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Expanding Menopause Research to Advance the Health of All Women
Posted on by Janine Austin Clayton, M.D., FARVO, NIH Office of Research on Women’s Health
Since 2017, NIH’s Office of Research on Women’s Health (ORWH) has hosted the Vivian W. Pinn Symposium during National Women’s Health Week (NWHW) in May. This event honors the first full-time director of the office, Dr. Vivian W. Pinn, and serves as a critical forum for experts across sectors to communicate and collaborate for the advancement of women’s health.
This week marks the beginning of the 2023 NWHW, and on May 16, ORWH will host the 7th Annual Vivian W. Pinn Symposium. It’s titled: Menopause and Optimizing Midlife Health of Women.
Topics to be discussed include: the menopausal transition (also known as perimenopause), the accumulation of morbidity after menopause, menopause in special populations, the influence of social determinants of health on the experience of menopause, the use of menopausal hormone therapy (MHT), and interventions to promote healthy aging.
This year, JoAnn Manson, Harvard Medical School, Cambridge, MA, will deliver the keynote speech, titled “Menopausal Hormone Therapy: 30 Years of Lessons from the Women’s Health Initiative.” I encourage everyone with an interest in women’s health to register for the event.
In 1992, NIH’s National Heart, Lung, and Blood Institute launched the Women’s Health Initiative (WHI), seeking to improve the health of women through research on prevention of serious health conditions in postmenopausal women. Over three decades later, WHI remains an extraordinary example of centering research around the health needs of women, and WHI research results “definitively established that menopausal hormone therapy should not be used to prevent heart disease, stroke, and other chronic diseases.” These results were practice-changing and led to a dramatic decline in the use of MHT.
Menopause is a natural and irreversible life course stage marked by the cessation of menstrual cycling for 12 consecutive months. Common symptoms associated with menopause include hot flashes, sleep disturbances, mood changes, headaches, and heart palpitations. An article, co-authored by Dr. Manson, summarizes effective hormonal and non-hormonal treatments to manage menopausal symptoms [1].
The WHI’s longer-term follow-up of the treatment of these women, however, has demonstrated many nuanced findings [2]. For example, MHT’s risks and benefits are complex and vary based upon patient-level characteristics, including the age at which the therapy is initiated and the formulation of the MHT prescribed. Importantly, WHI was designed to assess the efficacy of MHT in preventing chronic disease, not to assess the efficacy or safety of MHT when used to treat menopausal symptoms. The average study participant was older, with over a decade since the start of their menopausal transition.
When considering any treatment, people should consult a health care professional, and MHT may be an option for some women, especially those who are experiencing menopausal symptoms and are at low risk for adverse events. The Food and Drug Administration (FDA) offers a fact sheet to answer questions and provide guidance about menopause and hormones, and has evaluated the risks and benefits of MHT for specific age groups of women [3].
In addition to WHI, there are two other valuable NIH-funded studies helping to make progress in our understanding of the health of midlife and older women:
• Study of Women’s Health Across the Nation (SWAN)
• Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH)
A major health concern for women during perimenopause, menopause, and post menopause is cardiovascular health. More research is needed to understand how different stages of menopause affect women’s cardiovascular health and how different doses and formulations of MHT may affect risk.
Among the many speakers at the Vivian W. Pinn Symposium will be Wendy Kohrt, a co-author on a recent comprehensive review of cardiovascular health and menopause [4]. She is director of the University of Colorado Specialized Centers of Research Excellence on Sex Differences (SCORE), Aurora. Also, a recent issue of ORWH’s Women’s Health in Focus at NIH discussed current NIH-funded research on menopause, resources, future menopause-related research, and more.
In response to a Congressional request to address NIH efforts related to women’s health research, ORWH hosted, along with the NIH Advisory Committee on Research on Women’s Health, “Advancing NIH Research on the Health of Women: A 2021 Conference.” The importance of menopause research as it relates to chronic debilitating conditions, which pose a significant burden on the health of women, was addressed during the conference, and the full report is available on the ORWH website.
