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

The nature of the neurophysiological effects of opioids, especially those responsible for their analgesic properties, are unknown, hindering efforts to develop non-addictive alternatives. Fentanyl and hydromorphone were administered to patients experiencing semi-chronic, clinically-relevant pain after surgical implantation of electrodes for the localization of seizure onset. Opioids suppressed beta oscillations in lateral amygdala, ventral and dorsolateral prefrontal cortices, and increased beta in medial amygdala and hippocampus. Opioids also suppressed high gamma oscillations in insula and lateral amygdala, and increased high gamma in cingulate cortex and hippocampus. The amplitude of these beta effects in the ventral prefrontal cortex, medial amygdala and hippocampus, and of gamma effects in the insula, were positively correlated with the magnitude of pain relief in response to a constant dose. These findings identify electrophysiological events in a network of limbic structures that may participate in opioidergic pain relief through nociceptive gating and a decreased concerned fixation on pain, providing insights into the neural basis of pain relief and suggesting possible biomarkers for developing non-addictive opioid alternatives.