14. Dopaminergic compounds - clinical data
Editors: Spanagel, Rainer; Mann, Karl F.
Title: Drugs for Relapse Prevention of Alcoholism, 1st Edition
Copyright 2005 Springer
> Table of Contents > Dopaminergic compounds: clinical data
Dopaminergic compounds: clinical data
Gerhard A. Wiesbeck
Department of Substance Use Disorders, Psychiatric University Hospital, Wilhelm-Klein-Str. 27, 4025 Basel, Switzerland
Introduction
There is reliable evidence from animal research that alcohol, like other drugs of abuse, exerts its reinforcing effects by acting on the brain dopaminergic systems [1, 2, 3, 4 and 5]. Neuroadaptive transformations (sensitization) of these systems are considered to cause the transition from controlled to uncontrolled use of alcohol [6, 7].
It was assumed that the primary role of dopamine systems in reward is to mediate the so-called subjective pleasurable and hedonic effects of addictive drugs. This opinion was expressed most explicitly in the anhedonia hypothesis of dopamine function [8]. Others offered contradicting evidence in that dopamine systems do not mediate the pleasurable or euphoric effects. Rather sensitization-like persisting neuroadaptations of dopamine systems may result in a hyperactive reaction to the effects of drugs, even after long-term abstinence (incentive-sensitization hypothesis) [9]. Dopamine neurons seem to respond to salient stimuli and are thus involved in the anticipation of reward [1, 10].
There is increasing evidence from human studies implicating dopaminergic neurotransmission in alcohol dependence. For example, after the administration of apomorphine, which is a dopamine receptor agonist, maximal growth hormone (GH) response was significantly reduced in alcoholics who were two months abstinent, when compared to controls [11]. Additionally, only alcoholics with a positive family history for alcoholism (those with a biological loading) revealed an impaired dopamine receptor function [13]. Finally, relapsed alcoholics were characterized by a more blunted GH response to apomorphine than abstinent alcoholics, suggesting that a reduced sensitivity of dopamine receptors is associated with a higher risk for relapse [14].
There is additional evidence regarding the involvement of the brain dopaminergic systems in alcohol dependence from studies employing brain imaging techniques such as photon emission computed tomography (PECT) or positron emission tomography (PET) in humans [15]. For example, striatal dopamine D2 receptor density and affinity to dopamine were found to be reduced in alcoholics compared to controls [16]. This finding is supported by another PET study showing decreased dopamine D2 receptor availability in
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alcoholics [17]. PECT studies reported decreased striatal dopamine transporter densities in late-onset alcoholics [18] and interestingly, suggested a relationship between low striatal dopamine D2 receptor levels and the risk for early relapse in detoxified alcoholics [19].
Finally, there are genetic studies giving support to the implication of dopamine systems in alcoholism [20, 21]. For example, bromocriptine, a dopamine agonist, was reported to reduce craving selectively in alcoholics carrying the A1 allele of the dopamine D2 receptor gene [22] and recently it has been hypothesized that the D2 dopamine receptor gene is a reinforcement or reward gene for the effects of alcohol and other drugs of abuse [23]. Given this importance of dopamine in alcoholism, there is a legitimate interest in dopaminergic agents as treatments for alcohol dependence. Reports from animal studies suggest that dopamine agonists and antagonists both decrease alcohol consumption (see Chapter 15). The present chapter selectively reviews dopaminergic compounds experienced in human studies (Tab. 1). It discusses their putative mechanisms of action and their efficacy.
Table 1. Dopaminergic compounds tested in randomised, double-blind, placebo-controlled trials with an intention-to-treat analysis and outcome parameters related to abstinence | |||||||||||||||
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Lisuride
The ergot derivative lisuride is a dopamine agonist which exerts its activity primarily at postsynaptic dopamine D2 receptor sites. It also has weak dopamine D1 antagonistic as well as serotonin 5-HT1a agonistic effects. The substance is approved for the treatment of Parkinson's disease and hyperprolactinemia. Animal research and human studies on acute withdrawal suggested favorable effects in psychostimulant addiction as well [24, 25 and 26].
