These Pesky Grapes of Wrath

I stumbled.
Turning, I looked in the
Bathroom and saw the
Evidence.

Shower curtain torn,
Laying on the floor
In a pool of vomit.
Not again!

Powerless.
Not my favorite word
To say the least.
Sounds like, failure.

Small.
Sweet.
Fermented.
Steeped in brokenness.

Killer of relationships
Thief of dreams.
The mortar of excuses,
Able to destroy.

Yet impossible to
Resist
No matter the cost.
Regardless of consequence.

I know where it leads,
Yet I have no human capacity
To resist
These pesky grapes of wrath.

©2019 Steven Barto

The Importance of Prevention in Addressing the Opioid Crisis

NIDA Banner Science of Abuse and Addiction

From the Blog of Dr. Lora Volkow
Director, National Institute on Drug Abuse

June 27, 2019

As our communities, healthcare systems, and government agencies join in the effort to reverse the epidemic of opioid overdoses and solve the opioid crisis, it is not enough to focus all our resources on treating people who are already addicted to opioids. Keeping people who do not have an opioid use disorder from becoming addicted is an equally important task [italics mine]. Addressing over-prescribing of pain medications through improved pain management and prescription monitoring has been one important prevention approach; and as illicit opioids like heroin and imported fentanyl become more prevalent, reducing the supply of those substances through law enforcement efforts is also crucial. But reducing the demand for opioids by addressing the reasons people turn to them and become addicted in the first place is just as vital and fundamental to ensuring that a new drug epidemic does not follow once the opioid crisis is contained.  

Research on preventing drug use by addressing vulnerability factors that increase the risk for substance use disorders is an important component of the National Institutes of Health (NIH) HEAL (Helping to End Addition Long-Term™) Initiative. Specifically, the HEALthy Brain and Child Development (HBCD) study being partially funded by HEAL will examine how the human brain develops in the transition from infancy into early adolescence. Evaluating the effects of fetal drug exposures, adverse environments, genetics, mental illness will provide knowledge to help us understand how these risk factors operate in conferring vulnerability for substance use disorders.

Abundant research by NIDA-funded investigators over the past few decades has shown that positively altering a child’s life trajectory by reducing various risk factors, strengthening protective factors, and increasing access to resources can reduce or delay later drug use as well as minimize other adverse outcomes like criminality or other mental illness. Risk factors addressed by early childhood interventions can include poor self-regulation, aggression, or insecure attachment to parents. Those addressed in family and school prevention interventions at all ages through the teen years include lack of parental supervision, exposure to drugs at home or at school, and stresses from poverty, neglect, or abuse.

Prevention programs can take many forms, but all in one way or another address these risk factors and/or bolster factors like self-control, peer relationships, or other age-appropriate skills. These forms of resilience may make all the difference in the young person’s life when faced with the opportunities and temptations to begin smoking, drinking, or using drugs when they are adolescents, despite whatever adversity they may have experienced when younger. Effective prevention can even begin as early as the prenatal period: For example, an intervention in which trained nurses visit and provide guidance to first-time mothers during their pregnancy and in the first two years of their child’s life was shown to be effective at improving various cognitive and behavioral outcomes into adolescence, including reduced substance use and involvement with the juvenile justice system.

The stresses of impoverished environments negatively impact brain development, but a striking finding from prevention research is that interventions can protect against or reverse some of these neurobiological impacts. For example, a family-focused intervention with poor families in rural Georgia protected against poverty-associated neurobiological changes to brain areas involved in learning and stress reactivity. And maltreated children in foster care who received a prevention intervention for preschoolers were better able to regulate stress, as measured by cortisol levels.

Because risk factors for drug use are common to other behavioral problems, most prevention interventions do not focus solely on preventing drug use or on preventing a single type of drug use. A wide range of problems can be addressed or averted by addressing core risk or protective factors. A few programs, however, such as a middle-school intervention called PROSPER, have shown specific benefits at preventing nonmedical use of prescription drugs.

