1.3 A DOUBLE-BLIND EVALUATION OF A NEW HYPNOTIC

4 Augustus 1973 S.-A. MEDIESE TVDSKRIF 1339
.A Double-Blind Evaluation of a New
Hypnotic-Flurazepam Hydrochloride *
D. A. SWANSON, l\LB. B.eR., D.P.M. UNI\'. RAND, Department of Psychiatry, Tara - The H. Morass Centre,
and University of the Witwatersrand, Johannesburg
SUMMARY
Flurazepam hydrochloride and amobarbital were used in
treating 60 hospitalized patients complaining of moderate
to severe insomnia, in a phase III double-blind, randomized
study. Over-all response was good to excellent, with both
drugs, with the edge towards f1urazepam. In the amobarbital
group a higher dosage and a longer duration of
exposure to the drug were needed to obtain the same
response. Side-effects were hardly noticeable; physical
findings and laboratory data were little affected with either
drug.
s. Afr. Med. l .. 47, 1339 (1973).
Flurazepam hydrochloride (Dalmadorm) is a new hypnotic
of the benzodiazepine class. It is, therefore, an
analogue of such familiar preparations as chlordiazepoxide
(Librium), diazepam (Valium), oxazepam (Serepax) and
nitrazepam (Mogadon). Studies in animals indicate that
f1urazepam exerts a centn\1 depressive effect with a muscular
relaxation, and it increases the arousal threshold of
the amygdala and thehypothalamus. A potent hypnotic
effect has been observed in humans.'"
The chemical designation of flurazepam is 7-chloro­
1-(2-diethylamino-ethyl)-5-(O-flurophenyl)-I, 3-dihydro-2H­
), 4·benzodiazepine-2-one dihydrochloride. The structural
formula of flurazepam is given in Fig. 1.
Reports in the literature appear encouraging insofar
as effectiveness, safety and convenience of administration
of flurazepam are concerned. ]n a controlled study, Kales
et al.' found that flurazepam at a dosage of 30 mg
decreased the time required for patients to fall asleep:
decreased the number of nocturnal awakenings; and increased
the total sleeping time.
Comparative studies of flurazepam and other hypnotics,
barbiturate and non-barbiturate, have suggested that
many hypnotics may not be as effective as flurazepam
in inducing and in maintaining sleep. Fick' found that
patients with insomnia preferred flurazepam 15 mg to
chloral hydrate 500 mg; or flurazeparn 30 mg to glutethimide
500 mg; or flurazepam 30 rng to secobarbital
100 mg. In a subsequent study, however, Fick et aI.'
could find no differences in efficacy between flurazepam
30 mg and secobarbital 100 mg.
The present controlled trial, conducted before marketing,
compares flurazepam hydrochloride with amobarbital in
the treatment of symptomatic insomnia among neuropsychiatric
patients.
'Date received: 28 February 1973.
Patients
Cl
Fig. 1. Flurazepam.
DESIGN AND STUDY
All the patients selected for the study were admitted
to the same neuropsychiatric institution (Tara-The H.
Moross Centre). They manifested moderate to severe
insomnia. Where it was considered essential, concomitant
medication was administered. Pregnant patients and those
under 18 years of age were excluded.
There were 60 patients, randomly assigned, using
double-blind techniques to either flurazepam or to amobarbital.
The ages of both groups were quite comparable:
the group receiving flurazepam had a mean age of 46,2
years (range 24 - 70), and the group receiving amobarbital
had a mean age of 46,3 years (range 20 - 78). There was
a preponderance of females in the study (2,3: 1), but
the distribution among the two groups was identical.
Table I presents a description of the patients selected
for the study.
The diagnostic categories, shown in Table H, were
quite similar; the vast majority (21 with f1urazepam and
24 with amobarbital) suffered from depression, reactive

