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

摘要 美国阿片类药物的流行在很大程度上是由于阿片类药物的广泛处方， 急性疼痛的治疗。中度和重度急性疼痛在许多医疗机构中普遍存在 并与不良结果相关（例如，心肌缺血风险增加，质量恶化 增加医疗费用）。当前急性疼痛管理策略（全身性镇痛药 和外周神经阻滞（PNB））不足以治疗疼痛。全身性镇痛药，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伤害感受纤维，而不是A-δ 伤害感受纤维），并且具有许多有害的副作用，经常导致成瘾。当前PNB 技术，通过在周围神经注射局部麻醉剂，改善急性疼痛的结果， 但某些患者具有限制使用的显著缺点（例如，它们是侵入性的、增加护理 复杂性，并且仅在有限的时间内管理急性疼痛）。FUS感应PNB是接地- 可作为传统局部麻醉剂替代品的突破性技术/技术 PNB，防止需要阿片类药物来管理急性疼痛，并降低发生慢性疼痛的风险。 痛苦该提案概述了将FUS技术转化为新型医疗器械的目的， 非侵入性PNB改善急性疼痛管理，导致急性疼痛的显著范式转变 治疗先前的调查支持FUS管理急性疼痛的潜力。调查人员 发现在离体和体内动物模型中将FUS应用于外周神经导致剂量- 周围神经复合动作电位振幅和瞬时依赖性可逆性降低 啮齿类动物神经病理性疼痛模型中伤害感受阈值的增加对神经具有可逆作用 结构在急性疼痛的体内啮齿动物模型中，我们测定了可逆性疼痛的FUS参数。 周围神经纤维阻滞。此外，我们已经证明，FUS可以应用于 经皮穿刺以阻断外周神经功能。FUS诱导的PNB作为一种新的临床工具， 急性疼痛的管理受到知识和需求方面的几个可解决的差距的阻碍， 技术发展：1）对最佳参数的了解不足， 经皮（非侵入性）FUS应用于外周神经，导致可逆性阻滞， 无不良反应; 2）无可用的频率和聚焦区FUS器械（高压 区域）几何形状要求应用于非人类灵长类动物（NHP）和人类外周神经; 和3）缺乏评价经皮FUS应用于外周神经的研究， 可逆PNB在急性疼痛的NHP模型。目前的目标将解决现有的障碍 阻止研究FUS诱导的PNB用于急性疼痛管理的临床试验。

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.