Multi-receptor whole-cortex adaptations with long-term opioid use in chronic pain

Millions of chronic (non-cancer) pain patients manage their pain with long-duration opioid use1-3, but the neurobiological implications of stable long-term opioid consumption remain unknown. Here, we contrasted the clinical profiles and brain structure and function of 70 chronic back pain patients prescribed opioids (CBP+O, average opioid exposure of 7.8 years) with 70 matched patients managing their pain without opioids (CBP−O) and 39 matched healthy subjects. Despite CBP+O exhibiting only modestly worse clinical profiles than CBP−O with small differences in brain morphology, CBP+O had starkly different brain activity (ALFF). These brain activity differences strongly reflected the cortical spatial distributions of serotonin (5-HT _1A and 5-HT _1B ) and mu-opioid (MOR) receptor densities: CBP+O had greater MOR- and lower serotonin-related activity. Serotonin and MOR-related activities were associated with patients’ functional disability, negative affect, opioid dose, abstinence status, and, in an independent sample, tapering success, indicating that receptor-related activity is a biomarker for multiple clinically relevant characteristics of CBP+O patients. Through pharmacological perturbations in two separate studies (opioid abstinence and 5-HT _1A agonist administration), we found that cortical serotonergic and opioidergic circuits comprise opponent processes. Our results show that long-term opioid use implicates multiple receptors; their interaction points to a molecular target and a molecule that may be exploited to aid opioid tapering.