitrazepam itself (Amrein, 1978).
2.S Blood levels and Pharmaoological Effects
Seru m concentrations of tlunitrazepam are
analysed with the electron capture chromatography
method of de Silva and 8ekersky ( 1974). In the fluni-
trazepa m literature there is some discrepancy con-
ceming the correlation between plasma concentra-
tions and clinical effects. Lader (1979) postulates that
the correlation between clinical response and plasma
concentration is weak or non -existent. plasm a con-
centrations being unrepresentative of the true phar-
macokinetic pattern ofthe dru g. However . A mrein et
al. (19 76) have reported a good correlation between
plasma concentrations and clinical effects, a con-
centration of 7ng /ml prod ucing appa rent dro wsiness.
and 12 to I Sng / ml heavy sedatio n or sleep.
Sim ilarly. Richardson and Man for d (t 979) have
demonstr ated good correlation between amnesia and
plasma concentration of Ilun itraz eparn, and have reo
Iated a low concentration with postanaesthetic
nausea. Correlation between effect and concentra tion
is logarit hmtc rather than linear (Amrein. 19781.
Thus, because it is not possible to measu re Ilunitraze-
pam coecentreuces at the benzodia.zepine receptors in
 Fkn1faz~m : A ReWrw
the brain , most clinicians accept plasma concentration
as a re flector of the expected effects. Against this
backgro und, unsatisfactory clinical sedation is consi-
dered a consequence of insufficient plasma concentra-
tion (Lindgren er al., 1979). Interestingly, and of con-
siderable potential practical importan ce in determin-
ing dosage (see section 7). Korttila et al, ( 1978b)
demon strated a clear corr elation between age and
plasma concentration.
J . Therapeutic Trials
3.1 Use as a Hypnoti c
1./ ./ Opel/Studies
The effects of flunitrazepam as an oral hypnotic
have been studied in both 'normal' people Ie.g. Monti
and Altier, 1973; Monti et al., 1975) and insom nK:
patients (e.g . Biller et al., 1977), w ith similar results
in both grou ps. Of interest with regard to the expert-
.,.
~---- ~
363
mental procedure in some such investigations,
Am rein et aI. (19 76) investigated the effects of Iluni-
trazepam on normal volun teer'S during the morning,
justifying th is by stating that for the insom niac, night
is as day. Biller et aI. () 977) demonstrated clearly
th at Img of Ilunitrazepam is not effective for either
inducing or maintaining sleep. In most studies, and
indeed in clinical practice, 2mg seems to be the prefer-
red dose Ie.g. Bixler et aI., 1977).
Open studies with 2mg of oral flunitrazepam have
shown similar results (Bixler et al., 1977; Jovanovic,
1978; Herrero, 1973. Monti and Altier , 1973): onset
of action is short, there are few awakenings during
sleep, awak e periods are short , and periods of deep
sleep are prolonged. Withdrawal of the 2mg dose
after adminis tration for 3 to 7 days did not result in
any deterioration of sleep compared with the baseline
level (Biller et al., 1977 ).
In anal yses concerning the qual ity of sleep, Mon ti
and Altter ( 1973) concluded that patients spent longer
periods in non-rapid eye movement (oon-RE M) sleep;
 Flunlr azepam : A Review
there was a decrease in REM-sleep, but not total sup-
pression. There was an increased latency until the
first REM period, with a shift of the REM.periods to
the last 2/3 of the night. The duration of individual
REM periods was unaltered, but the number of REM
periods decreased. Bixler et al. (1977) observed a
similar definite decrease in REM sleep with 2mg of
flunitrazepam and a slight decrease with Img. The
effect of the dose on REM sleep, and the uneven dis-
tr ibution of REM sleep towards morning, suggest
that suppression of REM sleep may also be related to
the plasma concentration.
