Understanding the Mechanistic, Neurophysiological, and Antinociceptive Effects of Transcutaneous Auricular Neurostimulation for Treatment of Chronic Pain

项目总结/摘要 尽管越来越迫切地需要将许多慢性疼痛患者从处方阿片类药物中过渡出来， 证据支持和混合成功率的替代治疗方法，旨在促进 中止开始阿片类药物减量的患者很少成功，并且一部分患者对阿片类药物有不良反应。 剂量减少，经历了显着恶化的疼痛和心理不稳定。这是特别 长期阿片类药物治疗的患者也是如此，其中生理依赖性的影响改变了 在神经疼痛基质内向失调和超敏状态起作用。神经调节 这些方法特别适合于这种临床挑战，也提供安全有效的镇痛 缓解阿片类药物戒断综合征。特别是，Sparrow治疗系统是FDA批准的 将经皮耳神经刺激（tAN）传递到迷走神经和三叉神经的器械， 治疗阿片类药物戒断期间的疼痛。然而，行动机制仍然很差， 明白缺乏公认的机制模型限制了tAN的临床应用， 了解支持镇痛的神经生理机制将使参数 优化导致精确实施和最大化的治疗益处。我们假设 我们的tAN方法的效果是1）依赖于内源性阿片类神经传递，2）最大限度地 参与同时迷走神经和三叉神经刺激，和3）赋予镇痛的好处， 脑干迷走神经传入的神经活动增加，但皮质和皮质下疼痛的激活减少 网络区域。为了阐明这些提出的机制，我们提供了一个协同的一系列研究，在健康 成人和慢性疼痛患者。Aim 1将使用一种实验性μ-阿片类药物阻滞范例和一种新的 并行疼痛和功能性磁共振成像（fMRI）范例，以评估大脑激活， 耳迷走神经和三叉神经刺激后的痛阈单独和组合呈现。目的2 同样需要同时进行神经刺激和fMRI范式，以观察 耳迷走神经刺激、耳三叉神经刺激、组合刺激或假刺激。 在接受急性阿片类药物治疗的疼痛患者中使用tAN的双盲、假对照临床机制试验 逐渐减少，目标3将建立基于tAN的镇痛的特定神经生理学特征，并区分 这种激活模式与次要结果无关。我们的跨学科方法和多元化的科学团队 生物工程师，神经科学家，临床疼痛和阿片类药物专家非常适合完成这些任务。 目标.该项目的结果将提供一种新兴治疗的具体治疗作用机制 这将扩大对高需求临床人群的益处，并直接导致优化临床方法。

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 population and lead directly to optimized clinical approaches.