Ondansetron for Reduction of Drinking Among Biologically Predisposed Alcoholic Patients

Department of Psychiatry, University of Texas Health Science Center, 7703 Floyd Curl Dr, Mail Stop 7792, San Antonio, TX 78229-3900, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 08/2000; 284(8):963-71. DOI: 10.1001/jama.284.8.963
Source: PubMed


Early-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent.
To test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT(3) (serotonin) antagonist ondansetron.
Double-blind, randomized, placebo-controlled clinical trial.
University of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999).
A total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization.
After 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 microg/kg (n = 67), 4 microg/kg (n = 77), or 16 microg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy.
Self-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption.
Patients with early-onset alcoholism who received ondansetron (1, 4, and 16 microg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P =.03, P =.01, and P =.02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P =.03, P =.004, and P =.03, respectively). Ondansetron, 4 microg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P =.02) and total days abstinent per study week (6.74 vs 5.92; P =.03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 microg/kg twice per day) compared with those who received the placebo (-0.17 and -0.19 vs 0.12; P =.03 and P =.01, respectively).
Our results suggest that ondansetron (particularly the 4 microg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality. JAMA. 2000;284:963-971

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Available from: John Roache, Oct 07, 2015
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    • "No benefit was seen in heavy drinkers (>10 drinks/day).121 Additional studies using weight-based dosing found benefits in craving,122 abstinence, and total drinks.123 One study showed increase in craving but reduced drinks per day. "
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    01/2014; 5:1-12. DOI:10.2147/SAR.S37907
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    • "In other words, the in silico experiments with alcohol dependence treatment use behavioral and social parameters that serve as generators of metabolic disturbances to the system (person), which are then processed through an individualized metabolic model, thereby allowing the formal decomposition and reconstruction of the patterns of drinking behavior and their modulation by placebo or medication treatment. We illustrate our proposed approach by re-analyzing data from a study of ondansetron for the treatment of alcohol dependence (Johnson et al., 2000) and include in the model the non-specific placebo effects that occurred before the active treatment phase of the study (Penberthy et al., 2007), with a special emphasis on the highly significant differences between heavy and non-heavy drinkers observed during the study. Such a quantitative approach has several potential advantages. "
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    ABSTRACT: In this paper we view alcohol dependence and the response to treatment as a recurrent bio-behavioral process developing in time and propose formal models of this process combining behavior and biology in silico. The behavioral components of alcohol dependence and treatment are formally described by a stochastic process of human behavior, which serves as an event generator challenging the metabolic system. The biological component is driven by the biochemistry of alcohol intoxication described by deterministic models of ethanol pharmacodynamics and pharmacokinetics to enable simulation of drinking addiction in humans. Derived from the known physiology of ethanol and the literature of both ethanol intoxication and ethanol absorption, the different models are distilled into a minimal model (as simple as the complexity of the data allows) that can represent any specific patient. We use these modeling and simulation techniques to explain responses to placebo and ondansetron treatment observed in clinical studies. Specifically, the response to placebo was explained by a reduction of the probability of environmental reinforcement, while the effect of ondansetron was explained by a gradual decline in the degree of ethanol-induced neuromodulation. Further, we use in silico experiments to study critical transitions in blood alcohol levels after specific average number of drinks per day, and propose the existence of two critical thresholds in the human - one at 5 and another at 11 drinks/day - at which the system shifts from stable to critical and to super critical state indicating a state of alcohol addiction. The advantages of such a model-based investigation are that (1) the process of instigation of alcohol dependence and its treatment can be deconstructed into meaningful steps, which allow for individualized treatment tailoring, and (2) physiology and behavior can be quantified in different (animal or human) studies and then the results can be integrated in silico.
    Frontiers in Psychiatry 02/2012; 3:4. DOI:10.3389/fpsyt.2012.00004
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    • "Studies have suggested that the 5-HT3 antagonist ondansetron at 4 μg/kg twice a day may be a particularly effective treatment option for alcohol dependence among patients with early-onset alcoholism.69 Johnson et al reported that treatment with ondansetron resulted in a significant increase in the number and percentage of days abstinent in patients with early-onset alcoholism but not late-onset alcoholism.81 "
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    Pharmacogenomics and Personalized Medicine 01/2012; 5(1):19-35. DOI:10.2147/PGPM.S23462
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