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Is R(+)-Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side

Abstract : For several decades, studies conducted to evaluate the efficacy of RS(+/-)-Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)-enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)-Baclofen or S(-)-Baclofen to that of RS(+/-)-Baclofen on ethanol intake, seeking, and relapse. R(+)-Baclofen was more effective than RS(+/-)-Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(-)-Baclofen and RS(+/-)-Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)-Baclofen group. At an intermediate dose of R(+)-Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(+/-)-Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)-Baclofen and RS(+/-)-Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(+/-)-Baclofen may come from the sensitivity to the R(+)-Baclofen but also to the one of the S(-)-Baclofen that can promote an increase in ethanol intake.
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https://hal-u-picardie.archives-ouvertes.fr/hal-03584911
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Soumis le : mardi 22 février 2022 - 16:52:47
Dernière modification le : jeudi 7 avril 2022 - 13:58:21

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Victor Echeverry-Alzate, Jerome Jeanblanc, Pierre Sauton, Vanessa Bloch, Laurence Labat, et al.. Is R(+)-Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side. ADDICTION BIOLOGY, 2021, 26 (2), ⟨10.1111/adb.12892⟩. ⟨hal-03584911⟩

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