Posted on by Lawrence Tabak, D.D.S., Ph.D.
While great progress has been made in controlling the COVID-19 pandemic, America’s opioid crisis continues to evolve in unexpected ways. The opioid crisis, which worsened during the pandemic and now involves the scourge of fentanyl, claims more than 70,000 lives each year in the United States . But throughout the pandemic, NIH has continued its research efforts to help people with a substance use disorder find the help that they so need. These efforts include helping to find relief for the millions of Americans who live with severe and chronic pain.
Recently, I traveled to Atlanta for the Rx and Illicit Drug Summit 2022. While there, I moderated an evening fireside chat with two of NIH’s leaders in combating the opioid crisis: Nora Volkow, director of the National Institute on Drug Abuse (NIDA); and Rebecca Baker, director of Helping to End Addiction Long-term® (HEAL) initiative. What follows is an edited, condensed transcript of our conversation.
Tabak: Let’s start with Nora. When did the opioid crisis begin, and how has it changed over the years
Volkow: It started just before the year 2000 with the over-prescription of opioid medications. People were becoming addicted to them, many from diverted product. By 2010, CDC developed guidelines that decreased the over-prescription. But then, we saw a surge in heroin use. That turned the opioid crisis into two problems: prescription opioids and heroin.
In 2016, we encountered the worst scourge yet. It is fentanyl, an opioid that’s 50 times more potent than heroin. Fentanyl is easily manufactured, and it’s easier than other opioids to hide and transport across the border. That makes this drug very profitable.
What we have seen during the pandemic is the expansion of fentanyl use in the United States. Initially, fentanyl made its way to the Northeast; now it’s everywhere. Initially, it was used to contaminate heroin; now it’s used to contaminate cocaine, methamphetamine, and, most recently, illicit prescription drugs, such as benzodiazepines and stimulants. With fentanyl contaminating all these drugs, we’re also seeing a steep rise in mortality from cocaine and methamphetamine use in African Americans, American Indians, and Alaska natives.
Tabak: What about teens? A recent study in the journal JAMA reported for the first time in a decade that overdose deaths among U.S. teens rose dramatically in 2020 and kept rising through 2021 . Is fentanyl behind this alarming increase?
Volkow: Yes, and it has us very concerned. The increase also surprised us. Over the past decade, we have seen a consistent decrease in adolescent drug use. In fact, there are some drugs that have the lowest usage rates that we’ve ever recorded. To observe this more than doubling of overdose deaths from fentanyl before the COVID pandemic was a major surprise.
Adolescents don’t typically use heroin, nor do they seek out fentanyl. Our fear is adolescents are misusing illicit prescriptions contaminated with fentanyl. Because an estimated 30-40 percent of those tainted pills contain levels of fentanyl that can kill you, it becomes a game of Russian roulette. This dangerous game is being played by adolescents who may just be experimenting with illicit pills.
Tabak: For people with substance use disorders, there are new ways to get help. In fact, one of the very few positive outcomes of the pandemic is the emergence of telehealth. If we can learn to navigate the various regulatory issues, do you see a place for telehealth going forward?
Volkow: When you have a crisis like this one, there’s a real need to accelerate interventions and innovation like telehealth. It certainly existed before the pandemic, and we knew that telehealth was beneficial for the treatment of substance use disorders. But it was very difficult to get reimbursement, making access extremely limited.
When COVID overwhelmed emergency departments, people with substance use disorders could no longer get help there. Other interventions were needed, and telehealth helped fill the void. It also had the advantage of reaching rural populations in states such as Kentucky, West Virginia, Ohio, where easy access to treatment or unique interventions can be challenging. In many prisons and jails, administrators worried about bringing web-based technologies into their facilities. So, in partnership with the Justice Department, we have created networks that now will enable the entry of telehealth into jails and prisons.
Tabak: Rebecca, it’s been four years since the HEAL initiative was announced at this very summit in 2018. How is the initiative addressing this ever-evolving crisis?
Baker: We’ve launched over 600 research projects across the country at institutions, hospitals, and research centers in a broad range of scientific areas. We’re working to come up with new treatment options for pain and addiction. There’s exciting research underway to address the craving and sleep disruption caused by opioid withdrawal. This research has led to over 20 investigational new drug applications to the FDA. Some are for repurposed drugs, compounds that have already been shown to be safe and effective for treating other health conditions that may also have value for treating addiction. Some are completely novel. We have also initiated the first testing of an opioid vaccine, for oxycodone, to prevent relapse and overdose in high-risk individuals.
Tabak: What about clinical research?
