Effects of naltrexone are influenced by childhood adversity during negative emotional processing in addiction recovery

Abstract

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone (n = 18, alcohol) and in combination with cocaine and/or opioid dependence (n = 21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence (n = 21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone.

Neuroimaging findings from an experimental pharmacology trial of naltrexone in heavy drinkers of East Asian descent

“…The few naltrexone studies that have examined functional connectivity vary in analysis parameters, populations of interest, and study designs. These studies have shown that naltrexone modulates connectivity between ACC and hippocampus as a function of childhood adversity during an emotional priming task among alcohol-dependent individuals (Savulich et al, 2017), and that naltrexone improves local network efficiency in alcohol dependent individuals, reaching that of healthy controls (Morris et al, 2018). Most notably, in a study of methamphetamine users, naltrexone decreased connectivity between precuneus and sensorimontor regions and increased connectivity between dorsal striatum and precuneus with frontal regions (Courtney et al, 2016).…”

A randomised, double‐blind study investigating the relationship between early childhood trauma and the rewarding effects of morphine

“…In-vivo microdialysis studies have linked receptor tone with drug reinforcement, where greater endogenous dopamine activity is associated with more adverse effects of cocaine-a dopamine reuptake inhibitor. 30 Greater activity in the medial pre-frontal cortex was found when responding to aversive images in people with a history of childhood adversity after receiving naltrexone, 31 although this study was confined to those with histories of drug and/or alcohol abuse. The authors suggest this may reflect greater effort to exert emotion regulation.…”

“…Prior research has linked childhood trauma to altered neural responses to naltrexone, potentially via existing differences in endogenous opioids. 31 Preclinical research has also reported that maternal separation results in hyposensitive endogenous opioid functioning, which is suggested as responsible for the heightened sensitivity to the rewarding effects of opioid drugs. 20 A hyposensitive endogenous opioid system could T A B L E 2 Plasma morphine and physiological outcomes (Ms and SDs) therefore potentially underlie the increased pleasurable effects and reduced aversive effects of morphine in the trauma group in the current study.…”

Naltrexone differentially modulates the neural correlates of motor impulse control in abstinent alcohol‐dependent and polysubstance‐dependent individuals

“…Clinical evidence also suggests that MOR blockade with naltrexone is effective in some impulse control disorders (Kim et al, 2001;Grant, 2005;Lahti et al, 2010;Grant et al, 2014), promotes abstinence in substance addiction populations (Krystal et al, 2001;Srisurapanont & Jarusuraisin, 2005;Grassi et al, 2007), possibly through the promotion of impulse control (Sanchez-Roige et al, 2015). There is evidence that naltrexone can also ameliorate neural disturbances in addiction (Savulich et al, 2017;Morris et al, 2018), including those related to impulsive choice (Boettiger et al, 2009), pointing to its potential efficacy as a neuromodulator of impulse control. Therefore, evidence of disturbances to prefrontal endogenous opioid functioning, together with the clinical efficacy of naltrexone in treating impulse control and addiction disorders, suggests that this system may be a viable target for relapse prevention, where there are deficits related to impulsivity.…”