Prescription opioid-related alterations to amygdalar and thalamic functional networks in chronic knee pain: A retrospective case control resting-state connectivity study

Objective Long-term opioid use is associated with diminished pain relief, hyperalgesia, and addiction which is not well understood. This study aimed to characterise opioid-related brain network alterations in chronic pain, focused on the right amygdala, and left mediodorsal thalamic nuclei that play key roles in affective pain processing, and are particularly rich in mu opioid receptors (MOR). Subjects Participants on opioid prescriptions with painful knee osteoarthritis and matched non-opioid using control pain participants. Methods and design Seed-based functional connectivity (FC) maps from resting-state fMRI data were compared between groups. Results We found right amygdala hyperconnectivity with the posterior default mode network (pDMN) and the dorsomedial prefrontal cortex in opioid users in contrast to anti-correlations in controls. Conversely, opioid users showed predominant hypoconnectivity of the left dorsomedial thalamic seed with the cingulate cortex except for the subgenual part displaying an anti-correlation in opioid users and no association in non-users. Opioid users also showed higher negative affect in exploratory post-hoc tests suggesting a potential contribution of trait anxiety to amygdala-pDMN FC alteration. Conclusion Opioid use related hyperconnectivity of the right amygdalar network likely reflects maladaptive mechanisms involving negative affect and network plasticity. Hypoconnectivity of the mediodorsal thalamic nuclei with the anterior and mid cingulate on the other hand may reflect impaired resilience in line with previously reported compensatory MOR upregulation. In conclusion, this study provides new insight into possible brain mechanisms underlying adverse effects of prolonged opioids in chronic pain and offer candidate network targets for novel interventions.