Harvard Mental Health Letter
April 2001

In Brief
Ondansetron for Alcoholics
Researchers at the University of Texas have found a potential new treatment for some alcoholic patients: ondansetron, an anti-nausea drug best known for its use in cancer chemotherapy. In a group of 271 alcoholic patients, equal numbers were given ondansetron (at three different doses) or a placebo twice daily for 2 1/2 months along with cognitive behavioral therapy. The outcome was judged by a blood test for excessive alcohol and by the reports of patients on their own symptoms. At the middle dose, ondansetron proved effective for one group of patients, those with early-onset alcoholism (before age 25) and a history of antisocial behavior. People with these characteristics may have a biological predisposition to alcoholism, and they often respond poorly to standard treatments. Ondansetron reduced their drinking to one-sixth of its previous level, and they were abstinent on 70% of days as compared with 50% of comparable patients taking a placebo. Unlike disulfiram (Antabuse), ondansetron does not alter the breakdown of alcohol in the body, so it is safer to take while drinking. In this study there were few side effects; about 5% of the patients developed constipation or a headache, rash, or racing heart.

The authors speculate that ondansetron changes the balance of activity among several neurotransmitters, especially dopamine and serotonin. In particular, it reduces activity at a certain serotonin nerve receptor; in animals, blocking this receptor has been found to reduce the consumption of alcohol. Early-onset alcoholics may carry a genetic variant of the receptor that makes them more vulnerable to alcohol addiction.

The blood test used in the study is a new one. It measures a substance called carbohydrate-deficient transferrin (CDT), which accumulates in the blood with sustained heavy drinking and persists at high levels for several weeks even after drinking stops. The FDA has recently approved the test: it will be given to patients in alcohol treatment centers at first but may eventually be used more widely.

Johnson BA et al. “Ondansetron for Reduction of Drinking among Biologically Predisposed Alcoholic Patients: A Randomized Controlled Trial,” JAMA (August 23/30, 2000): Vol. 284, pp. 963–71.

http://www.health.harvard.edu/medline/Mental/M401g.html

Furthermore:

Alcohol Clin Exp Res 2001 Jun;25(6):847-9 Related Articles, Books, LinkOut
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Combining ondansetron and naltrexone treats biological alcoholics: corroboration of self-reported drinking by serum carbohydrate deficient transferrin, a biomarker.

Ait-Daoud N, Johnson BA, Javors M, Roache JD, Zanca NA.

Department of Psychiatry and the Southwest Texas Addiction Research and Technology (START) Center, University of Texas Health Science Center at San Antonio, San Antonio 78229-3900, Texas, USA. tiouririne@uthscsa.edu

BACKGROUND: Recently, we showed by using self-report that combining ondansetron (4 microg/kg twice a day) and naltrexone (25 mg twice a day) was effective at reducing drinking and increasing abstinence among early-onset alcoholics (EOAs), who are characterized by a range of antisocial behaviors and high biological and familial disease predisposition. Here, we investigated whether the self-reported differences in drinking would be corroborated by measurements of serum carbohydrate-deficient transferrin (CDT) level, a sensitive, reliable, and well-validated marker of transient alcohol consumption. METHOD: An 8-week double-blind clinical trial was performed in which 20 EOAs were randomized to receive ondansetron (4 microg/kg twice a day) and naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized cognitive behavioral therapy. Serum CDT was assessed at weeks 0 (baseline), 4, and 8. RESULTS: Log serum CDT was significantly lower in the ondansetron and naltrexone group (group mean, 1.44 +/- 0.076) compared with the placebo group (group mean, 1.82 +/- 0.113), as evidenced by a main effect of group [F(1,15) = 7.2, p = 0.017; effect size = 0.32], visit [F(1,16) = 11.2, p = 0.004; effect size = 0.41], and an interaction between group and visit [F(1,16) = 27.54, p < 0.001; effect size = 0.63]. CONCLUSIONS: The combination of ondansetron plus naltrexone was superior to placebo at reducing serum CDT. This corroborated our self-reported drinking data and demonstrated that the medication combination is an effective treatment for EOAs.

Publication Types:
PMID: 11410720 [PubMed - indexed for MEDLINE]
 
Psychopharmacology (Berl) 2001 Feb;154(1):23-7 Related Articles, Books, LinkOut
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Combining ondansetron and naltrexone reduces craving among biologically predisposed alcoholics: preliminary clinical evidence.

