Combined varenicline and naltrexone attenuates alcohol cue-elicited activation in heavy drinking smokers

Abstract

Background: There is a strong bidirectional relationship between the use of alcohol and cigarettes which results in various challenges for treating those who co-use both substances. While varenicline and naltrexone each have FDA-approval for nicotine and alcohol use disorder, respectively, there is evidence that their clinical benefit may extend across the two disorders. Critically, the effect of combined varenicline and naltrexone on neural reactivity to alcohol cues among heavy drinking smokers has not yet been studied. Probing the effect of the combination therapy on alcohol cue-reactivity may give insight to the mechanisms underlying its efficacy.

Methods: Forty-seven heavy drinking smokers enrolled in two medication studies were randomized to receive varenicline alone (n = 11), varenicline plus naltrexone (n = 11), or placebo (n = 25). Participants completed an fMRI alcohol cue-reactivity task and rated their in-scanner alcohol craving. Whole-brain analyses examined the effect of medication on alcohol cue-elicited neural response.

Results: Varenicline plus naltrexone attenuated alcohol cue-elicited activation in mesolimbic regions relative to varenicline alone and to placebo (Z > 2.3, p < 0.05). The combination varenicline and naltrexone group also endorsed lower in-scanner alcohol craving relative to varenicline alone group (p = 0.04).

Conclusions: These findings provide evidence for the benefit of combined therapy of varenicline and naltrexone over varenicline alone for the attenuation of alcohol cue-elicited neural activation. This study provides a preliminary proof-of-mechanism for this combination pharmacotherapy and suggests that naltrexone may be driving the reductions in cue-elicited alcohol craving in the brain. Further clinical studies using the combined therapy to treat heavy drinking smokers are warranted.

Keywords: Alcohol cue reactivity; Heavy drinking smoker; Naltrexone; Varenicline; fMRI.

Fig. 1.. Whole-Brain Alcohol vs. Beverage Results.

(A) There was a main effect of group on activation to alcohol vs, beverage cues in the medial prefrontal cortex, cingulate gyrus, caudate, and midbrain. (B) The varenicline only group had higher activation to alcohol vs. beverage cues in the caudate and thalamus relative to the varenicline + naltrexone group. (C) The placebo group had higher activation to alcohol vs. beverage cues in the thalamus, parahippocampus, and hippocampus, relative to the varenicline + naltrexone group. Z-statistic maps are whole-brain cluster corrected, Z > 2.3, p = .05. Coordinates are in Montreal Neurological Institute space. Brain is displayed in radiological convention (L=R).