Reprinted from THE BRITISH JOURNAL OF ADDICTION to alcohol and other drugs E.
s S. Livingstone |
Br. It. Addict., 11376, Vol. 71, pp. 321-326. Longman. Printed in Great Britain.
A Comparison of the Effects of Propranolol
and Diazepam in Alcoholics Carl Carlsson M.D. and Bengt-Goran Fasth Ph.D.Dept. II, Lillhagen Hospital,
Gothenburg, Sweden
Abstract
In a double-blind cross-over study, propranolol in a
dosage of 120 mg daily vaas more effective than 30 mg
a day of diaz.epam in relieving symptoms of tension
and depression in chronic alcoholics. Speculations are made regarding the
mechanism of action.
A number of studies showing the effect of propranolol
on tension symptoms in neurosis have been reviewed by Gardos
(1973).
In chronic
alcoholics, as in anxiety neurosis, hyperkinetic circulation is a common
finding and out of twenty alcoholics who had passed the abstinence phase, only
four had a cardiac output within normal limits at rest (Carlsson,
unpublished). During the abstinence phase everyone
of eight alcoholics had raised cardiac output at rest and during exercise (Carlsson, 1969). Propranolol (Inderal R) was found to normalise the circulation in all cases and, unexpectedly,
in five out of eight patients, symptoms of tension appeared to decrease after
40 mg propranolol.
In a later
study propranolol was shown to have a significant effect on tension and
depressive symptoms in the abstinence phase of alcoholism (Carlsson
& Johansson 1971). This has been confirmed by Gallant et al. (1973).
There is
conflicting evidence as to the effect of propranolol on psychiatric symptoms.
In small doses it appears to have a sedative effect and in larger doses an
antipsychotic effect (Atsmon et al., 1972). One of
its active metabolites is 4-hydroxypropranolol which is formed in the liver
(Fitzgerald, 1971) and this may be the cause of the different effects of
propranolol when given by mouth and by injection.
In the
treatment of alcoholics there is a gre at need for
drugs which reduce tension and depression without the risk of habituation.
Formerly we used diazepam. but alcoholics are much
more likely to become habituated to such preparations than other people. It was
difficult to find other suitable drugs, phenothiazine derivatives are liable to
cause too many side-effects, but propranolol seemed to be the drug of choice in
a number of cases. Thus we felt that there was a need for a double-blind
comparison between propranolol and diazepam.
Material
The
material consisted of 52 males diagnosed Oll medical
grounds as chronic alcoholics or as gamma-alcoholics according to the
classification of Jellinek (1960). They could also be
described as alcohol addicts. The mean age was 39 8 years (range 25-26) and
most of them had at least a ten year history of alcohol abuse. They were
treated voluntarily as inpatients in a mental hospital in an open ward used
specifically for the treatment of alcoholics. All patients showed marked signs
of tension and depression.
_______________________________________________________________________________________
322 Carl Carlsson
Method
A double-blind cross-over technique was used. Every patient was treated
for 14 days with each drug in random order and the code was broken only after
the study had been completed. The dose of diazepam was 30 mg a day and that of
propranolol 120 mg a day. Both drugs were given in identical capsules in three
daily doses. The trial started one to three weeks after admission. All other
medicines were discontinued before the trial started and no disulfiram was
given. In a few cases a shortacting hypnotic was
given at night ( 1 tablet of Modirax
R = 0 4 g hexapropymate) .
Table 1. Results of a double-blind,
cross-over study propranolol-diazepam.
DIAZEPAM 30 mg/d-PROPRANOLOL 120 mg/d; DOUBLE-BLIND
CROSS-OVER 14 + 14 days; P=propranolol; D =diazepam; n =40 chronic alcoholics
Results of the
statistical analyses of treatment effects zeith the
Chi-Square test.
