NIH HEAL Initiative®: A Promising Path Forward for Pain Research

Chronic pain affects over 50 million people in the United States. The estimated annual economic burden of pain management for people with chronic pain is $725 billion dollars. It can be invisible to others, but it’s a daily reality for those who experience it—it adversely affects physical, mental, and emotional health and often limits participation in work, school, family life, and society. Though distinct experiences, pain and suffering are tightly linked. 

The need for safe, effective, and non-addictive pain care has never been more urgent. Chronic pain is becoming more common. Nearly 25% of adults in the U.S. had chronic pain in 2023. This is higher than 2019, when about 20% of adults had chronic pain. Millions of people with back pain, migraine, neuropathic pain, or other pain conditions struggle to find relief. Opioids have been a staple in pain treatment for over 5,000 years, but they don’t work for many people and have led to multiple epidemics of opioid use disorder and addiction. We’ve made progress in understanding fundamental aspects of human pain and are now poised to use that knowledge to develop new pain treatments and advance the goal to end addiction long term. 

In 2018, the National Institutes of Health (NIH) launched the Helping to End Addiction Long-term Initiative®, or NIH HEAL Initiative®, to speed scientific solutions to the nation’s opioid crisis by improving the understanding, management, and treatment of pain and the prevention and treatment of opioid use disorder, addiction, and overdose. As the opioid and overdose crises have evolved and pain has grown more common – surpassing other chronic diseases like diabetes, depression, and high blood pressure – the NIH HEAL Initiative is setting its sights on priority research areas to solve the challenge head-on. This aggressive effort is co-led by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Drug Abuse (NIDA). NINDS leads a collaborative effort that pools the expertise of 15 NIH Institutes and Centers to transform how we understand and treat pain so that people have more options for care that works for them.

Now in its eighth year, HEAL has grown into one of the world’s most productive pain research efforts. HEAL has developed an array of programs to support pain treatment development—from target validation through Phase II clinical trials—and launched real-world studies to improve the effectiveness of pain management in communities. Here’s a closer look at some of the initiative’s progress in pain research.

  • The Pain Therapeutics Development Program (PTDP) advances non-opioid small molecules and biologics through a milestone-driven approach designed to accelerate the early-stage development of therapeutic analgesics. PTDP plays a key role in de-risking the drug development process for industry. Since 2019, PTDP has supported 18 projects, two of which have achieved Food and Drug Administration (FDA) IND clearance and launched first-in-human trials for neuropathic and inflammatory pain. One program has been licensed to a pharmaceutical company, and two others have formed industry partnerships for further development.
  • In parallel, the Preclinical Screening Platform for Pain (PSPP) provides academic and commercial teams with access to rigorous in vitro and in vivo testing models that incorporate internal and external safeguards and controls to reduce bias and increase reproducibility. Over 55 assets have been profiled to date: five have progressed to clinical development and 31 are still under continued evaluation.
  • HEAL has built a national pipeline of device-based innovation for pain management, funding over 25 projects through its Translational Devices Program. These include high-resolution spinal cord stimulators, non-invasive neuromodulation systems, and wearable diagnostics. The FDA has approved five Investigational Device Exemptions (IDEs), and many devices have progressed from early prototyping into clinical testing.
  • HEAL’s Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Program is developing novel pain therapies, diagnostics, and medical devices. These programs provide early-stage funding to U.S.-based small businesses to advance high-impact, high-risk technologies that traditional investors may overlook. Since its launch, HEAL has supported over 60 small U.S.-based companies through 66 awards, investing more than $60 million in federal funding, which has helped leverage over $560 million in follow-on private capital. HEAL-supported small businesses have achieved critical regulatory milestones, including multiple INDs and several Phase 1 clinical trials.
  • The Back Pain Consortium (BACPAC) Program is a transdisciplinary research effort focused on understanding and treating chronic low back pain, one of the most common and disabling conditions in the U.S. BACPAC brings together mechanistic science, clinical research, data science, and technology development to create personalized, non-opioid pain care solutions. A major achievement of BACPAC is the development and validation of the CAPER (Comprehensive Assessment and Prioritization Evaluation for Treatment) tool. This clinical decision support system helps providers tailor treatment selection based on patient-specific characteristics. This tool is designed for real-world clinical use and has been piloted in multiple health care settings to support shared decision-making and optimize non-surgical treatment pathways.
  • To accelerate discovery, promote reproducibility, and maximize the return on public investment, HEAL created the HEAL Data Ecosystem (HDE)—a cloud-based platform that supports open science and cross-disciplinary collaboration. This innovative federated data resource enables researchers, clinicians, and the public to access and analyze data from HEAL-funded studies in one centralized environment. Currently, the platform houses 1,015 curated datasets across the pain and opioid use disorder portfolios, with more added as studies mature. The HDE supports data harmonization, visualization tools, and standardized documentation, making it easier to integrate and reuse information across studies.

