An official website of the United States governmentConcept: A Holistic Approach To Study Nonaddictive Natural Products for Pain Management
Project Concept Review
Council Approval: April 17, 2026
Program Directors: Patrick Still, Ph.D.; Inna Belfer, M.D., Ph.D.
Background
Pain is increasingly recognized as a dynamic, systems-level condition that arises from multiple coordinated interactions among the nervous system, vascular and metabolic tissues, and musculoskeletal structures. Traditional analgesic development, including the Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative-supported portfolio, has largely followed a pharmacologic paradigm centered on single molecular targets within isolated pathways. Although substantial progress has been achieved through classical pharmaceutical approaches, these strategies often do not reflect the multisystem, multifactorial complexity of pain and may carry risks of adverse effects, particularly with long-term use.
Natural products, including botanical compounds and dietary-derived bioactives, are nonpharmacologic alternatives widely used by the U.S. public for pain management. Compounds such as curcumin and cannabidiol (CBD) are commonly used for arthritis, back pain, and post-exercise soreness, while Food and Drug Administration-approved products derived from natural sources, including capsaicin (brand name Qutenza) and ziconotide (brand name Prialt), demonstrate the clinical potential of natural product-based therapies. In contrast to single-target pharmaceuticals, many natural products exert pleiotropic effects across multiple biological pathways and may engage coordinated adaptive stress response networks. Consistent with this view, an NCCIH-led workshop on Natural Products and Pain, conducted in collaboration with other National Institutes of Health (NIH) Institutes and Centers, concluded that the experience of pain is unlikely to be mediated by a single receptor and that limited efficacy observed with some therapeutics may reflect the underlying complexity of pain mechanisms. Furthermore, a translational gap remains with the lack of integrated mechanistic models that account for how interventions, particularly natural products, interact with spatially distributed biological systems, time-dependent pain processes, and dose-responsive adaptive mechanisms to influence pain management. Together, these observations highlight a need for a holistic research framework that systematically examines multiorgan and multisystem mechanisms of action, optimizes dosing through hormetic principles, and identifies intervention timing aligned with the dynamic phases of pain and inflammation to maximize therapeutic benefit and support effective pain management.
Purpose of Proposed Initiative
The purpose of this concept is to introduce a conceptual shift in pain research by explicitly integrating spatial (multiorgan), hormetic (dose-dependent adaptive), and temporal (phase-specific) dimensions within a single mechanistic framework. By focusing on natural products already widely used by the public, the initiative enhances real-world relevance and positions findings for near-term translational impact. Within the broader NIH HEAL Initiative portfolio, which has significantly strengthened target-based analgesic discovery and Investigational New Drug-enabling development, this initiative will occupy a complementary but distinct role by generating systems-level mechanistic knowledge that informs and strengthens future therapeutic development efforts without centering on product advancement itself.
Objectives
This concept seeks to support coordinated, interdisciplinary team science efforts. Projects are expected to bring together complementary expertise in pain neuroscience, immunology, natural product chemistry, systems biology, pharmacology, and translational research, leveraging integrative approaches that cannot be achieved through isolated or parallel investigations.
In this context, the objectives are to:
- Identify and characterize multiorgan, multisystem mechanisms by which natural products modulate acute pain and influence recovery trajectories
- Define hormetic dose-response relationships for selected natural products, establishing adaptive windows that maximize benefit and minimize disruption of endogenous repair processes
- Identify optimal intervention timing to align with the dynamic phases of pain and inflammation, maximizing therapeutic outcomes while supporting physiological healing
By integrating these domains, the initiative will advance research that reframes how pain therapeutics are studied and optimized. These activities will generate foundational mechanistic knowledge that informs safe, effective, and biologically aligned integration of natural products into pain management strategies.
Examples of research topics of interest include, but are not limited to:
- Studies mapping coordinated immune–nervous–metabolic–vascular responses to natural product exposure in preclinical and clinical models
- Transcriptomic, proteomic, and metabolomic profiling of phase-specific inflammatory responses during pain resolution
- Characterizing tissue-specific metabolomics and/or distribution of metabolites across organ systems
- Identifying windows during which natural product interventions enhance endogenous resolution pathways
- Experimental evaluation of biphasic (hormetic) dose-response curves in pain models