The opioid crisis continues to devastate communities across America. Dangerous synthetic opioids, like fentanyl, have flooded the illicit drug supply with terrible consequences. Tragically, based on our most-recent data, about 108,000 people in the U.S. die per year from overdoses of opioids or stimulants . Although this complex public health challenge started from our inability to treat pain effectively, chronic pain remains a life-altering problem for 50 million Americans.
To match the size and complexity of the crisis, in 2018 NIH developed the NIH Helping to End Addiction Long-term® (HEAL) Initiative, an aggressive effort involving nearly all of its 27 institutes and centers. Through more than 1,000 research projects, including basic science, clinical testing of new and repurposed drugs, research with communities, and health equity research, HEAL is dedicated to building a new future built on hope.
In this future:
- A predictive tool used during a health visit personalizes treatment for back pain. The tool estimates the probability that a person will benefit from physical therapy, psychotherapy, or surgery.
- Visits to community health clinics and emergency departments serve as routine opportunities to prevent and treat opioid addiction.
- Qualified school staff and pediatricians screen all children for behavioral and other mental health conditions that increase risk for harmful developmental outcomes, including opioid misuse.
- Infants born exposed to opioids during a mother’s pregnancy receive high-quality care—setting them up for a healthy future.
Five years after getting started (and interrupted by a global pandemic), HEAL research is making progress toward achieving this vision. I’ll highlight three ways in which scientific solutions are meeting people where they are today.
A Window of Opportunity for Treatment in the Justice System
Sadly, jails and prisons are “ground zero” for the nation’s opioid crisis. Eighty-five percent of people who are incarcerated have a substance use disorder or a history of substance use. Our vision at HEAL is that every person in jail, prison, or a court-supervised program receives medical care, which includes effective opioid use disorder treatment.
Some research results already are in supporting this approach: A recent HEAL study learned that individuals who had received addiction treatment while in one Massachusetts jail were about 30 percent less likely to be arrested, arraigned, or incarcerated again compared with those incarcerated during the same time period in a neighboring jail that did not offer treatment . Research from the HEAL-supported Justice Community Opioid Innovation Network also is exploring public perceptions about opioid addiction. One such survey showed that most U.S. adults see opioid use disorder as a treatable medical condition rather than as a criminal matter . That’s hopeful news for the future.
A Personalized Treatment Plan for Chronic Back Pain
Half of American adults live with chronic back pain, a major contributor to opioid use. The HEAL-supported Back Pain Consortium (BACPAC) is creating a whole-system model for comprehensive testing of everything that contributes to chronic low back pain, from anxiety to tissue damage. It also includes comprehensive testing of promising pain-management approaches, including psychotherapy, antidepressants, or surgery.
Refining this whole-system model, which is nearing completion, includes finding computer-friendly ways to describe the relationship between the different elements of pain and treatment. That might include developing mathematical equations that describe the physical movements and connections of the vertebrae, discs, and tendons.
Or it might include an artificial intelligence technique called machine learning, in which a computer looks for patterns in existing data, such as electronic health records or medical images. In keeping with HEAL’s all-hands-on-deck approach, BACPAC also conducts clinical trials to test new (or repurposed) treatments and develop new technologies focused on back pain, like a “wearable muscle” to help support the back.
Harnessing Innovation from the Private Sector
The HEAL research portfolio spans basic science to health services research. That allows us to put many shots on goal that will need to be commercialized to help people. Through its research support of small businesses, HEAL funding offers a make-or-break opportunity to advance a great idea to the marketplace, providing a bridge to venture capital or other larger funding sources needed for commercialization.
This bridge also allows HEAL to invest directly in the heart of innovation. Currently, HEAL funds nearly 100 such companies across 20 states. While this is a relatively small portion of all HEAL research, it is science that will make a difference in our communities, and these researchers are passionate about what they do to build a better future.
A couple of current examples of this research passion include: delivery of controlled amounts of non-opioid pain medications after surgery using a naturally absorbable film or a bone glue; immersive virtual reality to help people with opioid use disorder visualize the consequences of certain personal choices; and mobile apps that support recovery, taking medications, or sensing an overdose.
In 2023, HEAL is making headway toward its mission to accelerate development of safe, non-addictive, and effective strategies to prevent and treat pain, opioid misuse, and overdose. We have 314 clinical trials underway and 41 submissions to the Food and Drug Administration to begin clinical testing of investigational new drugs or devices: That number has doubled in the last year. More than 100 projects alone are addressing back pain, and more than 200 projects are studying medications for opioid use disorder.
The nation’s opioid crisis is profoundly difficult and multifaceted—and it won’t be solved with any single approach. Our research is laser-focused on its vision of ending addiction long-term, including improving pain management and expanding access to underused, but highly effective, addiction medications. Every day, we imagine a better future for people with physical and emotional pain and communities that are hurting. Hundreds of researchers and community members across the country are working to achieve a future where people and communities have the tools they need to thrive.
