PAR-28-009: NCCIH's New Bet on Natural Products for Non-Addictive Pain Management

Academic pharmacology, neuroscience, and complementary medicine PIs have until an estimated May 25, 2027 to prepare for PAR-28-009, a new NCCIH program announcement posted on Grants.gov that targets interdisciplinary research on non-addictive natural products for chronic pain management.

What PAR-28-009 Funds — and What Makes It Different

The National Center for Complementary and Integrative Health forecasted PAR-28-009 on April 22, 2026, under the title "A Holistic Approach to Study Non-Addictive Natural Products for Pain Management." The full Notice of Funding Opportunity is expected to publish on February 2, 2027, with applications due by May 25, 2027 and awards anticipated for April 3, 2028 in fiscal year 2028.

This is not another general pain research solicitation. NCCIH is specifically seeking collaborative, interdisciplinary teams that can study how natural products — botanicals, dietary supplements, and other naturally derived compounds — influence chronic pain through coordinated biological pathways across multiple organ systems simultaneously. The listing under Assistance Listing 93.473 (Complementary and Integrative Health — Research Projects) makes the programmatic home clear, and the PAR designation signals that applications will go through a dedicated review process rather than competing in a general study section.

The eligible applicant pool is unusually broad for an NIH mechanism: government entities, universities and colleges both public and private, nonprofits, small businesses, Native American tribal organizations, faith-based organizations, and even non-domestic entities. NCCIH is casting a wide net because the science it wants requires expertise that does not live in any single department or institution type.

No cost-sharing is required.

A Systems-Level Bet on Chronic Pain

The most distinctive feature of PAR-28-009 is its insistence on multi-organ, system-oriented research. NCCIH is not interested in proposals that study how a single compound acts on a single receptor in an isolated pain pathway. The program explicitly calls for research examining how natural products influence pain through coordinated biological mechanisms across the digestive, immune, vascular, musculoskeletal, lymphatic, metabolic and adipose tissue, and nervous systems.

This reflects a fundamental shift in how NCCIH conceptualizes pain biology. The classical pharmacological approach — identify a molecular target, design a ligand, test it in a disease model — produced opioids, NSAIDs, and gabapentinoids. Each addresses one pain mechanism. None addresses the integrated systems dysfunction that underlies most chronic pain conditions. NCCIH is making an explicit bet that natural products, which often contain dozens of bioactive compounds acting on multiple pathways simultaneously, may be better suited to a systems-level intervention than single-target synthetic drugs.

For researchers, this framing creates both opportunity and challenge. The opportunity is dedicated funding for work that the traditional R01 parent announcement often struggles to review fairly — holistic, multi-system, multi-compound studies that do not fit cleanly into a single study section's domain expertise. The challenge is that proposals must be genuinely interdisciplinary, not merely claim to be. An ethnobotanist studying turmeric's effects on NF-κB signaling alone will not satisfy PAR-28-009's mandate. A team combining ethnobotany, immunology, gastroenterology, and computational biology to study turmeric's coordinated effects across gut-immune-neural axes is closer to what NCCIH envisions.

The bar for collaboration here is structural, not cosmetic. Expect review panels to scrutinize whether each investigator's contribution is integral to the systems-level design or whether "interdisciplinary" is simply a label applied to a collection of loosely related aims.

Dose Optimization Through Hormesis

PAR-28-009 also introduces a requirement that will be unfamiliar to many traditional pharmacologists: dose optimization based on the principles of hormesis. Hormesis is the biphasic dose-response phenomenon in which low doses of a substance produce beneficial or adaptive effects while higher doses are ineffective or harmful. The concept has robust evidence in toxicology and radiation biology, but its systematic application to natural product pharmacology remains relatively nascent.

NCCIH's inclusion of hormesis signals that the center expects applicants to move beyond simple dose-escalation study designs. Proposals should account for the possibility — increasingly supported by published evidence — that the therapeutic window for many natural products may be narrower and lower than conventional pharmacology would predict, and that dose-response relationships may be distinctly non-linear. This has practical implications for everything from in vitro assay design to clinical dosing protocols to statistical analysis plans.

Researchers unfamiliar with hormesis literature should start with Edward Calabrese's foundational work at the University of Massachusetts Amherst, which has established much of the conceptual and empirical framework now being adopted across pharmacology and toxicology. Understanding hormetic dose-response curves will be essential for competitive proposals under this mechanism.

The Chronic Pain Numbers Driving This Investment

The timing of PAR-28-009 is not accidental. Chronic pain in the United States has reached what the CDC now characterizes as its highest recorded prevalence. According to the most recent National Health Interview Survey data, published in a CDC data brief in November 2024, an estimated 60 million American adults — 24.3 percent of the adult population — experienced chronic pain in 2023. That figure is up from 20.5 percent in 2019, representing an 18 percent increase in just four years. Of those 60 million, roughly 21 million reported high-impact chronic pain that substantially limits work, social activities, and daily life.