Further, ORWH and partnering institutes released two notices of funding opportunities titled Understanding Chronic Conditions Understudied Among Women (R01 and R21), and ORWH sponsored the forthcoming Framework for the Consideration of Chronic Debilitating Conditions in Women from the National Academies of Sciences, Engineering, and Medicine.
I wish everyone a happy and healthy NWHW and look forward to gathering virtually for the 7th Annual Vivian W. Pinn Symposium. For more information and resources on menopause, visit the FDA’s Office of Women’s Health and NIH’s National Institute on Aging (NIA) websites. Also, My Menoplan, developed by NIA-funded researchers, offers information and personalized tools to help plan for perimenopause and menopause. Please stay connected to ORWH by visiting our website for updates; signing up for our monthly newsletter, The Pulse; liking us on Facebook; and following ORWH on Twitter.
References:
[1] Management of menopausal symptoms: A review. Crandall CJ, et al. JAMA. 2023 February 7: 329(5):405-420.
[2] Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. Manson JE, et al. JAMA. 2013 October 2: 310(13)1353-1368.
[3] Randomized trial evaluation of the benefits and risks of menopausal hormone therapy among women 50-59 years of age. Prentice RL, et al. Am J Epidemiol. 2021 February 1: 190(3):365-375.
[4] Body composition and cardiometabolic health across the menopause transition. Marlatt KL, et al. Obesity. 2022 January; 30(1)14-27.
Links:
Office of Research on Women’s Health (NIH)
7th Annual Vivian W. Pinn Symposium (ORWH)
Specialized Centers of Research Excellence on Sex Differences (SCORE) (ORWH)
National Women’s Health Week (Office on Women’s Health, U.S. Department of Health and Human Services, Rockville, MD)
Women’s Health Initiative (WHI)
Study of Women’s Health Across the Nation (SWAN)
Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) (Fred Hutchinson Cancer Center, Seattle)
Office of Women’s Health (U.S. Food and Drug Administration, Silver Spring, MD)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes, Centers, and Offices to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 30th in the series of NIH guest posts that will run until a new permanent NIH director is in place.
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)
Taking a Community-Based Approach to Youth Substance Abuse Prevention
Posted on by Dr. Francis Collins
As a child born and raised in a low-income, urban neighborhood of Jersey City, NJ, Ijeoma Opara counted herself lucky. She had strong support from her parents, both college-educated Nigerian immigrants. But she also saw firsthand the devastating effects that gang violence, crime, drugs, and alcohol were having on too many young people in her community. When she was in high school, her family bought their first house about 20 miles away in the middle-class, suburban neighborhood of Roselle, NJ. The dramatic differences between these two worlds drove home for her how significant a zip code can be in determining a child’s outlook and opportunities.
Today, inspired by this childhood moment of truth, Opara, an assistant professor of social work at The State University Stony Brook University, NY, is the recipient of an NIH Director’s Early Independence Award, tackling the complex relationships between neighborhoods, substance use, and mental health among urban youth. She’s focusing her efforts on Paterson, NJ, a city of about 150,000 people where the rates of substance abuse are among the highest in the country. She hopes to develop community engagement models that will work not only in Paterson, but in struggling urban communities across the United States.
Opara first explored the streets of Paterson, which is located about 20 miles west of New York City, and ultimately fell in love with the place as a PhD fellow studying substance abuse and mental health services. She got to know the youth of Paterson and heard from them directly about what their community was lacking to help them build a brighter future.
She also fell in love with community-based participatory research (CBPR). In this approach, researchers immerse themselves in a community and work as partners with community members, leaders, and organizations to understand the issues that matter, gather essential information and data, and translate them into efforts needed for a community and its youth to thrive.
When Opara decided to apply for the high-risk, high-reward Early Independence Award, she knew her proposal must be innovative and creative. Ultimately, though, Opara realized she needed to propose an idea about which she was passionate.
Opara remembered her love for Paterson and decided to go back there, focusing her attention on filling the many gaps in that community to prevent substance abuse among young people. True to her CBPR approach to research, she also spent weeks meeting with the people of Paterson to ensure that her work would address the community’s most-critical needs and strongest desires from day one.
Opara’s first aim is to look at neighborhoods across the city of Paterson and their relationship to substance abuse and mental health symptoms, including anxiety and depression among its youth. Her work will factor in access to safe housing, healthy food, parks, and playgrounds.