In a double-blind, placebo-controlled trial, 120 detoxified alcohol-dependent subjects were randomly assigned a low dose of lisuride (1.0 mg/day), a high dose of lisuride (1.8 mg/day) or placebo. Time-to-first-drink within six months of treatment was defined as the primary parameter of efficacy. In contrast to the original hypothesis, lisuride treatment significantly reduced the period of abstinence as compared to placebo (effect size: 0.51). Additionally, the authors
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found a significant effect of drug expectancy on outcome, with the best outcome in patients who were expecting lisuride but had received placebo [27].
In summary, there is only one randomized controlled trial on lisuride. It reports a significantly better outcome under placebo. Therefore, lisuride cannot be recommended for relapse prevention in alcoholics.
Tiapride
Tiapride is a benzamide derivative which is often categorized as an atypical neuroleptic. It selectively antagonizes dopamine D2 receptors while lacking affinity for dopamine D1 receptors. There are regional differences in the binding of tiapride within the central nervous system (CNS). The substance preferentially binds to extrastriatal receptors, particularly in the hippocampus. Tiapride is characterized by antidyskinetic properties as well as by anxiolytic effects that have been shown in several animal models, including those involving ethanol withdrawal [27].
Tiapride has demonstrated clinical efficacy in ameliorating symptoms of acute alcohol withdrawal [28, 29] and earlier reports suggested promising effects in alcohol relapse prevention as well [30, 31, 32 and 33]. However, due to their less rigorous methodology, the level of evidence of those early reports is limited.
In a double-blind, placebo-controlled trial, 100 detoxified alcohol-dependent subjects were randomly assigned to either tiapride (300 mg/day) or placebo. Tiapride proved significantly better than placebo in maintaining abstinence and in reducing alcohol intake on heavy drinking days, after both three and six months of treatment [34]. The authors did not apply an intention-to-treat analysis but restricted their statistical evaluation to solely studying completers. Regarding relapse prevention, their study's level of evidence is limited.
So far, there is only one study on tiapride using a rigorous methodology in combination with an intention-to-treat analysis. Here, 300 detoxified alcohol-dependent subjects were randomly assigned to either tiapride (300 mg/day) or placebo. Primary parameters of efficacy were time-to-first-drink and relapse rate after six months of double-blind treatment. The final result revealed no difference between tiapride and placebo treatment (Bender et al., personal communication).
In summary, earlier reports on tiapride are of poor quality and their positive results have not been confirmed by a study with a more rigorous methodology. So far, there is no convincing evidence for a superiority of tiapride to placebo in alcohol relapse prevention.
Bromocriptine
Bromocriptine, an ergot alkaloid derivative, is structurally related to dopamine and it activates postsynaptic dopaminergic receptors. Since bromocriptine has
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been used to treat Parkinson's disease for more than two decades, there exists broad clinical experience of this drug. Bromocriptine is classified as a potent dopamine D2 receptor agonist with partial dopamine D1 antagonist activity [35].
First experiences with respect to alcoholism were related to the treatment of withdrawal. Some authors suggested that the drug ameliorates withdrawal symptoms in chronic alcoholics, whilst others did not confirm these findings [36, 37]. Using bromocriptine as a challenge drug, [38] there was reported evidence for a reduced dopamine D2 receptor sensitivity in alcoholics.
The first study on relapse prevention was conducted in 50 chronic alcoholics using a double-blind, placebo-controlled design [39]. Oral bromocriptine (3 2.5 mg/day for 3 months, increased to 3 5 mg/day during months 4-6) reduced both craving and the number of patients drinking. However, alcohol consumption data were not reliably collected and the evaluation was solely restricted to completers.
Another study was performed so as to confirm and further extend these findings. In a double-blind, placebo-controlled trial, the dose of oral bromocriptine was gradually increased to 3 2.5 mg/day, and was given over a period of seven weeks. A total of 84 subjects were enrolled; however, the analysis of efficacy was restricted to only 38 treatment completers. Though there was a marked improvement in almost all parameters between baseline and the end of treatment, bromocriptine was not superior to placebo with respect to alcohol consumption, drinking days per week, craving or GGT activity [40].
Powell et al. [41] conducted a double-blind, placebo-controlled trial of nortriptyline and bromocriptine in 216 male alcoholics, who were subtyped into three groups according to the diagnosis (alcoholism only; alcoholism and affective/anxiety disorder; alcoholism and antisocial personality disorder). The only significant effect found, after six months of treatment, was with the antisocial personality disorder patients, who were receiving nortriptyline. In this group 64% of the trial completers remained sober (bromocriptine: 34%; placebo: 11%).
