An fMRI study of nalmefene on alcohol effects in reward anticipation in alcohol dependence

Nalmefene is an opiate receptor modulator recently licensed for the reduction of alcohol intake in alcohol dependence [1]. The brain mechanisms underpinning its actions beyond opioid receptor blockade are not fully understood in alcohol dependence, but may relate to a change in the reward system in the presence of alcohol [2]. This study investigated the effects of nalmefene on anticipation of reward using the monetary incentive delay (MID) fMRI task in men with alcohol dependence and high drinking risk level (>60 g/day) under an alcohol clamp. Methods: 22 non-treatment seeking alcohol dependent men were recruited to this cross-over, double blind study through advertisement (46+11yrs). The first study day was to confirm the participant would tolerate the 'alcohol clamp' with alcohol infused to achieve the target breath alcohol level (BrAC) of 0.8% within 20 minutes then maintained for another 30 minutes. On the 2nd and 3rd study days a week apart, either 18 mg nalmefene or matched placebo was given in a randomised order in the morning. After ∼4 hours, the MR scanning session began (Siemens Tim Trio 3T). Pulsed arterial spin labelling (pASL) pre and during alcohol infusion (BrAC: 0.8%) was undertaken to evaluate the impact of alcohol on blood flow. During the alcohol infusion, participants completed our fMRI protocol to assess reward, impulsivity and stress responsivity in addiction using the MID, go-nogo and an evocative tasks (ICCAM [3]). We report here only the primary outcome measures: pASL and MID (contrast: “reward anticipation > neutral anticipation”). A whole brain and an a priori striatal region of interest (ROI; 5mm radius spheres centred at ±14, +12, -4 encompassing parts of nucleus accumbens, putamen, caudate, and globus pallidus) were conducted. Results: Complete data were available for 18 men (44±11 yrs; exclusions: 1 did not tolerate MR; 2 excess motion, 1 poor task performance). As expected, alcohol infusion resulted in an increase in blood perfusion (eg thalamus: ∼15 ml/100 g/min) however perfusion difference between nalmefene and placebo on alcohol were not observed. Analysis revealed a significant decrease in the contrast “reward anticipation > neutral anticipation” on nalmefene compared with placebo in the striatal ROI: t = 2.78, p = 0.013, d.f. = 17.p = 0.013. Analysis confirmed that this was due to a decrease in BOLD response during reward, not an increase during neutral anticipation. Further, whole brain analyses observed three clusters (Z>2.3, p