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Research to Address the Real-Life Challenges of Opioid Crisis
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 [1]. 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 [2]. 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.
References:
[1] Drug overdose deaths, Centers for Disease Control and Prevention, February 22, 2022.
[2] 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.
Links:
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)
Fentanyl (NIDA)
Helping to End Addiction Long-term®(HEAL) Initiative (NIH)
Rebecca Baker (HEAL/NIH)
Nora Volkow (NIDA)
A Better Way to Talk About Problems with Alcohol Misuse
Posted on by George F. Koob, Ph.D., National Institute on Alcohol Abuse and Alcoholism
Did you know that language commonly used to describe alcohol misuse and alcohol use disorder (AUD) can influence treatment outcomes in people suffering from alcohol problems? Yes, that can often be the case. In fact, the stigma perpetuated by such language can decrease a person’s motivation to seek help for an alcohol problem.
The stigma also can affect one’s self-esteem, as well as how they are perceived by others. And, sadly, AUD is still often viewed as a moral failing or character flaw, rather than a chronic medical disorder from which people can—and do—recover. Less than 10 percent of people with AUD obtain treatment or help for alcohol problems. Reframing the way we talk and think about alcohol problems can encourage people to seek and receive the help they need to recover.
In a recent article published in the journal Neuropsychopharmacology, my NIH colleagues, National Institute on Drug Abuse Director Nora D. Volkow, and National Institute of Mental Health Director Joshua Gordon, and I discuss the impact of stigma on people who have a mental illness or an alcohol or other substance use disorder [1]. We discuss how word choice can perpetuate stigma, leading to lower self-esteem, decreased interest in seeking help, and consequent worsening of symptoms.
We also point to evidence that stigma-related bias among clinicians can contribute to a treatment-averse mindset and to suboptimal clinical care, including failure to implement evidence-based treatment [2]. Studies have shown that the use of clinically accurate language and terms that centralize the experience of patients reduces stigma, resulting in higher quality health care.
Although more evidence-based treatment options for AUD are available today than ever before, stigma is a barrier that prevents some people from accessing treatment. Understanding that AUD is a medical condition and choosing our words carefully when discussing alcohol-related problems are important steps toward changing the conversation. It will empower people to seek treatment for AUD and help clinicians to deliver optimal care.
We can help alleviate the stigma associated with alcohol-related conditions in all settings by consistently using non-pejorative, non-stigmatizing, person-first language to describe such conditions and the people who are affected by them.
Here is some recommended language for reducing alcohol-related stigma that might be helpful:
- Use alcohol use disorder, or AUD, instead of alcohol abuse, alcohol dependence, and alcoholism. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), AUD replaces the older categories of alcohol abuse and alcohol dependence with the single disorder, AUD, which ranges from mild to severe.
- Use alcohol misuse instead of alcohol abuse when referring broadly to drinking in a manner, situation, amount, or frequency that could cause harm to the person who is engaging in drinking or to those around that person. For some individuals, any alcohol use constitutes alcohol misuse.
- Use person-first language to describe people with alcohol-related problems such as:
- Person with alcohol use disorder instead of alcoholic or addict
- Person in recovery or person in recovery from alcohol use disorder instead of recovering alcoholic
- Person who misuses alcohol or person who engages in alcohol misuse instead of alcohol abuser and drunk
- Use alcohol-associated liver disease instead of alcoholic liver disease. Also use alcohol-associated hepatitis, alcohol-associated cirrhosis, and alcohol-associated pancreatitis instead of alcoholic hepatitis, alcoholic cirrhosis, and alcoholic pancreatitis. The use of “alcoholic” as an adjective may perpetuate stigma for people with alcohol-associated liver disease and other alcohol-related health conditions.
April is Alcohol Awareness Month, which is a good time to think about how alcohol is affecting your life. If you or a loved one need help for alcohol-related problems, the NIAAA Alcohol Treatment Navigator is a one-stop resource for learning about AUD and evidence-based AUD treatment. The Navigator teaches what you need to know and what you need to do to find evidence-based treatment options in your area.
References:
[1] Choosing appropriate language to reduce the stigma around mental illness and substance use disorders. Volkow ND, Gordon JA, Koob GF. Neuropsychopharmacology 2021 Dec; 46(13):2230–2232.
[2] Discrimination against people with mental illness: What can psychiatrists do? Thornicroft G, Rose D, Mehta N. Advances in Psychiatric Treatment 2010 Jan; 16:53–59.
Links:
Alcohol Facts and Statistics (National Institute on Alcohol Abuse and Alcoholism, NIH)
When It Comes to Reducing Alcohol-Related Stigma, Words Matter (NIAAA)
NIAAA Alcohol Treatment Navigator (NIAAA)
Rethinking Drinking (NIAAA)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the cool science that they support and conduct. This is the sixth in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.]
‘Decoy’ Protein Works Against Multiple Coronavirus Variants in Early Study
Posted on by Lawrence Tabak, D.D.S., Ph.D.
The NIH continues to support the development of some very innovative therapies to control SARS-CoV-2, the coronavirus that causes COVID-19. One innovative idea involves a molecular decoy to thwart the coronavirus.
How’s that? The decoy is a specially engineered protein particle that mimics the 3D structure of the ACE2 receptor, a protein on the surface of our cells that the virus’s spike proteins bind to as the first step in causing an infection.
The idea is when these ACE2 decoys are administered therapeutically, they will stick to the spike proteins that crown the coronavirus (see image above). With its spikes covered tightly in decoy, SARS-CoV-2 has a more-limited ability to attach to the real ACE2 and infect our cells.
Recently, the researchers published their initial results in the journal Nature Chemical Biology, and the early data look promising [1]. They found in mouse models of severe COVID-19 that intravenous infusion of an engineered ACE2 decoy prevented lung damage and death. Though more study is needed, the researchers say the decoy therapy could potentially be delivered directly to the lungs through an inhaler and used alone or in combination with other COVID-19 treatments.
The findings come from a research team at the University of Illinois Chicago team, led by Asrar Malik and Jalees Rehman, working in close collaboration with their colleagues at the University of Illinois Urbana-Champaign. The researchers had been intrigued by an earlier clinical trial testing the ACE2 decoy strategy [2]. However, in this earlier attempt, the clinical trial found no reduction in mortality. The ACE2 drug candidate, which is soluble and degrades in the body, also proved ineffective in neutralizing the virus.
Rather than give up on the idea, the UIC team decided to give it a try. They engineered a new soluble version of ACE2 that structurally might work better as a decoy than the original one. Their version of ACE2, which includes three changes in the protein’s amino acid building blocks, binds the SARS-CoV-2 spike protein much more tightly. In the lab, it also appeared to neutralize the virus as well as monoclonal antibodies used to treat COVID-19.
To put it to the test, they conducted studies in mice. Normal mice don’t get sick from SARS-CoV-2 because the viral spike can’t bind well to the mouse version of the ACE2 receptor. So, the researchers did their studies in a mouse that carries the human ACE2 and develops a severe acute respiratory syndrome somewhat similar to that seen in humans with severe COVID-19.
In their studies, using both the original viral isolate from Washington State and the Gamma variant (P.1) first detected in Brazil, they found that infected mice infused with their therapeutic ACE2 protein had much lower mortality and showed few signs of severe acute respiratory syndrome. While the protein worked against both versions of the virus, infection with the more aggressive Gamma variant required earlier treatment. The treated mice also regained their appetite and weight, suggesting that they were making a recovery.
Further studies showed that the decoy bound to spike proteins from every variant tested, including Alpha, Beta, Delta and Epsilon. (Omicron wasn’t yet available at the time of the study.) In fact, the decoy bound just as well, if not better, to new variants compared to the original virus.
