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Alcohol & Alcoholism Vol. 45, No. 2, pp. 214–216, 2010 Advance Access publication 18 January 2010 Disulfiram, an Option for the Treatment of Pathological Gambling? Jochen Mutschler1,3,*, Mira Bühler1, Martin Grosshans1, Alexander Diehl2, 1Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Square J 5 68159 Mannheim, Germany, 2Department of Psychiatry, Klinikum Braunschweig, Salzdahlumer Str. 90, Braunschweig, Germany and 3University Hospital Zurich, Department of General and Social Psychiatry, Militärstrasse 8, P.O. Box 1930, CH-8021 Zürich *Corresponding Author: University Hospital Zurich, Department of General and Social Psychiatry, Militärstrasse 8, P.O. Box 1930, CH-8021 Zürich, Switzerland.
Tel: +41-(0)44-296-7393; Fax: +41-(0)44-296-7469; E-mail: (Received 21 September 2009; in revised form 9 November 2009; accepted 24 December 2009) Abstract — Aim: Pathological gambling and comorbid alcohol dependence often occur in combination. Disulfiram is one of theproven drugs for alcohol dependence. In addition to its inhibiting acetaldehyde dehydrogenase, disulfiram inhibits dopamine β-hydroxylase and may thereby increase dopamine and decrease norepinephrine cerebral concentrations. Because there may becommon neurochemical substrates and neuronal circuits for pathological gambling and addiction, we wished to explore the effectof disulfiram in gambling. Method: We describe the outcome of a patient with alcohol dependence and pathological gamblingtreated with disulfiram D. Results: During treatment with disulfiram, the patient reported that his desire to gamble disappearedentirely. Follow-up indicated that he has not gambled for >12 months. Conclusions: Although uncontrolled case observations should be interpreted with caution, disulfiram deserves further investigation in pathological gambling.
Recent evidence indicates that similar mechanisms are in- volved in PG and drug addiction. Neuroimaging data suggest Pathological gambling (PG) is a public health problem char- that in PG and drug addiction, the same brain areas are in- acterized by recurrent and pathological patterns of gambling.
volved. Reduced activity in the ventral striatum and the PG is associated with a range of social and psychological pro- ventromedial and ventrolateral prefrontal cortex has been re- blems like high rates of bankruptcy, divorce, suicide and ported in PG, which is also a hallmark of drug addiction reduced quality of life. Although the lifetime prevalence rate of pathological gambling in the German population is 0.2– gamblers found that gambling elevated dopamine levels in 0.4%, it often remains unrecognized and, therefore, untreated problem gamblers more than in healthy controls ( ). The mesocorticolimbic dopaminergic system has gambling and other psychiatric disorders are very common. In been found to be implicated in rewarding and reinforcing be- particular, high comorbidity rates have been reported between haviours. It has been suggested that PG might be related to a PG and drug dependence. Rates vary from 34 to 80% for sub- deficiency of the mesocorticolimbic dopaminergic reward sys- stance use disorders (excluding tobacco) (; tem, as has been shown for drug addiction.
Another hallmark of drug addiction that also holds for path- dependent patients is at least three times higher than in the ological gambling is the inability to inhibit inappropriate general population ). In cocaine-dependent responses. Accumulating evidence points towards an impor- patients, lifetime comorbidity rates have been reported that tant role of brain dopamine and noradrenergic systems in are even five times higher as in the general population ( impulsive behaviour. The inferior frontal gyrus is critically in- These observations suggest that common patho- volved in response inhibition and might be particularly physiological factors might underlie PG and drug addiction.
impacted by the brain’s noradrenergic system.
However, this hypothesis is not proven yet.
Other preclinical studies suggest that engaging in casino gam- PG is currently classified as an ‘impulse control disorder bling elevates activity of the hypothalamic–pituitary axis in (ICD) not elsewhere categorized’ in the DSM, although the problem and non-problem gamblers, as indicated by increased current diagnostic criteria indeed share many features with plasma levels of norepinephrine, cortisol and increased heart those for drug dependence, including (i) continued engage- rate. Roy and colleagues found higher levels of norepineph- ment in a behaviour despite adverse consequences, (ii) rine or its metabolites in urine, blood or cerebrospinal fluid diminished self-control over engagement in the behaviour, (iii) compulsive engagement in the behaviour and (iv) an ap- The similarities between PG and drug addiction suggest petitive urge or craving state prior to engaging in the that patients with pathological gambling may also benefit behaviour as well as tolerance and withdrawal ( from medication used for the treatment of drug addiction.
