History of Childhood Adversity May Predict Naltrexone Response

A history of childhood adversity is known to be common in people with alcohol use disorder (AUD), but a study in Translational Psychiatry suggests such history might also help to predict AUD patients most likely to respond to naltrexone.

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Specifically, this study led by Karen Ersche, Ph.D., a lecturer in the Department of Psychiatry at the University of Cambridge, found that the more severe the adversity, the greater the potential ameliorative effect of naltrexone.

Some preclinical research has suggested there is link between abuse and response to naltrexone, but this study is the first to show an effect in humans, Ersche said.

Naltrexone acts on opioid receptors to dampen the brain’s reward pathways and make alcohol less appealing. However, trials of people with substance use disorders also suggest naltrexone may increase negative feelings and anxiety in response to stressful stimuli—a response Ersche noted may explain why many people do not respond to naltrexone therapy.

Previous research in combat veterans found that exposure to stress changes the activity of some opioid receptors known to be targets of naltrexone. Ersche wondered if the same was true of people who experienced significant childhood adversity. If so, could this lead them to respond differently to naltrexone compared with others without a history of abuse?

To answer this question, Ersche and colleagues recruited 60 adults to take part in a task that measured their responses to a series of images, using functional MRI (fMRI). The participants included 21 people with a diagnosed history of alcohol dependence, 21 with a history of co-dependence on alcohol and drugs, and 18 controls. To prevent alcohol or drugs from interfering with the imaging, all the participants had to be abstinent for at least four weeks.

At the beginning of the trial, all participants completed a Childhood Trauma Questionnaire (CTQ), from which the researchers were able to determine exposure to physical, sexual, and emotional abuse.

Each participant was then given either 50 mg of naltrexone or placebo orally and proceeded to look at various neutral or emotionally aversive images during fMRI. The study was a crossover design, so each participant did the test under both naltrexone and placebo conditions, but in a random order.

When exposed to the negative images, participants in the placebo group demonstrated heightened activity in the prefrontal cortex and anterior cingulate cortex—two areas associated with mood regulation. This activity was the greatest in people who had higher CTQ scores. When participants took naltrexone, this activity decreased, with the greatest decreases seen in people with the highest CTQ scores. This trend was seen across all three groups; it was not limited to people with substance use problems.

“This paper does not actually show that naltrexone reduces stress-related alcohol cravings or propensities to drink,” said John Krystal, M.D., director of Yale’s Center for the Translational Neuroscience of Alcoholism, who was not involved with this study. “But the data might be interpreted to suggest that naltrexone could be helpful in this regard,” he told Psychiatric News. Krystal is also the chair of the Department of Psychiatry at Yale School of Medicine.

Ersche said she believes these results are ready to be applied in alcohol treatment programs, since a lot of the elements in effective relapse prevention are already in place; it’s just a matter of pairing the right interventions with the right people.

“People with a history of severe childhood adversity might make good candidates for a combined approach of naltrexone and coping strategies like skills training or stress resilience training,” she said.

She explained that for people with an alcohol disorder and a history of adversity, coping strategies may induce too many negative feelings since they involve managing one’s emotions.

“Giving naltrexone can take the edge off, and help with the training needed to learn important coping skills,” she said. “And the improvements in coping can then make naltrexone more effective at reducing cravings.”

An interesting secondary finding of this imaging study was that people with co-occurring alcohol and drug use showed heightened amygdala activity in response to aversive images as well as neutral ones (this was regardless of trauma history). Naltrexone reduced this abnormal response to neutral stimuli in this group. The amygdala is a key regulator of stress response, and Ersche suggested these findings may point to naltrexone being effective in people with an addiction and comorbid stress disorder like posttraumatic stress disorder.

This study was supported by the National Institute for Health Research (NIHR) Clinical Research Facility at Imperial College Healthcare NHS Trust, the NIHR/Wellcome Trust Cambridge Research Facility, and Clinical Trials Unit at Salford Royal NHS Foundation Trust. ■