Project Summary/Abstract Despite growing urgency to transition many chronic pain patients off prescription opioids, there is limited evidentiary support and mixed success rates for alternative treatment approaches that aim to facilitate discontinuation. Few patients who initiate opioid tapers succeed, and a subset of patients react adversely to dose reductions, experiencing significantly worsened pain and psychological destabilization. This is particularly true with patients on prolonged opioid therapy, in which the effects of physiological dependence alter functioning within the neural pain matrix towards a dysregulated and hypersensitized state. Neuromodulation approaches are particularly well suited for this clinical challenge, offering safe and effective analgesia as well as mitigation of opioid withdrawal syndrome. In particular, the Sparrow Therapy System is an FDA-cleared device that delivers transcutaneous auricular neurostimulation (tAN) to the vagal and trigeminal nerves and is therapeutically indicated for pain during opioid withdrawal. Yet, the mechanisms of action remain poorly understood. The absence of an accepted mechanistic model poses limits on tAN clinical application, as an understanding of the neurophysiological mechanisms supporting analgesia would enable parameter optimization leading to precision implementation and maximized therapeutic benefit. We hypothesize that the effects of our tAN approach are 1) dependent on endogenous opioid neurotransmission, 2) are maximally engaged by simultaneous vagal and trigeminal stimulation, and 3) confer analgesic benefits associated with increased neural activity in brainstem vagal afferents but decreased activation in cortical and subcortical pain network regions. To elucidate these proposed mechanisms, we offer a synergistic series of studies in healthy adults and chronic pain patients. Aim 1 will use an experimental µ-opioid blockade paradigm and a novel concurrent pain and functional magnetic resonance imaging (fMRI) paradigm to assess brain activation and pain thresholds following auricular vagal and trigeminal stimulation presented alone and in combination. Aim 2 will likewise entail a concurrent neurostimulation and fMRI paradigm to observe the direct brain effects of auricular vagus stimulation, auricular trigeminal stimulation, combination stimulation, or sham stimulation. Using a double-blind, sham-controlled clinical mechanistic trial of tAN in pain patients undergoing acute opioid tapering, Aim 3 will establish the specific neurophysiological signature of tAN-based analgesia and differentiate this activation profile from secondary outcomes. Our interdisciplinary approach and diverse scientific team of bioengineers, neuroscientists, and clinical pain and opioid specialists is well suited for accomplishing these goals. Results of this project will deliver specific therapeutic mechanisms of action of an emerging treatment that will expand benefits for a high-need clinical popul...