International Journal of

Clinical Pharmacology and

Biopharmacy

Sonderdruck

Carlsson C, et al. Int J Clin Pharmacol Biopharm. 1977.

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(This document has been sent to me by Dr Carlsson, so there's no problem of copyright)

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Carlsson et al.: Apomorphine in chronic alcoholics

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Apomorphine/Placebo - chronic alcoholics

A double-blind cross-over study:

apomorphine/placebo in chronic alcoholics

C. Carlsson, P. R. Johansson, B. Gullbergt

Nordhemspolikliniken, Gothenburg, Sweden

In a double-blind study in chronic alcoholics apomorphine was shown to have a significant effect on alcoholic crax g and on tension. The effect on depression approached, but did not reach, statistical significance. Theoretical aspects are discussed.

Apomorphine, a dopamine agonist, has been used for 75 years in small non-emetic doses to treat the acute alcohol intoxication phase of chronic alcoholism. The drug has been claimed to have sedative properties and to decrease the craving for alcohol [5]; furthermore, it has been used as an emetic in aversion therapy. Lal and Schlatter [4] reported that apomorphine decreased the craving for alcohol when administered to hospitalized patients and recently Buus et al. [1] found in a double-blind study that a group of alcoholics were statistically significantly more sober the day after apomorphine administration than a similar group receiving chlordiazepoxide or placebo.

Apomorphine is a difficult drug to study. It is rapidly metabolized by the liver and the dosage required to produce an emetic effect varies from subject to subject.

In broad clinical experience we have found that capsules of 20 mg apomorphine in lactose seem to be a good sedative for chronic alcoholics. Very few alcoholics seem to develop emesis on this dose, but it appears to have an effect on the craving and tension symptoms. We were therefore very interested to conduct a double-blind study.

Subjects

Twenty chronic alcoholics in an open ward in a special alcoholism treatment center entered the study. They all had passed the abstinence phase. All of them were chronic alcoholics from the medical point of view (gamma alcoholics according to the classification of Jellinek) and this implies alcohol addiction. The age of the patients ranged from 27 to 54 years. All were voluntary patients and the only other drugs administered were, if necessary, short-acting sedatives (1 g acetylglycinamidchloral, Ansopal) at night.

Methods

The study had a double-blind cross-over design. The patients were treated for a period of 14 days and received either capsules containing lactose (placebo) or 20 mg apomorphine hydrochloride in lactose. One capsule was given three times a day. After the study a representative sample of apomorphine capsules were analyzed. The activity was at least 17.5mg apomorphine. A simple questionnaire was used each day during the study; each patient was asked four questions about 1 hour after the morning dose:

1. ("Tension") Do you feel more, equally or less nervous today than you used to do ?

2. ("Depression") Do you feel more, equally or less depressed today than you used to do ?

3. ("Craving") Do you long more, equally or less for alcohol today than you used to do ?

4. ("Sleep") Have you slept better, equally or worse tonight than you used to do ?

Drinking episodes, side-effects, consumption of sleeping pills were also registered.

The need of sleeping tablets (acetylglycerinamidchloral 1 g, Ansopal) was greater during the first period than

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Side-effect apomorphine placebo

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Nausea 5 3

Vomiting 1 -

Diarrhea 4 2

Vertigo 1 3

Sweating 2 3

Dysphoria 1 1

Tiredness 2 -

Bad appetite 6 - (pa = 0.016, one-tailed test)

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Table 1. Side-effects, number of reported occurences.

l Statistic analysis, University of Lund, Sweden.

Int. J. Clin. Pharmacol. 15 (1977), 211-213

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Carlsson et al.: Apomorphine in chronic alcoholics

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*14 + 14 days. ** + = Improvement, scores. Table 2. comparison of effects of apomorphine or placebo (20 mg 3 times daily) in a double-blind, cross-over study> of 20 chronic akoholics.

Lost days Tension Depression Craving Sleep Apomorphine,239 days 41 + **112 + 99 + 97 + 93 Placebo, 246 days 34 + 70 + 62 + 69 + 99 Statistical analysis Tension : apomorphine better than placebo, p = 0.048 Depression: apomorphine better than placebo, p = 0.066 Craving : apomorphine better than placebo, p = 0.012

during the second and about equal for apomorphine and placebo groups. During the second period statistically significantly more patients on placebo needed sleeping tablets (p=0.029, Fischer's one-tailed test). There were few side-effects (Table 1).

