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.