The researchers will continue their preclinical work. If all goes well, they hope to move their ACE2 decoy into a clinical trial. What’s especially promising about this approach is it could be used in combination with treatments that work in other ways, such as by preventing virus that’s already infected cells from growing or limiting an excessive and damaging immune response to the infection.
Last week, more than 17,500 people in the United States were hospitalized with severe COVID-19. We’ve got to continue to do all we can to save lives, and it will take lots of innovative ideas, like this ACE2 decoy, to put us in a better position to beat this virus once and for all.
References:
[1] Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants.
Zhang L, Dutta S, Xiong S, Chan M, Chan KK, Fan TM, Bailey KL, Lindeblad M, Cooper LM, Rong L, Gugliuzza AF, Shukla D, Procko E, Rehman J, Malik AB. Nat Chem Biol. 2022 Jan 19.
[2] Recombinant human angiotensin-converting enzyme 2 (rhACE2) as a treatment for patients with COVID-19 (APN01-COVID-19). ClinicalTrials.gov.
Links:
COVID-19 Research (NIH)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (NIH)
Asrar Malik (University of Illinois Chicago)
Jalees Rehman (University of Illinois Chicago)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases
Breakthrough Infections in Vaccinated People Less Likely to Cause ‘Long COVID’
Posted on by Dr. Francis Collins
There’s no question that vaccines are making a tremendous difference in protecting individuals and whole communities against infection and severe illness from SARS-CoV-2, the coronavirus that causes COVID-19. And now, there’s yet another reason to get the vaccine: in the event of a breakthrough infection, people who are fully vaccinated also are substantially less likely to develop Long COVID Syndrome, which causes brain fog, muscle pain, fatigue, and a constellation of other debilitating symptoms that can last for months after recovery from an initial infection.
These important findings published in The Lancet Infectious Diseases are the latest from the COVID Symptom Study [1]. This study allows everyday citizens in the United Kingdom to download a smartphone app and self-report data on their infection, symptoms, and vaccination status over a long period of time.
Previously, the study found that 1 in 20 people in the U.K. who got COVID-19 battled Long COVID symptoms for eight weeks or more. But this work was done before vaccines were widely available. What about the risk among those who got COVID-19 for the first time as a breakthrough infection after receiving a double dose of any of the three COVID-19 vaccines (Pfizer, Moderna, AstraZeneca) authorized for use in the U.K.?
To answer that question, Claire Steves, King’s College, London, and colleagues looked to frequent users of the COVID Symptom Study app on their smartphones. In its new work, Steves’ team was interested in analyzing data submitted by folks who’d logged their symptoms, test results, and vaccination status between December 9, 2020, and July 4, 2021. The team found there were more than 1.2 million adults who’d received a first dose of vaccine and nearly 1 million who were fully vaccinated during this period.
The data show that only 0.2 percent of those who were fully vaccinated later tested positive for COVID-19. While accounting for differences in age, sex, and other risk factors, the researchers found that fully vaccinated individuals who developed breakthrough infections were about half (49 percent) as likely as unvaccinated people to report symptoms of Long COVID Syndrome lasting at least four weeks after infection.
The most common symptoms were similar in vaccinated and unvaccinated adults with COVID-19, and included loss of smell, cough, fever, headaches, and fatigue. However, all of these symptoms were milder and less frequently reported among the vaccinated as compared to the unvaccinated.
Vaccinated people who became infected were also more likely than the unvaccinated to be asymptomatic. And, if they did develop symptoms, they were half as likely to report multiple symptoms in the first week of illness. Another vaccination benefit was that people with a breakthrough infection were about a third as likely to report any severe symptoms. They also were more than 70 percent less likely to require hospitalization.
We still have a lot to learn about Long COVID, and, to get the answers, NIH has launched the RECOVER Initiative. The initiative will study tens of thousands of COVID-19 survivors to understand why many individuals don’t recover as quickly as expected, and what might be the cause, prevention, and treatment for Long COVID.
In the meantime, these latest findings offer the encouraging news that help is already here in the form of vaccines, which provide a very effective way to protect against COVID-19 and greatly reduce the odds of Long COVID if you do get sick. So, if you haven’t done so already, make a plan to protect your own health and help end this pandemic by getting yourself fully vaccinated. Vaccines are free and available near to you—just go to vaccines.gov or text your zip code to 438829.
Reference:
[1] Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Antonelli M, Penfold RS, Merino J, Sudre CH, Molteni E, Berry S, Canas LS, Graham MS, Klaser K, Modat M, Murray B, Kerfoot E, Chen L, Deng J, Österdahl MF, Cheetham NJ, Drew DA, Nguyen LH, Pujol JC, Hu C, Selvachandran S, Polidori L, May A, Wolf J, Chan AT, Hammers A, Duncan EL, Spector TD, Ourselin S, Steves CJ. Lancet Infect Dis. 2021 Sep 1:S1473-3099(21)00460-6.
Links:
COVID-19 Research (NIH)
Claire Steves (King’s College London, United Kingdom)
U.S. Surgeon General on Emotional Well-Being and Fighting the Opioid Epidemic
Posted on by Dr. Francis Collins
From September 2019 to September 2020, the Centers for Disease Control and Prevention reported nearly 90,000 overdose deaths in the United States. These latest data on the nation’s opioid crisis offer another stark reminder that help is desperately needed in communities across the land. NIH’s research efforts to address the opioid crisis have been stressed during the pandemic, but creative investigators have come up with workarounds like wider use of telemedicine to fill the gap.
Much of NIH’s work on the opioid crisis is supported by the Helping to End Addiction Long-term (HEAL) Initiative. Recently, the more-than 500 investigators supported by HEAL came together virtually for their second annual meeting to discuss the initiative’s latest research progress and challenges.
As part of the meeting, I had a conversation with Dr. Vivek Murthy, the U.S. Surgeon General. Dr. Murthy served as the 19th U.S. Surgeon General under the Obama Administration and was recently confirmed as the 21st Surgeon General under the Biden Administration. In his first term as America’s Doctor, in which I had the privilege of working with him, Dr. Murthy created initiatives to tackle our country’s most urgent public health issues, including addiction and the opioid crisis. He also issued the nation’s first Surgeon General’s Report on addiction, presenting the latest scientific data and issuing a call to action to recognize addiction as a chronic illness—and not a moral failing.
In 2016, Dr. Murthy sent a letter to 2.3 million healthcare professionals urging them to join a movement to tackle the opioid epidemic. This was the first time in the history of the office that a Surgeon General had issued a letter calling the medical profession to action on this issue. In 2017, Dr. Murthy focused his attention on chronic stress and isolation as prevalent problems with profound implications for health, productivity, and happiness.
Our conversation during the HEAL meeting took place via videoconference, with the Surgeon General connecting from Washington, D.C., and me linking in from my home in Maryland. Here’s a condensed transcript of our chat:
Collins: Welcome, Dr. Murthy. We’ve known each other for a few years, and I know that you’ve talked extensively about the national epidemic of loneliness. What have you learned about loneliness and how it affects our emotional wellbeing?
Murthy: Thanks, Francis. Loneliness and perceived social isolation are profound challenges for communities struggling with addiction, including opioid use disorders. I had no real background in these issues when I started as Surgeon General in 2014. I was educated by people I met all across the country, who in their own way would tell me their stories of isolation and loneliness. It’s a common stressor, especially for those who struggle with opioid use disorders. Stress can be a trigger for relapse. It’s also connected with overdose attempts and overdose deaths.
But loneliness is bigger than addiction. It is not just a bad feeling. Loneliness increases our risk of anxiety and depression, dementia, cardiac disease, and a host of other conditions. However you cut it, addressing social isolation and loneliness is an important public-health issue if we care about addiction, if we care about mental health—if we care about the physical wellbeing of people in our country.