An important research priority is finding out how to widen the adoption and effective implementation of evidence-supported prevention programs. The menu of such interventions is diverse, but few of the options are widely used. Part of the problem is that high-quality intervention programs are costly, and communities may be reluctant to invest the needed resources when the payoff may be years or more in the future. However, studies have strikingly shown that many programs more than pay for themselves. Like other investments—saving for retirement, for instance—primary prevention of substance use and addiction requires long-term thinking and balancing the short-term costs in money and time against the long-term benefits of a healthier society down the road.

The HEAL initiative will also prioritize research on developing interventions targeted towards the transition from late adolescence into adulthood, the age where there is the largest increase in initiating opioid use. NIDA will be funding research to create an evidence base for new strategies and interventions to prevent opioid initiation and opioid use disorder (OUD) in older adolescents and young adults in healthcare, justice, and other settings.

In a new Commentary, Targeting Youth to Prevent Later Substance Use Disorder: An Underutilized Response to the US Opioid Crisis, in the American Journal of Public Health, colleagues at NIDA, the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Centers for Disease Control (CDC) highlight the importance of research on primary prevention for helping to address the opioid crisis. Such research will provide us not only with scientific solutions to address the current opioid crisis but will provide us with the knowledge and tools to protect us from future drug crises.

The following website can help you find substance abuse or other mental health services in your area: www.samhsa.gov/Treatment. If you are in an emergency situation, people at this toll-free, 24-hour hotline can help you get through this difficult time: 1-800-273-TALK. Or click on: www.suicidepreventionlifeline.org. We also have step by step guides on what to do to help yourself, a friend or a family member on our Treatment page.

AT-121: A Promising Alternative to Opioid Pain Medications

By Eric Sarlin, M.Ed., M.A.
NIDA Notes Contributing Writer
National Institute on Drug Abuse

Dr. Eric Sarlin’s recent research reveals an experimental compound with a dual action at two opioid receptors which may provide powerful pain relief without many of the usual harmful opioid side effects. The compound may also have potential as a treatment for opioid addiction.

The reason AT-121 is promising is because it provides pain relief without producing the side-effect of euphoria.

This is a novel compound representing potential advancement toward the goal of non-addictive pain medications that are at least as effective as opioids but without typical opioid liabilities. The new compound—called AT-121—may also have potential as a treatment alternative for opioid addiction. Most of the potent analgesics currently in use act through mu-opioid receptors. AT-121 seems to relieve pain in monkeys without causing physical dependence. Most pain medications work by activating a receptor in the neurons the mu-opiate receptor. Mei-Chuan Ko, a professor of physiology and pharmacology at the Wake Forest School of Medicine, says “Oxycodone, morphine, fentanyl, heroin—they all work through the mu-receptor.” Ko is one of the authors of the study.

Dr. Nurulain Zaveri and colleages at Astraea Therapeutics, manufacturer of AT-121, used medicinal chemistry, computer modeling, and structure-based drug design to create and develop AT-121. Like opioids—such as morphine and oxycodone—AT-121 also binds to the mu-opioid receptor. Unlike those opioids, AT-121 also binds to another opioid receptor called the nociceptin/orphanin FQ peptide receptor. According to Dr. Zaveri, this interaction with the NOP receptor enhances AT-121’s analgesic effect and blocks unwanted side effects often seen with current opioid medications.

References

NIDA. (February 12, 2019). “A Promising Alternative to Opioid Pain Medications.”

How People with Substance Use Disorders (SUDs) Can Lend a Needed Hand in Addiction Research

FROM THE MONTHLY BLOG OF DR. LORA VOLKOW
April 22, 2019

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One of the major challenges in health science today is that not enough patients participate in clinical trials and similar studies. Without volunteers willing and able to participate in studies testing new treatments or therapeutic approaches for cancer or Alzheimer’s, for example, researchers cannot test their effectiveness. There are many reasons for the lack of participation in medical research: Patients often are not aware of studies, or they don’t see any direct benefit from participating. Many clinical trials for new cancer treatments, for example, have been delayed or even cancelled altogether because of the difficulty of recruiting participants.

