The heavy alcohol consumption that typifies alcohol dependence and increases the risk of mortality and morbidity may be explained by animal models of addiction that demonstrate that extended exposure to a drug can lead to a gradual upward shift in the dose-response function; such an increase requires heavier consumption in order to achieve and maintain a desirable level of intoxication.36 Other animal models have shown that administration of a small dose of an opioid agonist increases motivation to consume more drug.37,38 The small dose may serve as a priming dose for higher levels of consumption in order to reinstate or increase opioid activity. Opioid antagonists, like nalmefene, bind competitively with opioid receptor sites and displace opioid agonists. Through this mechanism, the pleasurable and priming effects associated with alcohol consumption may be reduced, thereby reducing risk of relapse.39,40 However, one third of patients treated with nalmefene did relapse, there was no apparent advantage to higher nalmefene dosing, and measures of alcohol craving did not differ between nalmefene and placebo groups. Preclinical studies have shown alcohol consumption to be mediated by multiple neurotransmitters and neuromodulators, including nonopioid systems, that interact to optimize the rewarding properties of alcohol.41 Thus, antagonism of opioid receptors alone, even in higher doses, may not entirely eliminate alcohol consumption in individuals with alcohol dependence. Additionally, much of the activity of brain reward systems occurs subcortically. Therefore, self-report measures of craving, like the OCDS or the visual craving scale, may not be sensitive to drug effects on these systems that are manifest behaviorally as nonrelapse. An earlier dose-ranging pilot study found 0- and 10-mg doses of nalmefene to be ineffective in preventing relapse, whereas a 40-mg dose significantly reduced risk of relapse,11 as did 20- and 80-mg doses relative to administration of placebo in the present study. Preclinical studies looking at higher doses also lend support to a ceiling effect for nalmefene treatment, as was observed in the present study.34,35 Occurrence of specific adverse drug experiences did not differ between the groups treated with 20- and 80-mg doses of nalmefene, but the 3 patients discontinuing treatment due to adverse drug experiences were assigned to treatment with 80-mg doses, suggesting that nalmefene dosing in the 20- to 40-mg/d range may be preferable for treating alcohol dependence. All patients received CBT and showed overall improvement on the percentage of days abstinent and in the number of drinks consumed per drinking day, as did patients receiving CBT in Project MATCH.29 The skills to avoid or cope with drinking triggers learned in CBT may have contributed to the reduction in drinking frequency, intensity, and self-reported craving severity across treatment groups. However, those patients receiving nalmefene showed added benefit in terms of lower risk for relapse to the heavy drinking associated with negative consequences of alcoholism.