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The Department of Health and Human Services, through the National Institutes of Health (NIH), has issued a funding opportunity under the HEAL Initiative to develop safe, effective, and non-addictive analgesics for pain treatment. The initiative aims to address the opioid crisis by supporting the preclinical optimization and development of small molecules and biologics leading to clinical trials. The funding opportunity operates as a two-phase program (UG3 and UH3), expecting projects to start with a promising therapeutic candidate for optimization and end with an Investigational New Drug application and Phase I clinical studies. The program encourages collaborations between researchers and NIH contractors, providing substantial NIH guidance and resources. Key dates include the application opening on December 24, 2023, with ongoing reviews leading to funding decisions based on milestone achievements. Eligible applicants include various organizational types, promoting diversity and engagement of individuals with lived experiences in the research process. The initiative specifically seeks to move beyond opioid treatment options by exploring innovative therapeutic targets for a variety of pain conditions. With an estimated total of $11 million available, the initiative emphasizes cooperative agreements and substantial federal involvement in project management.