______________________________________________________________________________________
Subscales: Period
I Period 2
_______________________________________________________________________________________
THE MIDDLESEX HOSPITAL QUESTIONNAIRE (MHQ)
Anxiety: Phobic: Obsessional: Somatic: Depressive: Hysteric: Total Score: |
P>D
X2 =2=0.78 P>D
X2=0.92 P>D
X2=0.96 P<D
X2=3.l3 P<D
X2=2.84 P>D
X2=2.84 P>D
X2=5.62 s.
|
P>D
X2=1.67 P<D
X2=0.10 P>D
X2=7.03 s. P<D
X2=0.10 P>D
X2=0.12 P<D
X2=0.ll P>D X2=0.96
|
ZUNG
SELF-RATING DEPRESSION SCALE
P<D
X2=l 39 |
P=D X2=0 |
TAVISTOCK
SELF-ASSESSMENT INVENTORY
P>D X2 =2 67 |
P<D X2=0.40 |
ADJECTIVE
CHECK LIST
Version A: Anxiety: Anxiety-Depression: Version B: Anxiety: Anxiety-Depression: |
Version
A: P=D
X2=0 P>D
X2=3.13 . P=D
X2=0 P>D X2=0.17 |
Version A: P>D X2=1.29 P>D X2=5.58 s. P>D X2=11.12 s. P>D X2= 5.71 s. |
________________________________________________________________________________________
s.=Significant at 0 05 level (Critical value=3 84)
Loss Diazepam 8, propranolol 3, between diazepam and
propranolol 1.
____________________________________________________________________
A Comparison of the Effects of Propranolol and
Diazepam in Alcoholics 323
The patients were told that we wanted to investigate a
new drug (Inderal R) which had not been used before in the treatment of
alcoholics. Diazepam was not mentioned. The patients were asked not to take
alcohol or any other drug and told that they could leave the trial if they
wished. They were examined three times by the psychologist (B.G.F.): prior to
the start of the study and after 14 and 28 days of treatment. The following psychological
methods of assessment were used:
The Middlesex Hospital Questionnaire (Crown &
Crisp, 1966).
The Zung Self Rating Scale (Zung, 1965) .
The Tavistock Self Assessment Inventory (Sandler et al. 1958) .
The Adjective Check List (Gough, 1960).
Results
The results
are given in Table 1. Whichever method of assessment is used, the significant
differences of psychic symptoms in alcoholics are in favour
of propranolol compared to diazepam. Tiredness appeared as a side effect in
some patients taking diazepam and insomnia occurred in a few patients under
propranolol treatment.
Twelve
patients left the trial because of alcohol intoxication; of these, eight were
lost during diazepam treatment and three while taking propranolol. One patient
left after he had completed treatment with diazepam and was due to start
treatment with propranolol.
Discussion
All the
significant differences in the trial results were in favour
of propranolol and this was an unexpected and remarkable finding. Neither the staffnor we were able to guess which drug the patients had
received. The patients were not asked about drug preference as they were not
aware that two drugs were being used.
Figure 1
shows a very speculative and simplified scheme. There is a rewarding system in
the brain, ascending from the brain stem to the lateral hypothalamus and
through the middle forebrain bundle to the cerebral cortex. Several studies
indicate that noradrenaline is a transmitter substance, at least to some
extent, in this system (Arbuthnott et al., 1971) . If electrodes are placed in the lateral hypothalamus of
the rat, self-stimulating behaviour can be elicited,
sometimes even to the extent of killing the animal. This can be called a new
kind of "addiction". There is reason to believe that d-amphetamine,
for example, operates on this system. The learning theories of behaviour may have their biochemical basis in the rewarding
centre, and even also in the punishment centre, where serotonin may be the transmitter. Like
d-amphetamine alcohol has a central stimulating effect (Carlsson
et al., 1973) and these effects of both d-amphetamine and alcohol can be
blocked by alfa-methyl-ptyrosine which blocks the
synthesis of catecholamines in the CNS (Ahlenius et al., 1973) .