). Similarities between PG and drug dependence Pharmacotherapy research and validated treatment options include not only phenomenological criteria but also epidemi- for PG are limited. At the present time, there is no medication ological, clinical, genetic and neurobiological characteristics for treatment of PG that is approved by the Food and Drug Administration. Controlled clinical trials provide some evi- PG might best be characterized as a non-substance-related dence for beneficial effects of opiate antagonists (naltrexone or behavioural addiction with a compulsive urge for a non- The Author 2010. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved Disulfiram in the Treatment of Pathological Gambling and selective serotonin reuptake inhibitors, which have hol had disappeared but that he surprisingly had no urge to been shown to reduce craving for gambling. Additionally, cog- nitive behavioural therapy has been shown to be an effective In conclusion, we found that, since initiating the supervised treatment for some patients with PG. However, all these thera- treatment with disulfiram, the patient has been abstinent from alcohol and gambling for >12 months.
Disulfiram is well known as a treatment for alcohol depen- dence (e.g. ; Disulfiram also helps in the treatment of cocaine addiction (; possibly by reducing cocaine craving by This case report suggests that disulfiram might provide treat- increasing neurotransmitter levels of dopamine and decreasing ment in PG. Disulfiram helps in the treatment of alcoholism, the norepinephrine levels by blocking the activity of the en- cocaine addiction, human cancers and fungal infections zyme dopamine beta hydroxylase (DBH) involved in the For more than half a century, disulfiram has been successfully used for alcohol aversion therapy (Disulfir- neurochemical disturbances have been reported in PG, disul- am’s pharmacokinetics have been extensively studied; it firam might not only be effective in the treatment of cocaine also has a good safety record (). It is a well- addiction but also in the treatment of PG ( known vicious circle that substance use may lead to more gambling and more gambling may lead to substance use. Per- We present a case in which a patient with PG and comorbid sonality traits like impulsivity and reward sensitivity may alcohol dependence was treated with disulfiram. We suggest contribute to excessive engagement in both behaviours.
that disulfiram has the potential to reduce craving and patho- In the presented case, the patient has abstained from alcohol consumption for >12 months now and, notably, he has notgambled either since treatment with disulfiram started. Onepossible explanation might be that the patient was abstinent from alcohol. However, it can be argued that the patient was treated for alcohol dependence several times, but PG Mr K. is a 48-year-old married male working as a part-time was never markedly affected. Furthermore, despite numerous nurse. His alcohol dependence developed 25 years ago. He previous detoxifications, the patient had never been treated also started problematic gambling at slot machines at around the same time. He met all of the criteria for PG according to Psychological aspects of the supervised disulfiram therapy DSM-IV and ICD-10 for ∼20 years. The patient has no crim- and the high placebo response rate seen in treatment studies of inal history, but has run up about 10,000 euros in debts due to pathological gambling may have contributed to the good clin- PG. Mr K is a smoker and nicotine-addicted but has never tak- ical outcome, and this is a methodological limitation of this He was treated for alcohol dependence for the first time However, we propose that a possible neurobiological con- ∼10 years ago. He has undergone 28 inpatient detoxifications.
tributant might be that disulfiram directly modulates reward In 2000, he had long-term residential treatment for alcohol de- sensitivity and craving for gambling by increasing the level pendence. Afterwards, he participated in a self-help group on of the brain chemical dopamine and decreasing the norepi- a regular basis but did not receive specific treatment for PG.
nephrine levels through blocking the activity of the DBH, He remained completely abstinent from alcohol for 6–7 months. However, he continued to gamble during those alco- , ). Most strikingly, these two neurotransmitter systems are thought to be altered in PG (; After the first contact with our team in 2008, he was treated for 5 weeks in our inpatient department, which specializes in The disappearance of the patient’s desire to gamble during addiction medicine. The treatment included behavioural ther- treatment with disulfiram points towards the potential of disul- apy as well as relapse prevention medication with disulfiram firam in reward modulation in PG, similar to that described in (dosage 500 mg/3 days per week). The patient tolerated the medication without any side effects (apart from short-term, ). Our preliminary clinical data support the hypothesis moderate fatigue at the beginning of the treatment).
that disulfiram affects the desire to gamble, thereby promoting After discharge from our inpatient treatment, we continued gambling abstinence. The possible involvement of DBH was treating the patient over a period of 12 months in our outpa- tient programme for chronic alcohol patients. The disulfiram Previous studies in drug-dependent patients and patients medication was supervised by a physician three times per with PG have shown that a combination of pharmacological week, establishing a therapeutic ritual with high frequency treatment in combination with psychosocial treatment meth- of short-term individual contacts. During this therapeutic rit- ods, group therapies or contingency management therapies ual, the therapist praised the patient for taking disulfiram and is more effective than either treatment alone ( for maintaining abstinence, thereby providing continuous rein- forcement of an alcohol-free lifestyle. Additionally, alternative the potential of combined treatment approaches using disulfi- coping skills were developed and breathalyzer tests to monitor ram and cognitive behavioural therapies are necessary.
abstinence from alcohol were conducted. Throughout this In summary, this report suggests that disulfiram might be treatment, the patient reported that not only craving for alco- a promising pharmacological agent in the treatment of PG.
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