This month 10 years ago, the Institute of Medicine’s Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research was released. This landmark report alerted the nation to the substantive public health challenge created by unmanaged pain – affecting one-third of Americans and costing $560‒$635 billion annually. It remains a huge problem that hasn’t improved in the decade since this report was published.

The Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, supports more than 200 pain research projects to turn this tide. Nearly half of this research support is devoted to preclinical and translational research to develop non-addictive new therapies, and HEAL’s investment in clinical pain research supports clinical trials to evaluate innovative therapies for pain management and compare specific strategies for treating a number of different pain conditions.

Drs Christine Colvis and Michael Oshinsky

Dr. Christine Colvis (left) and Dr. Michael Oshinsky (right)

To learn more about the HEAL preclinical pain research strategy, we spoke with Dr. Michael Oshinsky, a program director at the National Institute of Neurological Disorders and Stroke (NINDS), and Dr. Christine Colvis, Director of Drug Development Partnership Programs at the National Center for Advancing Translational Sciences (NCATS). Together they lead the NIH HEAL Initiative’s Preclinical and Translational Research in Pain Management focus area (NINDS and NCATS lead programs in this HEAL research focus area in collaboration with several NIH Institutes and Centers). Below, they describe how HEAL-funded research strives to meet the needs of patients and providers who urgently need pain relief.

NIH supports a wide array of research to better understand causes of the hundreds of types of pain and figure out ways to manage it. Research through the NIH HEAL Initiative aims to provide scientific solutions to the national opioid crisis, including reducing the risks of opioid medications for pain management. The HEAL pain research investment is pursuing targeted strategies toward this goal, including ways to get effective, non-addictive pain relief in the hands of healthcare providers and patients. We’re trying to fill treatment gaps to help people right away – and we’re focusing on solutions that don’t worsen the opioid epidemic.

Companies have tried, and failed, many times to come up with different pain drugs. There have been hundreds of clinical trials, costing billions of dollars. Some of the reasons for this include the large number of different types of pain disorders that require specialized types of treatments. Another issue is that pain is quite hard to measure consistently between people and among different pain conditions – a problem HEAL is addressing, such as research to identify biomarkers to standardize measurement of pain and establishing links to populations of patients interested in participating in clinical research.

One problem is that historically scientists have focused on finding the source of pain and then getting rid of it: whether it’s in the lower back, the spine, or elsewhere in the body. We’ve learned through research, however, that pain conditions don't always arise from the body part where they appear. Rather, pain conditions often involve different parts of the brain and nerves all around the body. A lot of HEAL preclinical pain research is seeking to find those pain-specific targets in the brain and elsewhere and match them with non-opioid molecules.

Developing any new drug can take decades, and that is definitely true for pain treatments. One example is a new class of migraine drugs that was approved by the FDA in 2018. It’s a “biologic” therapy that targets the neurotransmitter calcitonin gene-related peptide, or CGRP. CGRP is a fundamental chemical in the body that is linked to migraine, and blocking its effects basically blocks migraine attacks. The research that got us to this point has been going on for 30 years. That’s a lifetime that someone in pain does not have.

We designed the HEAL pain research portfolio to cover all of the beginning stages of pain treatment research. The first step is finding new targets for pain treatments in the body and “validating” them using animal and human tissue models. Screening and testing platforms like organ-on-a-chip, stem cells, or other technologies can help with this.

Ultimately, you can only predict so much with preclinical research. The only way a promising drug becomes an FDA-approved drug is through definitive testing in people. So-called pivotal clinical trials ask a very specific question: Does it work or does it not? For pain – that might mean less discomfort, but also more function, like being able to work or drive. HEAL research aims to get promising leads onto this runway, by “optimizing” them to work properly in the body, then rapidly getting them into clinical trials. EPPIC-Net is designed for this next step.

It’s very exciting that HEAL research has identified a completely new type of pain treatment for neuropathic pain (that now has a cleared IND from the FDA) that’s totally different from both opioids and common over-the-counter pain relievers like ibuprofen.

Two teams of HEAL researchers have filed patents for small molecule modulators of pain receptors involved in chronic pain and migraine. In addition, a HEAL-funded small business team has shown through preclinical research that a portable thermoelectric device can block pain signals. We are working on more innovative strategies, and we are optimistic that focused investment will lead to results.

We’ve set up a framework, setting milestones and creating hand-off points for moving promising leads straight into clinical testing. In the past, NIH support for these research endeavors occurs separately – with the next step only starting after the previous step was totally done. In the HEAL-supported team-based research approach, potential new pain drugs can be tried, validated in various models, and prepped for effective use in the human body in parallel research studies. This will allow the potential treatments to be moved quickly into clinical testing. This framework was modeled after the NINDS Innovation Grants to Nurture Initial Translational Efforts (IGNITE) program and the Blueprint Neurotherapeutics Network (BPN) for Small Molecules.

One key aspect is failure: we expect many of these potential drugs to fail, after which they’ll be rapidly dropped (and reported publicly so no one else tries the same pathway and fails). This way, the few successes can advance quickly. Remember, biology is very tricky, and we humans are learning more each day about how to manipulate it.

One of the reasons drug development takes so long is that all the steps along the way occur on their own. So, for example, a pain researcher at a university comes up with an idea for a different way to target pain. That research would be funded by a grant to work out the underlying biology. Separately, a pharmaceutical or biotech company might learn about the new research and decide to see whether it can be “turned into” a drug – by testing it in animal models and seeing how it behaves in the human body. Can it be given as a pill? Will it survive the acidic environment of the stomach?

In this approach, we’re putting all of that together – like a company’s research and development team, but without the risk involved with committing to one or a few ideas. In this HEAL research environment, which will be “open science” and all data will be shared, teams don’t have to worry about an idea failing, which usually happens due to our incomplete understanding of the biology of pain. In this environment, if a target fails, teams can quickly switch to other ideas and move on. If it looks promising, it can be refined for clinical testing – either within HEAL’s EPPIC-Net, other NIH clinical trials, or for further development by a pharmaceutical or biotech company.

We expect that teams will have a diverse membership of university-based scientists, small businesses, and small- to medium-sized biotech companies.

HEAL recently announced two funding opportunities to set up preclinical pain research teams. These awards will be cooperative agreements that involve a good amount of involvement and oversight from NIH staff, to keep projects on track and meeting milestones. To encourage a continual flow of fresh ideas, these awards won’t be renewable. Research teams can also apply for a planning award to assemble the best team and get everything ready.

The HEAL research investment to improve pain management is distinct from other, important pain research funded by NIH. It is complementary to these ongoing efforts, but also targeted to addressing challenges created, and worsened, by the opioid epidemic. Working across the research continuum from preclinical science to clinical trials to implementation research, HEAL aims to fill gaps and speed improvements in care for the millions enduring ongoing pain.