RFA-NS-25-023: HEAL Initiative Studies to Enable Analgesic Discovery (R61/R33, Clinical Trial Not Allowed)
NIH HEAL funds preclinical translational work to build stronger evidence for non-addictive analgesic discovery through a two-stage R61/R33 mechanism with no clinical trials and strict peer-review criteria.
RFA-NS-25-023: HEAL Initiative Studies to Enable Analgesic Discovery (R61/R33, Clinical Trial Not Allowed)
Current status and next application date
The NIH funding notice remains active. Its September 17, 2026 application date has passed, and the next listed due date is January 15, 2027. The notice expires January 16, 2027. Applications are due by 5:00 p.m. in the applicant organization’s local time. The January date is a scheduled application date, not a continuous or rolling intake. The NIH encourages applicants to submit early enough to identify and correct submission errors before the deadline.
The official notice lists a sequence of dates: January 28, 2025; May 16, 2025; September 17, 2025; January 16, 2026; May 15, 2026; September 17, 2026; and January 15, 2027. The review and award schedule pairs the January 2027 submission with scientific merit review in July 2027, Advisory Council review in October 2027, and an earliest start date in December 2027. Those are NIH’s published planning dates, not a promise of award or a substitute for the official notice if NIH posts an update. The notice itself gives January 16, 2027 as its expiration date.
The solicitation is RFA-NS-25-023, “HEAL Initiative: Studies to Enable Analgesic Discovery (R61/R33 – Clinical Trial Not Allowed),” run through the National Institutes of Health’s HEAL Initiative. The official source is the NIH Notice of Funding Opportunity. Use that notice as the authority for dates, forms, and detailed instructions.
Purpose and fit
This NIH HEAL Initiative grant supports early translational work that helps a drug-discovery program develop non-opioid, non-addictive treatments for pain. It is intended to move a promising approach toward the entry criteria for the Pain Therapeutics Development Program or another later-stage translational program. It can support assay development and validation, screening for initial hits or bioactive agents, and characterization that helps establish whether a therapeutic approach is worth advancing.
The opportunity is not tied to one pain diagnosis. The notice identifies a broad set of possible conditions, including acute and chronic pain, neuropathic and musculoskeletal pain, headache disorders, osteoarthritis, diabetic or chemotherapy-induced neuropathy, eye pain, sickle-cell pain, post-surgical pain, cancer pain, visceral, obstetric and gynecologic pain, post-stroke pain, myofascial pain, orofacial pain, pain with substance use disorders, and pain across the lifespan. Work focused on underserved populations can be responsive. NIH strongly encourages meaningful input from people with lived experience on therapeutic goals.
A strong application starts with a plausible, druggable target and a rigorous biological rationale connected to a particular human pain condition. The proposal should explain unmet medical need, the therapeutic landscape, why the target or modality could improve on existing pain management, and why the approach is expected to have little or no addiction liability. Preliminary support should come from well-designed experiments, published evidence, other data sources, or investigator-generated results. A project whose main goal is to discover or validate a target without a solid starting rationale is a weaker fit; the notice points those applicants toward other NIH opportunities.
Research activities supported
The notice focuses on a testing funnel that can make therapeutic discovery decisions more reliable. Examples include assays that measure potency, specificity, selectivity, purity, identity, stability, cellular uptake, target engagement, functional effects, or biophysical properties. Projects may optimize assays for medium- or high-throughput screening, use computational or biophysical methods to identify initial hits, synthesize and characterize a focused set of agents, or develop bioanalytical methods that measure an agent and relevant metabolites.
Eligible agent types include small molecules, biologics such as peptides, proteins, oligonucleotides, gene or cell therapies and emerging modalities, and natural products. For this notice, natural products include extracts, chromatographic fractions, or isolated secondary metabolites from herbal, botanical, marine, microbial, or animal sources. Assay work can use targeted or phenotypic approaches, including cell-based assays and some non-mammalian model organisms. Computational screening must be followed by in vitro work that confirms hit activity and, where relevant, other key properties. For a proposed screening project, identify the source and size of the library; there is no minimum library size, but it must be suitable for the proposed screen.
Limited in vitro or ex vivo biology studies may fill a specific gap in an otherwise robust package. Preliminary in vivo pharmacokinetic, pharmacodynamic, or efficacy work may also be supported when the agent or tool compound is already sufficiently characterized to make those studies interpretable. Applicants need to describe the agent and provide the evidence that supports its use. NIH cautions that this notice is not intended to fund a project that combines screening activities with follow-on in vivo testing of newly identified hits. Projects with a well-characterized agent and a credible downstream development path should compare their plans with the Pain Therapeutics Development Program criteria and consider contacting NIH program staff about fit.
R61/R33 structure and milestones
This is a phased R61/R33 award. The R61 phase generally supports preparatory or prerequisite work that establishes feasibility for the R33 phase. The phases cannot overlap. Their activities should match the project’s stage: for example, early screening, synthesis, or biophysical characterization may belong in R61, followed by functional assays in R33. When an application already has a predefined, well-characterized agent, the notice gives pharmacokinetic work in R61 followed by informed in vivo studies in R33 as an example.
Transition to R33 depends on successful completion of the proposed milestones. Each milestone should be a quantitative goal with a timeline and measurable criteria that supports a go/no-go decision. It should show progress toward the overall therapeutic discovery goal, rather than merely listing work to be done. NIH program staff may discuss or revise milestones before an award, and the final approved milestones are specified in the Notice of Award. The application should explain what evidence will count as success, what result would stop or redirect the work, and how the planned R33 activities depend on the R61 outcome.