There is a
very interesting theory that, in schizophrenia, 6-hydroxydopamine is an
abnormal metabolite which blocks the noradrenaline in the rewarding centre (Stein & Wise, 1971). In the peripheral nerve
endings, at least, 6-hydroxydopamine is blocked by propranolol and the effect
in the CNS may be similar (Atsmon et al., 1971).
___________________________________________________________________________________________
324.
Carl Carlsson
In vitro experiments in mouse brains show that tetrahydropapaveroline is formed from dopamine in the
presence of alcohol. This gives rise to a hypothesis for the biological basis
of alcoholism (Walsh & Davis, 1970). Tetrahydropapaveroline
is an alkaloid found in opium and is the precursor of, for example morphine and
papaverine. Pharmacologically, it acts as a beta
receptor stimulant in the sympathetic nervous system, like amphetamine and
noradrenaline. It is very interesting that the closely related substance apomorphine can prevent the craving for alcohol (Schlatter & Samarthji, 1972).
Apomorphine has a
suppressive effect on self-stimulation in rats
___________________________________________________________________________________________
A Comparison of the Effects of Propranolol and
Diazepam in Alcoholics 325
and this can be reversed by
d-amphetamine (Stein & Wise, 1973). It is possible that all addictions have
factors in common and that toxic psychosis could be explained from such
theoretical speculations as are outlined in the figure. Of course, systems
with, for instance, serotonin as the transmitter substance could be involved
and the figure must be regarded as a "biochemical trans-section".
Propranolol has been found to be of value in the
treatment of heroin and morphine addiction (Grosz, 1972) and the mode of action
may resemble that of apomorphine which is also used
successfully in sub-emetic doses in the treatment of various kinds of addiction
(Feldman, 1952, Martensen-Larsen, 1973).
Apart from this controlled study, we have had a great
deal of clinical experience in treating alcoholics as out-patients with
propranolol. The only notable side-effects at a dosage of 12s160 mg a day have
been bradycardia in a few cases and emesis. We have the impression that the
greater the tension symptoms the better the effect of propranolol. The same
clinical results are reported by (Drew et al., 1973). We have received reports
from patients of decreased craving for alcohol, but these may be due to a
placebo effect, as may be the reports of diminished euphoria during alcohol
intoxication. In mice propranolol is an inhibitor of ethanol-induced narcosis
(Smith et al., 1970). We also have the impression that 10 mg capsules of apomorphine are of value in the treatment of alcohol
addiction.
In conclusion, there is reason to believe that there
is a system of beta adrenergic receptors in the central nervous system. This
system seems to be involved in both the satisfaction of drives (reward) and
tension symptoms (the defence-alarm reaction).
Propranolol has effects on the CNS which could explain its action in essential
hypertension, formerly believed to be mainly peripheral. It is possible that
propranolol could be of value in the treatment of various kinds of addiction,
perhaps in each through an effect on a beta receptor mechanism in the central
nervous system. Of course the effects on CNS by propranolol can be explained in
other ways, i.e. propranolol is an inhibitor of aldehyde dehydrogenases
(Duncan, 1973) and this may influence amine metabolism.
References
AHLENIUS, S. et al. Antagonism by alfa-methyltyrosine
of the ethanol-induced stimulation and euphoria in man. Clin. Pharmacol. Ther. 14, 586-592, 1973.
ARBUTHNOTT, G. et al. Central
catecholamine turnover and self-stimulation behaviour. Brain Research 27,406413, 1971.
ATSMON, A. et al. The short-term
effects of adrenergic-blocking agents in a small group of psychotic patients.
Psychiat.
Neurol. Neurochir. 74, 251-258,
1971.
ATSMON, A. et al. Further studies
with propranolol in psychotic patients. Psychopharmacol. (Berl.) 27, 249-254,1972
CARLSSON, A., MAGNussoN, T.,
SVENSSON, T. H. and WALDECK, B. Effect of ethanol on the metabolism of brain catecholamines. Psychopharmaeol.
