Development of A Focused Ultrasound Device for Noninvasive, Peripheral Nerve Blockade to Manage Acute Pain

摘要 美国阿片类药物流行在很大程度上是由于阿片类药物在 急性疼痛的治疗。中度和重度急性疼痛在许多医疗保健环境中普遍存在 并与不良结果相关(例如，心肌缺血风险增加、质量恶化 生活成本增加，医疗保健成本增加)。当前的急性疼痛管理策略(全身性止痛药 和周围神经阻滞(PNBs))不足以治疗疼痛。全身性止痛药，例如阿片类药物， 不足以控制急性疼痛(因为它们主要阻断C伤害性纤维，而不是A-三角洲 伤害性纤维)，并有许多有害的副作用，经常导致成瘾。当前的PNB 通过在周围神经注射局部麻醉剂，技术可以改善急性疼痛结果 但一些患者有限制使用的重大缺点(例如，他们是侵入性的，增加了护理 复杂性，并且只能在有限的时间内处理急性疼痛)。FUS诱导的PNB是一个接地- 可替代传统局部麻醉剂的突破性技术/技巧 PNB，防止需要阿片类药物来治疗急性疼痛，并降低发展为慢性疼痛的风险 疼痛。该提案旨在将FUS技术转化为一种新的医疗设备，用于 非侵入性PNB改善急性疼痛管理，导致急性疼痛的戏剧性范式转变 治疗。先前的研究支持FUS治疗急性疼痛的潜力。调查人员已经 在体外和体内动物模型中，将FUS应用于周围神经可导致剂量- 周围神经复合动作电位波幅的依赖性可逆性降低和一过性 神经可逆性啮齿动物神经病理性疼痛模型伤害性阈值的提高 结构。在急性疼痛的活体啮齿动物模型中，我们确定了可逆的FUS参数 阻断周围神经纤维。此外，我们还证明了FUS是可以应用的 经皮下注射以阻断周围神经功能。FUS诱导的PNB作为一种新的临床工具 管理急性疼痛被知识和需求方面的几个可解决的差距所阻碍 技术发展：1)对最佳参数的了解不足 经皮(非侵入性)FUS应用于周围神经，导致可逆性阻断和 没有不良影响；2)没有可用的频率和焦域(高压)的FUS设备 应用于非人灵长类(NHP)和人类周围神经所需的几何形状； 3)缺乏评估经皮FUS应用于周围神经的研究 NHP急性疼痛模型中的可逆性PNB。目前的目标将解决现有的障碍。 预防研究FUS诱导的PNB用于急性疼痛治疗的临床试验。

Abstract The US opioid epidemic developed in large part as a result of the widespread prescription of opioids for the treatment of acute pain. Moderate and severe acute pain are prevalent in many healthcare settings and associated with adverse outcomes (e.g., increased risk of myocardial ischemia, worsened quality of life, increased healthcare costs). Current acute pain management strategies (systemic analgesics and peripheral nerve blocks (PNBs)) insufficiently treat pain. Systemic analgesics, e.g., opioids, are inadequate for controlling acute pain (as they primarily block C nociceptive fibers, not A-delta nociceptive fibers) and have many harmful side effects, frequently resulting in addiction. Current PNB techniques, via the injection of local anesthetics at peripheral nerves, improve acute pain outcomes for some patients but have significant shortcomings limiting use (e.g, they are invasive, increase care complexity, and only manage acute pain for a limited amount of time). FUS-induced PNB is a ground- breaking technology/technique that may serve as an alternative to traditional local anesthetic-based PNB, preventing the need for opioids to manage acute pain, and reducing the risk of developing chronic pain. This proposal outlines aims to translate FUS technology into a novel medical device for noninvasive PNB to improve acute pain management leading to a dramatic paradigm shift in acute pain treatment. Prior investigations support FUS’s potential for managing acute pain. Investigators have found that application of FUS to peripheral nerves in ex vivo and in vivo animal models results in dose- dependent reversible reduction in peripheral nerve compound action potential amplitude and a transient increase in nociceptive thresholds in rodent neuropathic pain models with reversible effects on nerve structure. In an in vivo rodent model of acute pain, we determined FUS parameters for reversible blockade of peripheral nerve fibers. Further, we have demonstrated that FUS can be applied transcutaneously to block peripheral nerve function. FUS-induced PNB as a novel clinical tool for managing acute pain is held back by several addressable gaps in knowledge and need for technological development: 1) An insufficient understanding of the optimal parameters for transcutaneous (noninvasive) FUS application to peripheral nerves resulting in reversible blockade and without adverse effects; 2) No available FUS device with the frequency and focal zone (high pressure area) geometry required for application to non-human primate (NHP) and human peripheral nerves; and 3) Absence of studies evaluating transcutaneous FUS application to peripheral nerves for reversible PNB in a NHP model of acute pain. The present Aims will address the existing barriers preventing clinical trials investigating FUS-induced PNB for acute pain management.