Collins: Vivek, you made the diagnosis of an epidemic of American loneliness back before COVID-19 came along. With the emergence of COVID-19 a little more than a year ago, it caused us to isolate ourselves even more. Now that you’re back as Surgeon General and seeing the consequences of the worst pandemic in 103 years, is loneliness even worse now than before the pandemic?
Murthy: I think there are many people for whom that sense of isolation and loneliness has increased during the pandemic. But the pandemic has been a very heterogenous experience. There are some people who have found themselves more surrounded by their extended family or a close set of friends. That has been, in many ways, a luxury. For many people who are on the frontlines as essential workers, whose jobs don’t permit them to just pick up and leave and visit extended family, these have been very stressful and isolating times.
So, I am worried. And I’m particularly worried about young people—adolescents and young adults. They already had high rates of depression, anxiety, and suicide before the pandemic, and they’re now struggling with loneliness. I mention this because young people are so hyperconnected by technology, they seem to be on TikTok and Instagram all the time. They seem to be chatting with their friends constantly, texting all the time. How could they feel isolated or lonely?
But one of the things that has become increasingly clear is what matters when it comes to loneliness is the quality of your human connections, not the quantity. For many young people that I spoke to while traveling across the country, they would say that, yes, we’re connected to people all the time. But we don’t necessarily feel like we can always be ourselves in our social media environment. That’s where comparison culture is at its height. That’s where we feel like our lives are always falling short, whether it’s not having a fancy enough job, not having as many friends, or not having the right clothing or other accessories.
We talk a lot about resilience in our country. But how do we develop more resilient people? One of the keys is to recognize that social connections are an important source of resilience. They are our natural buffers for stress. When hard things happen in our lives, so many of us just instinctively will pick up the phone to call a friend. Or we’ll get into the car and go visit a member of our family or church. The truth is, if we want to build a society that’s healthier mentally and physically, that is more resilient, and that is also more happy and fulfilled, we have to think about how we build a society that is more centered around human connection and around relationships.
My hope is that one of the things we will reevaluate is building a people-centered society. That means designing workplaces that allow people to prioritize relationships. It means designing schools that equip our children with social and emotional learning tools to build healthy relationships from the earliest ages. It means thinking about public policy, not from just the standpoint of financial impact but in terms of how it impacts communities and how it can fracture communities.
We have an opportunity to do that now, but it won’t happen by default. We have to think through this very proactively, and it starts with our own lives. What does it mean for each of us to live a truly people-centered life? What decisions would we make differently about work, about how we spend time, about where we put our attention and energy?
Collins: Those are profound and very personal words that I think we can all relate to. Let me ask you about another vulnerable population that we care deeply about. There are 50 million Americans who are living with chronic pain, invisible to many, especially during the pandemic, for whom being even more isolated has been particularly rough—and who are perhaps in a circumstance where getting access to medical care has been challenging. As Surgeon General, are you also looking closely at the folks with chronic pain?
Murthy: You’re right, the populations that were more vulnerable pre-pandemic have really struggled during this pandemic—whether that’s getting medications for treatment, needed counseling services, or taking part in social support groups, which are an essential part of the overall treatment approach and staying in recovery. It’s a reminder of how urgent it is for us, number one, to improve access to healthcare in our country. We’ve made huge strides in this area, but millions are still out of reach of the healthcare system.
A potential silver lining of this pandemic is telemedicine, which has extraordinary potential to improve and extend access to services for people living with substance use disorders. In 2016, I remember visiting a small Alaskan fishing village that you can only get to by boat or plane. In that tiny village of 150 people, I walked into the small cabin where they had first-aid supplies and provided some basic medical care. There I saw a small monitor mounted on the wall and a chair. They told me that the monitor is where people, if they’re dealing with a substance use disorder, come and sit to get counseling services from people in the lower 48 states. I was so struck by that. To know that telemedicine could reach this remote Alaskan village was really extraordinary.
I think the pandemic has accelerated our adoption of telemedicine by perhaps five years or more. But we must sustain this momentum not only with investment in broadband infrastructure, but with other things that seem mundane, like the reimbursement structure around telemedicine. I talk to clinicians now who say they are seeing some private insurers go back on reimbursement for telemedicine because the pandemic is starting to get better. But the lesson learned is not that telemedicine should go away; it’s that we should be integrating it even more deeply into the practice of medicine.
The future of care, I believe, is bringing care closer to where people are, integrating it into their workflow, bringing it to their homes and their neighborhoods. I saw this so clearly for many of the patients I cared for who fell into that category of being in vulnerable populations. They were working two, three jobs, trying to take care of their children at the same time. Having a conversation with them about how they could find time to go to the gym was almost a laughable matter because they were literally dealing with issues of survival and putting food on the table for their kids. As a society we have to do more to understand the lives of people who fall into those categories and provide services that bring what they need to them, as opposed to expecting them to come to us.
If we continue in a purely fee-for-service-based environment where people must go multiple places to get their care, we will not ultimately get care to the vulnerable populations that have struggled the most and that are hoping that we will do better this time around. I think we can. I think we must. And I think COVID may just be, in part, the impetus to move forward in a different way that we need.
Collins: Let’s talk a minute about the specifics of the opioid crisis. If we’re going to move this crisis in the right direction, are there particular areas that you would say we really need more rigorous data in order to convince the medical care system—both the practitioners and the people deciding about reimbursement—that these are things we must do?
Murthy: There are a few areas that come to mind, and I’ve jotted them down. It is so important for us to do research with vulnerable populations, recognizing they often get left out. It’s essential that we conduct studies specifically for these populations so that we can better target interventions to them.
The second area is prevention programs. People want to prevent illnesses. I have not met anybody anywhere in the United States who has said, “I’d rather get diabetes first and treat it versus prevent it in the first place.” As silly as that might sound, it is the exact opposite of how we finance health interventions in our country. We put the lion’s share of our dollars in treatment. We do very little in prevention.
The third piece is the barriers faced by primary-care clinicians, who we want to be at the heart of providing a lot of these treatment services. I’ll tell you, just from my conversations with primary-care docs around the country, they worry about not having enough for their patients in the way of social work and social support services in their offices.
Finally, it has become extraordinarily clear to me that social support is one of the critical elements of treatment for substance use disorders. That it is what helps keep people in recovery. I think about the fact that many people I met who struggle with opioid use disorders had family members who were wondering how they could be helpful. They weren’t sure. They said, “Should I just keep badgering my relative to go to treatment? Should I take a tough love approach? What should I do to be helpful?”
This actually is one of the most pressing issues: social support is most often going to come from family, from friends, and from other community members. So, being able to guide them in an evidence-based way about what measures, what forms actually can be helpful to people struggling with opioid use disorders could also be immensely helpful to a group that is looking to provide assistance and support, but often is struggling to figure out how best to do that.
Collins: Vivek, you were focused as Surgeon General in the Obama Administration on the importance of changing how America thinks about addiction—that it is not a moral failing but a chronic illness that has to be treated with compassion, urgency, skill, and medical intervention. Are we getting anywhere with making that case?
Murthy: Sometimes people shy away from addressing the stigma around addiction because it feels too hard to address. But it is one of the most important issues to address. If people are still feeling judged for their disorders, they are not going to feel comfortable coming forward and getting treatment. And others will hesitate to step up and provide support.
I will always remember the young couple I met in Oklahoma who had lost their son to an opioid overdose. They told me that previously in their life whenever they had a struggle—a job loss or other health issue in the family—neighbors would come over, they would drop off food, they would visit and sit with them in their living room and hold their hands to see if they were okay. When their son died after opioid use disorder, it was silent. Nobody came over. It’s a very common story of how people feel ashamed, they feel uncomfortable, they don’t know quite what to say. So they stay away, which is the worst thing possible during these times of great pain and distress.