In a pharmacogenetic approach, bromocriptine (3 2.5 mg/day) or placebo were double-blindly administered to 83 alcoholics with either the A1 allele (A1/A1 and A1/A2 genotypes) or only the A2 allele (A2/A2 genotype) of the dopamine D2 receptor gene [21]. The greatest improvement in craving was reported in bromocriptine-treated alcoholics carrying the A1 allele, while attrition was highest in the placebo-treated A1 alcoholics. The study indicates that pharmacogenetic strategies for subtyping alcoholics may be useful for treatment trials. However, since abstinence was not the goal of this study, it hence does not shed light on the question of whether bromocriptine might, in fact, be useful for relapse prevention.
So far, there is only one study [42] attempting to answer that question, by using a randomized, double-blind, placebo-controlled design in combination with an intention-to-treat analysis: 366 alcohol-dependent subjects were assigned to one of three treatment groups (long-acting injectable preparations of bromocriptine 25 mg/month or 50 mg/month or placebo). The primary variables
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of efficacy were time-to-first-drink and time-to-relapse (defined as drinking on five days per month and three drinks per day) assessed after six months of treatment. The intention-to-treat analysis revealed no differences between placebo and any dose of bromocriptine. Relapse rates to any drinking were 73%, 71% and 76% (bromocriptine 25 mg, bromocriptine 50 mg, placebo), while relapse rates to heavy drinking were 35%, 42% and 38% (bromocriptine 25 mg, bromocriptine 50 mg, placebo).
In summary, earlier reports on bromocriptine suffer from methodological shortcomings and their data have not been conclusive. So far, there is no study demonstrating a superiority of bromocriptine to placebo in maintaining abstinence or in reducing alcohol consumption. Therefore, bromocriptine cannot be recommended for relapse prevention in alcoholism.
Flupenthixol
The thioxanthene neuroleptic flupenthixol is an antipsychotic drug that antagonizes dopamine binding at a number of receptor subtypes, primarily at D1, D2, D3 and with less affinity at D4 receptors. It also affects serotonin and noradrenaline binding [43]. Besides anecdotal reports and small-sample-size studies in cocaine addicts, there are only a few studies investigating flupenthixol treatment in alcoholism [44]. For example, a six-month treatment of 21 schizophrenic patients with comorbid alcoholism resulted in a significant reduction of alcohol consumption in the intra-individual pre-/post-treatment comparison [45].
So far, there is only one randomized, double-blind, placebo-controlled study in alcoholism. In this trial 281 alcohol-dependent women and men, without comorbid psychiatric disorder, received either 10 mg flupenthixol decanoate or placebo as intramuscular injections. Primary efficacy parameters, which were based on absolute abstinence, were rated after six months of active treatment as well as after another six-month follow-up period. Subjects treated with flupenthixol revealed a significantly higher relapse rate (85.2%) after six months than those treated with placebo (65.5%). Flupenthixol was also inferior to placebo regarding the cumulative abstinence duration and the relapse rate after 12 months [46].
Two re-analyses were then calculated using these data. The first was done according to the Lesch typology [47]. It revealed that the negative outcome under flupenthixol treatment was restricted to patients belonging to Type I and Type III, indicating the importance of specific patients' characteristics and their relevance for relapse [48, 49]. The second re-analysis, which was done according to sex, discovered a significant gender-related effect. While men had an almost four-fold higher risk to relapse under flupenthixol (odds ratio: 3.95), this risk was barely elevated in women (odds ratio: 1.51). That is, the unfavorable outcome under flupenthixol was restricted to male alcoholics [50].
In summary, there is only one double-blind, placebo-controlled trial with an intention-to-treat analysis and outcome variables based on abstinence.
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According to this study, flupenthixol treatment was associated with a significantly higher relapse rate as compared to placebo. Therefore, this substance cannot be recommended for relapse prevention in alcoholism.