Drug Lab Research

In research testing new medications or behavioral treatments for substance use disorders, the obstacles to recruiting study volunteers are even more daunting. Just finding participants can be a challenge, since they may not intersect with the healthcare system for their addiction, the same way someone with cancer or Alzheimer’s would. Only a fraction of people with substance use disorders receive care from physicians who may be in a position to know about or link them to research studies being planned. Most recruitment for clinical trials related to opioid addiction medications, for instance, is done via ads placed at large opioid treatment centers where patients on methadone receive their daily doses. 

People with substance use disorders already face stigma and the fear of further social or legal consequences of their addiction, and this deters potential volunteers from signing up to participate in research. Some distrust the medical profession altogether. Many people with addiction do not want or believe they need treatment at all. Additionally, because many people with addictions who might otherwise want to participate in a trial are unemployed, poor, or homeless (perhaps as a result of their substance use), they may lack the resources or access to transportation necessary to visit a hospital or research center regularly. Often as many as half or even more than half of participants recruited for a trial are not able to complete it.

Homeless and Hungry.jpg

Scientists studying new treatment approaches for addiction must always be thinking about how they can make their research studies more practical and feasible in the real world. They must make study participation easy and appealing and the studies accessible—including access at odd hours or weekends for those whose jobs or school prevent participation during regular work hours. Also, people with addictions often use multiple substances, and this commonly excludes them from studies testing treatments for a single substance, due to strict criteria on who can be included in a trial. Yet the reality is that addiction is complex, and often involves not only use of multiple drugs but also co-occurring mental and physical illnesses. Designing more inclusive studies and clinical trials that can take this complexity into account will be necessary for scientific advancement in treating and preventing addiction.

An all-hands-on-deck approach is needed in order to confront America’s current drug crisis, and the needed hands must include families and individuals directly affected by substance use disorders. By increasing participation in research by those who most stand to benefit, we can find solutions to the complex addiction issues facing our nation today. It is also an opportunity for individuals suffering from addiction to participate in clinical research, just as people with other medical conditions do.

Clinical Trials logo

For more information on the benefits of participating in a clinical trial—for addiction or any other disease—please feel free to visit https://www.nih.gov/health-information/nih-clinical-research-trials-you. Are you a provider? You can learn about trials to recommend to your patients here: https://www.nih.gov/health-information/nih-clinical-research-trials-you/finding-clinical-trial.

FIND HELP NEAR YOU

The following website can help you find substance abuse or other mental health services in your area: www.samhsa.gov/Treatment. If you are in an emergency situation, people at this toll-free, 24-hour hotline can help you get through this difficult time: 1-800-273-TALK. Or click on: www.suicidepreventionlifeline.org. In addition, you can find contact information in your phone book or online for Alcoholics Anonymous, Narcotics Anonymous, Celebrate Recovery, or other 12-step programs.

 

 

Prenatal and Early Childhood Brain Development in Mom’s Using Drugs

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From the blog of Dr. Nora Volkow
Director, National Institute on Drug Abuse
March 11, 2019

The National Institutes of Health HEAL (Helping to End Addiction Long-Term) Initiative, which was launched last April, will support a wide range of studies aimed at improving prevention and treatment strategies for opioid use disorder and pain, including efforts to enhance treatments for infants born with Neonatal Abstinence Syndrome/Neonatal Opioid Withdrawal Syndrome. Specifically, HEAL funds will help support an ambitious longitudinal study—The HEALthy Brain and Child Development (HBCD) Study—co-funded by NIDA and several other NIH institutes and offices, to better understand the impact of early exposure to opioids, other substances, and social stressors on brain development in children.

The HBCD study will follow a large population of children from the prenatal period to age 10 and utilize some of the same assessment methods and imaging technologies used in the 10-year Adolescent Brain Cognitive Behavior (ABCD) study. HBCD is expected to enroll women during their second trimester of pregnancy or after birth of their baby. The study will gather data on potentially important factors about their environment, including drug and alcohol use, and follow them and their children over the subsequent decade.