3./ .2 ComparattveStudtes
The hypnotic properties of flunitrazepam have
been compared in double-blind studies with those of
several other commonly used drugs (phenobarbitone,
secobarbitone, butobarbitone, methaqualone + di-
phenhydramine, nitrazepam, flurazepam) and a
placebo. In sleep laboratory studies it is important to
chart baseline sleeping behaviour for comparison
with the effects of the drug under study. Also, at the
end of the investigation there should be a placebo
period to determ ine possible withdrawal effects of the
drug. In studies using such design principles (Bond
and Lader, 1975; Bixler et aI., 1977; Hartelius et aI.,
1978: Jovanovic, 1978; Monti and Altier, 1973) Ilu-
nitrazepam 2mg was superior Ip <0.0 1 or 0.05) in all
evaluation parameters to a placebo or to flunitraze-
pam Img (e.g. Bixler et al., 1977). It was also said to
be more effective than phenobarbitone 100mg and
200mg (Jovanovic, 1978), and was superior to
methaqualone 2S0mg + diphenhydramine 25mg
(p < 0.001; Wickstrom, 1974) and aprobarbitone
100mg (p <O .OI or 0.05; Wickstrom, 1973). In a
comparison with another benzodiazepine, Ilunitraze-
pam I to 2mg was significantly more effective than
nitrazepam (5 to IOmg) in sleep induction and main-
tenance (p < 0.01: Hartelius er aj ., 1978).
3 ./.3 Residual Effects
Some residual effects may be inevitable attributes
of those hypnotics which provide both a fast onset of
sleep and continuous sleep maintenance throug hout
364
the night. The practical importa nce of these effects de-
pends on the 'activity needs' of the patient on the day
after drug intake. In hospitalised patients, anxiolytic
residual effects may be desirable (e.g. if the drug is
used as a hypnotic the night before surgery: see sec-
tion 3.2.1I, but for ambulant insomniacs who have to
perform skilled mental or physical work on the
following day residual effects can be seriously disad·
vantageou s.
Considering the slow elimination of Ilunitraze-
pam, it seems logical to expect residual effects in the
mor ning (Amrein et al., 1979), but most clinical in-
vestigations (e.g . Hartelius et al., 197 8; Herrero,
1973; Wickstrom , 1979) stress the rarity of clinically
apparent hangover symptoms. However, although
the patient may feel refreshed in the morning after a
hypnotic dose, there is some motor impairment at 12
hours and an altered EEG characteristic of
benzodiazepines (decreased slow waves, increased fast
waves) up to 18 hours after 1 and 2mg of flumtraze-
pam orally (Bond and Lader, 1975). Such effects were
correlated with feelings of noontime drowsiness in
normal subjects the day after a night-time dose. Such
residual effects of flunitrazepam Img were equipotent
with nitrazepam 6.5mg and Ilurazepam 19.5mg
(Bond and Lader, 1975).
Interestingly, Hartelius et al. (1978) did not ob-
serve any difference in 'hangover' effects between
hypnotic doses of Ilunitrazepam and nitrazepam or a
placebo, either subjectively or with objective tests.
The explanation may be related to the fact that these
patients were chronic insomniacs regularly requiring
hypnotics for insom nia. Such a group may experience
'physiological hangover' after insufficient sleep, when
they are without a hypnotic, or receive an ineffective
drug or an inadequate dose.
3.2 ClinicalTrials in Anaesthesiology
3.2./ Use as Premedication
As a Hypnotic f or the Night Prior to Anaesthesia:
Besides the visit of the anaesthesiologist on the pre-
ceding day, it is important to support a patient
 Flunlt r81epam : A Review
scheduled for su rgery with an effective hypnotic: to
ens ure an adequate amount an d quality of sleep. The
natura l reasons for difficulties in falling asleep include
both anxiety about su rgery and environmental factors
assoc iated with hospital design and nurs ing care. The
hypnotic act ion of the benzodiazepines is at least par-
tially indirect, via anxiolysis, and for this reason they
sho uld be appropriate in these patients. Co ntrary to
act ive outpatients, there is no need for hospitalised
s urgical patients to wake up on the operatio n morn -
ing totally refres hed; rather a residual anxiolytic effect
is desirab le. Indeed, this is of course one of the aims
of premedication , wh ich is often given to the patient
on the morn ing of surgery. Benzodiazepines have
achieved an important role for use in th is way. as is
supported by several open or controlled studies (e.g.