She’ll also recruit young people, including those who are most at risk, to get their take on their community including the prevalence of drug use. Opara won’t just be checking with kids at school. She’ll also spend lots of time with them on basketball courts, in grocery store parking lots, or wherever they like to congregate. What she learns will help her craft evidence-based and community-driven substance abuse interventions for young people at risk. She’ll then work with her partners in the community to help put the interventions to the test.
She recognizes that many consider urban youth too hard to reach. In her view, that’s simply not true. It’s her job to meet these young people where they hang out, learn to engage them, and listen to their needs.
In Paterson, she wants to build vibrant neighborhood models that will enrich the community and help more of its children get ahead. Most of all, she wants to change the way substance abuse and mental health work is done in urban communities like Paterson, and see to it that more resources for youth are put into place.
Opara hopes one day to inhabit a world where urban kids have access to the emotional and mental health resources that they need to cope with the many challenges that confront them. She also wants to inhabit a world where young girls growing up in the inner-city, as she did not so long ago, will be nurtured to move upward and onward as leaders. Her efforts and the strength of her example are certainly a push in the right direction.
Links:
Ijeoma Opara (The State University Stony Brook University, NY)
The Substance Abuse and Sexual Health Lab (Stony Brook)
Opara Project Information (NIH RePORTER)
NIH Director’s Early Independence Award
NIH Support: Common Fund
Coping with the Collision of Public Health Crises: COVID-19 and Substance Use Disorders
Posted on by Dr. Francis Collins
For the past half-dozen years, I’ve had the privilege of attending the Rx Drug and Heroin Abuse Summit. And I was counting on learning more about this national crisis this April in Nashville, where I was scheduled to take part in a session with Dr. Nora Volkow, Director of NIH’s National Institute on Drug Abuse. But because of the physical distancing needed to help flatten the deadly curve of the coronavirus-19 (COVID-19) pandemic, it proved to be impossible for anyone to attend in person. Still, the summit did go on for almost three days—virtually!
Dr. Volkow and I took part by sharing a video of a recent conversation we had via videoconference. Since we couldn’t take live questions, we solicited some in advance. Here’s a condensed transcript highlighting portions of our dialogue that focused on the impact of the COVID-19 pandemic on individuals struggling with substance abuse disorders, along with all those who are trying to help them.
VOLKOW: Hello, Francis. Nice to see you, virtually!
COLLINS: Nice to see you too. I’m in my home office here, where I’ve been pretty much for the last three weeks. I’ve been stepping outdoors to occasionally get a breath of fresh air, but trying to live up to all those recommendations about social distancing—or at least physical distancing. I’m trying to keep my social connections going, even if they’re electronic.
I think we’re all feeling this is a time of some stress for us at NIH. We are trying to do everything we can to address this COVID crisis and speed up the process of developing vaccines and therapeutics and all kinds of other things. How are you doing? What’s it like being sequestered back in your home space when you are somebody with so much energy?
VOLKOW: Francis, it’s not easy. I actually am very, very restless. We probably are all experiencing that anxiety of uncertainty, looking at the news and how devastating it is. But I think what makes it easier is if we can do something. Working with everything that we have to try to help others, I think, provides some relief.
COLLINS: Yes, we’re going to talk about that right now. In fact, let’s talk about the way in which this crisis, the global pandemic called COVID-19, is colliding with another public health crisis, which is that of substance use disorder. You recently wrote about this collision in an article in the Annals of Internal Medicine. What does this mean? What are some of the unique challenges that COVID-19 brings to people suffering from addiction?
VOLKOW: I’m glad you are bringing up this point because it’s one of the issues of greatest concern for all of us who are working in the field of substance use disorders. We had not yet been able to contain the epidemic of opioid fatalities, and then we were hit by this tsunami of COVID.
We immediately can recognize the unique challenges of COVID-19 for people having an addiction. Some of these are structural; the healthcare system is not prepared to take care of them. They relate also to stigma and social issues. The concept of social distancing makes such people even more vulnerable because it interferes with many of the support systems that can help them to reach recovery. And, on top of that, drugs themselves negatively influence human physiology, making one more vulnerable to getting infected and more vulnerable to worse outcomes. So that’s why there is tremendous concern about these two epidemics colliding with one another.
