2074 Current Pharmaceutical Design, 2010, Vol. 16, No. 19
Pharmacotherapy of Alcohol Dependence
Pharmacotherapy of Alcohol Dependence: Past, Present and Future Research Lorenzo Leggio1,2 & Giovanni Addolorato2 1 2
Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA; E-mail:
[email protected] Institute of Internal Medicine, Catholic University of Rome, Rome, Italy; E-mail:
[email protected] Abstract: Alcohol dependence represents a chronic, relapsing condition with a multifactorial aetiology that includes genetic, neurobiological, psychological, and environmental components. Evidence for the effectiveness of medications in alcohol dependence treatment along with the increased number of compounds available is increasing the use of adjunctive pharmacotherapies. In particular, pharmacotherapies could conceivably address some of the biological aspects of alcohol dependence. Treating a complex behavioral disorder such as alcohol dependence with both pharmacotherapy and psychosocial therapy may give people the best options for recovery. To address the exciting developments in the use of pharmacotherapies for alcohol dependence, we planned this special issue for Current Pharmaceutical Design, entitled “Old and new pharmacotherapies in the management of patients with alcohol dependence”. The overall purpose of this special issue is to provide a resource, that researchers and clinicians interested in the pharmacotherapy of alcohol dependence may use, as well as to stimulate how current findings and ongoing research may improve the treatment of our alcohol-dependent patients.
Alcohol use disorders (AUDs) - alcohol abuse and alcohol dependence - are among the most prevalent illnesses in our society and causes serious morbidity and mortality, increased health care costs and lost work hours [1]. Thus, AUDs have a significant social impact and the prevalence of AUDs and the associated morbidity are similar to other common psychiatric disorders (e.g. major depression and anxiety disorders). Furthermore, the financial cost of AUDs is considerable and similar to the costs of other common medical problems, such as cardiovascular diseases and diabetes. In the last decades, thinking about AUDs has been changing significantly (see also Table 1). Although there is still some reluctance to see alcohol dependence as a medical problem, there is more awareness that alcohol dependence represents a chronic, relapsing condition with a multifactorial aetiology that includes genetic, neurobiological, psychological, and environmental components [2-4]. In this regard, alcohol dependence, as well as other addictive disorders, is similar to other “medical” illnesses (e.g. asthma and type 2 diabetes), in which there are both biological (e.g. genetic) and behavioural (e.g. psychosocial) causes and for which the ideal treatment combines both biological (usually pharmacological) and psychosocial treatments [5,6]. However, at present, treatments for AUDs are mostly psychosocial interventions, conducted outside medical settings and not effective for everyone. Nevertheless, the evidence for the effectiveness of medications in alcohol dependence treatment along with the increased number of compounds available Table 1.
Changing Attitudes about Alcohol Dependence.
The Past: - Alcohol dependence as a moral failing - Behavior to be punished - Treatment is predominately non-medical The Future: - Alcohol dependence as a brain disease (similar to other psychiatric disorders) - Support for a genetic predisposition - Exposure of the brain to alcohol produces long-lasting and/or permanent changes in neuronal gene expression and neurotransmitters - alcohol dependence treatment is integrated into the medical system The Present: somewhere in-between
is increasing the use of adjunctive pharmacotherapies. In particular, pharmacotherapies could conceivably address some of the biological aspects of alcohol dependence. Treating a complex behavioral disorder such as alcohol dependence with both pharmacotherapy and psychosocial therapy may give people the best options for recovery. To address the exciting developments in the use of pharmacotherapies for alcohol dependence, we planned this special issue for Current Pharmaceutical Design, entitled “Old and new pharmacotherapies in the management of patients with alcohol dependence”. In the first article of this series, Henning Krampe, PhD, and Hannelore Ehrenreich, MD, from the Charité University of Berlin and the Max Planck Institute of Experimental Medicine, respectively, discuss the use of disulfiram [7]. Disulfiram represents the first