Dolp and Heyden. 1978; Freuchen et al.• 1978; Kan-
to et al., 1979b; Pearce. 1974; Powell and Co mer.
1973).
In studies with flunitrazepa m. Dolp and Heyden.
H 978) reported that 83 % of surgical patients had
subjectively excellent sleep the night before su rgery
with a dose of 2mg. Similarly. Kanto et al. ( 1979b)
recorded 'good' sleep with 2mg Ilunn razepam in
93 % of pa tients compared with 22 % in a placebo
group . Pearce ( 1974) reported excellent sleep for all of
his patients with 2mg of flunitrazepam in the even-
ing, including patients with anam nestic insomnia.
In com parisons with other benzcdiazepmes,
Freuchen et al. ( 1978) compared 2mg Ilcrutrazepam,
5mg nitr azepam and 100mg aprobarbitone as oral
hypnotics on the night preceding surgery, reporting
flunitrazepam to be superior with respect to onset
(p <0 .05) and depth of sleep (p <0 .0 1). There was no
difference between drugs in th e duration of sleep.
Some sleepiness in the morn ing which occu rred in the
flunitrazepam group was considered an advantag e in
th is special situation. In another similar stud y. but
us ing a smaller dose, the effect of flunitraz epam Img
did not diITer fro m diazepam 10mg (Heinzl and
Hossn. 1978). There are no repo rted comparisons
with Iorazepa.m . which has been shown to be an effec-
tive hypnot ic under such condi tio ns Ie.g. Powell and
Comer . 1973 ).
,.,
As Oral Premedication: Oral premedication has 0b-
vious advantages over the classic intramuscular or
subcutaneous injoc1ions. The re is seldom a need to in-
clude an analgesic in premedication . and the impor-
tance of an antichol inergic is dispu table. Th e phar-
maco kinetic: properties of Ilumtrazepam Ii.e. abso rp-
tion and onset of action) are suitable for oral pre-
med ication. This was shown by Kanto et al. ( 1979b)
in a placebo-controlled doubl e-blind investigation
employing flunitrazepam 2mg in the evening and
morn ing prior to surgery. Th ey concluded that such a
regimen provided adequate premedication for all
patients in the morning. including an an xiolytic effect
for the waiti ng time. Richardson and Man ford ( 1979 )
com pared ora l flunitrazepam with diazepam as a pre-
medication for children. Th ey observed satisfactory
sedation in 99 % of patients in the flunitrazepam and
89 % in the diazepam group. After operation Iluni-
trazepa m was associated with a lesser incidence of
vomiting than diazepam (23 % and 39 % . respec-
tively. overall). They also demonstrated a correlation
between plasma concentra tio n and desirable eITects.
Thus. flunitrazepam is suitable for oral premedica-
tio n providing an adeq uate dose is used . The
minimum time for optimal absorption is 90 minutes
(Amrein. 1978). and the effect is longstandi ng
enou gh to permit premedication of all patients on the
morn ing of surgery .
As Intram uscular Premedication: The classical in-
tramuscular premedication ro ute is also suitable for
Ounitr azepam. Dolp and Heyden (1978) achieved
good sedation in 90 % of patients with ~ mg of in-
tra muscular flunitr azepam . Th ey did not observe any
undesirable effects on respiration; in fact, oxygen
saturat ion of capillary blood rose (as a result of vaso-
dilatation). Lindgren et al. ( 1979 ) observ ed similar
sedative effects in children unde r 5 years of age with
either 0.0 2mg/kg flunitrazepam intr am uscu larly, or
with I mg /kg pethidine (meperidine). These 2 dru gs
were considered better than O.25mg/ kg diazepam
given intramuscu larly. The re were no diITeret'ICZS in
sedatio n in children aged over 5 years between the
dru gs studied. In such studies Ilumtrazepam was ab-
sorbed more reliably after ir.tra muscu lar injection
 Flunitrazepam: A Review
than diazepam , for which intramuscular use may be
unreliable (e.g. Dundee et al., 1974 ; Korttila et al.,
1976). Besides sedation , amnesia associated with in-
tramuscu lar nunitrazepam is an advantage, protect-
ing th e patient fro m unpleasant memories dur ing the
perioperative period.