Baker: We’re testing multiple different treatments for both pain and addiction. Not everyone with pain is the same, and not every treatment is going to work the same for everyone. We’re conducting clinical trials in real-world settings to find out what works best for patients. We’re also working to implement lifesaving, evidence-based interventions into places where people seek help, including faith, community, and criminal justice settings.
Tabak: The pandemic highlighted inequities in our health-care system. These inequities afflict individuals and populations who are struggling with addiction and overdose. Nora, what needs to be done to address the social determinants of racial disparities?
Volkow: This is an extraordinarily important question. As you noted, certain racial and ethnic groups had disproportionately higher mortality rates from COVID. We have seen the same with overdose deaths. For example, we know that the most important intervention for preventing overdoses is to initiate medications such as methadone, buprenorphine or vivitrol. But Black Americans are initiated on these medications at least five years later than white Americans. Similarly, Black Americans also are less likely to receive the overdose-reversal medication naloxone.
That’s not right. We must ask what are the core causes of limited access to high-quality health care? Low income is a major contributing factor. Helping people get an education is one of the most important factors to address it. Another factor is distrust of the medical system. When racial and ethnic discrimination is compounded by discrimination because a person has a substance use disorder, you can see why it becomes very difficult for some to seek help. As a society, we certainly need to address racial discrimination. But we also need to address discrimination against substance use disorders in people of all races who are vulnerable.
Baker: Our research is tackling these barriers head on with a direct focus on stigma. As Nora alluded to, oftentimes providers may not offer lifesaving medication to some patients, and we’ve developed and are testing research training to help providers recognize and address their own biases and behaviors in caring for different populations.
We have supported research on the drivers of equity. A big part of this is engaging with people with lived experience and making sure that the interventions being designed are feasible in the real world. Not everyone has access to health insurance, transportation, childcare—the support that they may need to sustain treatment and recovery. In short, our research is seeking ways to enhance linkage to treatment.
Nora mentioned the importance of telehealth in improving equity. That’s another research focus, as well as developing tailored, culturally appropriate interventions for addressing pain and addiction. When you have this trust issue, you can’t always go in with a prescription or a recommendation from a physician. So in American and Alaskan native communities, we’re integrating evidence-based prevention approaches with traditional practices like wellness gatherings, cooking together, use of sage and spirituality, along with community support, and seeing if that encourages and increases the uptake of these prevention approaches in communities that need it so much.
Tabak: The most heartbreaking impact of the opioid crisis has been the infants born dependent on opioids. Rebecca, what’s being done to help the very youngest victims of the opioid crisis born with neonatal opioid withdrawal syndrome, or NOWS?
Baker: Thanks for asking about the infants. Babies with NOWS undergo withdrawal at birth and cry inconsolably, often with extreme stomach upset and sometimes even with seizures. Our research found that hospitals across the country vary greatly in how they treat these babies. Our program, ACT NOW, or Advancing Clinical Trials in Neonatal Opioid Withdrawal, aims to provide concrete guidance for nurses in the NICU treating these infants. One of the studies that we call Eat, Sleep, Console focuses on the abilities of the baby. Our researchers are testing if the ability to eat, sleep, or be consoled increases bonding with the mother and if it reduces time in the hospital, as well as other long-term health outcomes.
In addition to that NOWS program, we’ve also launched the HEALthy Brain and Child Development Study, or HBCD, that seeks to understand the long-term consequences of opioid exposure together with all the other environmental and other factors the baby experiences as they grow up. The hope is that together these studies will inform future prevention and treatment efforts for both mental health and also substance use and addiction.
Tabak: As the surge in heroin use and appearance of fentanyl has taught us, the opioid crisis has ever-changing dynamics. It tells us that we need better prevention strategies. Rebecca, could you share what HEAL is doing about prevention?
Baker: Prevention has always been a core component of the HEAL Initiative in a number of ways. The first is by preventing unnecessary opioid exposures through enhanced and evidence-based pain management. HEAL is supporting research on new small molecules, new devices, new biologic therapeutics that could treat pain and distinct pain conditions without opioids. And we’re also researching and providing guidance for clinicians on strategies for managing pain without medication, including acupuncture and physical therapy. They can often be just as effective and more sustainable.
HEAL is also working to address risky opioid use outside of pain management, especially in high-risk groups. That includes teens and young adults who may be experimenting, people lacking stable housing, patients who are on high-dose opioids for pain management, or they maybe have gone off high-dose opioids but still have them in their possession.