medication approved by the Food and Drug Administration (FDA) for alcohol dependence. As highlighted by their title (“Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment”), Drs Krampe and Ehrenreich discuss how disulfiram can be used in clinical settings to treat alcohol-dependent patients [7]. The second article by James Garbutt, MD, from the University of North Carolina at Chapel Hill, focuses on naltrexone, including both alcohol dependence studies testing the well-known oral formulation as well as the more recent intramuscular formulation [8]. In the third article, Falk Kiefer, MD, and Karl Mann, MD, from University of Heidelberg, review and discuss “how, where, and for whom” acamprosate works in alcohol dependence [9]. Together with disulfiram and naltrexone, acamprosate is approved in US and in some European countries, as a pharmacological treatment for alcohol dependence. Then, our special issue moves forward to discuss more recent pharmacotherapies, which are under investigation and not approved for alcohol dependence. One of the most studied new medications is topiramate, the use of which in alcohol dependence is discussed by Bankole Johnson, DSc, MD, PhD, and Nassima Ait-Daoud, MD, from the University of Virginia [10]. The next article, by our group, discusses the studies performed by our and other groups with baclofen in alcohol dependence [11]. A variety of studies have also tested other GABAergic medications in alcohol dependence (e.g. gabapentin, carbamazepine and others), reviewed in the next article by Fabio Caputo, MD, PhD, and Mauro Bernardi, MD, from the “SS Annunziata” Hospital of Cento (Ferrara) and the University of Bologna, respectively [12]. Medications acting on the serotonergic system, such as ondansetron, holds promise to treat at least a sub-
Pharmacotherapy of Alcohol Dependence
type of alcoholics, as discussed in the next article by George Kenna, PhD, RPh, from Brown University [13]. Recent research is also focusing on drugs working – either directly or indirectly – in the dopaminergic system, as discussed in the article by Robert Swift, MD, PhD, from Brown University [14].
Current Pharmaceutical Design, 2010, Vol. 16, No. 19
ence Publishers for their assistance in coordinating the publication of this special issue of the journal. REFERENCES [1]
Together, all of the articles listed above reflect the growing interest in testing more and more medications, which may help alcoholics to quite or at least reduce harmful alcohol consumption. As expected for any kind of pharmacotherapy in Medicine, these reviews also provide evidence that most of the medications have not provided positive results in some trials. This aspect, however, does not represent a failure. Indeed, this aspect does suggest that there is a need not only to test pharmacotherapies for alcohol dependence, but also – and more importantly – to understand who is the best alcohol-dependent patient that can benefit from a specific medication. We need to move to a personalized approach to treat alcohol dependence [15,16]. We know that no all alcoholics are the same and therefore, different patients may benefit from different medications [17]. On this regards, studies on pharmacogenetics of alcohol and alcohol dependence treatment represent an important gain in knowledge, as discussed in the next article by Henry Kranzler, MD, and Howard Edenberg,PhD, from the University of Connecticut Health Center and the Indiana University School of Medicine, respectively [18]. Furthermore, we also need to better understand not only if a pharmacotherapy works, but also how such a pharmacotherapy works. On this regards, human laboratory studies may shed the light on the biobehavioral mechanisms how pharmacotherapies for alcohol dependence work, as discussed by Lara Ray, PhD, Kent Hutchison, PhD and Molly Tartter, BA from the University of California Los Angeles (Dr. Ray and Ms. Tartter) and the University of New Mexico (Dr. Hutchison) [19]. Finally, there is an amazing and growing amount of preclinical research on a variety of new possible pharmacotherapy targets, which may turn into developing new medications for alcohol dependence. This preclinical research, and some related human studies, are the focus of the last review – authored by our group - of this special issue [20].
[2]
The overall purpose of this special issue is to provide a resource that researchers and clinicians interested in the pharmacotherapy of alcohol dependence may use and to stimulate how current findings and ongoing research may improve the treatment of our alcoholdependent patients.
