Naltrexone ameliorates functional network abnormalities in alcohol-dependent individuals

Abstract

Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol-dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly-substance-dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology.

Keywords: Addiction; alcohol; cocaine; naltrexone; opiate; substance use.

Figure 1

Neural network local efficiency under placebo and naltrexone. Local efficiency was captured based on a whole brain ROI‐to‐ROI correlation coefficient matrix, binarized with a 5 percent density threshold and is plotted for naltrexone and placebo for alcohol‐dependent (Alc, unbroken line), poly‐substance‐dependent (Poly, broken line) and healthy volunteers (HV, dotted line). For the comparison between drugs, there was a significant effect of naltrexone (P = 0.006), a significant drug × group interaction (P = 0.029) and no effect of group (P = 0.106)

Figure 2

Correlations between neural network efficiency and drug exposure. Top: local efficiency is plotted against opiate exposure (R = 0.365, P = 0.044) and cocaine exposure (R = 0.295, P = 0.058). Bottom: global efficiency plotted against alcohol exposure and age

Figure 3

Network cluster of reduced functional connectivity in alcohol‐dependent subjects. Network‐based statistics demonstrated a large network of reduced connectivity in alcohol‐dependent compared with healthy subjects. Node size indicates number of connections with reduced functional connectivity. The largest nodes are annotated. Inf, inferior; SMA, supplementary motor area; L, left; R, right

Figure 4

Network cluster of reduced functional connectivity in alcohol‐dependent subjects compared with poly‐drug substance‐dependent subjects. Network‐based statistics demonstrated a network of reduced connectivity in alcohol‐dependent subjects compared with poly‐drug SD subjects. Node size indicates number of connections with reduced functional connectivity. The largest nodes are annotated. Sup, superior; Med, medial; Inf, inferior; L, left; R, right