I do think we have made progress in the last few years. There are more people stepping forward to tell their stories. There are more people and practitioners who are embracing the importance of talking to their patients about substance use disorders and getting involved in treating them. But the truth is, we still have many people in the country who feel ashamed of what they’re dealing with. We still have many family members who feel that this is a source of shame to have a loved one struggling with a substance use disorder.
To me, this is much bigger than substance use disorders. This is a broader cultural issue of how we think about strength and vulnerability. We have defined strength in modern society as the loudest voice in the room or the person with the most physical prowess, the person who’s aggressive in negotiations, and the person who’s famous.
But I don’t think that’s what strength really is. Strength is so often displayed in moments of vulnerability when people have the courage to open up and be themselves. Strength is defined by the people who have the courage to display love, patience, and compassion, especially when it’s difficult. That’s what real strength is.
One of my hopes is that, as a society, we can ultimately redefine strength. As we think about our children and what we want them to be, we cannot aspire for them to be the loudest voice in the room. We can aspire for them to be the most-thoughtful, the most-welcoming, the most-inviting, the most-compassionate voice in the room.
If we truly want to be a society that’s grounded in love, compassion, and kindness, if we truly recognize those as the sources of strength and healing, we have to value those in our workplaces. They have to be reflected in our promotion systems. We have to value them in the classroom. Ultimately, we’ve got to build our lives around them.
That is a broader lesson that I took from all of the conversations I’ve had with people who struggle with opioid use disorders. What I took was, yes, we need medication and assisted treatment; yes, we need counseling services; yes, we need social services and wraparound services and recovery services. But the engine that will drive our healing is fundamentally the love and compassion that come from human relationships.
We all have the ability to heal because we all have the ability to be kind and to love one another. That’s the lesson that it took me more than two decades to learn in medicine. More important than any prescription that I could write is the compassion that I could extend to patients simply by listening, by showing up, by being present in their lives. We all have that ability, regardless of what degrees follow our name.
Collins: Vivek, this has been a wonderful conversation. We are fortunate to have you as our Surgeon General at this time, when we need lots of love and compassion.
Murthy: Thank you so much, Francis.
Links:
Opioids (National Institute on Drug Abuse/NIH)
Opioid Overdose Crisis (NIDA)
Vice Admiral Vivek H. Murthy (U.S. Department of Health and Human Services, Washington, D.C.)
Helping to End Addiction Long-term (HEAL) Initiative (NIH)
Video: Emotional Well Being and the Power of Connections to Fight the Opioid Epidemic (HEAL/NIH)
Study Finds 1 in 10 Healthcare Workers with Mild COVID Have Lasting Symptoms
Posted on by Dr. Francis Collins
It’s become increasingly clear that even healthy people with mild cases of COVID-19 can battle a constellation of symptoms that worsen over time—or which sometimes disappear only to come right back. These symptoms are part of what’s called “Long COVID Syndrome.”
Now, a new study of relatively young, healthy adult healthcare workers in Sweden adds needed information on the frequency of this Long COVID Syndrome. Published in the journal JAMA, the study found that just over 1 in 10 healthcare workers who had what at first seemed to be a relatively mild bout of COVID-19 were still coping with at least one moderate to severe symptom eight months later [1]. Those symptoms—most commonly including loss of smell and taste, fatigue, and breathing problems—also negatively affected the work and/or personal lives of these individuals.
These latest findings come from the COVID-19 Biomarker and Immunity (COMMUNITY) study, led by Charlotte Thålin, Danderyd Hospital and Karolinska Institutet, Stockholm. The study, launched a year ago, enlisted 2,149 hospital employees to learn more about immunity to SARS-CoV-2, the coronavirus that causes COVID-19.
After collecting blood samples from participants, the researchers found that about 20 percent already had antibodies to SARS-CoV-2, evidence of a past infection. Thålin and team continued collecting blood samples every four months from all participants, who also completed questionnaires about their wellbeing.
Intrigued by recent reports in the medical literature that many people hospitalized with COVID-19 can have persistent symptoms for months after their release, the researchers decided to take a closer look in their COMMUNITY cohort. They did so last January during their third round of follow up.
This group included 323 mostly female healthcare workers, median age of 43. The researchers compared symptoms in this group following mild COVID-19 to the 1,072 mostly female healthcare workers in the study (median age 47 years) who hadn’t had COVID-19. They wanted to find out if those with mild COVID-19 coped with more and longer-lasting symptoms of feeling unwell than would be expected in an otherwise relatively healthy group of people. These symptoms included familiar things such as fatigue, muscle pain, trouble sleeping, and problems breathing.
Their findings show that 26 percent of those who had mild COVID-19 reported at least one moderate to severe symptom that lasted more than two months. That’s compared to 9 percent of participants without COVID-19. What’s more, 11 percent of the individuals with mild COVID-19 had at least one debilitating symptom that lasted for at least eight months. In the group without COVID-19, any symptoms of feeling unwell resolved relatively quickly.
The most common symptoms in the COVID-19 group were loss of taste or smell, fatigue, and breathing problems. In this group, there was no apparent increase in other symptoms that have been associated with COVID-19, including “brain fog,” problems with memory or attention, heart palpitations, or muscle and joint pain.
The researchers have noted that the Swedish healthcare workers represent a relatively young and healthy group of working individuals. Yet, many of them continued to suffer from lasting symptoms related to mild COVID-19. It’s a reminder that COVID-19 can and, in fact, is having a devastating impact on the lives and livelihoods of adults who are at low risk for developing severe and life-threatening COVID-19. If we needed one more argument for getting young people vaccinated, this is it.
At NIH, efforts have been underway for some time to identify the causes of Long COVID. In fact, a virtual workshop was held last winter with more than 1,200 participants to discuss what’s known and to fill in key gaps in our knowledge of Long COVID syndrome, which is clinically known as post-acute sequelae of COVID-19 (PASC). Recently, a workshop summary was published [2]. As workshops and studies like this one from Sweden help to define the problem, the hope is to learn one day how to treat or prevent this terrible condition. The NIH is now investing more than $1 billion in seeking those answers.
References:
[1] Symptoms and functional impairment assessed 8 Months after mild COVID-19 among health care workers. Havervall S, Rosell A, Phillipson M, Mangsbo SM, Nilsson P, Hober S, Thålin C. JAMA. 2021 Apr 7.
[2] Toward understanding COVID-19 recovery: National Institutes of Health workshop on postacute COVID-19. Lerner A, et al. Ann Intern Med, 2021 March 30.
Links:
COVID-19 Research (NIH)
Charlotte Thålin (Karolinska Institutet, Stockholm, Sweden)
Lessons Learned About Substance Use Disorders During the COVID-19 Pandemic
Posted on by Dr. Francis Collins
Every spring, I and my colleague Dr. Nora Volkow, Director of NIH’s National Institute on Drug Abuse (NIDA), join with leaders across the country in the Rx Drug Abuse and Heroin Summit. Our role is to discuss NIH’s continued progress in tackling our nation’s opioid crisis. Because of the continued threat of COVID-19 pandemic, we joined in virtually for the second year in a row.
While the demands of the pandemic have been challenging for everyone, biomedical researchers have remained hard at work to address the opioid crisis. Among the many ways that NIH is supporting these efforts is through its Helping to End Addiction Long-Term (HEAL) Initiative, which is directing more than $1.5 billion to researchers and communities across the country.
Here’s a condensed transcript of our April 6th video dialogue, which focused on the impact of the COVID-19 pandemic on people struggling with substance use disorders and those who are trying to help them.