The potential fruits of a longitudinal cohort study of this magnitude will include much new knowledge about the effects of opioids and other substance exposures during fetal development.  It will also yield a better understanding of the effects of genes that are driving brain development. The study additionally will look at many other exposures, including social interactions, environmental toxins, nutrition, and physical activity. Medicine has thus far lacked detailed baseline standards of normative brain development in childhood, and HBCD will help produce such standards. The information gained from the study will create an invaluable reference for pediatricians, pediatric neurologists, and psychiatrists.

The ABCD study recently accomplished its baseline recruitment of close to 12,000 nine- and ten-year-olds, and already the data gathered from the initial neuro-imaging is yielding interesting findings, such as associations between neuro-development and screen time. Likewise, the HBCD study will gather a rich data set that will be freely available to the wider research community to answer a wide range of research questions. For example, researchers can use the data to investigate how the human brain develops and characteristics that might be associated with the early manifestations of brain diseases, as well as those [with an] underlying resilience to adverse environments. As the data are being collected, they will be released so that discoveries can start well before the completion of these 10-year prospective studies. 

As with ABCD, the HBCD study will have multiple research sites across the country to ensure the study population is representative of the larger population, including all ethnic groups and demographics and even including women who use opioids. Exposure to many substances in the womb or through breast milk may have significant developmental consequences, and a study of this magnitude will greatly clarify the effects of prenatal and early opioid exposure on children. It will also greatly increase our understanding of the developmental consequences of environmental stressors like neglect, abuse, economic uncertainty, and the influence of parental opioid and other drug use during the post-natal period.

As you might imagine, there are many potential challenges to conducting regular brain imaging on young children—being able to remain still in MRI scanners is just one of them. There are also special legal and ethical challenges involved in recruiting and studying opioid-using mothers. In September and October of last year, NIDA in partnership with other NIH Institutes and Centers, hosted two expert panel meetings to discuss, respectively, the methodological challenges of studying neuro-development in children and recruitment and retention of high-risk populations in the study, including bio-ethical questions.

Based on input received during these expert panel meeting, it was determined that before soliciting grant proposals for the HBCD study per se, an initial planning period would be necessary. Thus, NIDA along with the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Child Health and Human Development (NICHD), the National Institute of Environmental Health Sciences (NIEHS), the National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Minority Health and Health Disparities (NIMHD), the Office of Research on Women’s Health (ORWH), and the Office of Behavioral and Social Sciences Research (OBSSR) issued two funding opportunity announcements, one for individual research sites and one for linked, collaborative applications.

The planning grants will be awarded for a period of 18 months, during which time we expect to determine many critical facets of the experimental design. These include how to conduct neuro-imaging in prenatal and early postnatal stages, how to address the legal challenges associated with recruiting opioid- (and other drug-) using participants (which vary by state), how to form partnerships with state agencies and substance use treatment programs, how to retain the mothers in the study, and other practical and ethical issues. Applications are due in the last week of March, 2019. Researchers interested in applying for one of these grants can find more information on RFA-DA-19-029 and RFA-DA-19-036 from grants.nih.gov.

It is a very exciting time for all the sciences that study child health, human development, and the roots of mental health and psychiatric and neurological illnesses. We now have the tools to characterize human brain development in the transition from infancy into adulthood, a time when many of the medical conditions that afflict us later in life originate. The data from the HBCD study will ultimately lead to scientific solutions to addiction, pointing the way to new prevention and treatment interventions and thereby reducing the impact of opioid and other substance use disorders on American families.

Scientific Findings and Achievements in Drug Abuse Research for 2018

From the Blog of Dr. Nora Volkow, Director
National Institute on Drug Abuse
January 7, 2019

Dr. Volkow noted, “As we enter 2019, it is a good time to take stock of what NIDA accomplished over the past year. As always when I look back at the research being done by NIDA grantees and partners, I am amazed at the wealth of knowledge being created from our investments. Here I want to highlight just a few of the many outstanding developments in basic science, new therapeutics, and epidemiology and prevention research from the year that just ended.”