Long COVID accounts for approximately 13 percent of the observed increase, but the upward trajectory predates the pandemic and reflects deeper structural factors: an aging population, rising rates of obesity, increased sedentary work, and the lingering consequences of two decades of opioid overprescription that left millions of patients cycling between chemical dependence and undertreated pain.

The opioid crisis itself is the political and scientific backdrop against which NCCIH's natural products agenda becomes viable at scale. The HEAL (Helping to End Addiction Long-term) Initiative, NIH's signature program for addressing opioid use disorder and improving pain management, has invested billions across multiple institutes since its 2018 launch. PAR-28-009 explicitly aligns with HEAL's objectives, positioning natural products research as part of the federal government's broader strategy to develop non-addictive alternatives to opioid analgesics.

NCCIH has historically been one of the smaller NIH institutes, with an annual budget of approximately $170 million — a fraction of what NCI or NIAID command. That budget survived the FY2026 appropriations process intact despite the administration's proposal to eliminate the center entirely. Congress rejected the elimination and maintained NCCIH funding at FY2025 levels as part of the $48.7 billion NIH discretionary package. The fact that PAR-28-009 emerged from a center that recently fought for its institutional survival tells you something about how seriously NCCIH takes this research direction.

Where PAR-28-009 Fits in the Broader Funding Landscape

PAR-28-009 does not exist in isolation. The HEAL Initiative committed an estimated $2.5 million in FY2025 to fund four to five awards specifically for natural products pain research. The Pain Research Enhancement Program (PREP), issued under RFA-AT-25-003, is offering up to $1.25 million per year through FY2026 and FY2027 for up to three awards via the R15 mechanism — a vehicle designed for investigators at institutions that have not historically received large NIH funding.

What PAR-28-009 adds is a dedicated, named program announcement specifically designed for the systems-level, multi-organ research that existing mechanisms do not explicitly encourage. An R01 submitted through the parent announcement can fund natural products research, but general study section reviewers may lack the cross-disciplinary expertise to evaluate a truly holistic, multi-organ proposal. A dedicated PAR with a focused review panel changes that calculus considerably.

This also matters in the context of NIH's recent structural overhaul. With the agency consolidating more than 800 NOFOs into fewer than 500, dedicated program announcements like PAR-28-009 are becoming rarer and more strategically significant. When NCCIH creates a new targeted mechanism rather than routing this research through parent announcements, it sends an unmistakable signal about institutional priority — one that program officers, review panels, and advisory council members all receive.

Who Should Start Assembling Teams Now

Although the full NOFO will not publish until February 2027, the ten-month lead time between now and that date is not as generous as it appears. Competitive proposals under a program demanding collaborative, interdisciplinary teams require significant preparation — building partnerships, generating preliminary data, and aligning institutional support.

If you work in any of the following areas, PAR-28-009 should be on your active planning horizon:

Pharmacognosy and natural product chemistry. If your lab isolates, characterizes, or synthesizes bioactive compounds from botanical sources, this program needs your expertise — but not in isolation. Start identifying clinical and translational collaborators now.

Pain neuroscience. Researchers studying peripheral and central sensitization, nociceptor biology, or pain circuitry who have not worked with natural products before should consider this an entry point. NCCIH is explicitly seeking cross-pollination between pain biologists and natural product specialists.

Immunology and gut-brain axis research. The multi-organ mandate makes investigators studying neuroimmune interactions, gut microbiome-pain connections, and systemic inflammatory mediators highly attractive collaborators for PAR-28-009 teams.

Computational biology and systems pharmacology. Multi-compound, multi-target research generates complex datasets that demand sophisticated analytical approaches. Teams with capabilities in network pharmacology, multi-omics integration, and systems modeling will be best positioned to propose — and execute — the kind of work NCCIH envisions.

Clinical researchers in integrative medicine. If you have existing data on natural product interventions for pain in clinical populations, your preliminary findings could anchor a translational proposal and demonstrate feasibility.

The immediate next step is to search active NIH pain management and natural products opportunities on Granted to identify complementary funding mechanisms that could support pilot work while you assemble your PAR-28-009 team. Monitor the NIH Guide for Grants and Contracts for the official NOFO publication in early February 2027, and contact NCCIH program staff in the interim to discuss whether your research concept aligns with the program's scope. The forecast is now public, which means program officers can discuss it.

What This Signals About Federal Pain Research

PAR-28-009 is a small but telling indicator of where federal pain funding is heading. At a moment when NIH is consolidating opportunities and retreating from targeted mechanisms, NCCIH is creating a new one — and building it around a research paradigm that did not have a dedicated home at NIH five years ago: systems biology, hormesis-informed dosing, and multi-organ integration applied to naturally derived compounds.

For the pharmacology and neuroscience communities, this is worth watching whether or not you plan to apply. The emphasis on systems-level approaches, non-linear dose-response relationships, and mandatory cross-disciplinary collaboration reflects a broader intellectual shift in how federal funders conceptualize complex chronic conditions. The investigators who build those capabilities now — even outside the natural products space — will be better positioned for wherever NIH pain research priorities move next.

Applications are estimated to be due May 25, 2027. The clock is already running.