More than 25 million Americans suffer from daily chronic pain, a highly debilitating medical condition that is complex and difficult to manage. In recent decades, there has been an overreliance in the prescription of opioids for chronic pain despite their poor ability to improve function and high addiction liability. This contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative scientific solutions to develop alternative pain treatment options are thus critically needed. Through targeted research efforts, the NIH HEAL Initiative aims to support the development of safe and effective devices to treat pain with little or no addiction liability. This funding opportunity announcement (FOA) is designed to support interdisciplinary research teams of multiple PD/PIs to investigate the mechanism of action of pain relief by medical devices with the overall goal of optimizing therapeutic outcomes for FDA-approved or -cleared technologies. Program teams are expected to accomplish goals that require considerable synergy and collaborative interactions. Teams must leverage appropriate multi-disciplinary expertise to develop new principles and methods for experimentation, analysis, and interpretation. Teams are encouraged to consider objectives that will produce major advances in the field of pain relief by medical devices.