Collins: What have we learned so far through HEAL? Well, one thing HEAL is doing is tackling the need for pain treatments that help people avoid the risks of opioids. This research has uncovered new targets and therapeutics for different types of pain, including neuropathic, post-surgical, osteoarthritic, and chemotherapy induced. We’re testing implanted devices, such as electrodes and non-invasive nerve stimulation; and looking at complementary and integrative approaches, such as phone-based physical therapy for low back pain.
Through HEAL, we’ve launched a first-in-human test of a vaccine to protect against the harmful effects of opioids, including relapse and overdose. We’re also testing a tool that provides pharmacists with a validated opioid use disorder risk measure. The goal is to identify better who’s at high risk for opioid addiction and to determine what kind of early intervention could be put in place.
Despite COVID, many clinical studies are now recruiting participants. This includes family-based prevention programs, culturally tailored interventions for hard-hit American Indian populations, and interventions that address social inequities, such as lack of housing.
We are also making progress on the truly heart-breaking problem of babies born dependent on opioids. HEAL has launched a study to test the effectiveness of a new approach to care that measures the severity of a baby’s withdrawal, based on their ability to eat, sleep, and be consoled. This approach helps provide appropriate treatment for these infants, without the use of medication when possible. We’re also developing novel technologies to help treat neonatal opioid withdrawal syndrome, including a gently vibrating hospital bassinet pad that’s received breakthrough device designation from the FDA.
2020 was an extraordinary year that was tragic in so many ways, including lives lost and economic disasters that have fallen upon families. The resilience and ingenuity of the scientific community has been impressive. Quick pivoting has resulted in some gains through research, maybe you could even call them silver linings in the midst of this terrible storm.
Nora, what’s been at the forefront of your mind as we’ve watched things unfold?
Volkow: When we did this one year ago, we didn’t know what to expect. Obviously, we were concerned that the stressors associated with a pandemic, with unknowns, are factors that have been recognized for many years to increase drug use. Unfortunately, what we’ve seen is an increase in drug use of all types across the country.
We have seen an exacerbation of the opioid epidemic, as evidenced by the number of people who have died. Already, in the 12 months ending in July 2020, there was a 24 percent increase in mortality from overdoses. Within those numbers, there was close to a 50 percent increase in mortality associated with fentanyl. We’re also seeing an increase, not just in deaths from fentanyl and other synthetic opioids, but in deaths from stimulant drugs, like cocaine and methamphetamine. And the largest increases have been very much driven by drug combinations.
So, we have the perfect storm. We have people stressed to their limits by decreases in the economy, the loss of jobs, the death of loved ones. On the other hand, we see dealers taking the opportunity to bring in drugs such as synthetic opioids and synthetic stimulants and distribute them to a much wider extent than previously seen.
Collins: On top of that, people are at risk of getting sick from COVID-19. What have we learned about the risks of coronavirus illness for people who use drugs?
Volkow: It is a double whammy. When you look at the electronic health records about the outcomes of people diagnosed with substance use disorders, you consistently see an increased risk for getting infected with COVID-19. And if you look at those who get infected, you observe a significantly increased risk of dying from COVID.
What’s driving this vulnerability? One factor is the pharmacological effects of these drugs. Basically, all of the drugs of abuse that result in addiction, notably opioids, damage the cardiopulmonary system. Some also damage the immune system. And we know that individuals who have any disruption of cardiovascular health, pulmonary health, immune function, or metabolism are at higher risk of getting infected with COVID-19 and having adverse outcomes.
But there’s another factor that’s as important—one that’s very tractable. It is the way in which our society has dealt with substance use disorders: not actually treating them as a disease that requires intervention and support for recovery. The stigmatization of individuals with addiction, the lack of access to treatment, the social isolation, have all created havoc by making these individuals so much more vulnerable to get infected with COVID-19.
They will not go to a doctor. They don’t want to be stigmatized. They need to go out into the streets to get access to the drugs. Many times, they don’t have a choice of what drugs to take because they cannot afford anything except what’s offered to them. So, many, especially those who are minorities, end up homeless or in jails or prison. Even before COVID, we knew that prisons and jails are places where infections can transmit extraordinary rapidly. You could see this was going to result in very negative outcomes for this group of individuals.
Collins: Nora, tell us more about the trends contributing to the current crisis. Maybe three or four years ago, what was going straight up was opioid use, especially heroin. Then, fentanyl started coming up very fast and that has continued. Now, we are seeing more stimulants and mixing of different types of drugs. What is the basis for this?
Volkow: At the beginning of the opiate pandemic, mortality was mainly associated with white Americans, many in rural or semi-suburban areas of the Appalachian states and in New Mexico and Arizona. That has shifted. The highest increase in mortality from opioids, predominantly driven by fentanyl, is now among Black Americans. They’ve had very, very high rates of mortality during the COVID pandemic. And when you look at mortality from methamphetamine, it’s chilling to realize that the risk of dying from methamphetamine overdose is 12-fold higher among American Indians and Alaskan Natives than other groups. This should make us pause to think about what’s driving these terrible racial disparities.
As for drug combinations, many deaths from methamphetamine or cocaine—an estimated 50 percent—are linked to these stimulant drugs being combined with fentanyl or heroin. Dealers are lacing these non-opioid drugs with cheaper, yet potent, opioids to make a larger profit. Someone who’s addicted to a stimulant drug like cocaine or methamphetamine is not tolerant to opioids, which means they are going to be at high risk of overdose if they get a stimulant drug that’s laced with an opioid like fentanyl. That’s been contributing to the sharp rise in mortality from non-opioid drugs.
Collins: I’m glad you raised the issue of health disparities. 2020 will go down as a year in which our nation had to focus on three public health crises at once. The first is the crisis of opioid use disorder and rising mortality from use of other drugs. The second is COVID-19. And the third is the realization, although the problem has been there all along, that health disparities continue to shorten the lives of far too many people.
The latter crisis has little to do with biology, but everything to do with the way in which our society still is afflicted by structural racism. We at NIH are looking at this circumstance, realizing that our own health disparities research agenda needs to be rethought. We have not fully incorporated all the factors that play out in health inequities and racial inequities in our country.
You were also talking about how stimulants have become more widespread. What about treatments for people with stimulant use disorders?
Volkow: For opioid addiction, we’re lucky because we have very effective medications: methadone, buprenorphine, naltrexone. On top of that, we have naloxone, Narcan, that if administered on time, can save the life of a person who has overdosed.
We don’t have any FDA-approved medication for methamphetamine addiction, and we don’t have any overdose reversal for methamphetamine. At the beginning of this year, we funded a large clinical trial aimed at investigating the benefits of the combination of two medications that were already approved as anti-depressants and for the treatment of smoking cessation and alcoholism. It found this combination significantly inhibits the urge to take drugs and therefore helps people stay away from use of methamphetamine. Now, we want to replicate these findings, and to tie that replication study in with guidelines from the FDA on what is needed to approve our new indication for these medications. Why? Because then insurance can cover it, and that will increase the likelihood that people will get treated.
Another exciting possibility is a monoclonal antibody against methamphetamine that’s in Phase 2 clinical trials. If someone comes into the emergency room with an overdose of a combination of opioid and methamphetamine, naloxone often will not work. But this monoclonal antibody with naloxone may offer a greater likelihood of success.
Another thing that’s promising is that investigators have been able to modify monoclonal antibodies so they stay in the bloodstream for a longer time. That means we may someday be able to use this passive immunization approach as a treatment for methamphetamine addiction.
Collins: That’s good to hear. Speaking of progress, is there any you want to point to within HEAL?