[15]
[3] [4]
[5]
[6]
[7] [8] [9]
[10] [11]
[12] [13]
[14]
[16] [17]
ACKNOWLEDGEMENTS We would like to thank all of the contributing authors for their outstanding articles submitted for this special issue. We also would like to thank all of the anonymous reviewers who kindly reviewed the articles of this special issue. Finally, we would also like to thank the Editor-in-Chief Dr. William A. Banks, MD, the Editorial Director Mr. Mirza Kazim Ali Baig and, the Editorial Assistant Mr. Aamer Muhammad Khan, and the staff members of Bentham Sci-
2075
[18] [19] [20]
Room R, Babor T, Rehm J. Alcohol and public health. Lancet 2005; 365(9458): 519-30. Koob GF. The neurobiology of addiction: a neuroadaptational view relevant for diagnosis. Addiction 2006; 101(Suppl 1): 23-30. Koob GF. Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 2006; 27: 232-43. Addolorato G, Leggio L, Abenavoli L, Gasbarrini G; Alcoholism Treatment Study Group. Neurobiochemical and clinical aspects of craving in alcohol addiction: a review. Addict Behav 2005; 30: 1209-24. McLellan AT, Lewis DC, O'Brien CP, Kleber HD. Drug dependence, a chronic medical illness, implications for treatment, insurance, and outcomes evaluation. JAMA 2000; 284: 1689-95. Swift RM, Leggio L. Adjunctive pharmacotherapy in the treatment of alcohol and drug dependence. In: Peter Miller Ed. Evidencebased addiction treatment. Chapter 17. USA: Elsevier 2009; pp. 287-310. Krampe H, Ehrenreich H. Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Curr Pharm Des 2010; 16(19): 2076-90. Garbutt JC. Efficacy and tolerability of naltrexone in the management of alcohol dependence. Curr Pharm Des 2010; 16(19): 2091-7. Kiefer F, Mann K. Acamprosate: how, where, and for whom does it work? Mechanism of action, treatment targets, and individualized therapy. Curr Pharm Des 2010; 16(19): 2098-102. Johnson BA, Ait-Daoud N. Topiramate in the new generation of drugs: efficacy in the treatment of alcoholic patients. Curr Pharm Des 2010; 16(19): 2103-12. Addolorato G, Leggio L. Safety and efficacy of baclofen in the treatment of alcohol-dependent patients. Curr Pharm Des 2010; 16(19): 2113-17. Caputo F, Bernardi M. Medications acting on the GABA system in the treatment of alcoholic patients. Curr Pharm Des 2010; 16(19): 2118-25. Kenna GA. Medications acting on the serotonergic system in the treatment of alcoholic patients. Curr Pharm Des 2010; 16(19): 2126-35. Swift RM. Medications acting on the dopaminergic system in the treatment of alcoholic patients. Curr Pharm Des 2010; 16(19): 2136-40. Addolorato G, Abenavoli L, Leggio L, Gasbarrini G. How many cravings? Pharmacological aspects of craving treatment in alcohol addiction: a review. Neuropsychobiology 2005; 51: 59-66. Leggio L. Understanding and treating alcohol craving and dependence: recent pharmacological and neuroendocrinological findings. Alcohol Alcohol 2009; 44: 341-52. Leggio L, Kenna GA, Fenton M, Bonenfant E, Swift RM. Typologies of alcohol dependence. From Jellinek to genetics and beyond. Neuropsychol Rev 2009; 19: 115-29. Kranzler H, Edenberg, HJ. Pharmacogenetics of alcohol and alcohol dependence treatment. Curr Pharm Des 2010; 16(19): 2141-8. Ray LA, Hutchison KE, Tartter M. Application of human laboratory models to pharmacotherapy development for alcohol dependence. Curr Pharm Des 2010; 16(19): 2149-58. Leggio L, Cardone S, Ferrulli A, Kenna GA, Diana M, Swift RM, Addolorato G. Turning the clock ahead: potential preclinical and clinical neuropharmacological targets for alcohol dependence. Curr Pharm Des 2010; 16(19): 2159-81.
