MEDIAL PREFRONTAL NEUROPLASTICITY DURING EXTENDED-RELEASE NALTREXONE TREATMENT OF OPIOID USE DISORDER – A LONGITUDINAL STRUCTURAL MAGNETIC RESONANCE IMAGING STUDY
Authors: Shi *Zhenhao , Li Xinyi , Todaro Dustin R , Cao Wen , Lynch Kevin G , Detre John A , Loughead James , Langleben Daniel D , Wiers Corinde E 
Published: February 2025

Abstract

Background
Opioid use disorder (OUD) has been linked to macroscopic structural alterations in the brain [1]. The monthly injectable, extended-release formulation of μ-opioid antagonist naltrexone (XR-NTX) is highly effective in reducing opioid craving and preventing opioid relapse [2,3].

Aims & Objectives
We aimed to investigate the neuroanatomical effects of XR-NTX by examining the changes in cortical thickness during treatment for OUD.

Method
Forty-seven OUD patients underwent structural magnetic resonance imaging (sMRI) and were assessed for opioid craving on two sessions: less than 1 day before the first XR-NTX injection (i.e., pre- treatment session); and an average of 11 days after the first injection (i.e., on-treatment session). A sample of fifty-six non-OUD individuals who completed a single imaging session served as a comparison group. sMRI images were analyzed using the volume-based cortical thickness pipeline implemented in the Advanced Normalization Tools. A publicly available [11C]Carfentanil positron emission tomography (PET) dataset was used to assess the relationship between cortical thickness change and mu-opioid receptor (MOR) binding potential across brain regions.

Results
The thickness of the medial prefrontal and anterior cingulate cortices (mPFC/aCC) was comparable between the non-OUD individuals and the OUD patients at pre-treatment, but showed a significant reduction among the OUD patients from pre-treatment to on-treatment (whole-brain familywise error-corrected p&lt;0.05) (see Figure 1A &1B). Patients with greater reduction in mPFC/aCC thickness also showed greater reduction in opioid craving from pre-treatment to on-treatment (R2=0.19, p=0.002) (see Figure 1C). Analysis with the [11C]Carfentanil PET data indicated that, across brain regions, there was a positive association between MOR binding potential and cortical thickness reduction in regions with relatively high MOR binding potential (R2=0.29, p&lt;0.001) (see Figure 1D).

Discussion & Conclusion
XR-NTX treatment for OUD is associated with reduced cortical thickness in the mPFC and aCC regions. The reduction does not appear to indicate a restoration to the non-OUD level but rather reflects XR-NTX’ s distinct therapeutic impact on an MOR-rich brain structure. Our findings highlight the neuroplastic effects of XR-NTX that may inform the development of novel OUD interventions.

References
[1]Shi Z, Li X, Byanyima JI, O’ Brien CP, Childress AR, Lynch KG, et al. Effects of current smoking severity on brain gray matter volume in opioid use disorder– a voxel-based morphometry study. American Journal of Drug and Alcohol Abuse. 2023;49(2):180-9.
[2]Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL. Injectable extended- release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011;377(9776):1506-13.
[3]Shi Z, Wang A-L, Jagannathan K, Fairchild VP, O’ Brien CP, Childress AR, et al. Effects of extended- release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder. Journal of Psychiatry and Neuroscience. 2018;43(4):254-61.