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

Addict Biol. 2021 Mar;26(2):e12892. doi: 10.1111/adb.12892. Epub 2020 Mar 8.

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.

Keywords: GABAB receptor; R(+)-Baclofen; RS(±)-Baclofen; S(−)-Baclofen; alcohol use disorder; operant oral alcohol self-administration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / drug therapy
  • Alcoholism / drug therapy*
  • Animals
  • Baclofen / administration & dosage
  • Baclofen / adverse effects
  • Baclofen / chemistry*
  • Baclofen / therapeutic use*
  • Dose-Response Relationship, Drug
  • GABA-B Receptor Agonists / administration & dosage
  • GABA-B Receptor Agonists / adverse effects
  • GABA-B Receptor Agonists / chemistry*
  • GABA-B Receptor Agonists / therapeutic use*
  • Male
  • Rats
  • Rats, Long-Evans
  • Recurrence
  • Substance Withdrawal Syndrome / drug therapy

Substances

  • GABA-B Receptor Agonists
  • Baclofen