Thus, intramuscular nunitrazepam is a reliable
premed ication. A minimum of90 minutes after injec-
tion is needed for sufficient effect to occur, with the
maximal effect occurring at 2 to 3 hours after injec-
tion. The onset of action can be shortened using the
techn ique described in section 2. 1.
A side effect of Ilunitrazepam premed ication is
dizziness, which means that the patient cannot walk,
stand or sit alone safely. Based on the specific vasodi-
latating effect of flun itrazepam, orthostatic hypoten-
sion may also occur after premed ication.
As i ntra venous Premedication: Reaching th e cen-
tral nervou s system rapidl y after an int ravenous in-
jection , flunitrazepam is effective with in 2 to 5
minutes. In the sense ofa premedication . intravenou s
nunitrazepam can be admin istered only shortly
before induction . when usua l premed ication sched-
ules are inapprop riate . However . an intravenou s dose
of O.5mg resul ts in significant respiratory depressio n
and a fall in arterial oxygen tension (Doenicke er al.,
1978), and th is type of premedication must thus be
limit ed to the induction room .
3.2.2 Use as on Induction Agent
The original investigation of flunitrazepam in an-
aesthesiology was as an induction agent (Vega, 197 1),
and duri ng the last several years flunitrazepam has
become an accepted induction agent via trials and
erro rs . If one tries to induct a patient with flunitraze-
pam using a similar techn ique as with th iopentone, an
overdose of flunitrazepam will res ult (Dundee et al.,
1976). If an anaest hetist has used diazepam for ind uc-
tion (Brown and Dun dee, 1968), or applied neurolep-
tic techniques, it is much easier to adapt to the charac-
teristics of nunitrazepam . Several points are typical of
flunitrazepam induction. The induction period is long
(it takes 2 to 3 minutes before the patient falls asleep)
an d the maximum effect will be reached late (Cole-
366
man et al.• 1973 ). Before sleeping the patient has a
short period of eupho ria often associated with logor-
rhoea , then mental cloud ing and a pleasant gradual
passage into the unconscious state (Rizzi et aI., 1975).
Dur ing induction the eyes often remain open, there is
slow lateral nystagmus and the eyelid reflex does not
disappear in all cases (84 % ; Riui et al., 1975). Res-
pirat ion is often noisy due to relaxed masseter
muscles and a consequent sagging of the mandible.
The mandibula has to be supported and an oro-
phary ngeal airway is net always tolerated (Pearce,
1974).
The acceptance of th is type of an unusual course of
indu ction is a prerequisite for Ihe use of Ilunitr aze-
pam as an induction agent. Th is type of agent also re-
quires a different manner of dosage and a different
rate of injection. It is preferable to slowly inject a pre-
calculated dose (usually 0.02 to 0.03mg /kg) and wait
for 2 to 3 minutes. If there is insufficient effect sup-
plemen tary doses of 0.5 to 1.0mg may be given.
Events duri ng induction are effectively covered by the
am nesia typical of flunitrazepam.
In a few cases it is not possible 10 achieve anaes-
thesia with Ifunitrazepam: e.g. 7 1 out of 93 3 cases
failed to fall asleep in the series of Rizzi et al. (J975).
In s uch cases it is advisable to supplement inductio n
with nit rou s oxide /oxygen inhalat ion, with fentany l
0.1 mg or with thiopentone in relatively smal l doses .
These resistant patients are usual ly chronic users of
alcohol or benzodiazepines.
On the basis of the induction characteristics of flu-
nitrazepam it is understandable th at reports concem -
ing its use as an induction agent are controversial.