COLLINS: How has this influenced treatment delivery for people with substance use disorders, who are counting on that to be able to keep themselves from slipping backward?
VOLKOW: Well, that has been very challenging. We’re hearing from multiple sources that it’s become harder for patients to be able to access treatment. And that relates, for example, to access of medications for opioid use disorders, which are the main strategy—and the most effective one—that we have to prevent people from dying from overdoses.
Some clinics are decreasing the number of patients that they can take care of. The healthcare system is also much less able to initiate persons on buprenorphine. And because of social isolation, if you overdose, the likelihood that someone can rescue you with naloxone is much lower. We don’t yet have statistics on about how that’s influencing fatalities, but we are very concerned.
COLLINS: Nora, you are one of the lead persons for NIH’s Helping to End Addiction Long-term (HEAL) initiative. How has the COVID-19 pandemic affected all the grand research plans that we had put in place as part of our big vision of how NIH could help with the substance use disorder crisis?
VOLKOW: Well, $900 million had recently been deployed on research. That is incredibly meritorious, and some of that research had already started. Unfortunately, it has had to stop almost completely. Why? Because the research that’s relying on the healthcare system, for example, is no longer able to focus on research when they have other clinical needs to meet.
Also, research to bring medication-assisted treatments to prison inmates has stopped. Prisons are not allowing the researchers to go on site because they are closing the doors to outsiders, since they are places at high risk for the spread of COVID-19. Furthermore, some institutional review boards (IRBs) are actually closing, making it impossible to recruit patients for the clinical trials. So, most studies have come to a halt. The issue now is how can we become creative and use virtual technologies to advance some of the goals that we aim to achieve with the HEAL initiative.
COLLINS: Of course, this applies to many other areas of NIH-supported research. Most clinical trials, unless they’re for life-threating conditions, are pretty much in a state of hibernation. We can’t justify having people get out there in ways that might put them at risk of COVID-19. So, yes, it’s a tough time for clinical research all over. And that’s certainly what’s happened with the opioid use disorder problems. Still, I think our teams are really devoted to making sure they make the best of this time, doing things that they can do in terms of planning and setting up data systems.
Meanwhile, bring us up to date on what’s happened as far as the state of the opioid crisis. Are there trends there that we ought to look at for a minute?
VOLKOW: Yes, it’s important to actually keep our eyes on the epidemic, because it’s changing so very rapidly. It’s gone from prescription opioids to heroin to synthetic opioids like fentanyl. And what we have observed ramping up over the past two or three years is an increase in fatalities from the use of psychostimulant drugs.
For example, the number of deaths from methamphetamine has increased five-fold over a period of six years. Similarly, deaths from cocaine are going up. The reality is that people are now dying not just from opioids, but from mixtures of drugs and stimulant drugs, most notably methamphetamine.
COLLINS: So, what can we learn from what we’ve been doing about opioid addiction, and try to apply that to this emerging methamphetamine crisis?
VOLKOW: Unfortunately, we do not have effective medications to treat methamphetamine addiction like we do for opioid use disorders. We also do not have an overdose reversal like we have with naloxone. So, in that respect, it is more challenging.
COLLINS: People sometimes think we’re only focused on trying to treat the problems that we have now. What about prevention? One of the questions we received in our HEAL mailbox was: How can small town communities create an environment where addiction does not take root in the next generation of young people? I’m sure you want to talk about the rewarding power of social interactions, even though right now we’re being somewhat deprived of those, at least face-to-face.
VOLKOW: I’m glad you’re bringing up that question, Francis. Because when you asked at the start of our conversation about how I am doing, I sort of said, “Well, it’s not easy.” But the positive component was that sense that we have a shared mission: we can help others. And the lack of a sense of mission, the lack of a purpose in life, has been identified as one of the factors that make people more vulnerable to take drugs.
Feeling irrelevant, feeling that no one cares for you, is probably one of the most devastating feelings a human being can have. Epidemiological studies show that social isolation and neglect increase dramatically the risk of taking drugs, and, if you are trying to stop taking drugs, it increases that risk of relapse. And so that’s an issue right now of great concern. The challenge is “How do we provide social support for people at risk of substance abuse during the COVID-19 pandemic?”