1340 S.A. MEDICAL JOURNAL 4 August 1973
TABLE I.
No. of patients
Sex
Male
Female ...
Average age (range)
Marital status
Single ._
Married
Divorced/separated/
widowed ..
Concomitant medication
Yes
No
DESCRIPTION OF PATIENTS
Treatment groups
Flurazepam Amobarbital
30 30'
.. Two patients from this group were withdrawn. one after an at·
tempted suicide, and the other because of suspected porphyria.
g
21 21
46,2 (24 - 70) 46,3 (20 - 78)
g
3 8
18 16
g 6
18 23
12 7
administered 30 - 60 minutes before bedtime to all the
selected patients. To start with a single capsule was
given; the dosage being increased by 1 capsule on the
following night to a final dose of 3 capsules, if the
insomnia remained unaltered. either tbe patient, nor
the nursing staff, nor the investigator knew which was
administered until the code was broken at the end of
the study.
Two patients were withdrawn from the study: one
when it was suspected that she was suffering from
porphyria; and the other after he had attempted suicide.
When the code was broken at the end of the study.
both were receiving amobarbital.
RESULTS
The over-all (global) therapeutic response, as - evaluated
at the conclusion of treatment in each patient, is presented
in Table Ill. The efficacy ratings for each of the comor
endogenous. The endogenous depressive group included
those patients who manifested either the unipolar or
the bipolar form (i.e. tbose wbo had both manic and
depressive phases). The remaining patients fell into a
heterogeneous group of neuropsychiatric conditions.
TABLE 11. DIAGNOSTIC CATEGORIES
Treatment groups
TABLE Ill. GLOBAL THERAPEUTIC RESPONSE RATING
Flurazepam
Amobarbital
Over-all
response Doctor Patient Doctor Patient
Very good 21 22 13 15
Good 7 8 10 7
Moderate 2 Q 4 4
No effect 0 0 1 2
Worse 0 0 0 0
Diagnoses
Reactive depression
Endogenous depression
Schizo-affective disorder
Schizophrenia
Anxiety reaction
Myasthenia gravis
Presenile dementia
Involutional psychosis
Obsessional personality
Psychopathic personality
Flurazepam
8
13
3
2
1
1
o
2
o
o
Total 30
Amobarbital
4
20'
1
2
o
o
1
o
1
1
30
parison drugs shows a bias towards flurazepam. This
becomes more evident when the dosage which provided
the optimum response is analysed. With flurazepam the
majority of patients (800~-24 patients) required only
30 mg (1 capsule) to effect a good .response, and the
remainder (20°{,-6 patients) required 60 mg (2 capsules).
The distribution with amobarbital was more attenuated:
46,4% (13 patients) requiring 50 mg (l capsule); 25%
(7 patients) requiring 100 mg (2 capsules); and the
remaining 28,6')0 (8 patients) requiring 150 mg (3 capsules).
Table IV shows the optimum response per dosage
ratio.
• Includes 2 patients withdrawn from study. TABLE IV. DOSAGE RESPONSE
Procedure
The study period was 2 weeks: I week of observation
before medication was begun (baseline period) followed
by I week (7 nights) of treatment. On the morning
before starting medication and on each subsequent morning
of the trial period, patients were interviewed as to
(a) time required to fall asleep; (b) duration of sleep;
(c) condition upon awakening; and (d) any adverse
reactions.
A mndomized. double-blind method of study, statistically
generated, was employed. Flurazepam (30 mg) or
amobarbital (50 mg) in matching gelatin capsules was
Flurazepam
Amobarbital
1 tab
24 (80%)
13 (46,4/'0)
Dosage
2 tabs
6 (20/'0)
7 (25%)
3 tabs
o
8 (28,6/'0)
A comparison of the effects of both trial substances on
sleep induction and duration is shown schematicaIly in
Fig. 2. The results indicate that flurazepam is more
effective for inducing and maintaining sleep. Approximately
60% (19 patients) receiving flurazepam showed
an immediate and sustained response on both parameters,
whereas with amobarbital the response rates were much
lower. In the amobarbital group an immediate response

4 Augustus 1973 S.-A. MEDIESE TVDSKRIF 1341
for sleep induction occurred in 35~~ (7 patients), while
the duration of sleep was less sustained in 37,5"'0 (10
patients).
Number of 20
patients
15
SLEEP INDUCTION
---- Flurazepam
- - - - - - - Amobarbital
Both groups of patients reported similar states on
awakening and tills appeared to be directly related to the
dosage of the particular drug and the response to that
dosage.
No serious adver e reactions to medication were reported.
With f1urazepam 9 patients complained of mild
drowsiness and 2 patients reported having had nightmares.
Of those patients receiving amobarbital, 4 complained of
drowsiness. while 2 others reported marked drowsines
which was interpreted as a 'hangover' effect on awakening.
In both study group these reactions did not appear to
be dose-related.
10
"­ ,
,-
DISCUSSION
5
Number of 20
patients
15
0 1 2 3 4
Day when onset 20 minutes
SLEEP DURATION
I
10 I
I
I
I
5
I
/
/
_L--
0 2 3 4
Day when duration 6 hours
Fig. 2. Sleep induction and duration.
This study utilized the subjective evaluation of patients,
wlllch was interpreted as a 'hangover' effect on awakening.
effective single method for assessing the hypnotic potency
of drugs'"
In this particular double-blind study of f1urazepam
hydrochloride with amobarbital controls, the results indicate
that f1urazepam is effective for inducing and maintaining
sleep in patients with insomnia. Most patients
felt rested and alert on awakening; they tended to get
to sleep more quickly; to sleep better and longer than on
amobarbital.
Conclusions from this subjective comparative study agree
with those obtained in other studies regarding the efficacy
of f1urazepam for the induction and maintenance of sleep
in subjects with insomnia:"
T should like to thank Dr B. de Wet for his help and advice;
and Roche Products (Pty) Ltd, Isando, for supplying the drugs.
REFERENCES
I. Department of Clinical Research, Roche Laboratories, lsando. Tvl:
Unpublished data.
2. Fick, H. (t967): CUrT. Thee. Res.• 9. 355.
3. Kales, A., Tan, L. T., Scharf, M., Kales, J. and Malmstrom, E.
(1969): Psychophysiology, 6. 260.
4. Fick. H. (1972): J. Clin. Pharmacol., 12. 2t7.
5. Z mmerman. A. M. (1971): Curr. Ther. Res., 13, 18.
6. Hare, E. H. (1955) Brit. J. Prey. Soc. Med., 9, t40.
7. Exton-Smith, A. N., Hodkinson, H. M. and Cromie, B. W. (1963): Brit.
Med. J., 2, 1037.