Dundee et al. (f 976) did not consider flunitraz epam
suitable for rou tine induction, and Clarke and Lyons
(1977) preferred thio pentone over benzodiazepines. In
our own study (Mattila et al., 1977) we did not find
differences in the qual ity of induction between
althesi n and Ilunitrazepam . The obvious reasons for
these relatively disappointing results are too high a
dose of flunitrazepam (O.05mg/ kg) and too rapid an
injection rate. Since the time of th is investigatio n we
have fundamentally changed th e induction technique
with nun itrazepam to accommodate its particu lar
 Flunilfaz epam : A Review
properties, and the results are much improved.
What advantages can flunitrazepam offer to
'counter-balance' the potential disadvantage of the ex-
ceptional course of induction? The most important
advantage is its amnesic effect, which protects the
patient against memories of events during anaes-
thesia. The amnesic effect of barbiturates is highly
unreliable (Clarke and Lyons, 1977), and 'awareness'
can be considered a serious shortcoming of many
general anaesthesia techniques (Eisele et al., 1976;
Editorial, 1979; Mattila et al., 1979c). Additionally,
the course of anaesthesia with flun itrazepam is even
and quiet (Mattila et al., 1977). Induction with Iluni-
trazepam causes a lesser decrease in cardiac output
(Rolly et al.• 1974) and in cardiac performance (List,
1978) than occurs with thiopentone (4 to Smg! kg).
Especially advantageous is the direct dilatory effect on
peripheral vessels (Pasch and Bugsch, 1979 ; see sec-
tion 1.2).
3 .2.3 Use as a Part a/General Anaesthesia
It is virtually impossible to induce an anaesthetic
state in an animal or in man with a benzodiazepine
alone, because the subject will react defensively to any
surgical pain. In this aspect benzodiazepines differ
fundamentally from drugs such as barbiturates
(Haefely. 1977). Thus, flunitrazepam cannot be used
as an anaesthetic alone, but only in combination with
other agents, and for practical purposes it is therefore
important to be aware of the interactions between nu-
mtrazepam and certain other anaesthetics. Of great
importance is the potentiating effect with nitrous ox-
ide (Stumpfet al., 1975). These autho rs demonst rated
that 1.6mg of flunitrazepam potentiated the effect of
nitrous oxide as much as 8.3ml ot Thatamonar" (con-
taining 20.7mg dehydrobenzperidol and O.4mg fen-
tanyl). This effect was also clearly demonstrated by
Stovner et at. (197 3), who neededonly 1/ 3 of the nor-
mal dose of Ilunitrazepam when giving 67 % nitrous
oxide du ring induction. This synergism of llunitraze-
pam with nitrous oxide has led to some conclusions
that other analgesics should be unnecessary during
maintenance(Kurka, 1978; Marti et al.• 1974). How-
ever, other authors have emphasised the need for sup-
367
plementation with fentanyl (Bergmann, 1978;
Haldemann et al., 1977; Milewski and Dick, 1978)or
with pentazocine (Milewski and Dick, 1978; Rizzi et
al., 1975) or pethidine (Mattila et al., 1977). A poten-
tiating effect of flunitrazepam on fentanyl and other
analgesics also occurs, and the doses needed are
smaller than in other 'balanced anaesthesia' tech-
niques. This synergism may result in respiratory
depression at the end of anaesthesia, with a need for
naloxone in incremental titrated doses.
Another way to use flunitrazepam is as a supple-
ment to a barbiturate-ana lgesic-muscle relaxant se-
quence, timing the small supplementary dose of
O.5mg to I .Omg just before skin incision in order to
prevent arousal symptoms (Mattila et al., I979c).
Compared with diazepam IOmg, flunitrazepam 1mg
proved to be a better supplement and especially a bet-
ter amnesic adjuvant .
Synergism between flunitrazepam and muscle
relaxants is not as established as that with analgesics.
Stovner et al. (1973) did not find any effect on the
dose of alcuronium needed. Lindgren et aI. (1979) ob-
served fewer fasciculations after succinylcholine in
patients premedicated with flunitrazepam than with
diazepam. Our own experience is that the dose of suc-
cinylcholine required, even in the continuous injec-
tion method, is reduced during llunitrazepam com-
bination anaesthesia.
