Abstract not available

Background: Alcohol Use Disorder (AUD) is a devistating disease, afflicting 100 million people and causing 3 million deaths/year and generating enormous costs. With a treatment gap of 90% and few available pharmacothreapies, with low efficacy, there is a need for new treatment options. Based on the reward deficiency hypothesis of AUD, a novel path for developing new treatments is targeting the negative reinforcement generated by a low dopamine state in the brain.

Objective: Exploring if co-administration of two drugs with complementary dopamine enhancing actions, varenicline (a partial nicotinic acetylcholine receptor agonist; 1 mg b.i.d.) and bupropion (a weak dopamine reuptake inhibitor; 150 mg b.i.d.) reduces alcohol intake in moderate/severe AUD.

Methods: A thirteen-week, four-armed, multicenter Randomized Controlled Study (RCT) (n=388; ClinicalTrials.gov NCT04167306) with co-primary outcomes; specific alcohol biomarker phosphatidylethanol (B-PEth), and % heavy drinking days (%HDD) by Time Line Follow Back.

Results: In the modified Intention to Treat (ITT)-analysis (n=384), varenicline+bupropion significantly reduced B-PEth (p<0.004, Cohen´s d=0.39) and %HDD (p<0.008, Cohen´s d=0.31), compared to placebo. Varenicline+placebo also reduced B-PEth (p<0.005, Cohen´s d=0.30) and %HDD (p<0.023, Cohen´s d=0.36), whereas placebo+bupropion was ineffective. In the Per Protocol (PP)-analyses (n=257(B-PEth)/264(%HDD)) effect sizes compared to placebo were larger for varenicline+bupropion (Cohen’s d=0.43 (B-PEth); 0.41 (%HDD)) than for varenicline+placebo (Cohen’s d=0.29 (B-PEth); 0.34 (%HDD)). Secondary outcome alcohol intake (g/day) was also significantly reduced in the varenicline+bupropion group (ITT p<0.002, Cohen´s d=0.44; PP p<0.005, Cohen’s d=0.47). Also, varenicline induced nausea was significantly counteracted both in incidence (p<0.048) and duration (number of days; p<0.010) by bupropion

Conclusion: The results support the reward deficiency hypothesis of AUD by demonstrating that drugs elevating brain dopamine levels reduce alcohol consumption. Effects sizes were largest for the var+bup combination, in the high compliance (PP) population. Bupropion counteracted varenicline-induced nausea. The study further supports B-PEth as an outcome variable in AUD RCTs.

New approaches for the treatment of alcohol dependence (AD) may improve patient outcomes. Substitution maintenance therapy is one of the most effective treatment options for opioid and nicotine use disorders. So far, there has been little attention to substitution therapy for the treatment of AD. This session will explain the main mechanistic foundations of alcohol substitution maintenance therapy. Alcohol has many primary targets in the brain (and other organs) and the physical interaction of ethanol molecules with these specific ethanol-sensitive sites on a variety of ionotropic receptors (e.g. GABA-A, NMDA, and nicotinic acetylcholine (nACh) receptors) and ion channels provides the rationale for substitution. As such, a variety of compounds can interact with those ethanol-sensitive sites and can thus substitute for some of the effects of alcohol. For some of these compounds, alcohol discrimination studies have shown their substitution potential. Accordingly, potential substitution treatments include agonists acting at GABA receptors such as sodium oxybate (SMO). This session will explore whether SMO fulfills the criteria of substitution therapy for AD and will present a detailed analysis of the international clinical development of SMO for AD, focusing on efficacy and safety data in the treatment of Alcohol Withdrawal Syndrome (AWS) and in the maintenance of abstinence. Results will show that SMO is probably the closest to a substitution therapy for AD and is already approved for the treatment of AWS and in the long-term treatment of AD in some countries.