Basic Science Advances

Recent years have seen major advances in the understanding of receptor functioning. In March 2018, a team of researchers at NIDA’s Intramural Research Program (IRP) reported in Nature Communications on an advance in understanding G protein-coupled receptors (GCPRs), a large family of receptors that play an important role in the brain’s response to drugs. These receptors often assemble into larger complexes, but it has been unknown whether those complexes are merely the product of random collision between signaling molecules as they move across the membrane or whether they pre-form into complexes that serve specific functions.

The IRP team found that two common GCPRs in the reward pathway, adenosine A2A and dopamine D2 receptors (along with their G proteins and target enzyme), assemble into preformed macromolecular complexes that act as computation devices processing incoming information and enabling the cell to change its function based on that information. This knowledge could facilitate the development of more precise medication targets.

In June 2018, a team of NIDA-funded researchers at the University of California–San Francisco, along with colleagues in Belgium and Canada, reported in Neuron magazine that they had developed a genetically-encoded biosensor that can detect activation of opioid receptors and map the differences in activation within living cells produced by different opioids. The fact that opioids bind to receptors on structures within the cell—and not just on the cell membrane—was itself a novel finding, but the team also discovered striking differences in how endogenous versus synthetic opioids interact with these structures.

While endogenous peptides activated receptors on membrane-bound compartments within the cell called endosomes, synthetic opioid drugs activated receptor sites on a separate structure called the Golgi apparatus (which acts as a hub for routing proteins to various destinations in the cell). These very different patterns of activation within the cell may lead to greater understanding of why non-peptide opioid drugs produce tolerance as well as the behavioral distortions seen with opioid misuse and addiction whereas the body’s endogenous opioid peptides do not.

The same month, a team led by neuroscientists at UCLA studying narcolepsy reported research in Science Translational Medicine based on their discovery that postmortem brains from individuals who had been addicted to heroin show greatly increased numbers of neurons producing the neuropeptide hypocretin. Hypocretin helps regulate wakefulness and appetite, and a diminished number of cells in the brain producing it is associated with narcolepsy. The researchers went on to conduct a study administering morphine to mice, which as observed in the postmortem study produced increased numbers of hypocretin neurons. The results suggest that increases in these cells and in brain hypocretin could underlie the complaints of sleep problems in patients with an opioid use disorder (OUD). Since insomnia is a factor that contributes to drug taking in OUD and other addictions, strategies to counteract hypocretin signaling might have therapeutic benefits.

Prevention and Treatment

Last year, NIDA-funded research resulted in new therapeutics and apps for opioid use disorder. In May, the FDA approved lofexidine, the first medication approved to treat physical symptoms of opioid withdrawal. In December, the FDA cleared the first mobile health app intended to help retain patients with OUD in treatment, called reSET-O. It uses interactive lessons to deliver a community reinforcement approach therapy and enables users to report cravings and triggers to their health care provider between office visits, along with whether or not they have used Suboxone. NIDA funded the clinical trial that led to this app’s approval. A version called reSET was approved in 2017 to help with behavioral treatment of several non-opioid substance use disorders.

NIDA-funded research in epidemiology and prevention also added greatly to the knowledge of new drug trends in 2018. Last month’s striking findings on monitoringthefuture.org alerted us to escalating use of vaping devices among adolescents. Although most adolescents in 2017 claimed they used vaping devices only to vape flavors, this year most reported they used them to vape nicotine. Alarmingly, there was also an increase in vaping of cannabis.

Several other studies published in 2018 increased our understanding of factors that may lead youth to experiment with vaping. For example, a longitudinal cohort study by researchers at Yale and reported in Addictive Behavior found that exposure to ads for e-cigarettes on social media sites like Facebook significantly increased the likelihood of subsequent e-cigarette use among middle and high school students in Connecticut. In another study published in Preventive Medicine, the researchers also found that higher socioeconomic status was associated with greater exposure to e-cigarette advertising (which in turn was associated with increased likelihood of use)—important data that can help with targeting prevention efforts. Other work by UCSF researchers and published in Pediatrics found that e-cigarette use in adolescents was positively associated with being a smoker of conventional cigarettes, lending further support to the view that these devices are not diverting youth from smoking cigarettes but may be having the opposite effect in some users.