References
1 Spanagel R, Weiss F (1999) The dopamine hypothesis of reward: past and current status. Trends Neurosci 22: 521-527
2 Olds ME (1990) Enhanced dopamine receptor activation in accumbens and frontal cortex has opposite effects on medial forebrain bundle self-stimulation. Neuroscience 35: 313-325
3 Samson HH, Hodge CW, Tolliver G et al. (1993) Effect of D1 and D2 dopamine agonists and antagonists on ethanol-reinforced behaviour: the involvement of the nucleus accumbens. Brain Res Bull 30: 133-141
4 Grace AA (2000) The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving. Addiction 95: S119-S128
5 Heinz A (2002) Dopaminergic dysfunction in alcoholism and schizophrenia - psychopathological and behavioural correlates. Eur Psychiatry17: 9-16
6 Hunt WA, Lands WEM (1992) A role for behavioural sensitisation in uncontrolled ethanol intake. Alcohol 9: 327-328
7 Robinson TE, Berridge KC (1993) the neural basis of drug craving: an incentive-sensitisation theory of addiction. Brain Res Rev 18: 247-291
8 Wise RA (1996) Neurobiology of addiction. Curr Opin Neurobiol 6: 243-251
9 Berridge KC, Robinson TE (1998) What is the role of dopamine in reward hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev 28: 309-369
10 Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275: 1593-1599
11 Balldin J, Berggren UC, Lindstedt G (1992) Neuroendocrine evidence for reduced dopamine receptor sensitivity in alcoholism. Alcohol Clin Exp Res 16: 71-74
12 Balldin J, Berggren UC, Lindstedt et al. (1993) Further neuroendocrine evidence for reduced D2 receptor function in alcoholism. Drug Alcohol Depend 32: 159-162
13 Wiesbeck GA, Mauerer C, Thome J et al. (1995) Alcohol dependence, family history and D2 dopamine receptor function as neuroendocrinologically assessed with apomorphine. Drug Alcohol Depend 40: 49-53
14 Heinz A, Dettling M, Kuhn S et al. (1995) Blunted growth hormone response is associated with early relapse in alcohol-dependent patients. Alcohol Clin Exp Res 19: 62-65
15 Volkow ND, Fowler JS, Wang GJ (2003) Positron emission tomography and single-photon emission computed tomography in substance use research. Seminars in Nucl Med 33: 114-128
16 Hietela J, West C, Syv lahti E et al. (1994) Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence. Psychopharmacology 116: 285-290
17 Volkow ND, Wang GJ, Fowler JS et al. (1996) Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin Exp Res 20: 1594-1598
18 Repo E, Kuikka JT, Bergstrom KA et al. (1999) Dopamine transporter and D2-receptor density in late-onset alcoholism. Psychopharmacology 147: 314-318
19 Guardia J, Catafau AM; Batle F et al. (2000) Stratal dopaminergic D2 receptor density measured by [(123)I]iodobenzamide SPECT in the prediction of treatment outcome of alcohol-dependent patients. Am J Psychiatry 157: 127-129
20 Sander T, Harms H, Podschus J et al. (1995) Dopamine D1-, D2-, and D3 receptor genes in alcohol dependence. Psych Genetics 5: 177-181
21 Thome J, Gerwitz JC, Weijers HG et al. (2000) Genome polymorphism and alcoholism. Pharmacogenomics 1: 63-71
22 Lawford BR, Young RM, Rowell JA et al. (1995) Bromocriptine in the treatment of alcoholics with the D2 dopamine receptor A1 allele. Nat Med 1: 337-341
23 Noble EP (2003) D2 Dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet 116B: 103-125
P.161
24 Pulvirenti L, Koob GF (1993) Lisuride reduces psychomotor retardation during withdrawal from chronic intravenous amphetamine self-administration in rats. Neuropsychopharmacology 8: 213-218
25 Pulvirenti L, Koob GF (1994) Dopamine receptor agonists, partial agonists and psychostimulant addiction. Trends Pharmacol Sci 15: 374-379
26 Gillin JC, Pulvirenti L, Withers N et al. (1994) The effects of lisuride on mood and sleep during acute withdrawal in stimulant abusers: a preliminary report. Biol Psychiatry 35: 843-849
27 Schmidt LG, Kuhn S, Smolka M et al. (2002) Lisuride, a dopamine D2 receptor agonist, and anticraving drug expectancy as modifiers of relapse in alcohol dependence. Prog Neuropsychopharmacol Biol Psychiatry 26: 209-217
