Neural correlates of adherence to extended-release naltrexone pharmacotherapy in heroin dependence

Abstract

Injectable extended-release naltrexone (XRNTX) presents an effective therapeutic strategy for opioid addiction, however its utility could be hampered by poor adherence. To gain a better insight into this phenomenon, we utilized blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) in conjunction with a validated cue-induced craving procedure to examine neural correlates of XRNTX adherence. We operationalized treatment adherence as the number of monthly XRNTX injections (range: 0-3) administered to a group of fully detoxified heroin-dependent subjects (n=32). Additional outcomes included urine toxicology screening and self-reported tobacco use. The presented heroin-related visual cues reliably elicited heroin craving in all tested subjects. Nine, five, three and 15 of the participants, respectively, received zero, one, two and three XRNTX injections, predicted by the individual baseline fMRI signal change in response to the cues in the medial prefrontal cortex, a brain region involved in inhibitory self-control and emotional appraisal. The incidence of opioid-positive urines during the XRNTX therapy was low and remained about half the pre-treatment rate after the XRNTX ended. During the treatment, cigarette smoking behaviors followed patterns of opioid use, while cocaine consumption was increased with reductions in opioid use. The present data support the hypothesis that medial prefrontal cortex functions are involved in adherence to opioid antagonist therapy. A potential role of concurrent non-opioid addictive substances consumption during the XRNTX pharmacotherapy warrants further investigation. Our findings set the stage for further bio-behavioral investigations of the mechanisms of relapse prevention in opioid dependence.

Figure 1

Self-reported craving for heroin before and after cue exposure, during the Pre-XRNTX session (blue line) and Post-XRNTX session (red line). Error bars present s.e.m. X axis: before cue exposure rating (before) and after cue exposure rating (after). Y axis: heroin craving ratings (0–9). XRNTX, extended-release naltrexone.

Figure 2

Changes of positive UDS in cocaine and opioid over the treatment period (that is, baseline, Pre-XRNTX, first (1st)-XRNTX, second (2nd)-XRNTX, third (3rd)-XRNTX and Post-XRNTX). UDS, urine drug screen; XRNTX, injectable extended-release naltrexone.

Figure 3

Brain regions associated with response to drug cues before the XRNTX treatment. Statistical maps (red–yellow scale) are superimposed on the Montreal Neurological Institute (MNI) brain template and thresholded at z=2.3 (cluster corrected at P<0.05). XRNTX, injectable extended-release naltrexone.

Figure 4

Medial prefrontal and anterior cingulate cortical response to drug cues was positively correlated with the number of XRNTX injections received. Statistical map (red–yellow scale) is displayed over the MNI brain template and thresholded at z=2.3 (cluster corrected at P<0.05). MNI, Montreal Neurological Institute; XRNTX, injectable extended-release naltrexone.

Figure 5

Predictive value of % BOLD signal change in the mPFC for adherence to more than one XRNTX injection. PPV is 60% and NPV is 100% when the mPFC % signal change threshold is −0.51 (highlighted in grey), whereas PPV is 100% and NPV is 58% when the mPFC % signal change threshold is 0.12 (highlighted in orange). BOLD, blood-oxygen-level dependent; mPFC, medial prefrontal cortex; NPV, negative predictive value; PPV, positive predictive value; XRNTX, injectable extended-release naltrexone.