 Provisional drug overdose death counts. Ahmad FB, Cisewski JA, Rossen LM, Sutton P. National Center for Health Statistics. 2023.
 Recidivism and mortality after in-jail buprenorphine treatment for opioid use disorder. Evans EA, Wilson D, Friedmann PD. Drug Alcohol Depend. 2022 Feb 1;231:109254.
 Social stigma toward persons with opioid use disorder: Results from a nationally representative survey of U.S. adults. Taylor BG, Lamuda PA, Flanagan E, Watts E, Pollack H, Schneider J. Subst Use Misuse. 2021;56(12):1752-1764.
SAMHSA’s National Helpline (Substance Abuse and Mental Health Services Administration, Rockville, MD)
Small Business Programs (HEAL)
Rebecca Baker (HEAL)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes, Centers, and Offices to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 28th in the series of NIH guest posts that will run until a new permanent NIH director is in place.
Posted on by Dr. Francis Collins
It usually takes more than a decade to develop a safe, effective anti-viral therapy. But, when it comes to coronavirus disease 2019 (COVID-19), we don’t have that kind of time. One way to speed the process may be to put some old drugs to work against this new disease threat. This is generally referred to as “drug repurposing.”
NIH has been doing everything possible to encourage screens of existing drugs that have been shown safe for human use. In a recent NIH-funded study in the journal Nature, researchers screened a chemical “library” that contained nearly 12,000 existing drug compounds for their potential activity against SARS-CoV-2, the novel coronavirus that causes COVID-19 . The results? In tests in both non-human primate and human cell lines grown in laboratory conditions, 21 of these existing drugs showed potential for repurposing to thwart the novel coronavirus—13 of them at doses that likely could be safely given to people. The majority of these drugs have been tested in clinical trials for use in HIV, autoimmune diseases, osteoporosis, and other conditions.
These latest findings come from an international team led by Sumit Chanda, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA. The researchers took advantage of a small-molecule drug library called ReFRAME , which was created in 2018 by Calibr, a non-profit drug discovery division of Scripps Research, La Jolla, CA.
In collaboration with Yuen Kwok-Yung’s team at the University of Hong Kong, the researchers first developed a high-throughput method that enabled them to screen rapidly each of the 11,987 drug compounds in the ReFRAME library for their potential to block SARS-CoV-2 in cells grown in the lab. The first round of testing narrowed the list of possible COVID-19 drugs to about 300. Next, using lower concentrations of the drugs in cells exposed to a second strain of SARS-CoV-2, they further narrowed the list to 100 compounds that could reliably limit growth of the coronavirus by at least 40 percent.
Generally speaking, an effective anti-viral drug is expected to show greater activity as its concentration is increased. So, Chanda’s team then tested those 100 drugs for evidence of such a dose-response relationship. Twenty-one of them passed this test. This group included remdesivir, a drug originally developed for Ebola virus disease and recently authorized by the U.S. Food and Drug Administration (FDA) for emergency use in the treatment of COVID-19. Remdesivir could now be considered a positive control.
These findings raised another intriguing question: Could any of the other drugs with a dose-response relationship work well in combination with remdesivir to block SARS-CoV-2 infection? Indeed, the researchers found that four of them could.
Further study showed that some of the most promising drugs on the list reduced the number of SARS-CoV-2 infected cells by 65 to 85 percent. The most potent of these was apilimod, a drug that has been evaluated in clinical trials for treating Crohn’s disease, rheumatoid arthritis, and other autoimmune conditions. Apilimod is now being evaluated in the clinic for its ability to prevent the progression of COVID-19. Another potential antiviral to emerge from the study is clofazimine, a 70-year old FDA-approved drug that is on the World Health Organization’s list of essential medicines for the treatment of leprosy.
Overall, the findings suggest that there may be quite a few existing drugs and/or experimental drugs fairly far along in the development pipeline that have potential to be repurposed for treating COVID-19. What’s more, some of them might also work well in combination with remdesivir, or perhaps other drugs, as treatment “cocktails,” such as those used to successfully treat HIV and hepatitis C.
This is just one of a wide variety of drug screening efforts that are underway, using different libraries and different assays to detect activity against SARS-CoV-2. The NIH’s National Center for Advancing Translational Sciences has established an open data portal to collect all of these data as quickly and openly as possible. As NIH continues its efforts to use the power of science to end the COVID-19 pandemic, it is critically important that we explore as many avenues as possible for developing diagnostics, treatments, and vaccines.
 Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Riva L, Yuan S, Yin X, et al. Nature. 2020 Jul 24 [published online ahead of print]
 The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Janes J, Young ME, Chen E, et al. Proc Natl Acad Sci USA. 2018;115(42):10750-10755.
