Opioidergic pain relief in humans is mediated by beta and high-gamma modulation in limbic regions.

The neurophysiological mechanisms underlying opioid analgesia remain poorly understood, limiting progress toward nonaddictive alternatives. Fentanyl and hydromorphone were administered to patients experiencing semi-chronic, clinically relevant pain following surgical implantation of intracranial electrodes for seizure localization. Pooling recording sites by brain region, opioids significantly suppressed beta oscillations in ventral and dorsolateral prefrontal cortices and high-gamma amplitude in the insula, while enhancing both bands in the hippocampus and posterior cingulate. In an exploratory analysis, beta enhancement in the anterior hippocampus and high-gamma suppression in the insula accompanied pain relief in response to a constant dose. Under conservative modeling, ventral prefrontal beta suppression remained a robust predictor of analgesic efficacy in the sampled cohort. These findings bridge classical models of nociceptive gating with the elusive cerebral substrates that confer pain's distressing salience, identifying potential biomarkers for the development of nonaddictive opioid alternatives.