AMERICAN JUNKIES

Scientists take another step toward building a better opioid

Scientists teamed up to publish detailed structures of the entire human opioid receptor family to guide the creation of more targeted pain medications.

Peer-Reviewed Publication

UNIVERSITY OF NORTH CAROLINA HEALTH CARE

 

IMAGE: ALIGNMENT OF PEPTIDE-BOUND OPIOID RECEPTORS REVEALS STRUCTURAL FEATURES, SUCH AS STERIC EFFECTS, THAT CONTRIBUTE TO THE SUBTYPE-SELECTIVE BINDING AND FUNCTIONAL OUTCOMES OBSERVED IN BIOCHEMICAL ASSAYS. view more 

CREDIT: ROTH LAB, UNC SCHOOL OF MEDICINE

CHAPEL HILL, NC – In the continuing effort to improve upon opioid pain relievers, American and Chinese scientists used cryoEM technology to solve the detailed structures of the entire family of opioid receptors bound to their naturally occurring peptides. Subsequent structure-guided biochemical studies were then performed to better understand the mechanisms of peptide-receptor selectivity and signaling drugs.

This work, published in Cell, provides a comprehensive structural framework that should help drug developers rationally design safer drugs to relieve severe pain.

This work was spearheaded by the lab of Eric Xu, PhD, at the CAS Key Lab of Receptor Research in China, in collaboration with the lab of Bryan L. Roth, MD, PhD, at the UNC School of Medicine, where graduate student Jeff DiBerto led the pharmacological experiments to understand the receptors’ signaling mechanisms.

Opioid drugs relieve pain by mimicking a naturally occurring pain-relief function within our nervous symptoms. They are the best, strongest pain relievers we have. Unfortunately, they come with side effects, some severe such as numbness, addiction, and respiratory depression, leading to overdose deaths.

Scientists have been trying for many years to overcome the side-effect problem in various ways, all involving one or more of four opioid receptors to no avail. One way scientists continue to explore is the creation of peptide or peptide-inspired small molecule drugs.

Peptides are short chains of amino acids; think of them as short proteins. Certain naturally occurring, or endogenous, peptides bind to opioid receptors on the surface of cells to create an analgesic effect, also known as pain relief. Think of an analgesic like an anesthetic, except that analgesics do not “turn off” the nerves to numb the body or alter consciousness. So, the idea is to create a peptide drug that has a strong analgesic effect, without numbing nerves or altering consciousness or causing digestive, respiratory, or addiction issues.

“The problem in the field is we’ve lacked the molecular understanding of the interplay between opioid peptides and their receptors,” said Roth, co-senior author and the Michael Hooker Distinguished Professor of Pharmacology. “We’ve needed this understanding in order to try to rationally design potent and safe peptide or peptide-inspired drugs.”

Using cryogenic electron microscopy, or cryoEM, and a battery of biomechanistic experiments in cells, the Xu and Roth labs systematically solved the detailed structures of endogenous peptides bound to all four opioid receptors. These structures revealed details and insights into how specific naturally occurring opioid peptides selectively recognize and activate opioid receptors. The researchers also used exogenous peptides, or drug-like compounds, in some of their experiments to learn how they activate the receptors.

The cryoEM structures of agonist-bound receptors in complex with their G protein effectors (called their “active state”) represents what these receptors look like when they are signaling in cells, giving a detailed view of peptide-receptor interactions. The Roth lab used the structures solved by the Xu lab to guide the design of mutant receptors, and then tested these receptors in biochemical assays in cells to determine how they alter receptor signaling. Understanding these interactions can then be used to design drugs that are selective for opioid receptor subtypes, as well as to produce certain signaling outcomes that may be more beneficial than those of conventional opioids.

“This collaboration revealed conserved, or shared, mechanisms of activation and recognition of all four opioid receptors, as well as differences in peptide recognition that can be exploited for creating subtype-selective drugs,” said DiBerto, first author and PhD candidate in the Roth lab. “We provide more needed information to keep pushing the field forward, to answer basic science questions we hadn’t been able to answer before now.”

Previous research showed the structure of opioid receptors in their inactive or active-like states, with active state structures only existing for the mu-opioid receptor subtype, the primary target of drugs like fentanyl and morphine. In the Cell paper, the authors show agonist-bound receptors in in complex with their G protein effectors, made possible through cryoEM technology that did not exist when currently used medications were being developed.

Drugs such as oxycontin, oxycodone, and morphine cause various effects inside cells and throughout the nervous symptom, including pain relief. But they have effects in the digestive and respiratory systems, too, and interact with cells to lead to addiction. Fentanyl, meanwhile, is another powerful pain reliever, but it binds to opioid receptors in such a way as to cause severe side effects, including the shutdown of the respiratory system.