30, 27-36, 1973.
CARLSSON, C. Haemodynamic
effects of adrenergic beta-receptor blockade in the withdrawal phase of
alcoholism. Int. 7. Clin. Pharmacol., Beiheft 3, 61-63, 1969.
CARLSSON, C. and JOHANSSON, T. The psychological
effects of propranolol in the abstinence phase of chronic alcoholics. Brit. 7. Psychiat. 119, 605-606, 1971.
CROWN, S. and CRISP, A. H. A. A short clinical diagnostic self-rating scale for
psychoneurotic patients. Brit. J. Psychiat. 112, 917-923, 1966.
DREW, L. R. H. et al. Inderal (propranolol) in the
treatment of alcoholism. Med j~. Aust.
2, 282-285, 1973.
DUNCAN, R. J. S. The inhibition of
alcohol and aldehyde dehydrogenases by propranolol. Mol. Pharmacol.
9, 191-198, 1973.
FELDMAN, H. Le
traitement de l'alcoolisme chronique par l'apomorphine. Etude de 500 cas.
Schwei2erische Rundschau f ur Medi2in 40, 871-874, 1952.
FITZGERALD, J. D. and O DONNELL, S. Pharmacology of
4-hydroxy-propranolol, a metabolite of propranolol. J. Pharmac. 43, 222-235,
1971.
__________________________________________________________________________________________
326 Carl Carlsson
GALLANT, D. M. A controlled evaluation of propranolol in chronic alcoholic
patients presenting the symptomatology of anxiety and tension. i. Clin. Pharmacol. 13, 41-43, 1973.
GARDOS, G. CNS effects of propranolol in man. Psychopharmacol. 29, 299-306, 1973.
GOUGH, H. J. The adjective check
list as a personality assessment research technique. Psychological
Report 6, 107-122, 1960.
GROSZ, H. J. Narcotic withdrawal symptoms in heroin
users treated with propranolol. Lancer, Sept. 16, ii,
564-566, 1972.
JELLINEK, E. M. The disease of conept of alcoholism. Hillhouse
Press. New Haven, Connecticut, 1960.
MARTENSEN-LARSEN, O. Personal communication, 1973.
SANDLER, J. Patterns of anxiety: the correlates of
social anxieties. Brit. i. Med.
Psychol. 31, 24-31, 1958.
SCHLATTER, E. K. E. and SAMARTHJI LAL, M B. Treatment
of alcoholism with Dent s oral apomorphine method. Quart. 7. Stud. Alc. 33,
430-436, 1972.
SMITH, A. et al. Inhibition by propranolol of
ethanol-induced narcosis. ,7. Pharm. Pharmac. 22, 644-645, 1970.
STEIN, L. and WISE, C. D. Possible etiology of
schizophrenia: progressive damage to the noradrenergic reward system by
6-hydroxydopamine. Science 171, 1032-1036, 1971.
STEIN, L. and WISE, C. D. Amphetamine and
noradrenergic reward pathways. Frontiers
in Catecholamine Research (edited by Usdin, E. and
Snyder, S.), Pergamon Press, N.Y., 963-968, 1973.
WALSH, M. J. and DAVIS, V. E. Alcohol, amines, and
alkaloids: a possible biochemical basis for alcohol addiction. Science 167, 1055-1066, 1970.
ZUNG, W. W. K. A self-rating depression
scale. Arch. Gen. Psychiat. 12,
63-70, 1965.
Requests for reprints should be addressed to Carl Carlsson, Nordhemspolikliniken,
Fjarde Langgatan 7 A, 413 05
Gothenburg, Sweden.
_____________
A double-blind cross-over study: apomorphine/placebo
in chronic alcoholics
by C. Carlsson, P. R. Johansson, B. Gullbergt
Nordhemspolikliniken, Gothenburg, Sweden
The Psychological Effects of Propranolol in the
Abstinence Phase of Chronic Alcoholics
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