Effects of extended-release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder

Effects of extended-release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder

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J Psychiatry Neurosci 2018;43(4):254-261

Zhenhao Shi, PhD; An-Li Wang, PhD; Kanchana Jagannathan, MS; Victoria P. Fairchild, BA; Charles P. O’Brien, MD, PhD; Anna Rose Childress, PhD; Daniel D. Langleben, MD


Background: Heightened response to drug-related cues is a hallmark of addiction. Extended-release naltrexone (XR-NTX) is a US Food and Drug Administration–approved pharmacotherapy for relapse prevention in patients with opioid use disorder (OUD). In these patients, XR-NTX has been shown to reduce brain responses to opioid-related visual stimuli. To assess the biomarker potential of this phenomenon, it is necessary to determine whether this effect is limited to opioid-related stimuli and whether it is associated with key OUD symptoms.

Methods: Using functional MRI (fMRI), we measured the brain responses to opioid-related and control (i.e., sexual and aversive) images in detoxified patients with OUD before, during and after XR-NTX treatment. Craving and withdrawal severity were evaluated using clinician- and self-administered instruments during each session.

Results: We included 24 patients with OUD in our analysis. During XR-NTX treatment, we found reduced responses to opioid-related stimuli in the nucleus accumbens (NAcc) and medial orbitofrontal cortex (mOFC). The reduction in mOFC response was specific to the opioid-related stimuli. The reduced NAcc and mOFC opioid cue reactivity was correlated with reduction in clinician-assessed and self-reported withdrawal symptoms, respectively.

Limitations: The study was not placebo-controlled owing to ethical, safety and feasibility concerns.

Conclusion: Extended-release naltrexone reduces the NAcc and mOFC cue reactivity in patients with OUD. This effect is specific to opioid-related stimuli in the mOFC only. The reduction in neural response to opioid-related stimuli is more robust in patients with greater decline in withdrawal severity. Our results support the clinical utility of mesocorticolimbic cue reactivity in monitoring the XR-NTX treatment outcomes and highlight the link between opioid withdrawal symptomatology and neural opioid cue reactivity.

Submitted Feb. 10, 2017; Revised July 22, 2017; Revised Sept. 25, 2017; Accepted Oct. 7, 2017; Published online first Feb. 27, 2018

Affiliations: From the Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa. (Shi, Wang, Jagannathan, Fairchild, O’Brien, Childress, Langleben); the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY (Wang); the Annenberg Public Policy Center, University of Pennsylvania, Philadelphia, Pa. (Langleben); and the Corporal Michael J. Crescenz Veterans Administration Medical Center, Philadelphia, Pa. (Langleben).

Funding: ThisThe study was supported by the Commonwealth of Pennsylvania CURE grant SAP#4100055577 (PI: A. Childress) and the following NIH grants: T32 Translational Addiction Research postdoctoral fellowship DA028874 to Zhenhao Shi (PI: A. Childress and R. Pierce); DA024553 (PI: C. O’Brien); DA036028 (PI: D. Langleben); N01DA-14-7788 (PI: D.E. Moody); and HD084746 (PI: A. Wang). Study medicine was donated by the manufacturer (Alkermes plc).

Competing interests: C. O’Brien declares having received consulting fees from Alkermes plc. D. Langleben received honoraria from Alkermes plc in 2016 and 2017 for participation on its scientific advisory board. No other competing interests declared.

Contributors: C. O’Brien, A. Childress and D. Langleben designed the study. A Childress and D. Langleben acquired the data, which all authors analyzed. Z. Shi, A. Childress and D. Langleben wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.170036

Correspondence to: D.D. Langleben, Center for Studies of Addiction, 3535 Market St, Suite 500, Philadelphia, PA 19104; langlebe@pennmedicine.upenn.edu