3. 2.4 Use with Ketamin e
Benzodiazepines are widely used to prevent side
effects of ketamine anaesthesia Ie.g. Mattila et al.,
I 979a). There are several reports of Ilunitrazepam-
ketamine combinations with favourable results (e.g.
de Castro, 1972b; Freuchen et al., 1976; Knoche et
aI., 1978). In this so called 'ataralgesia', addition of
tlunitrazepam significantly reduced elevation of blood
pressure, motor restlessness, confusion during recov-
ery, dreams and other psychotomimetic effects com-
pared with ketamine alone (Freuchen et al., 1976a).
3 .2.5 Use with Neuroleptanalges ia
F1unitrazepam has been used in order to improve
neuroleptanalgesia(Seitz et al., 1977), which at times
 FkJnitralepa m : A All'.Ilew
is insufficient for surgical purposes (Riui et al .,
1975).
3.2.6 Use as a Supplement 10 Local Anaesthesia
Local anaesthesia techniques often require comple-
mentary treatment with sedative drugs to prevent
other unpleasant experiences during procedures , even
though the local anaestheti c prevents pain per Sf?
Korttila et al. (l978a) used flunitrazepam in an intra-
venous dose of 0.01 to 0.03mg /kg with excellent
results in patients undergoing bronchoscopies, es-
pecially concerning amnesia for recall of procedures.
Heermann and Candas (197 7) gave Ilumtrazepam 0.5
to 2.0mg intravenously before performing local an-
aesthesia. Patients retained their ability to cooperate ,
but fell asleep when they were undisturbed. Similarly,
other authors have reported advantageously combin -
ing relatively small doses (0.2 to 0.8mg) of intraven-
ous Ilunitrazepam with local anaesthesia procedures
(e.g. Schulte-Steinberg, 1978; Tolksdorf et al. ,
1979a) . Oral or intramuscular flunitrazepam , as a
premedication and as incremental supplementary
doses during longer procedures may also be useful as
a supplement to local anaesthesia.
3.2.7 Use in Intensive Care
For the patient in critical condition , intensive care
is often a combination of unpleasant procedures.
There is a real need to protect the patient against such
experiences, and for this reason diazepam has
achieved wide use in intensive care units. However ,
flunitrazepam or lorazepam may offer some advan -
tages over diazepam . Pasch and Rugheimer (J 978)
have reviewed the use of flunitrazepam in intensive
care and give a dosage schedule designed to reach and
maintain plasma concentrations at a desired level of
15 to 20ng /ml. In these circumstances the synergism
with analgesics , and thus the requirement of smaller
doses. and the specific dilation of peripheral circula-
tion resulting in reduced cardiac work due to
decreased afterload , are clearly advantageou s. When
the first dose of flunitrazepam is given. it is important
to follow the circulatory response, which can be pro-
nounced in the presence of latent hypovolaemia.
368
4. Side Effects
4.1 Hypnotic Use
The only potentially important side effect reported
during use as a hypnoti c is the occurrence of some
residual effects in the morning (see section 3.1.3).
which appear to be less prominent in patients who are
chronic users of hypnotics. The relative importance of
such residual effects (psychomotor impairment: occa-
sionally clinically apparent dr owsiness) should be
evaluated with regard to the duties wh ich individual
patients perform.
4.2 Use in Anaesthesia
4.2.1 Slow Recovery
Depending on the dose and duration of procedures
patients may be more sleepy after flunitrazepam than
generally after 'balanced anaesthesia ', which may
result in poor acceptance by nursing staff (Marti et
al., 1974). F1unitrazepam is in fact not a short acting
anaesthetic (Bergmann. 1978; Deacock, 1975); how-
ever . during recovery patients sleep quietly, without
anxiety and nausea. They are arousable and coopera-
tive, but when undisturbed they fall asleep again. This
may be considered a suitable state for a postoperative
patient , when proper observation is available. A short
restless phase may occur during recovery (Mattila et
al.• t 977), possibly connected to the need for an anal-
gesic. The extent of prolongation of recovery is
naturally dependent on the anaestheti c combination
used. For example, Kurka (\974) reported patients
awake on the operating table, who subsequently fell
asleep again. using only nitrous oxide and flunitraze-
pam . without other analgesics.