Coronavirus (COVID-19) (NIH)
ReFRAMEdb (Scripps Research, La Jolla, CA)
The Chanda Lab (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA)
Yuen Kwok-Yung (University of Hong Kong)
OpenData|Covid-19 (National Center for Advancing Translational Sciences/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences
Posted on by Dr. Francis Collins
Amid all the headlines and uncertainty surrounding the current COVID-19 pandemic, it’s easy to overlook the important progress that biomedical research is making against other diseases. So, today, I’m pleased to share word of what promises to be the first effective treatment to help young people suffering from the consequences of a painful, often debilitating genetic disorder called neurofibromatosis type 1 (NF1).
This news is particularly meaningful to me because, 30 years ago, I led a team that discovered the gene that underlies NF1. About 1 in 3,000 babies are born with NF1. In about half of those affected, a type of tumor called a plexiform neurofibroma arises along nerves in the skin, face, and other parts of the body. While plexiform neurofibromas are not cancerous, they grow steadily and can lead to severe pain and a range of other health problems, including vision and hearing loss, hypertension, and mobility issues.
The good news is the results of a phase II clinical trial involving NF1, just published in the New England Journal of Medicine. The trial was led by Brigitte Widemann and Andrea Gross, researchers in the Center for Cancer Research at NIH’s National Cancer Institute.
The trial’s results confirm that a drug originally developed to treat cancer, called selumetinib, can shrink inoperable tumors in many children with NF1. They also establish that the drug can help affected kids make significant improvements in strength, range of motion, and quality of life. While selumetinib is not a cure, and further studies are still needed to see how well the treatment works in the long term, these results suggest that the first effective treatment for NF1 is at last within our reach.
Selumetinib blocks a protein in human cells called MEK. This protein is involved in a major cellular pathway known as RAS that can become dysregulated and give rise to various cancers. By blocking the MEK protein in animal studies and putting the brakes on the RAS pathway when it malfunctions, selumetinib showed great initial promise as a cancer drug.
Selumetinib was first tested several years ago in people with a variety of other cancers, including ovarian and non-small cell lung cancers. The clinical research looked good at first but eventually stalled, and so did much of the initial enthusiasm for selumetinib.
But the enthusiasm picked up when researchers considered repurposing the drug to treat NF1. The neurofibromas associated with the condition were known to arise from a RAS-activating loss of the NF1 gene. It made sense that blocking the MEK protein might blunt the overactive RAS signal and help to shrink these often-inoperable tumors.
An earlier phase 1 safety trial looked promising, showing for the first time that the drug could, in some cases, shrink large NF1 tumors . This fueled further research, and the latest study now adds significantly to that evidence.
In the study, Widemann and colleagues enrolled 50 children with NF1, ranging in age from 3 to 17. Their tumor-related symptoms greatly affected their wellbeing and ability to thrive, including disfigurement, limited strength and motion, and pain. Children received selumetinib alone orally twice a day and went in for assessments at least every four months.
As of March 2019, 35 of the 50 children in the ongoing study had a confirmed partial response, meaning that their tumors had shrunk by more than 20 percent. Most had maintained that response for a year or more. More importantly, the kids also felt less pain and were more able to enjoy life.
It’s important to note that the treatment didn’t work for everyone. Five children stopped taking the drug due to side effects. Six others progressed while on the drug, though five of them had to reduce their dose because of side effects before progressing. Nevertheless, for kids with NF1 and their families, this is a big step forward.
Drug developer AstraZeneca, working together with the researchers, has submitted a New Drug Application to the Food and Drug Administration (FDA). While they’re eagerly awaiting the FDA’s decision, the work continues.
The researchers want to learn much more about how the drug affects the health and wellbeing of kids who take it over the long term. They’re also curious whether it could help to prevent the growth of large tumors in kids who begin taking it earlier in the course of the disease, and whether it might benefit other features of the disorder. They will continue to look ahead to other potentially promising treatments or treatment combinations that may further help, and perhaps one day even cure, kids with NF1. So, even while we cope with the COVID-19 pandemic, there are reasons to feel encouraged and grateful for continued progress made throughout biomedical research.
 Selumitinib in children with inoperable plexiform neurofibromas. New England Journal of Medicine. Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. 18 March 2020. N Engl J Med. 2020 Mar 18. [Epub ahead of publication.]
 Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P1, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. N Engl J Med. 2016 Dec 29;375(26):2550-2560.
Neurofibromatosis Fact Sheet (National Institute of Neurological Disorders and Stroke/NIH)
Brigitte Widemann (National Cancer Institute/NIH)
Andrea Gross (National Cancer Institute/NIH)
NIH Support: National Cancer Institute