Also, independent of COVID-19, I think that we as a nation have to face the concept that we have made America vulnerable to drugs because we have eroded that social sense of community. If we are to prevent future generations from getting addicted to drugs, we should build meaningful interactions between people. We should give each individual an opportunity to be part of a society that appreciates them. We do need each other in very, very fundamental ways. We need others for our well-being. If we don’t have that then we become very vulnerable.
COLLINS: Well, here’s one last question from the mailbox. Somebody notes that the “L” in HEAL stands for “long-term.” That is, Helping End Addiction Long-term. The questioner asks: “What’s our vision of a long-term goal and how do we imagine getting there?”
Mine very simply is that we would have an environment that would support people in productive ways, so that the distractions of things that turn out to be destructive are not so tempting, and that the possibility of having meaning in everyone’s life becomes greater.
Ironically, because of COVID-19, we are in the midst of a circumstance where economic distress is pressing on people and social distancing is being required. Seems like we’re going the wrong way. But if you look back in history, often these times of national crisis have been times when people did have the chance to survey what really matters around them, and perhaps to regain a sense of meaning and significance. That’s my maybe slightly over-optimistic view of the current era that we’re in.
Nora, what do you think?
VOLKOW: Francis, I will agree with you. I think that we need to create a society that provides social support and allows people to participate in a meaningful way. If we want to achieve integration of people into society, one of the things that we need to do urgently is remove the stigma of addiction because when you stigmatise someone, you are socially isolating them.
No one likes to be mistreated or discriminated against. So, if you are a person who is addicted and you are afraid of discrimination, you will not seek help. You will continue to isolate. So I think as we’re dealing with the opioid crisis, as we’re dealing with COVID-19, we cannot tolerate discrimination. We cannot tolerate stigma. And we need to be very creative to identify it and to create models that will actually eliminate it.
COLLINS: That’s a wonderful view of where we need to get to. All of these developments give me hope for our capacity to deal with this crisis by working together.
I want to say to all of you who’re listening to this in your own virtual spaces, how much I admire the work that you all are doing, in a selfless way, to try to help our nation deal with what has clearly been a terrible tragedy in far too many lives. I wish you all the best in continuing those creative and energetic efforts, even in the midst of the COVID-19 pandemic. NIH wants to be your ally. We want to be your source of information. We want to be your source of evidence for what works. We want to be your friends.
So, thank you for listening, and thank you, Nora Volkow, for joining me in this discussion today with all of the talent and leadership that you represent. I wish the best health to all of you. Stay safe and keep the progress going!
Links:
Video: Fireside Chat Between NIH, NIDA Heads Addresses COVID-19, the HEAL Initiative, and the Opioids Crisis (National Institute on Drug Abuse/NIH)
COVID-19 Resources (NIDA)
COVID-19: Potential Implications for Individuals with Substance Use Disorders, Nora’s Blog (NIDA)
NIDA Director outlines potential risks to people who smoke and use drugs during COVID-19 pandemic (NIDA)
Collision of the COVID-19 and Addiction Epidemics. Volkow ND. Ann Intern Med. 2 April 2020. [Epub ahead of print]
Helping to End Addiction Long-term (HEAL) Initiative (NIH)
Rx Drug Abuse & Heroin Summit, A 2020 Virtual Experience
Study Suggests Repurposed Drugs Might Treat Aggressive Lung Cancer
Posted on by Dr. Francis Collins
Credit: Leanne Li, Koch Institute at MIT
Despite continued progress in treatment and prevention, lung cancer remains our nation’s leading cause of cancer death. In fact, more Americans die of lung cancer each year than of breast, colon, and prostate cancers combined [1,2]. While cigarette smoking is a major cause, lung cancer also occurs in non-smokers. I’m pleased to report discovery of what we hope will be a much-needed drug target for a highly aggressive, difficult-to-treat form of the disease, called small cell lung cancer (SCLC).