More objective psychomotor performance tests
have shown that with O.Olmg /kg flunitrazepam im-
paired eye-hand coordination lasts for up to 6 hours,
and after 0.02mg /kg and 0 .03mg /kg this impair-
ment is still significant at t a hours after injection
(Kortilla. 1979 ; Korttila and lJnnoila, 1976). The
clinical importance of these findings is dependent on
 flunitrazepam : A Review
whether the patient is hospitalised or is an outpatient.
In conclusion, it needs to be emphasised that the
recovery from flunitrazepam anaesthesia is dose-rel-
ated and is significantly dependent on age (Korttila et
al ., 1978b). In combination with other drugs, the
total doses required can be minimised by skilfully
utilising the potentiating effect of flunitrazepam on
other anaesthetics.
4.2 .2 RespiralOry Depression
As described earlier (section 1.3), flunitrazepam
has a depressive effect on respiration, which leads to a
significant decrease in arterial oxygen tension
(Schmitz et al., 1978). This may become clinically im-
portant when flunitrazepam is used intravenously for
premedication or as a supplement for local anaes-
thesia. In these circumstances respiratory sufficiency
must be ensured: for example, Niessner (1975)
recommends the use of oxygen durin g induction of
emergency cases to prevent a significant decrease in
arterial oxygen tension.
4.2.3 Cardiovascular Side Effects
The effects of flunitrazepam on circulation nave
been described earlier (section 1.2). Circulatory effects
are in general advantageous, as a consequence of pri-
mary peripheral vasodilatation. However, this neces-
sitates active fluid therapy at the time of induction.
F1unitrazepam administration in the presence of rela-
tive hypovolaemia will result in a significant fall in
venous return , and a secondary fall in cardiac output.
Reduction of the dose of flunitrazepam in elderly
patients, or in patients with cardiovascular disease, is
advisable (to 0.005 to O.Ol mg/ kg).
4.2.4 Venous Sequelae
During the past years much emphasis has been
placed on injection thrombophlebitis after intraven-
ous diazepam Ie.g. Hegarty and Dundee, 1977, 1978:
Mattila et al., 1979bl. This complication was associ-
ated with the propylene glycol used as a solvent for
diazepam. Because flunitrazepam contains the same
solvent, and since intravenous injection of flunitraze-
pam causes similar pain at injection sites as diazepam
369
(Stovner et al., 1973), it could be expected that fluni-
trazepam may also produce thrombophlebitis. How-
ever, Hegarty and Dundee (1977, 1978) have shown
that the frequency of injection thrombophlebitis after
intravenous flunitrazepam is low at 10 to 14 days
after injection (5 %). There was a significant differ-
ence in favour of flunitrazepam as compared with
diazepam in this study, but no difference was detected
between flunitrazepam and lorazepam. Paravenous
injection of flunitrazepam did not result in tissue
damage (Rizzi et al., 1975). In practice, it is important
to dilute the flunitrazepam concentrate with at least a
similar amount of water, and administer it into a
large vein. Indeed, it has been recommended that a
more dilute solution be used (flunitrazepam 2mg in
1ml diluted with 19m1 normal saline) to avoid pain
on injection (Kurka, 1978), although the effect of
such dilution on the solubility of flunitrazepam is
somewhat unclear.
4.2 .5 Oiher Side Effec ts
Postoperative nausea is usually reduced after pre-
medication or anaesthesia with flunitrazepam (Heer-
mann and Candas, 1977; Mattila et aI., 1979c).
Richardson and Manford (1979) demonstrated that
there was a correlation between a low frequency of
nausea and a high plasma concentrat ion of flunitraze-
pam.
Sudden coughing, which may disturb the operat-
ing surgeon or the respiration of the patient, some-
times occurs when flunitrazepam is used as a supple-
ment to local anaesthesia (Tolksdorf et al., I 979b).