Ait-Daoud N, Johnson BA, Prihoda TJ, Hargita ID.

Treatment Research Center, Department of Psychiatry, University of Texas, Health Science Center at San Antonio, 78229-3900, USA. tiouririne@uthscsa.edu

RATIONALE: Previously, we have reported that the combination of ondansetron (a 5-HT3 antagonist) and naltrexone (a mu opioid antagonist) appears to act synergistically at improving the drinking outcomes of early onset alcoholics (EOA). a subtype of alcoholic characterized by developing problem-drinking earlier, antisocial behaviors, high familial loading, and biological disease predisposition. Presumably, this medication combination counteracts the interaction between activated central 5-HT3 receptors and the endogenous opioid system during the mediation of alcohol-induced reward. We now hypothesize further that an important mechanism by which the combination diminishes alcohol consumption is through a reduction in craving. OBJECTIVE: To determine whether the combination of naltrexone and ondansetron is superior to a placebo at reducing craving among EOA, and the relationship between craving and drinking behavior in both treatment groups. METHODS: We conducted an 8-week double-blind placebo-controlled clinical trial in which 10 EOA were randomized to receive ondansetron (4 microg/kg b.i.d.) + naltrexone (25 mg b.i.d.) and 10 EOA had a placebo (total n=20) as an adjunct to weekly standardized group cognitive behavioral therapy. Craving was measured by using the obsessive compulsive drinking scale (OCDS). RESULTS: Craving ratings were scored on four subscales which where derived empirically by principal component structure analysis of the OCDS. EOA who received the medication combination, compared with the placebo, had significantly lower scores on "automaticity of drinking" and "alcohol consumption ". Reduction in automaticity of drinking was correlated with self-reported drinking for only the medication combination group. CONCLUSIONS: By reducing automaticity of drinking, the medication combination presumably decreased drinking salience and intensity. Larger scale studies testing these medications, both alone and together, among alcoholic subtypes are needed to establish and extend these promising findings.

Publication Types:
  • Clinical trial
  • Randomized controlled trial

PMID: 11292002 [PubMed - indexed for MEDLINE]
 
Alcohol Clin Exp Res 2000 May;24(5):737-42 Related Articles, Books, LinkOut
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Combining ondansetron and naltrexone effectively treats biologically predisposed alcoholics: from hypotheses to preliminary clinical evidence.

Johnson BA, Ait-Daoud N, Prihoda TJ.

Department of Psychiatry, University of Texas, San Antonio, USA. bjohnson@uthscsa.edu

BACKGROUND: Individuals considered to be early onset alcoholics (EOA) are characterized by an early onset age, a broad range of antisocial behaviors, high familial loading, and presumed biological disease predisposition. Ondansetron, a 5-HT3 antagonist, improves drinking outcomes and increases abstinence rates among EOA. Individuals with high familial loading for developing alcoholism have lower levels of beta-endorphin and demonstrate a more pronounced increase in beta-endorphin levels in response to alcohol administration compared with individuals who do not have alcoholic relatives. The propensity for naltrexone (a mu opioid antagonist) to reduce alcohol's rewarding effects and drinking in humans is greatest in individuals with high familial loading. Predicated on the added knowledge that 5-HT3 receptors may themselves mediate alcohol reward via activation of the endogenous opioid system, we hypothesized that the combination of ondansetron and naltrexone would act synergistically and would be an effective treatment in EOA. METHODS: We conducted an 8-week double-blind placebo controlled clinical trial in which 20 EOA were randomized to receive ondansetron (4 microg/kg twice a day) + naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized group Cognitive Behavioral Therapy. RESULTS: At endpoint, subjects who received ondansetron + naltrexone (n = 10), compared with those who received placebo (n = 10), had fewer drinks/day (covariate adjusted mean 0.99 +/- 0.60 vs. 3.68 +/- 0.63; F1, 16 = 9.35,p = 0.008; effect size = 1.42), drinks/drinking day (covariate adjusted mean 3.14 +/- 0.87 vs. 6.76 +/- 0.71; F1, 13 = 10.45, p = 0.007; effect size = 1.71), and a trend toward increased percent days abstinent (covariate adjusted mean 69.76 +/- 8.64 vs. 48.24 +/- 9.12; F1, 16 = 3.58, p = 0.08; effect size = 0.88). CONCLUSIONS: Ondansetron plus naltrexone seems to synergistically improve the drinking outcomes of EOA. Larger scale studies that test these medications, both alone and together, among various alcoholic subtypes are needed to establish and extend these promising findings.