Volkow: There’s a lot of excitement surrounding medication development. We’re interested in developing antidotes that will be more effective in reversing overdose deaths from fentanyl. We’re also interested in providing longer lasting medications for treatment of opioid use disorders, which would improve the likelihood of patients being protected from overdoses.
The Justice Community Opioid Innovation Network (JCOIN) is another HEAL landmark project. It involves a network of researchers that is working with judges and with the workers in jail and prison systems responsible for taking care of individuals with substance use disorders. Through this network, we’ve been able to start to harmonize practices. One thing that’s been transformative in the jail and prison system has been the embracing of telehealth. In the past, telehealth was not much of a reality in jails and prisons because of the fear of it could lead to communications that could perhaps be considered dangerous. That’s changed due to COVID-19. Now, telehealth is providing access to treatment for individuals in jail and prison, many of them with substance use disorders.
Also, because of COVID, many nonviolent individuals in jails and prisons were released. This gives us an opportunity to evaluate how best to help such individuals achieve recovery from substance use disorders. Hopefully we can generate data to show that there are much more effective strategies than incarceration for dealing with substance use disorders.
The HEALing Communities Study, involves Massachusetts, New York, Ohio, and Kentucky—four of the states with the highest rates of mortality from overdoses from the inception of the opioid epidemic. By implementing a battery of interventions for which there is evidence of benefit, this ambitious study set out to decrease overdose mortality by 40 percent in two years. Then, came COVID and turned everything upside down. Still, because we consolidated interactions between agencies, we’ve been able to apply support systems more efficiently in those communities in ways that have been very, very reinforcing. Obviously, there’ve been delays in implementation of interventions that require in-person interactions or that involve hospital emergency departments, which have been saturated with COVID patients.
We’ve learned a lot in the process. I may be too optimistic, but I do believe that we can stay on goal.
Collins: Now, I’d like to transition to a few questions from people who subscribe to the HEAL website. Announced at this meeting three years ago, the HEAL Initiative involves research participants and patients and stakeholders—especially people who have lived experience with pain, addiction, or both.
Let’s get to the first question: “What is NIH doing through HEAL to address the stigma that prevents people who need opioid medications for treatment from getting them?”
Volkow: A crucial question. As we look at the issue of stigma, we need to recognize that there are structural issues in how our society is prioritizing the importance of substance use disorders and the investments devoted to them. And we need to recognize that substance use disorder doesn’t exist in isolation; it is frequently comorbid with mental illness.
We need to listen. Some of the issues that we believe are most problematic are not. We need to empower these communities to speak up and help them do so. This is probably one of the most important things that we can do in terms of addressing stigma for addiction.
Collins: Absolutely. The HEAL Initiative has a number of projects that are focusing on stigma and coming up with tools to help reduce this. And here’s our second question: “In small communities, how can we provide more access to medications for opioid use disorder?”
Volkow: One project funded through HEAL was to evaluate the effectiveness of community pharmacies for delivering buprenorphine to individuals with opioid use disorder. The results show that patients receiving buprenorphine through community pharmacies in rural areas had as good outcomes as patients being treated by specialized clinicians on site.
Another change that’s made things easier is that in March 2020, the DEA relaxed its rules on how a physician can prescribe buprenorphine. In the past, you needed to go physically to see a doctor. Now, the DEA allows a patient to be initiated on buprenorphine through telehealth, and that’s opened the possibility of greater access to treatment in rural communities.
My perspective is let’s look at innovative ways of solving problems. Because the technology is changing in so many ways and so rapidly, let’s take advantage of it.
Collins: Totally with you on that. If there’s a silver lining to COVID-19, it’s that we’ve been forced to take stock of the ways we’ve been doing things. We will learn from this pandemic and change the way we approach so many things in health and medicine as a result. Certainly, opioid use disorder ought to be very high on that list. Let’s move on to another question: “What is the HEAL initiative doing to promote prevention of opioid use?”
Volkow: This is where the HEAL initiative is aiming to provide alternative treatments for the management of pain that reduce the risk of addiction.
Then there’s the issue of prevention in people who start to take opioids because they either want to get high or escape. With the COVID pandemic, we’ve seen increases in anxiety and in depression. Those are factors that can put a teenager or young adult on a trajectory for higher risk of substance use disorders.
So, what is HEAL doing? There is prevention research specifically targeted, for example, at the transition from adolescence to young adulthood. That is the period of greatest vulnerability of uptake of opioids, or drugs of misuse. We’re also targeting minority groups that may be at very, very high risk. We want to be able to understand the factors that make them more vulnerable to tailor prevention interventions more effectively.
Collins: Today, we’ve shared some of the issues that NIH is wrestling with in its efforts to address the crisis of opioid misuse and overdose, as well as other drugs that are now very much part of the challenge. To learn more, go to the HEAL website. You can also send us your thoughts through the HEAL Idea Exchange.
These developments give me hope in the wake of a very difficult year. Clearly, we still have the capacity to work together, we are resilient, and we are determined to put an end to our nation’s opioid crisis.
Volkow: Francis, I want to thank you for your incredible leadership and your support. I hope the COVID pandemic will bring forth a more equitable system, in which all people are given the chance for resilience that maximizes their life, happiness, and productivity. I think science is an extraordinary tool to help us do that.
Links:
Video: The 2021 Rx Drug Abuse & Heroin Summit: Francis Collins with Nora Volkow (NIH)
COVID-19 Research (NIH)
Helping to End Addiction Long-term (HEAL) Initiative (NIH)
HEAL Idea Exchange (NIH)
National Institute on Drug Abuse (NIH)
Predicting ‘Long COVID Syndrome’ with Help of a Smartphone App
Posted on by Dr. Francis Collins
As devastating as this pandemic has been, it’s truly inspiring to see the many innovative ways in which researchers around the world have enlisted the help of everyday citizens to beat COVID-19. An intriguing example is the COVID Symptom Study’s smartphone-based app, which already has been downloaded millions of times, mostly in the United States and United Kingdom. Analyzing data from 2.6 million app users, researchers published a paper last summer showing that self-reported symptoms can help to predict infection with SARS-CoV-2, the coronavirus that causes COVID-19 [1].
New work from the COVID Symptom Study now takes advantage of the smartphone app to shed more light on Long COVID Syndrome [2], in which people experience a constellation of symptoms long past the time that they’ve recovered from the initial stages of COVID-19 illness. Such symptoms, which can include fatigue, shortness of breath, “brain fog,” sleep disorders, fevers, gastrointestinal symptoms, anxiety, and depression, can persist for months and can range from mild to incapacitating
This latest findings, published in the journal Nature Medicine, come from a team led by Claire Steves and Tim Spector, King’s College London, and their colleagues, and that includes NIH grantee Andrew Chan, Massachusetts General Hospital, Boston, and others supported by the Massachusetts Consortium on Pathogen Readiness. The team began by looking at data recorded between March 24-Sept. 2, 2020 from about 4.2 million app users with an average age of 45, about 90 percent of whom lived in the U.K., with smaller numbers from the U.S. and Sweden.
For this particular study, the researchers decided to focused on 4,182 app users, all with confirmed COVID-19, who had consistently logged in their symptoms. Because these individuals also started using the app when they still felt physically well, the researchers could assess their COVID-19-associated symptoms over the course of the illness.
While most people who developed COVID-19 were back to normal in less than two weeks, the data suggest that one in 20 people with COVID-19 are likely to suffer symptoms of Long COVID that persist for eight weeks or more. About one in 50 people continued to have symptoms for 12 weeks or more. That suggests Long COVID could potentially affect many hundreds of thousands of people in the U.K. alone and millions more worldwide.