Consider a few examples of projects that have the potential to transform pain treatment and clinical care. 

Medical providers and the scientific community have long known that taking opioids to treat pain can lead to medication tolerance, requiring more opioids to achieve the same pain relief and even to an increased sensitivity to pain, or opioid-induced hyperalgesia (OIH)—sometimes called paradoxical pain. In a recent study, researchers identified a protein called Tiam1 as a key mediator of analgesic tolerance to morphine and of the development of OIH. This promising work could lead to the development of novel therapeutics targeting Tiam1 for achieving pain relief without the side effects of medication tolerance and hyperalgesia.

HEAL is supporting research into implantable devices as a more sustainable treatment option for acute and chronic pain. HEAL-supported Allay Therapeutics received approval from the FDA for its investigational new drug (IND) application to conduct a pivotal Phase II clinical trial for ATX101—an implantable treatment for post-surgical pain following knee replacement surgery. This implant slowly releases a local anesthetic that can provide relief for weeks after surgery and is then broken down naturally by the body.

For people undergoing hemodialysis, pain is common, and it’s challenging to treat with medication. The HOPE Consortium Trial tested non-drug coaching support to help people dependent on dialysis (or with end-stage renal disease) manage their pain. Many participants experienced meaningfully improved outcomes in pain intensity, quality of life, and depression. Crucially, people with lived experience of pain helped guide the design of the intervention, ensuring the study was grounded in real needs.

In a pioneering collaboration between the NIH's HEAL and BRAIN Initiatives, researchers recorded brain activity from individuals living with severe chronic pain due to stroke or amputation. Using implanted stimulation electrodes and machine learning, the study identified brain signatures of chronic pain in regions linked to emotional processing and decision-making. These early findings lay the groundwork for non-addictive, personalized treatments, such as adaptive deep brain stimulation. And they offer new hope for people with pain who haven't found relief through conventional therapies. By targeting the brain activity that underlies chronic pain itself, future interventions could provide relief where medications and other approaches have failed.

Another HEAL-funded study at Johns Hopkins University examines knee pain associated with osteoarthritis. Although highly prevalent, this condition still lacks consensus on the best treatment approaches. Researchers are testing multiple combinations—pain medications, an online program teaching pain coping skills, and physical therapy—through a sequential treatment strategy that tailors care to individual patient responses. This work aligns with HEAL's goal of personalizing pain treatment across various conditions and populations.

You can read more about HEAL’s recent accomplishments in both pain and opioid use disorder and overdose research in the 2025 HEAL Annual Report. Past Annual Reports are also available on the HEAL website.

To sustain and build on this momentum, NINDS convened a working group of its Advisory Council to chart the next five years of HEAL’s pain research investments. Through this effort, 10 research priorities were developed collaboratively with input from researchers, clinicians, and, importantly, people living with pain. 

The priorities call for research that will:

  1. Deepen our understanding of human pain biology and mechanisms
  2. Develop strategies to halt, prevent, or reverse chronic pain
  3. Explore new behavioral therapies or interventions, including those that use new devices and telehealth
  4. Identify biomarkers that can predict safe and effective treatment response to better track pain and tailor treatment
  5. Evaluate the impact of personalized treatments
  6. Generate evidence-based guidance on the timing and combination of therapies
  7. Conduct real-world, community-embedded studies for broad impact
  8. Address disparities by studying populations affected by pain and substance use disorders
  9. Support basic, clinical, and translational pain researchers across all career stages
  10. Support non-drug interventions, including those for people with co-occurring substance use disorders

These priorities recognize the complexities of pain and the intertwined issue of opioid use disorder. They also emphasize research on high-value, low-risk treatments—such as behavioral and physical therapy—often underutilized or insufficiently covered by insurance. You can read the full HEAL pain research priorities report and watch the NINDS Council meeting presentation.

Pain is a deeply human experience—and a profoundly human challenge. The good news is that we’re making progress. The research supported by HEAL is helping us move from “what might help” to “what works.” And people living with pain are not only participants in the research—they are partners in shaping it.

I encourage you to:

In closing, I’ll note that the proverb “faster alone, further together” feels especially apt for HEAL. By taking pain from any one silo and applying the full strength of NIH across disciplines and communities, we are making progress—progress that matters to the millions of people living with pain every day.