Multi-molecular adaptations of long-term opioid use in chronic pain

Millions of chronic pain patients are managed with opioids, yet the neuropsychological implications of stable long-term daily opioid consumption remain unknown. Here, we contrasted the psychosocial profiles and brain structure and function of 70 chronic back pain patients prescribed opioids (CBP+O, average current daily opioid exposure of 7.8 years) with tightly matched 70 opioid-naïve patients (CBP-O) and 30 healthy subjects. Despite CBP+O exhibiting only modestly worse psychosocial profiles and small differences in brain morphology relative to CBP-O, CBP+O showed stark differences in brain activity (ALFF). A large portion (38% of the variance) of this pattern was captured by a model using 19 receptor/transporter distributions. The patients' (across all 140 CBP) psychosocial profiles were summarized by three principal components (PCs, explaining 70% of variance): functional disability, pain quality, and negative affect. These PCs were respectively associated with serotonergic (5HT1a and 5HT6) and opioidergic (mu-opioid receptor, MOR) receptor-related activities. In additional analyses and new data, 5HT1a- and MOR-related activities tracked opioid dose, abstinence status, and tapering success, while 5HT6-related activity tracked pain intensity. Overall, our findings uncover molecularly defined brain circuits in opioid use and chronic pain.