The Changing Face of Alcoholism Treatment
By Markus Heilig, MD |
April 1, 2007
Dr Heilig is clinical director of the intramural research program at the National Institute of Alcohol Abuse and Addiction in Bethesda, Md. His laboratory uses translational approaches to develop new pharmacotherapies for alcohol dependence. Dr Heilig reports that he has no conflicts of interest concerning the subject matter of this article.
Topiramate is an antiepileptic agent with a complex pharmacology that includes antiglutamatergic effects.33 Two clinical studies showed topiramate(Drug information on topiramate) to decrease alcohol(Drug information on alcohol) use34 and reduce negative consequences of drinking.35 In this case, the preclinical literature is very limited and not consistent with the human data.36 It is presently difficult to assess whether topiramate will provide a useful addition to the treatment of alcoholism, since mechanistic understanding at the preclinical level is largely lacking, as is independent confirmation of clinical efficacy. Also, clinical management and tolerability are more challenging with topiramate than with current medications because it may cause language impairments (verbal fluency and word-finding difficulties).37,38
THE THIRD GENERATION
Animal models that reflect important aspects of alcoholism are a major catalyst for bringing about novel therapeutics. These models include genetically determined high alcohol preference, binge/intoxication type of drinking typical of early stages of alcoholism, neuroadaptive processes that evolve over time to recruit negative affect and increased sensitivity to stress and other such factors, and alcohol-associated cues that trigger relapse. The first compounds with documented clinical efficacy have initiated a bootstrapping process to evaluate the ability of animal models to predict clinically relevant outcomes.39,40
Using these models, more than a dozen novel mechanisms are currently being explored as candidates for new treatments. Two of these deserve particular mention because of their extensive preclinical validation and because molecules exist with potential for clinical development.
First, extensive animal work predicts that the predominant brain receptor for endogenous cannabinoids, the CB1 receptor, is a promising treatment target for alcoholism.41-44 A CB1 antagonist, rimonabant, has recently shown efficacy in reducing obesity and associated metabolic risk factors in the Rimonabant in Obesity studies.45 Rimonabant has recently been approved for treatment of the metabolic syndrome in Europe, and FDA approval is expected. Clinical efficacy for alcoholism by this or other CB1 antagonists remains to be demonstrated. A concern is a dose-dependent incidence of depressive symptoms observed with rimonabant. This may not be an issue in the treatment of obesity, since those effects are largely mediated by CB1 receptors in the liver46 and can be achieved with doses that yield low central receptor occupancy. However, therapeutic efficacy in alcoholism will require central actions. A decisive issue is, therefore, whether a dose window can be found in which this can be achieved with an acceptable tolerability and safety profile.
Second, corticotropin-releasing hormone (CRH) has long been known to mediate behavioral stress effects through extrahypothalamic mechanisms largely independent of its endocrine actions.47 More recently, it has become clear that the CRH system is recruited following a prolonged history of dependence and this system accounts for the long-term increase in negative affect and stress sensitivity in this state, as well as the up-regulated motivation to consume alcohol.48 Antagonists for the CRH1 subtype of CRH receptors selectively reduce alcohol self-administration in postdependent animals, but not in animals without a history of dependence.49 This reflects the fact that extrahypothalamic CRH systems are generally quiescent under baseline, unstressed conditions, in turn promising an attractive tolerability and safety profile for drugs that target them. Efforts to develop antagonists for the CRH1 receptor have long been frustrating, but important breakthroughs are currently being made.
Effective medications are now available for alcoholism, and additional breakthroughs are expected in the next decade. A major challenge is to deliver these treatments to patients.
US taxpayers fund alcohol research with almost half a billion dollars a year. This is an investment unparalleled by any other country and one that generates wonderful science. As inspiring as it is to be part of this effort, one has to ask the question: what point is there in investing in developing new treatments when those already available are not reaching patients who need them?
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