Finally, to prevent overdose we have to give naloxone to the people who need it. The HEALing Communities Study has taken some really innovative approaches to providing naloxone in libraries, on the beach, and places where overdoses are actually happening, not just in medical settings. And I think that will be, in our fight against the overdose crisis, a key tool.
Volkow: Larry, I’d like to add a few words on prevention. There are evidence-based interventions that have been shown to be quite effective for preventing substance use among teenagers and young adults. And yet, they are not implemented. We have evidence-based interventions that work for prevention. We have evidence-based interventions that work for treatment. But we don’t provide the resources for their implementation, nor do we train the personnel that can carry it over.
Science can give us tools, but if we do not partner at the next level for their implementation, those tools do not have the impact they should have. That’s why I always bring up the importance of policy in the implementation phase.
Tabak: Rebecca, the opioid crisis got started with a lack of good options for treating pain. Could you share with us how HEAL’s research efforts are addressing the needs of millions of Americans who experience both chronic pain and opioid use disorder?
Baker: It’s so important to remember people with pain. We can’t let our efforts to combat the opioid crisis make us lose sight of the needs of the millions of Americans with pain. One hundred million Americans experience pain; half of them have severe pain, daily pain, and 20 million have such severe pain that they can’t do things that are important to them in their life, family, job, other activities that bring their life meaning.
HEAL recognizes that these individuals need better options. New non-addictive pain treatments. But as you say, there is a special need for people with a substance use disorder who also have pain. They desperately need new and better options. And so we recently, through the HEAL Initiative, launched a new trials network that couples medication-based treatment for opioid use disorders, so that’s methadone or buprenorphine, with new pain-management strategies such as psychotherapy or yoga in the opioid use disorder treatment setting so that you’re not sending them around to lots of different places. And our hope is that this integrated approach will address some of the fragmented healthcare challenges that often results in poor care for these patients.
My last point would be that some patients need opioids to function. We can’t forget as we make sure that we are limiting risky opioid use that we don’t take away necessary opioids for these patients, and so our future research will incorporate ways of making sure that they receive needed treatment while also preventing them from the risks of opioid use disorder.
Tabak: Rebecca, let me ask you one more question. What do you want the folks here to remember about HEAL?
Baker: HEAL stands for Helping to End Addiction Long-term, and nobody knows more than the people in this room how challenging and important that really is. We’ve heard a little bit about the great promise of our research and some of the advances that are coming through our research pipeline, new treatments, new guidance for clinicians and caregivers. I want everyone to know that we want to work with you. By working together, I’m confident that we will tailor these new advances to meet the individual needs of the patients and populations that we serve.
Tabak: Nora, what would you like to add?
Volkow: This afternoon, I met with two parents who told me the story of how they lost their daughter to an overdose. They showed me pictures of this fantastic girl, along with her drawings. Whenever we think about overdose deaths in America, the sheer number—75,000—can make us indifferent. But when you can focus on one person and feel the love surrounding that life, you remember the value of this work.
Like in COVID, substance use disorders are a painful problem that we’re all experiencing in some way. They may have upset our lives. But they may have brought us together and, in many instances, brought out the best that humans can do. The best, to me, is caring for one another and taking the responsibility of helping those that are most vulnerable. I believe that science has a purpose. And here we have a purpose: to use science to bring solutions that can prevent and treat those suffering from substance use disorders.
Tabak: Thanks to both of you for this enlightening conversation.
 Drug overdose deaths, Centers for Disease Control and Prevention, February 22, 2022.
 Trends in drug overdose deaths among US adolescents, January 2010 to June 2021. Friedman J. et al. JAMA. 2022 Apr 12;327(14):1398-1400.
Video: Evening Plenary with NIH’s Lawrence Tabak, Nora Volkow, and Rebecca Baker (Rx and Illicit Drug Summit 2022)
SAMHSA’s National Helpline (Substance Abuse and Mental Health Services Administration, Rockville, MD)
Opioids (National Institute on Drug Abuse/NIH)
Rebecca Baker (HEAL/NIH)
Nora Volkow (NIDA)
Posted on by Dr. Francis Collins
Gene editing has shown great promise as a non-heritable way to treat a wide range of conditions, including many genetic diseases and more recently, even COVID-19. But could a version of the CRISPR gene-editing tool also help deliver long-lasting pain relief without the risk of addiction associated with prescription opioid drugs?
In work recently published in the journal Science Translational Medicine, researchers demonstrated in mice that a modified version of the CRISPR system can be used to “turn off” a gene in critical neurons to block the transmission of pain signals . While much more study is needed and the approach is still far from being tested in people, the findings suggest that this new CRISPR-based strategy could form the basis for a whole new way to manage chronic pain.
