Efficacy of Disulfiram for the Treatment of Alcohol Dependence Assessed with a Multicenter Randomized Controlled Trial

Yoshimura, Atsushi; Kimura, Masashi; Nakayama, Hisakazu; Matsui, Toshifumi; Okudaira, Fukiko; Akazawa, Shigeru; Ohkawara, Masao; Chô, Tetsuji; Kono, Yoshihiro; Hashimoto, Koji; Kumagai, Masahiro; Sahashi, Yukiko; Roh, Sungwon; Higuchi, Susumu

doi:10.1111/acer.12278

Cited by 35 publications

(24 citation statements)

References 41 publications

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“…Similarly, in humans, the success rate of treatment with disulfiram is quite low because many patients do not show aversion to ethanol ingestion and further develop tolerance to disulfiram. Recent placebo-controlled clinical work and meta-analyses also show that disulfiram—as a drug (in blind studies)—is not different from placebo in reducing ethanol relapse in alcoholics (Skinner et al, 2014; Yoshimura et al, 2014). These studies might be taken as an indication that following chronic ethanol intake a systemic elevation of acetaldehyde does not inhibit ethanol consumption.…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate Administration Reduces Alcohol and Saccharin Intake in Rats: Possible Effects at Peripheral and Central Levels

Rivera-Meza

Muñoz

Jerez

et al. 2017

Front. Behav. Neurosci.

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We have previously shown that the administration of fenofibrate to high-drinker UChB rats markedly reduces voluntary ethanol intake. Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARα) agonist, which induces the proliferation of peroxisomes in the liver, leading to increases in catalase levels that result in acetaldehyde accumulation at aversive levels in the blood when animals consume ethanol. In these new studies, we aimed to investigate if the effect of fenofibrate on ethanol intake is produced exclusively in the liver (increasing catalase and systemic levels of acetaldehyde) or there might be additional effects at central level. High drinker rats (UChB) were allowed to voluntary drink 10% ethanol for 2 months. Afterward, a daily dose of fenofibrate (25, 50 or 100 mg/kg/day) or vehicle (as control) was administered orally for 14 days. Voluntary ethanol intake was recorded daily. After that time, animals were deprived of ethanol access for 24 h and administered with an oral dose of ethanol (1 g/kg) for acetaldehyde determination in blood. Fenofibrate reduced ethanol voluntary intake by 60%, in chronically drinking rats, at the three doses tested. Acetaldehyde in the blood rose up to between 80 μM and 100 μM. Considering the reduction of ethanol consumption, blood acetaldehyde levels and body weight evolution, the better results were obtained at a dose of 50 mg fenofibrate/kg/day. This dose of fenofibrate also reduced the voluntary intake of 0.2% saccharin by 35% and increased catalase levels 2.5-fold in the liver but showed no effects on catalase levels in the brain. To further study if fenofibrate administration changes the motivational properties of ethanol, a conditioned-place preference experiment was carried out. Animals treated with fenofibrate (50 mg/kg/day) did not develop ethanol-conditioned place preference (CPP).In an additional experiment, chronically ethanol-drinking rats underwent two cycles of ethanol deprivation/re-access, and fenofibrate (50 mg/kg/day) was given only in deprivation periods; under this paradigm, fenofibrate was also able to generate a prolonged (30 days) decreasing of ethanol consumption, suggesting some effect beyond the acetaldehyde-generated aversion. In summary, reduction of ethanol intake by fenofibrate appears to be a consequence of a combination of catalase induction in the liver and central pharmacological effects.

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Section: Discussionmentioning

confidence: 99%

Fenofibrate Administration Reduces Alcohol and Saccharin Intake in Rats: Possible Effects at Peripheral and Central Levels

Rivera-Meza

Muñoz

Jerez

et al. 2017

Front. Behav. Neurosci.

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“…One recent exception involves disulfiram, a pharmacologic antagonist of ALDH2, the effects of which mimick those of the null ALDH2 allele. Yoshimura et al (2014) found that, in a small subsample of individuals treated with disulfiram, the presence of the ALDH2 variant was associated with a higher rate of abstinence from alcohol. A moderator effect of the ALDH2 variant variant has also been demonstrated in a human alcohol challenge study (Peng et al, 2014).…”

Section: Pharmacogenetics Of Subjective Effects Associated With Alcohmentioning

confidence: 90%

The Pharmacogenetics of Alcohol Use Disorder

Jones

Comer

Kranzler

2015

Alcohol Clin Exp Res

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Background Annually, the use and abuse of alcohol contributes to millions of deaths and billions of dollars in societ al costs. To determine the impact of genetic variation on the susceptibility to the disorder and its response to treatment, studies have been conducted to assess the contribution of a variety of candidate genetic variants. These variants, which we review here, were chosen based upon their observed or hypothesized functional relevance to AUD risk or to the mechanism by which medications used to treat the disorder exert their effects. Methods This qualitative review examines studies in which candidate polymorphisms were tested as moderator variables to identify pharmacogenetic effects on either the subjective response to alcohol or the outcomes of pharmacotherapy. Results Although findings from these studies provide evidence of a number of clinically relevant pharmacogenetic effects, the literature is limited and there are conflicting findings that require resolution. Conclusions Pharmacogenetic studies of AUD treatment that use greater methodological rigor and better statistical controls, such as corrections for multiple testing, may help to resolve inconsistent findings. These procedures could also lead to the discovery of more robust and clinically meaningful moderator effects. As the field evolves through methodological standardization and the use of larger study samples, pharmacogenetic research has the potential to inform clinical care by enhancing therapeutic effects and personalizing treatments. These efforts may also provide insights into the mechanisms by which medications reduce heavy drinking or promote abstinence in patients with an AUD.

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“…In a medium-risk-of-bias trial conducted in Japan (Yoshimura et al 2014), subjects (total N=109) were randomly assigned according to a 2×2 design with disulfiram 200 mg/day vs. placebo and receipt of educational material on drinking harms and craving management vs. no such education. At 26 weeks, there were no differences among groups in the percent of individuals who remained abstinent.…”

Section: Benefits Of Disulfirammentioning

confidence: 99%

The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder

2018

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Efficacy of Disulfiram for the Treatment of Alcohol Dependence Assessed with a Multicenter Randomized Controlled Trial

Cited by 35 publications

References 41 publications

Fenofibrate Administration Reduces Alcohol and Saccharin Intake in Rats: Possible Effects at Peripheral and Central Levels

Fenofibrate Administration Reduces Alcohol and Saccharin Intake in Rats: Possible Effects at Peripheral and Central Levels

The Pharmacogenetics of Alcohol Use Disorder

The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder

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