Award amount and duration
The notice says NIH HEAL intends to commit an estimated total of $2,500,000 for 4–5 awards in FY 2025. Awards depend on appropriations and a sufficient number of meritorious applications. This is the estimate stated in the solicitation, not a per-project award amount or a guarantee that any application will be funded in the next review cycle.
Application budgets are limited to $350,000 in direct costs per year and should reflect the actual project needs. The combined R61/R33 project period may not exceed three years. No more than two years may be assigned to either phase, and the phases cannot run at the same time. Cost sharing is not required. Build a budget that corresponds to the staged research plan and does not assume that the full annual ceiling will be awarded automatically.
Who may apply
The eligible applicant categories listed by NIH include public and private institutions of higher education; nonprofits with or without 501(c)(3) status; small businesses and other for-profit organizations; state, county, city or township, special district, and tribal governments; eligible federal agencies; U.S. territories or possessions; independent school districts; public housing authorities or Indian housing authorities; tribal organizations; faith-based or community-based organizations; and regional organizations.
Non-U.S. organizations may not apply. Non-U.S. components of U.S. organizations are also not eligible under this notice, while foreign components as defined in the NIH Grants Policy Statement are allowed. Applicants should check the notice’s definitions and their institution’s grants office for the distinction before building an international collaboration into the application. Multiple scientifically distinct applications from one organization are allowed. NIH will not accept duplicate or highly overlapping applications under review at the same time, subject to its resubmission and overlap policies.
The opportunity does not require cost sharing. The research must not propose a clinical trial: the title and eligibility section both state “Clinical Trial Not Allowed.” Keep the proposed scope within nonclinical discovery and preclinical work described in the notice.
How to prepare and submit
Start with the current NIH Research (R) application instructions and the full RFA-NS-25-023 text. The notice requires conformance to both. The application package is available through NIH ASSIST, Grants.gov Workspace, or an institutional system-to-system solution. Ask institutional sponsored research staff which route they use and follow its steps to prepare, submit, and track the application. NIH identifies eRA Commons as part of tracking through the institutional S2S or Grants.gov route.
The applicant organization must complete and maintain the registrations described in the NIH Application Guide. NIH specifically notes that obtaining an eRA Commons account can take up to two weeks, so confirm registration status early with the institutional grants office rather than waiting until submission week. Follow the current guide for SAM.gov, Grants.gov, and eRA Commons requirements, account roles, and organization records; the NOFO incorporates those instructions rather than replacing them. Resolve organization identity or account problems well before the due date.
Organize the research plan around the required sections in the notice. In Specific Aims, include separate headings titled “R61 Phase Specific Aims” and “R33 Phase Specific Aims,” state the technical questions and objectives for each phase, and make the dependency between phases clear. The Research Strategy must include Significance, Approach, Innovation, Therapeutic Discovery Plan, and Milestones and Timeline. Address the biological and therapeutic rationale, the intended pain condition, preliminary evidence, assay or agent plan, decision path, model and endpoint choices when applicable, and how the work advances toward a later translational program.
A required attachment titled IP Strategy is limited to two pages. Describe the intellectual-property landscape and known restrictions that could affect research or commercial development, including relevant compounds, biologics, assays, models, patents, licenses, or sharing agreements. Explain future filing plans and how IP will be managed if multiple investigators or institutions are involved. If the project uses an agent whose IP is owned by another entity, include the support letter described in the notice confirming that no restrictions will impede the program’s goals. The notice encourages consultation with institutional technology-transfer officials.
Use a realistic, quantitative milestone plan. If the work includes screening, specify the library source and size and the follow-up used to confirm hits. For in vivo work, explain why the agent is characterized well enough, and justify the model, controls, outcomes, and endpoints. The notice also calls for multidisciplinary expertise relevant to the plan, such as biostatistics, clinical context, drug development, or technical assay work. It strongly encourages meaningful engagement with people who have lived experience.
HEAL applicants must include a Data Management and Sharing Plan that addresses HEAL data requirements. Plans should cover submission of data, metadata, and applicable code to a HEAL-compliant repository, study registration with the HEAL platform within one year of award, study-level metadata, and data dictionaries where applicable. The notice also requires immediate public availability of resulting HEAL-funded publications; include any needed open-access costs in the budget. These are project and award requirements to plan for, not substitutes for the submission components in the Application Guide.
Submit through the selected system by 5:00 p.m. local time on January 15, 2027. NIH encourages early submission so errors can be corrected by the due date. Monitor the application in the relevant NIH systems after submission and address any warnings or errors within the allowed window. Consult the full NOFO for page limits, forms, review criteria, and agency contacts; this page is a guide to fit and planning, not a replacement for those official instructions.
Practical fit check
Before investing in a full application, ask whether the project has a defined therapeutic target, a credible relationship to a human pain condition, and enough evidence to justify the proposed experiments. Check whether the work is actually early translation toward a therapeutic discovery program, whether assay outputs will inform a real selection decision, and whether the non-addiction rationale is supported. Then test whether each R61 activity reduces a named uncertainty and whether its success criteria make the R33 transition defensible.
A proposal that primarily explores basic biology without a clear path to a therapeutic agent may not fit. A proposal requiring patient enrollment or another clinical trial is outside this notice. A proposed in vivo study without a sufficiently characterized agent is also difficult to justify. Conversely, an application that links an established rationale to validated assays, a plausible testing funnel, quantitative phase gates, appropriate expertise, and a workable data-sharing plan aligns with the structure NIH describes.