The team found that the individuals most likely to develop Long COVID were older people, women, and especially those who experienced five or more symptoms. The nature and order of symptoms, which included fatigue, headache, shortness of breath, and loss of smell, didn’t matter. People with asthma also were more likely to develop long-lasting symptoms, although the study found no clear links to any other pre-existing health conditions.
Using this information, the researchers developed a model to predict which individuals were most likely to develop Long COVID. Remarkably, this simple algorithm—based on age, gender, and number of early symptoms–accurately predicted almost 70 percent of cases of Long COVID. It was also about 70 percent effective in avoiding false alarms.
The team also validated the algorithm’s predictive ability in data from an independent group of 2,472 people with confirmed COVID-19 and a range of symptoms. In this group, having more than five symptoms within the first week also proved to be the strongest predictor of Long COVID. And, again, the model worked quite well in identifying those most likely to develop Long COVID.
These findings come as yet another important reminder of the profound impact of the COVID-19 pandemic on public health. This includes not only people who are hospitalized with severe COVID-19 but, all too often, those who get through the initial period of infection relatively unscathed.
Recently, NIH announced a $1.15 billion investment to identify the causes of Long COVID, to develop ways of treating individuals who don’t fully recover, and, ultimately, to prevent the disorder. We’ve been working diligently in recent weeks to identify the most pressing questions and areas of greatest opportunity to address this growing public health threat. As a first step, NIH is funding an effort to track the recovery paths of at least 40,000 adults and children infected with SARS-CoV-2, to learn more about who develops long-term effects and who doesn’t. If you’d like to find a way to pitch in and help, getting involved in the COVID Symptom Study is as easy as downloading the app.
References:
[1] Real-time tracking of self-reported symptoms to predict potential COVID-19. Menni C, Valdes AM, Freidin MB, Sudre CH, Nguyen LH, Drew DA, Ganesh S, Varsavsky T, Cardoso MJ, El-Sayed Moustafa JS, Visconti A, Hysi P, Bowyer RCE, Mangino M, Falchi M, Wolf J, Ourselin S, Chan AT, Steves CJ, Spector TD. Nat Med. 2020 Jul;26(7):1037-1040. doi: 10.1038/s41591-020-0916-2. Epub 2020 May 11.
[2] Attributes and predictors of long COVID. Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, Pujol JC, Klaser K, Antonelli M, Canas LS, Molteni E, Modat M, Jorge Cardoso M, May A, Ganesh S, Davies R, Nguyen LH, Drew DA, Astley CM, Joshi AD, Merino J, Tsereteli N, Fall T, Gomez MF, Duncan EL, Menni C, Williams FMK, Franks PW, Chan AT, Wolf J, Ourselin S, Spector T, Steves CJ. Nat Med. 2021 Mar 10.
Links:
NIH launches new initiative to study to “Long COVID”. 2021 Feb 23. (NIH)
COVID-19 Research (NIH)
Massachusetts Consortium on Pathogen Readiness (Boston)
Claire Steves (King’s College London, United Kingdom)
Tim Spector (King’s College London)
Andrew Chan (Massachusetts General Hospital, Boston)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases
ACTIV Update: Making Major Strides in COVID-19 Therapeutic Development
Posted on by Dr. Francis Collins
Right now, many U.S. hospitals are stretched to the limit trying to help people battling serious cases of COVID-19. But as traumatic as this experience still is for patients and their loved ones, the chances of surviving COVID-19 have in fact significantly improved in the year since the start of the pandemic.
This improvement stems from several factors, including the FDA’s emergency use authorization (EUA) of a number of therapies found to be safe and effective for COVID-19. These include drugs that you may have heard about on the news: remdesivir (an antiviral), dexamethasone (a steroid), and monoclonal antibodies from the companies Eli Lilly and Regeneron.
Yet the quest to save more lives from COVID-19 isn’t even close to being finished, and researchers continue to work intensively to develop new and better treatments. A leader in this critical effort is NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, a public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies.
ACTIV was founded last April to accelerate drug research that typically requires more than a decade of clinical ups and downs to develop a safe, effective therapy. And ACTIV has indeed moved at unprecedented speed since its launch. Cutting through the usual red tape and working with an intense sense of purpose, the partnership took a mere matter of weeks to set up its first four clinical trials. Beyond the agents mentioned above that have already been granted an EUA, ACTIV is testing 15 additional potential agents, with several of these already demonstrating promising results.
Here’s how ACTIV works. The program relies on four expert “working groups” with specific charges:
Preclinical Working Group: Shares standardized preclinical evaluation resources and accelerate testing of candidate therapies and vaccines for clinical trials.
Therapeutics Clinical Working Group: Prioritizes therapeutic agents for testing within an adaptive master protocol strategy for clinical research.
Clinical Trial Capacity Working Group: Has developed and organized an inventory of clinical trial capacity that can serve as potential settings in which to implement effective COVID-19 clinical trials.
Vaccines Working Group: Accelerates the evaluation of vaccine candidates.
To give you just one example of how much these expert bodies have accomplished in record time, the Therapeutics Clinical Working Group got to work immediately evaluating some 400 candidate therapeutics using multiple publicly available information sources. These candidates included antivirals, host-targeted immune modulators, monoclonal antibodies (mAb), and symptomatic/supportive agents including anticoagulants. To follow up on even more new leads, the working group launched a COVID-19 Clinical & Preclinical Candidate Compound Portal, which remains open for submissions of therapeutic ideas and data.
All the candidate agents have been prioritized using rigorous scoring and assessment criteria. What’s more, the working group simultaneously developed master protocols appropriate for each of the drug classes selected and patient populations: outpatient, inpatient, or convalescent.
Through the coordinated efforts of all the working groups, here’s where we stand with the ACTIV trials:
ACTIV-1: A large-scale Phase 3 trial is enrolling hospitalized adults to test the safety and effectiveness of three medicines (cenicriviroc, abatacept, and infliximab). They are called immune modulators because they help to minimize the effects of an overactive immune response in some COVID-19 patients. This response, called a “cytokine storm,” can lead to acute respiratory distress syndrome, multiple organ failure, and other life-threatening complications.
ACTIV-2: A Phase 2/3 trial is enrolling adults with COVID-19 who are not hospitalized to evaluate the safety of multiple monoclonal antibodies (Lilly’s LY-CoV555, Brii Biosciences’s BRII-196 and BRII-198, and AstraZeneca’s AZD7442) used to block or neutralize the SARS-CoV-2 virus. The Lilly monoclonal antibody LY-CoV555 received an EUA for high risk non-hospitalized patients on November 9, 2020 and ACTIV-2 continued to test the agent in an open label study to further determine safety and efficacy in outpatients. Another arm of this trial has just started, testing inhaled, easy-to-administer interferon beta-1a treatment in adults with mild-to-moderate COVID-19 who are not hospitalized. An additional arm will test the drug camostat mesilate, a protease inhibitor that can block the TMPRSS2 host protein that is necessary for viral entry into human cells.
ACTIV-3: This Phase 3 trial is enrolling hospitalized adults with COVID-19. This study primarily aims to evaluate safety and to understand if monoclonal antibodies (AstraZeneca’s AZD7442, BRII-196 and BRII-198, and the VIR-7831 from GSK/Vir Biotechnology) and potentially other types of therapeutics can reduce time to recovery. It also aims to understand a treatment’s effect on extrapulmonary complications and respiratory dysfunction. Lilly’s monoclonal antibody LY-CoV555 was one of the first agents to be tested in this clinical trial and it was determined to not show the same benefits seen in outpatients. [Update: NIH-Sponsored ACTIV-3 Clinical Trial Closes Enrollment into Two Sub-Studies, March 4, 2021]
ACTIV-4: This trial aims to determine if various types of blood thinners, including apixaban, aspirin, and both unfractionated (UF) and low molecular weight (LMW) heparin, can treat adults diagnosed with COVID-19 and prevent life-threatening blood clots from forming. There are actually three Phase 3 trials included in ACTIV-4. One is enrolling people diagnosed with COVID-19 but who are not hospitalized; a second is enrolling patients who are hospitalized; and a third is enrolling people who are recovering from COVID-19. ACTIV-4 has already shown that full doses of heparin blood thinners are safe and effective for moderately ill hospitalized patients.