The thrust behind such research led by Xu and Roth is to home in on the mechanistic reasons for pain relief potency without triggering the cellular mechanisms that lead to severe side effects and overdosing.

“We are attempting to build a better kind of opioid,” Roth says, “We’re never going to get there without these kind of basic molecular insights, wherein we can see why pain is relieved and why side effects occur.”

Co-first authors of the Cell paper are Yue Wang and Youwen Zhuang of the CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research at the Shanghai Institute of Materia Medica in the Chinese Academy of Sciences. Other authors are Edward Zhou and Karsten Melcher of the Van Andel Research Institute in Grand Rapids, MI, Gavin Schmitz and Manish Jain at the UNC School of Medicine, and Qingning Yuan, Weiyi Liu, and Yi Jiant at the CAS Key Laboratory.

UNC School of Medicine contact: Mark Derewicz

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JOURNAL

Cell

DOI

10.1016/j.cell.2022.12.026 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Cells

ARTICLE TITLE

Structures of the entire human opioid receptor family

New randomized trial shows simple letters promote better-informed opioid prescribing

Letters successfully encouraged clinicians to check patients’ prescribing records

Peer-Reviewed Publication

COLUMBIA UNIVERSITY'S MAILMAN SCHOOL OF PUBLIC HEALTH

Researchers reported new findings from a clinical trial of letters to promote safer and better-informed opioid prescribing. The study, which aimed to encourage clinicians to check on patients in a state database before prescribing them opioids, reported significant and durable gains toward this goal. The research will be published in the January issue of the journal Health Affairs.

The study enrolled clinicians who prescribed opioids with benzodiazepines or gabapentinoids. Taking these medications together can increase the risk of overdose. The researchers hypothesized that greater use of state prescription monitoring programs (PMPs), which track all prescriptions of these medications, could help clinicians avoid risky prescribing and safeguard their patients’ health. Nearly all states now run PMPs, but many clinicians still do not use them.

“PMPs could help clinicians prescribe opioids and other drugs more safely, but these databases will only move the needle if clinicians actually check them,” said Adam Sacarny, PhD of Columbia University Mailman School of Public Health, the study’s lead author. “Our research shows that simple letters can achieve that goal.”

To run the trial, the researchers partnered with the Minnesota Board of Pharmacy, which administers the PMP, and Minnesota Management and Budget Agency, which promotes the use of high-quality evidence to improve state decision-making. They enrolled 12,000 clinicians who prescribed opioids with benzodiazepines or opioids with gabapentinoids. The clinicians were then randomly assigned to a control group or to receive one of three types of letters: mandate letters focusing a new state requirement to check the PMP before prescribing opioids, information letters about their patients prescribed opioids with benzodiazepines or gabapentinoids, or combined letters that included both messages. The letters were sent in spring 2021.

Sacarny and co-authors analyzed the effects of the letters using de-identified data from the PMP. The data included all opioid, benzodiazepine, and gabapentinoid prescriptions dispensed throughout Minnesota, as well as all PMP account records and searches.

The researchers found that letters mentioning the mandate to check the PMP successfully increased engagement with the program. PMP search rates rose by 9 percent, and the effect persisted at least 8 months. The letters also encouraged clinicians to make PMP accounts, a prerequisite for searching. Effects were similar for the combined letters, which mentioned the mandate and also included prescribing information.

“The enduring impacts suggest that the letters encouraged engagement among clinicians who would not have otherwise created PMP accounts or searched the PMP. This finding is noteworthy because account creation is an important barrier to PMP use,” noted Mireille Jacobson, PhD, the study’s last author and associate professor of Gerontology at the University of Southern California.

The researchers note that other state PMPs or healthcare organizations could easily send similar letters as a part of a cost-effective evidence-based strategy to promote safer prescribing. Because the mandate letters contain no protected health information, they could also be sent over e-mail, further lowering the intervention cost.

The researchers detected no effects of the information letters, which did not focus on the new mandate to check the PMP. None of the letters led to detectable changes in prescribing.

“While the letters did not make a detectable difference in prescribing, we still think these results are encouraging,” noted Sacarny. “Letters focusing on the mandate successfully promoted PMP engagement through searching and account-holding, which meant clinicians had better access to key patient data as they decided on treatment.”

The study’s co-authors are Tatyana Avilova of the University of Tokyo, David Powell of the RAND Corporation, Ian Williamson and Weston Merrick of Minnesota Management and Budget, and Mireille Jacobson of the University of Southern California.

The study was supported by the Abdul Latif Jameel Poverty Action Lab and the National Institute for Health Care Management.

Columbia University Mailman School of Public Health

Founded in 1922, the Columbia University Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Columbia Mailman School is the fourth largest recipient of NIH grants among schools of public health. Its nearly 300 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change and health, and public health preparedness. It is a leader in public health education with more than 1,300 graduate students from 55 nations pursuing a variety of master’s and doctoral degree programs. The Columbia Mailman School is also home to numerous world-renowned research centers, including ICAP and the Center for Infection and Immunity. For more information, please visit www.mailman.columbia.edu.