Looking To The Future

This year the Adolescent Brain Cognitive Development (ABCD) Study successfully completed recruitment of 11,874 participants, ages 9-10, who will be followed for 10 years, through young adulthood. The study, which is being conducted at 21 research sites around the country, is using neuroimaging to assess each individual’s brain development while also tracking cognitive, behavioral, social, and environmental factors (including exposure to social media) that may affect brain development and other health outcomes. The first release of anonymized data was made available so that both ABCD and non-ABCD researchers can take advantage of this rich source of information to help answer novel questions and pursue their own research interests.  Last year alone, the data resulted in more than 20 publications.

 

New Funding Opportunities in Response to the Opioid Crisis

From the blog of Dr. Nora Volkow
Executive Director, National Institute on Drug Abuse
December 10, 2018

Today, NIDA is releasing several new funding opportunity announcements related to the NIH HEAL (Helping to End Addiction Long-term) Initiative. Researchers now can submit proposals for major projects funded through NIH HEAL in the areas of preventing opioid use disorder (OUD), improving OUD care in justice settings, determining the appropriate duration of treatment with medications to treat OUD, and better understanding how to manage mild or moderate OUD.

Prevention

Older adolescents and young adults (ages 16-30) are the group at highest risk for opioid initiation, misuse, OUD, and death from overdose, so targeting this age group for prevention interventions could have a sizeable impact on reducing the toll of opioid misuse and addiction. The research project called Preventing At-Risk Adolescents from Developing Opioid Use Disorder as they Transition into Adulthood will develop and test strategies to prevent initiation of opioid misuse and development of OUD in different healthcare settings (including primary care, emergency departments, urgent care, HIV/STI clinics, and school or college health clinics) as well as workplaces and justice settings. NIDA will fund a suite of integrated studies developing, testing, and validating screening and prevention tools in areas most affected by the opioid crisis or with indicators of an emerging crisis. For more information on funding opportunities related to this project, see the funding opportunity announcements for the Coordinating Center and research studies.

Criminal Justice System

Substantial research over the past several years has highlighted the consequences of untreated OUD in justice-involved populations—for instance, the high rates of overdose death among people recently released from prison—as well as showing the benefits of treating opioid-addicted prisoners using medication. It remains unknown what specific strategies are most effective at addressing opioid addiction in this population and reducing adverse outcomes. As part of the HEAL Initiative, NIDA will fund the creation of a network of researchers who can rapidly conduct studies aimed at exploring the effectiveness and adoption of medications, interventions, and technologies in justice settings.

The Justice Community Opioid Innovation Network will implement a survey of addiction treatment delivery services in local and state justice systems around the country and will develop new research methods to ensure that treatment interventions have the maximum impact.  For more information, please see the funding opportunity announcements for the Coordination and Translation Center, Methodology and Advanced Analytics Resource Center, and the research centers. 

Other Initiatives

In addition to the above referenced projects, NIDA will be partnering with other NIH institutes and centers on several opioid-related research projects. HEAL funds will also be used to answer some important research questions to address the opioid crisis. For example, NIDA’s Clinical Trials Network (CTN) will be utilized to determine the optimal length of medication treatment for opioid addiction and to identify treatment strategies to manage patients who present to primary or integrated care settings with low-level opioid misuse or OUD. Finally, HEAL funds are being considered to support a longitudinal study to understand the consequences of pre- and postnatal opioid and other substance exposure on the developing brain and behavior.

A silver lining of the dark cloud of the opioid crisis is that it has galvanized communities, healthcare systems, and government agencies to take significant steps toward ending opioid misuse and addiction in a compassionate, science-based way. The funds granted by Congress as part of the NIH HEAL. Initiative will accelerate scientific solutions to the crisis and generate new knowledge that will prevent future drug crises, as well as inform many other areas of medicine and public health. Information related to these projects is available on the NIH site.

Find Help Near You

The following website can help you find substance abuse or other mental health services in your area: www.samhsa.gov/Treatment. If you are in an emergency situation, people at this toll-free, 24-hour hotline can help you get through this difficult time: 1-800-273-TALK. Or click on: www.suicidepreventionlifeline.org