Alcohol dependence is a major public health problem with a huge social and economic burden. However, alcohol dependence is both underdiagnosed and undertreated, as it is estimated that less than 10% of people diagnosed with alcohol dependence or abuse in Europe receive any form of treatment. Among the factors that have contributed to this undertreatment is the fact that the therapeutic strategy has always been based on achieving and maintaining abstinence from alcohol, a goal often difficult to achieve. Recently it has been made available a new therapeutic approach to alcohol dependence, nalmefene, based on the reduction of alcohol consumption. In fact, nalmefene is the first drug to be approved in Europe for as-needed use to reduce alcohol consumption in alcohol-dependent adults with a high drinking risk level and who continue to have a high drinking risk level 2 weeks after initial assessment. Nalmefene reduces the reinforcing the effects of alcohol, helping to reduce alcohol consumption, through the modulation of the opioid system. Efficacy and tolerability of as-needed nalmefene for the reduction of alcohol consumption was evaluated in 3 double-blind, randomized, placebo-controlled clinical trials conducted in Europe: two (ESENSE 1 and ESENSE 2) evaluated the efficacy of 6 months as-needed treatment and a third (SENSE) examined the efficacy of one year as-needed treatment with nalmefene in patients with alcohol dependence. All patients took part in a motivational and adherence-enhancing psychosocial support (BRENDA). Post hoc subgroup analysis of ESENSE 1, ESENSE 2 and SENSE trials were conducted in patients who had at least a high drinking risk level according to WHO (> 60 g/day for men and > 40 g/day for women) at both screening and randomization (i.e. the target population). In the pooled target population of ESENSE 1 and ESENSE 2, there was a superior effect of nalmefene compared to placebo in reducing both the number of heavy drinking days (p < 0.0001) and total alcohol consumption (p < 0.0001) at the end of treatment, as well as in improving (p < 0.05) the adjusted mean change in the CGI-S score and the adjusted mean CGI-I score. Significantly improved (p ? 0.01) levels of ALT were demonstrated in patients treated with nalmefene compared to those treated with placebo in the analysis of the target population of ESENSE 1 and ESENSE 2. The reduction of GGT levels was significantly greater (p < 0.001) with nalmefene compared to placebo in the subgroup of the target population of ESENSE 1 study, but not in the ESENSE 2 study. SENSE trial gave results similar to ESENSE 1 and 2 studies. As-needed nalmefene was generally well tolerated in patients with alcohol dependence. These studies demonstrate the clinical efficacy and tolerability of nalmefene in patients with alcohol dependence: the effect is larger in patients with at least a high drinking risk level at the start of treatment. Nalmefene has the potential to engage in treatment patients who otherwise would not have sought help, thus representing a new pharmacological treatment paradigm, in terms of treatment goal (reduction of alcohol consumption) and dosing regimen (as-needed) in alcohol dependent patients.