ACTIV-5: This is a Phase 2 trial testing newly identified agents that might have a major benefit to hospitalized patients with COVID-19, but that need further “proof of concept” testing before they move into a registrational Phase 3 trial. (In fact, another name for this trial is the “Big Effect Trial”.) It is testing medicines previously developed for other conditions that might be beneficial in treatment of COVID-19. The first two agents being tested are risankizumab (the result of a collaboration between Boehringer-Ingelheim), which is already FDA-approved to treat plaque psoriasis, and lenzilumab, which is under development by Humanigen to treat patients experiencing cytokine storm as part of cancer therapy.
In addition to trials conducted under the ACTIV partnership, NIH has prioritized and tested additional therapeutics in “ACTIV-associated trials.” These are NIH-funded, randomized, placebo-controlled clinical trials with one or more industry partners. Here’s a table with a comprehensive list.
Looking a bit further down the road, we also seek to develop orally administered drugs that would potentially block the replication ability of SARS-CoV-2, the coronavirus that causes COVID-19, in the earliest stages of infection. One goal would be to develop an antiviral medication for SARS-CoV-2 that acts similarly to oseltamivir phosphate (Tamiflu®), a drug used to shorten the course of the flu in people who’ve had symptoms for less than two days and to prevent the flu in asymptomatic people who may have been exposed to the influenza virus. Yet another major long-term effort of NIH and its partners will be to develop safe and effective antiviral medications that work against all coronaviruses, even those with variant genomes. (And, yes, such drugs might even cure the common cold!)
So, while our ACTIV partners and many other researchers around the globe continue to harness the power of science to end the devastating COVID-19 pandemic as soon as possible, we must also consider the lessons learned this past year, in order to prepare ourselves to respond more swiftly to future outbreaks of coronaviruses and other infectious disease threats. Our work is clearly a marathon, not a sprint.
Links:
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)
COVID-19 Research (NIH)
Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)
Pull Up a Chair with Dr. Freire: The COVID Conversations (Foundation for the National Institutes of Health, Bethesda, MD)
SARS-COV-2 Antiviral Therapeutics Summit Report, November 2020 (NIH)
Trying to Make Sense of Long COVID Syndrome
Posted on by Dr. Francis Collins
More than 400,000 Americans have now lost their lives to COVID-19. But thousands of others who’ve gotten sick and survived COVID-19 are finding that a full recovery can be surprisingly elusive. Weeks and months after seemingly recovering from even mild cases of COVID-19, many battle a wide range of health problems.
Indeed, new results from the largest global study of this emerging “Long COVID syndrome” highlight just how real and pressing this public health concern really is. The study, reported recently as a pre-print on medRxiv, is based on survey results from more than 3,700 self-described COVID “Long Haulers” in 56 countries [1]. They show nearly half couldn’t work full time six months after unexpectedly developing prolonged symptoms of COVID-19. A small percentage of respondents, thankfully, seemed to have bounced back from brief bouts of Long COVID, though time will tell whether they have fully recovered.
These findings are the second installment from the online Body Politic COVID-19 Support Group and its Patient-Led Research for COVID-19, which consists of citizen scientists with a wide range of expertise in the arts and sciences who are struggling with the prolonged effects of COVID-19 themselves. In an earlier survey, this group provided a first-draft description of Long COVID syndrome, based on the self-reported experiences of 640 respondents.
In the new survey-based study led by Athena Akrami, with Patient-Led Research for COVID-19 and University College London, England, the goal was to characterize the experiences of many more people with Long COVID syndrome. They now define the syndrome as a collection of symptoms lasting for more than 28 days.
This second survey emphasizes the course and severity of more than 200 symptoms over time, including those affecting the heart, lungs, gastrointestinal system, muscles, and joints. It took a particularly in-depth look at neurological and neuropsychiatric symptoms, along with the ability of COVID-19 survivors to return to work and participate in other aspects of everyday life.
The 3,762 individuals who responded to the survey were predominately white females, between the ages of 30 and 60, who lived in the United States. As in the previous survey, the study included adults with symptoms consistent with COVID-19, whether or not the infection had been confirmed by a viral or antibody test. That is a potential weakness of the study, as some of these individuals may have had some other inciting illness. But many of the study’s participants developed symptoms early on in the pandemic, when testing was much more limited than it is now.
More than half never sought hospital care. Only 8 percent said that they’d been admitted to the hospital for COVID-19. And yet, 2,464 respondents reported COVID-19 symptoms lasting six months or longer. Most of the remaining respondents also continued to have symptoms, although they had not yet reached the six-month mark.
Among the most common symptoms were fatigue, worsening of symptoms after physical or mental activity, shortness of breath, trouble sleeping, and “brain fog,” or difficulty thinking clearly. The majority—88 percent—said they coped with some form of cognitive dysfunction or memory loss that to varying degrees affected their everyday lives. That includes the ability to make decisions, have conversations, follow instructions, and drive.
Those who had prolonged symptoms of COVID-19 for more than six months reported contending with about 14 symptoms on average. Most also reported that they’d had a relapse of symptoms, seemingly triggered by exercise, mental activity, or just everyday stress. When surveyed, nearly half of respondents said they’d had to reduce their hours at work due to the severity of their symptoms. Another 22 percent weren’t working at all due to their Long COVID.
The findings show that—even in those people who don’t require hospitalization for severe COVID-19—the condition’s prolonged symptoms are having a major impact on lives and livelihoods, both here and around the world. While the number of people affected isn’t yet known, if even a small proportion of the vast numbers of people infected with COVID-19 develop Long COVID syndrome, it represents a significant public health concern.
Another recent study from China further documents the tendency of COVID-19-related symptoms to linger past the usual recovery time for a respiratory virus [2]. The study, published in Lancet, showed that six months after the onset of illness, more than 75 percent of people hospitalized with COVID-19 in Wuhan between January and May 2020 continued to report at least one symptom. Fatigue, muscle weakness, sleep difficulties, anxiety, and depression all were common. More than half of individuals also had significant persistent lung abnormalities, which were more common in those who’d been more severely ill.
It’s essential for us to learn all we can about how SARS-CoV-2, which is the coronavirus that causes COVID-19, leads to such widespread symptoms. It’s also essential that we develop ways to better treat or prevent these symptoms. The NIH held a workshop last month to summarize what is known and fill in key gaps in our knowledge about Long COVID syndrome, which is clinically known as post-acute sequelae of COVID-19 (PASC). In December, Congress authorized funding for continued research on PASC, including an appropriation of funds for NIH to support continued study of these prolonged health consequences.
As these efforts and others proceed in the coming months, the hope is that we’ll gain much more insight and get some answers soon. And, if you’ve had or are currently experiencing symptoms of COVID-19, there’s still time to share your data by participating in the Patient-Led Research for COVID-19’s second survey.
References:
[1] Characterizing Long COVID in an international cohort: 7 months of symptoms and their impact. David HE et al. Medrxiv. 27 December 27 2020.
[2] 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Huang C, Huang L, et al. Lancet. 2021 Jan 16;397(10270):220-232.
Links:
COVID-19 Research (NIH)
Akrami Lab (Sainsbury Wellcome Center, University College London, England)
Patient-led Research for COVID-19
Video: Workshop on Post-Acute Sequelae of COVID-19 (NIH)
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