Results

The results are summarized in Table 2. Apomorphine has a highly significant effect on craving, a significant effect on tension, and the effect on depression nearly reaches significance.

Discussion

The results from the present double-blind cross-over study revealed that apomorphine decreased "craving" and tension significantly and that it had a slight but significant effect on depression. The lack of difference between effects on sleep could be due to higher consumption of sleeping tablets in the placebo group. The main purpose was to investigate the effect of apomorphine on the symptom of "craving" for alcohol in alcoholics, as phrased by the question: "Do you long for alcohol more, equally or less today than you used to do?" Apomorphine does reduce this craving in chronic alcoholics and thus the present findings are in agreement with those of earlier studies. It is unlikely that this effect is due to some kind of aversion therapy. The mode of action of this anti-craving effect of apomorphine remains to be elucidated. It is interesting that in animal experiments it has been found that apomorphine in doses which are more or less inactive can block the central stimulant action of morphine, amphetamine, oor ethanol. There is much evidence that alcohol has a central stimulant action, resembling amphetamine (for a review, see [3]). The present study provides further support for such a hypothesis.

There is a theory from Walsh and Davies that in the brain an alkaloid, tetrahydropapaveroline, derived from dopamine is formed in the presence of alcohol.

This alkaloid is also found in opium and is the precurser of morphine (Walsh and Davies, 1972). Our finding that apomorphine has effects on chronic alcoholism could perhaps give some support even to such theories.

In an early study Carlsson and Johansson found anxiolytic effects of propranolol in chronic alcoholics and later Carlsson and Fasth showed that all significant differences between propranolol and diazepam were in favor of propranolol in a double-blind cross-over study in chronic alcoholics. The effect of propranolol and apomorphine may be similar as clinically we have found a strong potentiation of the hypotensive effect of propranolol by apomorphine. There is a chemical relationship between transmitter substances in the brain, apomorphine and propranolol. For a review see [2]. From the practical point of view, apomorphine may be a good drug in the treatment of alcoholism. There is, however, the theoretical possibility of abuse if the emetic effect is blocked. In this case apomorphine may have central stimulating effects and may act on post-synaptic receptors. A further problem is posed by the rapid metabolism of the drug; occasionally it is used in Linguletters but this form of administration cannot conceal the distinctive taste and makes double-blind studies impossible. It is also unstable and perhaps different results in different studies are partly due to this. In our study there was a decrease in activity up 12.5% during the trial; this is somewhat high but was considered reasonable.

In the propranolol studies we used more sophisticated questionnaires with many questions [2]. However, such questionnaires have a strong tendency to measure how the patients used to be, not how they are at that moment. There is also a strong tendency to give similar answers to the same questions each time. We found it better to ask simpler questions more often, in fact daily. We think it is impossible to conduct a broad study in a few patients due to statistical difficulties.

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References

1. Buus, S., Christofferssen, A. Nörregaard: Apomorfin anvendt i rus og abstinensbehandling. Ugeskr. Laeg. 136 (1974), 1808.

2. Carlsson, C.: Propranolol in alcoholism: Advances in clin. pharmacol., vol. 12. Urban & Schwarzenberg, Munchen-BerlinWien 1976.

3. Engel, J., A. Carlsson: Catecholamines and behaviour. In: Valjelli, L., W.B. Essman (Ed.): Current developments in psychopharmacology, vol. 4. Spectrum Publ. Inc., New York 1976.

4. Lal, S., E. K. E. Schlatter: Treatment of alcoholism with Dent's oral apomorphine method. Quart. J. Stud. Alc. 33 (1972), 435.

5. Martensen-Larssen, O.: Pers. commun. 1976.

For the authors: C. Carlsson, Nordkempspolikliniken, Nordkemsg. 23, 41305 Goteborg, Sweden.

Int. J. Clin. Pharmacol. 15 (1977), 211-213 (No.5)

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A Comparison of the Effects of Propranolol and Diazepam in Alcoholics

by Carl Carlsson M.D. and Bengt-Goran Fasth Ph.D.

Documents from Doctor Carl Carlsson / Documents du docteur Carl Carlsson

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