This novel approach to treating chronic pain occurred to Ana Moreno, the study’s first author, when she was a Ph.D. student in the NIH-supported lab of Prashant Mali, University of California, San Diego. Mali had been studying a wide range of novel gene- and cell-based therapeutics. While reading up on both, Moreno landed on a paper about a mutation in a gene that encodes a pain-enhancing protein in spinal neurons called NaV1.7.
Moreno read that kids born with a loss-of-function mutation in this gene have a rare condition known as congenital insensitivity to pain (CIP). They literally don’t sense and respond to pain. Although these children often fail to recognize serious injuries because of the absence of pain to alert them, they have no other noticeable physical effects of the condition.
For Moreno, something clicked. What if it were possible to engineer a new kind of treatment—one designed to turn this gene down or fully off and stop people from feeling chronic pain?
Moreno also had an idea about how to do it. She’d been working on repressing or “turning off” genes using a version of CRISPR known as “dead” Cas9 . In CRISPR systems designed to edit DNA, the Cas9 enzyme is often likened to a pair of scissors. Its job is to cut DNA in just the right spot with the help of an RNA guide. However, CRISPR-dead Cas9 no longer has any ability to cut DNA. It simply sticks to its gene target and blocks its expression. Another advantage is that the system won’t lead to any permanent DNA changes, since any treatment based on CRISPR-dead Cas9 might be safely reversed.
After establishing that the technique worked in cells, Moreno and colleagues moved to studies of laboratory mice. They injected viral vectors carrying the CRISPR treatment into mice with different types of chronic pain, including inflammatory and chemotherapy-induced pain.
Moreno and colleagues determined that all the mice showed evidence of durable pain relief. Remarkably, the treatment also lasted for three months or more and, importantly, without any signs of side effects. The researchers are also exploring another approach to do the same thing using a different set of editing tools called zinc finger nucleases (ZFNs).
The researchers say that one of these approaches might one day work for people with a large number of chronic pain conditions that involve transmission of the pain signal through NaV1.7. That includes diabetic polyneuropathy, sciatica, and osteoarthritis. It also could provide relief for patients undergoing chemotherapy, along with those suffering from many other conditions. Moreno and Mali have co-founded the spinoff company Navega Therapeutics, San Diego, CA, to work on the preclinical steps necessary to help move their approach closer to the clinic.
Chronic pain is a devastating public health problem. While opioids are effective for acute pain, they can do more harm than good for many chronic pain conditions, and they are responsible for a nationwide crisis of addiction and drug overdose deaths . We cannot solve any of these problems without finding new ways to treat chronic pain. As we look to the future, it’s hopeful that innovative new therapeutics such as this gene-editing system could one day help to bring much needed relief.
 Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice. Moreno AM, Alemán F, Catroli GF, Hunt M, Hu M, Dailamy A, Pla A, Woller SA, Palmer N, Parekh U, McDonald D, Roberts AJ, Goodwill V, Dryden I, Hevner RF, Delay L, Gonçalves Dos Santos G, Yaksh TL, Mali P. Sci Transl Med. 2021 Mar 10;13(584):eaay9056.
 Nuclease dead Cas9 is a programmable roadblock for DNA replication. Whinn KS, Kaur G, Lewis JS, Schauer GD, Mueller SH, Jergic S, Maynard H, Gan ZY, Naganbabu M, Bruchez MP, O’Donnell ME, Dixon NE, van Oijen AM, Ghodke H. Sci Rep. 2019 Sep 16;9(1):13292.
 Drug Overdose Deaths. Centers for Disease Control and Prevention.
Congenital insensitivity to pain (National Center for Advancing Translational Sciences/NIH)
Opioids (National Institute on Drug Abuse/NIH)
Mali Lab (University of California, San Diego)
Navega Therapeutics (San Diego, CA)
NIH Support: National Human Genome Research Institute; National Cancer Institute; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke
Posted on by Dr. Francis Collins
For most people, pain eventually fades away as an injury heals. But for others, the pain persists beyond the initial healing and becomes chronic, hanging on for weeks, months, or even years. Now, we may have uncovered an answer to help explain why: subtle differences in a gene that controls how the body responds to stress.
In a recent study of more than 1,600 people injured in traffic accidents, researchers discovered that individuals with a certain variant in a stress-controlling gene, called FKBP5, were more likely to develop chronic pain than those with other variants . These findings may point to new non-addictive strategies for preventing or controlling chronic pain, and underscore the importance of NIH-funded research for tackling our nation’s opioid overuse crisis.