The Department of Health and Human Services, through the NIH HEAL Initiative, is issuing a funding opportunity aimed at encouraging research for the development of non-opioid analgesics. Known as RFA-NS-25-023, this program seeks applications for early-stage translational research that will develop and validate tests for identifying potential pain treatment agents, including small molecules and biologics. The goal is to establish a strong biological rationale for novel therapies that minimize addiction risks, thereby addressing the opioid crisis impacting millions suffering from chronic pain. Eligible applicants include various educational institutions, nonprofits, and government entities, with an anticipated funding pool of $2.5 million for around 4-5 awards in FY 2025. Applications are due by January 2027, with a clear emphasis on milestone-driven R61/R33 phased awards. Engagement with diverse research teams and collaboration with stakeholders, particularly individuals with pain experience, is encouraged. The document outlines detailed application requirements, including intellectual property strategies and the necessity for rigorous and transparent research methodologies, ensuring a comprehensive approach to advancing pain therapeutics development.