Hiccup was observed by Bergmann (J 978) in up to
20 % of patients receiving flunitrazepam anaesthesia,
occurr ing more frequently in unpremedicated
patients.
There are no reports of allergic reactions.
Doenicke and Lorenz (1978) observed a slight
histam ine liberation in 50 % of patients after fluni-
trazepam ; the frequency of such a reaction is the same
as, but the amount of histamine released is less than ,
after other anaesthetics.
There are no reports of liver or other organ tox-
icity after flunitrazepam.
 Flumtralepam: A Review
4.2.6 Precautions in Use/or Outpatients
Because of its long lasting effect, flunitrazepam is
usually considered unsuitable for outpatient anaes-
thesia. This contra indication is, however, dose-ret-
ated, since after small doses (0.0 Img/kg) patients are
able to walk and stand within 2 hours of Ilunitraze-
pam administra tion. The age of the patient must also
be taken into consideration (Korttila et al., I 978b).
Because there is impairment in functions such as eye-
hand coordination, the patient should not be allowed
to leave the hospital unaccompanied, and should not
dr ive a motor vehicle or operate machinery for at
least 24 hours after flunitrazepam administration.
5. The Place ofFl unilrazepam in
Anaesthesfology
Due to its excellent amnesic properties, associated
with a good hypnotic and sedative effect, flunitraze-
pam can be widely applied in anaesthesiology and in-
tensive care. However, the use of flunitrazepam as an
induction agent requires a new attitude toward the
course 'of induction. Induction is so unusual, com-
pared with thiopentone, that the pattern with fluni-
trazepam has to be accepted in its own right. The at-
titude to postanaesrhetic sleepiness must also alter
before flunitrazepam will be accepted universally.
Our personal experiences with routine use of this
dru g are impressively positive, and flunit razepam an-
aesthesia has been acceptedwith gratitude by patients
for its excellent amnesic effect. Its specific vasodilat-
ory effect may open furt her new areas of application,
such as in certain intensive care situations.
6. Comraindicat ions
At the present time Ilunitrazepam is generally con-
sidered contra indicated in Caesarean section, but re-
cent observations of Kanto et al. (1979a ) may
radically change this attitude (see section 2.2). For the
usual safety reasons flunitrazepam is considered con.
traindicated in the early months of pregnancy,
310
although no dysmorphogenic properties have been
observed in animal experiments . Like other muscle-
relaxing substances flunitrazepam is considered
relatively contraindicated in myasthenia gravis.
7. Dosage and Admini stration
As a hypnotic the usual dose is 2mg orally.
Similarly, the same dose may be used as a premedica-
tion the night before an operation. For premedication
on the morning of surgery, 2mg orally or in-
tra muscularly at least 1.5 hours prior to anaesthesia
may be employed.
For induction of anaesthesia, the usual dose is
0.02 to 0.0 3mg/ kg given slowly intravenously. If
necessary. an additional supplementary dose of 0.5 to
1.0mg may be given no sooner than 2 to 3 minutes
after the first induction dose. For anaesthesia mainte-
nance, du ring long operations, or for small arousal
symptoms, 0.2 to 0.5mg intravenously 2 to 3 hours
after induction may be used.
As a supplement for local anaesthesia, 0.5 to
1.0mg intravenously has been employed. In intensive
care doses should be individually titrated, usually in
the range of 0.5 to 2.0mg intravenously.
Dosage should be reduced in elderly patients or in
those with cardiac disease.
Acknowledgement
The aUlhol"S wish 10 upress their grealeslgratilude to the nu l"S-
ing staff of the anaeslhesiology depanmenl of Kuo pio Uni~el"Sity
Centra l Hos pital for their valuable help in performing clinical
trials with flunitrazepem .
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A uthor's add ress: Om MAK MOll ilo and H.M. Lom i, Depart-
ment of Anaesthesiology, Kuopio University Cenlral Hospital , SF
70 2 10 K ur1f/i" 11 (Finland).