Publication Types:
PMID: 10832917 [PubMed - indexed for MEDLINE]
 
Psychopharmacology (Berl) 2000 May;149(4):327-44 Related Articles, Books, LinkOut
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Neuropharmacological treatments for alcoholism: scientific basis and clinical findings.

Johnson BA, Ait-Daoud N.

Department of Psychiatry, University of Texas, Health Sciences Center at San Antonio 78212, USA. bjohnson@uthscsa.edu

Preclinical studies have exploded our knowledge about the behavioral and biological underpinnings of alcoholism. These studies suggest that certain neurotransmitters, particularly those interacting with the opioid, N-methyl-D-aspartate, and monoamine systems, may play a critical role in the expression of alcohol-drinking and other behaviors associated with its abuse liability. Built upon this foundation, important advances have been made in the development of therapeutic medications for the treatment of alcoholism. Of the medications reviewed, acamprosate's potential appears to be the most widely established. In the USA, naltrexone was approved by the Food and Drug Administration in 1995 for the treatment of alcoholism; however, the results of some studies have been less encouraging. Naltrexone's reliance on high compliance rates for efficacy may, eventually, limit its potential in clinical settings offering generic treatment for alcoholism. The relative paucity of dose-response studies on naltrexone's effects in treating alcoholics is an important gap in the literature. Recent data from a large clinical trial suggests that ondansetron, a serotonin3 antagonist, offers new hope for the treatment of early onset alcoholics; a type of alcoholism most difficult to manage with psychosocial measures alone. Different subtypes of alcoholic may, therefore, have varying treatment responses to serotonergic agents. Matching subtypes of alcoholic to effective treatment medications based upon their different biologies remains an important therapeutic goal. Combinations of effective pharmacological agents need exploration as they may prove to be synergistic, and could shepherd in a new era of treatments aimed at multiple neurotransmitter targets associated with the alcoholism disease. The coming decade promises more powerful tools for characterizing drug effects on alcohol drinking, thereby closing the gap between animal models of addiction and the human condition.

Publication Types:
PMID: 10867960 [PubMed - indexed for MEDLINE]
 
Alcohol Res Health 1999;23(3):207-13 Related Articles, Books, LinkOut

Medications and alcohol craving.

Swift RM.

Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, USA.

The use of medications as an adjunct to alcoholism treatment is based on the premise that craving and other manifestations of alcoholism are mediated by neurobiological mechanisms. Three of the four medications approved in the United States or Europe for treating alcoholism are reported to reduce craving; these include naltrexone (ReVia), acamprosate, and tiapride. The remaining medication, disulfiram (Antabuse), may also possess some anticraving activity. Additional medications that have been investigated include ritanserin, which has not been shown to decrease craving or drinking levels in humans, and ondansetron, which shows promise for treating early onset alcoholics, who generally respond poorly to psychosocial treatment alone. Use of anticraving medications in combination (e.g., naltrexone plus acamprosate) may enhance their effectiveness. Future studies should address such issues as optimal dosing regimens and the development of strategies to enhance patient compliance.

Publication Types:
PMID: 10890816 [PubMed - indexed for MEDLINE]
 
Alcohol Res Health 1999;23(2):99-106 Related Articles, Books, LinkOut

Medications to treat alcoholism.

Johnson BA, Ait-Daoud N.

University of Texas Health Sciences Center, San Antonio, USA.

Advances in neurobiology support the development of medications to treat alcoholism by modifying the activity of specific chemical messengers (i.e., neurotransmitters) in the brain. Among the most promising new medications is acamprosate, which appears to decrease the intensity of craving after a person has stopped drinking. Naltrexone (ReVia) has been shown to decrease alcohol consumption, although its practical effectiveness may be compromised by poor patient compliance and other factors. Ondansetron shows promise for decreasing drinking and increasing abstinence rates among early onset alcoholics, who respond poorly to psychosocial treatment alone. Researchers are investigating whether the use of specific medications in combination can further enhance their effectiveness. Additional research is needed to determine how medications interact with different psychosocial factors and treatments.

Publication Types:
  • Review
  • Review literature

PMID: 10890803 [PubMed - indexed for MEDLINE]