28 Peters DH, Faulds D (1994) Tiapride - A review of its pharmacology and therapeutic potential in the management of alcohol dependence syndrome. Drugs 47: 1010-1032
29 Agricola R, Mazzarino M, Urani R (1982) Treatment of acute alcohol withdrawal syndrome with carbamazepine: a double blind comparison with tiapride. J Int Med Res 10: 160-165
30 Lepola U, Kokko S, Nuutila J et al. (1984) Tiapride and chlordiazepoxide in acute alcohol withdrawal. A controlled clinical trial. Int J Clin Pharmacol Res 5: 321-326
31 Bonnaffoux D, Jeanparis F, Bourgeat P et al. (1982) Follow-up treatment after alcohol withdrawal: results after two years in 200 cases. La Semaine des hopitaux de Paris 58: 2079-2081
32 Delamaire D, Carpentier MC, Eudier F et al. (1986) Essai ambulatoire du tiapridal apr s sevrage alcoholique hospitalier. Etude randomis e de cinquante et une h patopathies alcooliques en double insu. La Semaine des hopitaux de Paris 62: 3109-3114
33 Sabourin A (1985) Effects of various therapeutic procedures on maintenance of abstinence in alcoholic patients: a statistical analysis. La Semaine des hopitaux de Paris 61: 669-676
34 Shaw GK, Majumdar SK, Waller S et al. (1987) Tiapride in the long-term management of alcoholics of anxious or depressive temperament. Br J Psychiat 150: 164-168
35 Shaw GK, Waller S, Majumdar SK et al. (1994) Tiapride in the prevention of relapse in recently detoxified alcoholics. Br J Psychiat 165: 515-523
36 Borg V, Weinholdt T (1982) Bromocriptine in the treatment of alcohol withdrawal syndrome. Acta Psychiatr Scand 65: 101-111
37 Burroughs AK, Morgan MY, Sherlock S (1985) Double-blind controlled trial of bromocriptine, chlordiazepoxide and chlormethiazole for alcohol withdrawal symptoms. Alcohol Alcoholism 20: 263-271
38 Farren CK, Clare AW, Ziedonis D et al. (1995) Evidence for reduced dopamine D2 receptor sensitivity in postwithdrawal alcoholics. Alcohol Clin Exp Res 19: 1520-1524
39 Borg V (1983) Bromocriptine in the prevention of alcohol abuse. Acta Psychiatr Scand 68: 100-110
40 Dongier M, Vachon L, Schwartz G (1991) Bromocriptine in the treatment of alcohol dependence. Alcoholism: Clin Exp Res 15: 970-977
41 Powell BJ, Campbell JL, Landon JF et al. (1995) A double-blind, placebo-controlled study of nortriptyline and bromocriptine in male alcoholics subtyped by comorbid psychiatric disorders. Alcohol Clin Exp Res 19: 462-468
42 Naranjo CA, Dongier M, Bremner KE (1997) Long-acting injectable bromocriptine does not reduce relapse in alcoholics. Addiction 92: 969-978
43 Glaser T, Fassbender M, Mauler F (1998) Receptor binding of flupenthixol and other neuroleptics. PT06004, XXIst CINP Congress Glasgow
44 Schilkrut R, Cabrera J, Morales E et al. (1988) Neuroleptics in the treatment of drug dependence in schizophrenics: A study with flupenthixol decanoate. Psychopharmacology 96: 342
45 Soyka M, Aichmuller C, v Bardeleben U et al. (2003) Flupenthixol in relapse prevention in schizophrenics with comorbid alcoholism: results from an open clinical study. Eur Addict Res 9: 65-72
46 Wiesbeck GA, Weijers H-G, Lesch OM et al. (2001) Flupenthixol decanoate and relapse prevention in alcoholics: results from a placebo-controlled study. Alcohol Alcoholism 36: 329-334
47 Walter H, Ramskogler K, Semler et al. (2001) Dopamine and alcohol relapse: D1 and D2 antagonists increase relapse rates in animal studies and inclinical trials. J Biomed Sci 8: 83-88
48 Lesch OM, Benda N, B ning J et al. (1999) Alcohol dependent patients characteristics and their relevance for relapse prevention. Alcohol Alcoholism 34: 433
49 Lesch OM, B ning J, Wiesbeck GA et al. (2000) Patients' characteristics and their implications for specific treatment. Sucht 46: 343
50 Wiesbeck GA, Weijers H-G, Wodarz N et al. (2003) Gender related differences in pharmacological relapse prevention with flupenthixol decanoate. Arch Women's Mental Health 6: 259-262
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