Substitution therapy for patients with alcohol dependence: Mechanisms of action and efficacy.

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. Here, we explain the 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, baclofen and benzodiazepines, NMDA receptor antagonists such as ketamine and memantine, or nAChRs agonists such as varenicline. All these compounds are already approved for other indications and we present clinical evidence for these drugs in the treatment of alcohol withdrawal syndrome (AWS) and in the long-term treatment of AD, and outline future steps for their acceptance as substitution treatment in AD. Finally, we discuss the substitution approach of managed alcohol programs for the most severely affected homeless populations. Results showed that sodium oxybate 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. In conclusion, we argue that better AD treatment can be provided if substitution maintenance treatments for alcohol are implemented at a similar scale as for opioid and nicotine use disorder.

Alcohol dependence and very high risk level of alcohol consumption: a life-threatening and debilitating disease.

Women and men with alcohol dependence and very high risk drinking level (VHRDL; defined as drinking >60 or 100 g of ethanol per day, respectively) experience severe health consequences; however, data on the number of these individuals and their health risks are limited. This study estimated (1) the prevalence of VHRDL in 13 European Union (EU) countries among people 15-65 years of age, (2) the risk of disease and injury occurrence associated with VHRDL, (3) the proportion of deaths in nine EU countries attributable to VHRDL and (4) the life expectancy of people in France with VHRDL. Prevalence estimates of VHRDL were based on data obtained from clinical trials and the Global Information System on Alcohol and Health. The risk of disease and injury occurrence was estimated using microsimulations. Population-attributable fractions (PAFs) were estimated using a Levin-based methodology. The estimated prevalence of VHRDL in the 13 EU countries examined was 0.74-0.85 percent, with a disease and injury occurrence risk of 13.5 per 100 people with VHRDL per year. For the nine EU countries examined, VHRDL caused 53.6 percent of all liver cirrhosis, 43.8 percent of all pancreatitis and 41.1 percent of oral cavity and pharyngeal cancers (all other PAFs were below 30 percent). Applying these PAFs to French mortality data resulted in a life expectancy of 47-61 years for people with VHRDL-21-35 years less than the general population. These results indicate that the health burdens of VHRDL are potentially large, and interventions targeting VHRDL should be considered when formulating public health policies.