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Editorial
August 23/30, 2000

Medications for Alcohol Dependence—New Vistas

Author Affiliations

Author Affiliation: Alcohol Research Center, University of Connecticut School of Medicine, Farmington.

JAMA. 2000;284(8):1016-1017. doi:10.1001/jama.284.8.1016

Since its approval by the Food and Drug Administration in 1949, the aversive agent disulfiram1 was, for nearly 50 years, the only drug approved in the United States to treat alcohol dependence. However, in 1994, the Food and Drug Administration approved naltrexone, an opioid antagonist, for that indication based largely on the results of 2 federally funded studies.2,3 The approval of naltrexone for alcoholism treatment has also increased interest on the part of the pharmaceutical industry in medications to treat alcohol dependence.

As a consequence of that increased interest, a number of compounds for alcoholism treatment are currently in clinical development in the United States. For example, acamprosate (calcium acetylhomotaurinate), an amino acid derivative that affects both γ-aminobutyric acid and excitatory amino acid (ie, glutamate) neurotransmission, has been studied in countries throughout Europe and is now in widespread clinical use there.4 Although the drug has not yet been approved for use in the United States, it is likely to become the third medication approved in this country for treatment of alcohol dependence.

The study of ondansetron by Johnson et al5 in this issue of THE JOURNAL is a direct outgrowth of an ambitious medications development program supported by the National Institute on Alcohol Abuse and Alcoholism. The current report is noteworthy for 2 reasons. First, the study shows a differential effect on alcohol consumption of the selective 5-HT3 (serotonin) antagonist as a function of age of alcoholism onset. This underscores the clinical relevance of a growing literature on the biological basis of alcohol dependence and its relationship to clinical subtypes. Second, the study exemplifies a potential role in alcoholism treatment for a medication with a well-defined mechanism of action, reinforcing the rational effort to identify medications to treat the disorder.6

Consistent with a literature supporting a role for serotonergic neurotransmission in the pathophysiology of alcohol dependence, particularly among patients with early onset of the disorder (ie, at age 25 years or younger),7 Johnson et al5 found a selective beneficial effect of ondansetron in this subgroup. Specifically, they found that at a dosage of 4 µg/kg twice per day, ondansetron was superior to placebo on the proportion of days abstinent (an increase of nearly 40% over placebo) and on the intensity of alcohol intake (a decrease of more than 39%) among study patients with early-onset alcoholism. Although these effects were based on self-report measures and were in the small range of effect sizes, they were validated by a more robust effect on levels of carbohydrate-deficient transferrin, an objective measure of alcohol consumption. Among study patients with late-onset alcoholism (ie, those with onset of alcohol dependence after the age of 25 years), the effects of ondansetron on drinking behavior were in nearly all respects comparable with those of placebo.

Early-onset alcoholism is characterized by a greater familial loading for alcoholism, more severe progression of the disorder, and a greater severity of comorbid psychiatric disorders, particularly antisocial personality disorder.8,9 Managing the care of such patients can be difficult. Consequently, if replicated, the findings reported by Johnson et al5 will have important clinical value. Together with 2 recent studies that showed differential effects of selective serotonin reuptake inhibitors among subgroups of alcoholic patients,10,11 the study by Johnson et al5 supports the clinical utility of subtyping prior to the initiation of pharmacological treatment. Based on these findings, ondansetron could be used to treat patients with early onset alcoholism,5 whereas a selective serotonin reuptake inhibitor might be used in patients with low-risk or low-severity alcoholism,11 a group that is characterized by late onset of alcohol dependence.8 Replication and extension of these findings is required, however, before this treatment matching strategy can be recommended clinically.

These findings also suggest a potential for the development of pharmacogenetic strategies to treat alcohol dependence. Identification of the genetic variation that mediates the differential medication effects in subgroups of patients with alcohol dependence (eg, in genes coding for the serotonin transporter or the 5-HT3 receptor proteins) may provide a basis for tailoring pharmacological treatments to individual patients. Rapid developments in genotyping technology promise to put the clinical application of this knowledge in the grasp of physicians12 who, working cooperatively with nonphysician therapists and counselors, can prescribe pharmacological and psychosocial treatments to meet the needs of their individual patients.13 Large-scale family studies of alcohol dependence have identified genetic loci that are linked to the disorder in humans,14 and the process of fine mapping these genomic regions is under way. Candidate gene studies in alcohol dependence, other than those involving alcohol metabolizing enzymes,15,16 have yielded equivocal findings.17-19 However, the sequencing of the human genome and the push for its annotation12 will provide continued impetus to identify genes that contribute to alcoholism risk and pharmacologic response. Refinements in the diagnosis of alcohol dependence and in the identification of biologically relevant subtypes (ie, "endophenotypes") of the disorder are likely to contribute substantially to this effort as well.7

More progress in basic and clinical sciences is required to sustain the pace of developments in the pharmacotherapy of alcoholism. Moreover, the introduction of new, efficacious medications will change the treatment system for persons with alcohol dependence. While the 12-month US prevalence of alcohol dependence is 4.4%,20 a figure that reflects a considerable market for effective medications, naltrexone has not been a commercial success in this country. This is, in large part, due to the disorder being underdiagnosed by physicians,13 which may reflect pessimism over the value of alcoholism treatment. Furthermore, when it is determined that intervention is warranted, the most common response by US physicians is to refer patients to Alcoholics Anonymous,13 where some alcoholics in recovery may manifest a bias against pharmacotherapy for alcoholism.

The growing interest by physicians in the diagnosis of major depression and of nicotine dependence appears, to a large degree, to be a response to the widespread availability of well-tolerated, efficacious medications to treat these disorders. New developments in the pharmacotherapy of alcoholism, of which the study by Johnson et al5 is a noteworthy example, promise to add alcohol dependence to that group of behavior disorders that can be effectively diagnosed and treated.

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