Using gene-editing technology to conduct a systematic, large-scale search for druggable vulnerabilities in certain types of cancer cells grown in lab dishes, NIH-funded researchers recently identified a metabolic pathway that appears to play a key role in SCLC. What makes this news even more encouraging is drugs that block this pathway already exist. That includes one in clinical testing for other types of cancer, and another that’s FDA-approved and has been safely used for more than 20 years to treat people with rheumatoid arthritis.
The new work comes from the lab of Tyler Jacks, Massachusetts Institute of Technology (MIT), Cambridge. The Jacks lab, which is dedicated to understanding the genetic events that lead to cancer, develops mouse models engineered to carry the same genetic mutations that turn up in human cancers.
In work described in Science Translational Medicine, the team, co-led by Leanne Li and Sheng Rong Ng, applied CRISPR gene-editing tools to cells grown from some of their mouse models. Aiming high in terms of scale, researchers used CRISPR to knock out systematically, one by one, each of about 5,000 genes in cells from the SCLC mouse model, as well in cells from mouse models of other types of lung and pancreatic cancers. They looked to see what gene knockouts would slow down or kill the cancer cells, because that would be a good indication that the protein products of these genes, or the pathways they mediated, would be potential drug targets.
Out of those thousands of genes, one rose to the top of the list. It encodes an enzyme called DHODH (dihydroorotate dehydrogenase). This enzyme plays an important role in synthesizing pyrimidine, which is a major building block in DNA and RNA. Cytosine and thymine, the C and T in the four-letter DNA code, are pyrimidines; so is uracil, the U in RNA that takes the place of T in DNA. Because cancer cells are constantly dividing, there is a continual need to synthesize new DNA and RNA molecules to support the production of new daughter cells. And that means, unlike healthy cells, cancer cells require a steady supply of pyrimidine.
It turns out that the SCLC cells have an unexpected weakness relative to other cancer cells: they don’t produce as much pyrimidine. As a result, the researchers found blocking DHODH left the cells short on pyrimidine, leading to reduced growth and survival of the cancer.
This was especially good news because DHODH-blocking drugs, including one called brequinar, have already been tested in clinical trials for other cancers. In fact, brequinar is now being explored as a potential treatment for acute myeloid leukemia.
Might brequinar also hold promise for treating SCLC? To explore further, the researchers looked again to their genetic mouse model of SCLC. Their studies showed that mice treated with brequinar lived about 40 days longer than control animals. That’s a significant survival benefit in this system.
Brequinar treatment appeared to work even better when combined with other approved cancer drugs in mice that had SCLC cells transplanted into them. Further study in mice carrying SCLC tumors derived from four human patients added to this evidence. Two of the four human tumors shrunk in mice treated with brequinar.
Of course, mice are not people. But the findings suggest that brequinar or another DHODH blocker might hold promise as a new way to treat SCLC. While more study is needed to understand even better how brequinar works and explore potentially promising drug combinations, the fact that this drug is already in human testing for another indication suggests that a clinical trial to explore its use for SCLC might happen more quickly.
More broadly, the new findings show the promise of gene-editing technology as a research tool for uncovering elusive cancer targets. Such hard-fought discoveries will help to advance precise approaches to the treatment of even the most aggressive cancer types. And that should come as encouraging news to all those who are hoping to find new answers for hard-to-treat cancers.
References:
[1] Cancer Stat Facts: Lung and Bronchus Cancer (National Cancer Institute/NIH)
[2] Key Statistics for Lung Cancer (American Cancer Society)
[3] Identification of DHODH as a therapeutic target in small cell lung cancer. Li L, Ng SR, Colón CI, Drapkin BJ, Hsu PP, Li Z, Nabel CS, Lewis CA, Romero R, Mercer KL, Bhutkar A, Phat S, Myers DT, Muzumdar MD, Westcott PMK, Beytagh MC, Farago AF, Vander Heiden MG, Dyson NJ, Jacks T. Sci Transl Med. 2019 Nov 6;11(517).
Links:
Small Cell Lung Cancer Treatment (NCI/NIH)
Video: Introduction to Genome Editing Using CRISPR Cas9 (NIH)
Tyler Jacks (Massachusetts Institute of Technology, Cambridge)
NIH Support: National Cancer Institute
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