JOURNAL

Health Affairs

DOI

10.1377/hlthaff.2022.00859 

Training nurses to fight against opioid addiction

Kennesaw State receives federal grant to implement curricular changes to increase access to early intervention

Grant and Award Announcement

KENNESAW STATE UNIVERSITY

 

IMAGE: KENNESAW STATE RESEARCHERS SUSAN BEIDLER AND KATHY BARNETT WILL INCORPORATE NEW CURRICULA INTO THE MASTER'S DEGREE PROGRAM TO ADDRESS DECREASING STIGMA AND INCREASING ACCESS TO EARLY INTERVENTIONS FOR SUBSTANCE USE DISORDERS. view more 

CREDIT: KENNESAW STATE UNIVERSITY

Kennesaw State University’s Wellstar School of Nursing has received a federal grant to teach graduate students how to help patients break increasingly deadly opioid addictions.

Assistant professor of nursing Kathy Barnett and Wellstar School of Nursing Associate Director of Graduate Programs Susan Beidler teamed to earn the nearly $729,000 grant, which comes from the Substance Abuse and Mental Health Services Administration (SAMHSA), a subsidiary of the U.S. Department of Health and Human Services (HHS). Barnett and Beidler will implement curricular revisions in the KSU Masters of Science in Nursing programs that address decreasing stigma and increasing access to early interventions for substance use disorders. 

“Opioid addiction is a growing problem in Georgia and across the United States and something Susan and I felt very strongly all our master’s students needed more expertise in,” said Barnett, who wrote her doctoral dissertation on substance use disorder. HHS has declared opioid addiction a public health emergency.

According to data from the Georgia Department of Public Health, drug overdose deaths increased by 61% from 2019 to 2021, and fentanyl-involved overdose deaths increased by 230%, illustrating the urgent need for more medical training in helping people with opioid addiction. Opioids include many prescription pain medicines, fentanyl and the illegal drug heroin.

KSU’s grant-funded program will cover 30 hours of instruction and will add another tool to the kit of nursing graduates from KSU in all three of the master’s degree tracks – education, administration and practice. Barnett said it shows the Wellstar School of Nursing’s commitment to reducing the negative impact of opioid use disorders.

“We do that by training more nurse practitioners and other master’s-prepared nurses in the treatment, assessment and referrals of those with opioid use disorders,” she said. “We're hoping that in our community there will be many more treatment options and more people that are trained solely in how to treat those with the disorders.”

The grant money will cover integration of the training components into the curricula, followed by evaluation via surveys of the impact of the program on students. Beidler, who joined the Wellstar School administration in 2021, after more than four decades teaching and practicing nursing, said KSU’s position at the forefront of nursing education in the state and region places the University perfectly to address addiction through this program.

“We’re not satisfied with the status quo. We’re always looking for creative and innovative ways for our graduates to be cutting-edge in their practice abilities, and this grant will add another tool to their ‘toolkit’ to address a critical public health problem in our communities,” Beidler said.

Combination therapy appears safe for treating opioid use disorder during pregnancy

Peer-Reviewed Publication

WILEY

Current guidelines recommend that pregnant women with opioid use disorder be prescribed either methadone or buprenorphine, but these drugs too have significant potential for abuse. A recent study published in Acta Obstetricia et Gynecologica Scandinavica indicates that combination therapy of buprenorphine and naloxone—which is known help to prevent such abuse—is as safe as buprenorphine alone during pregnancy for both mother and newborn.

In the study of 67 pregnant women, the buprenorphine-naloxone and buprenorphine groups showed similar outcomes and did not significantly differ from each other in terms of maternal health during pregnancies, deliveries, or newborn health.

“Combination therapy of buprenorphine and naloxone could be a choice for oral opioid maintenance treatment during pregnancy, but larger studies are needed before changing the official recommendations,” said corresponding author Minna M. Kanervo, of Helsinki University Hospital, in Finland. “Women on methadone treatment may have more severe substance abuse problems, so they require particularly cautious follow-up.”    

URL upon publication: https://onlinelibrary.wiley.com/doi/10.1111/aogs.14497

 

Additional Information

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About the Journal
Published monthly, Acta Obstetricia et Gynecologica Scandinavica is an international journal dedicated to providing the very latest information on the results of both clinical and research work from around the globe. The journal regularly publishes commentaries, reviews and original articles on a wide variety of topics.

About Wiley
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JOURNAL

Acta Obstetricia Et Gynecologica Scandinavica

DOI

10.1111/aogs.14497 

ARTICLE TITLE

Buprenorphine-naloxone, buprenorphine, and methadone throughout pregnancy in maternal opioid use disorder