Tag: user_id 13800

Newswise — New research led by UCLA Health has found a drug that treats insomnia works to prevent the addictive effects of the morphine opioids in mice while still providing effective pain relief.  

The study, published in the journal Nature Mental Health, concluded that suvorexant, which blocks brain receptors for a neurotransmitter called hypocretin, prevents opioid addiction. At high doses in humans, suvorexant induces sleep and is used to treat insomnia. But sleep was not induced, and behavioral alertness was maintained, at the much lower doses effective in preventing opioid addiction in mice. 

Hypocretin, also called orexin, is a peptide that is linked to mood, with hypocretin release in humans being maximal during pleasurable activities and minimal during pain or sadness. The loss of hypocretin neurons is the cause of narcolepsy, which is thought to be an autoimmune disease. People with narcolepsy and mice made narcoleptic have a greatly diminished susceptibility to opiate addiction.  

Researchers have found both humans addicted to heroin and mice addicted to morphine develop higher numbers of hypocretin producing neurons. Morphine causes hypocretin neurons to increase their anatomical connections to pleasure related brain regions. 

The latest study in mice found that administering opioids with suvorexant prevents opioid-induced changes in hypocretin neurons, prevents hypocretin neurons from increasing their connections to the brain’s reward related regions, greatly reduces opioid induced brain inflammation and prevents addictive behavior, such as running in mice expecting to receive their daily morphine dose. Suvorexant given with morphine also greatly reduces morphine withdrawal symptoms, according to the study. 

“The annual US rate of opioid overdose deaths now exceeds 80,000, greater than the annual rates of automobile or gun deaths,” said the study’s senior author, Dr. Jerome Siegel of UCLA Health’s Jane & Terry Semel Institute for Neuroscience and Human Behavior, the UCLA Brain Research Institute and U.S. Department of Veterans Affairs. “Non-opioid analgesics are able to relieve relatively minor pain. But severe burns, cancer, joint inflammation, sickle cell disease, bone damage and many other painful conditions often cannot be effectively treated with non-opioid analgesics.  

“Further studies are needed to determine if the addiction suppressive results seen in mice given suvorexant with morphine are also seen in humans, potentially allowing safer, more effective treatment of pain without the risk of addiction and opioid overdose death,” Siegel continued 

The study included 170 mice that were administered morphine for 14-day periods, 5 postmortem brains of humans with opiate use disorder and 5 control human brains. Trials are necessary to determine whether suvorexant will be as effective in suppressing addiction in humans using opioids for pain relief as it is in mice, Siegel said. 

“The annual US rate of opioid overdose deaths now exceeds 80,000, greater than the annual rates of automobile or gun deaths,” Siegel said. “Non-opioid analgesics are able to relieve relatively minor pain. But severe burns, cancer, joint inflammation, sickle cell disease, bone damage and many other painful conditions often cannot be effectively treated with non-opioid analgesics.  

“Further studies are needed to determine if the addiction suppressive results seen in mice given suvorexant with morphine are also seen in humans, potentially allowing safer, more effective treatment of pain without the risk of addiction and opioid overdose death,” Siegel continued 

Article Citation: McGregor R., Wu M.-F., Thannickal T.C., Li S., and Siegel J.M. (2024). Suvorexant blocks opiate induced anatomical and behavioral changes without diminishing opiate analgesia. Nature Mental Health, 2024. https://doi.org/10.1038/s44220-024-00278-2 

Newswise — The ongoing opioid epidemic in the U.S. kills tens of thousands of people every year. Naloxone, sold under the brand name Narcan, has saved countless lives by reversing opioid overdoses. But new and more powerful opioids keep appearing, and first responders are finding it increasingly difficult to revive people who overdose.

Now, researchers have found an approach that could extend naloxone’s lifesaving power, even in the face of ever-more-dangerous opioids. A team of researchers from Washington University School of Medicine in St. Louis, Stanford University and the University of Florida have identified potential drugs that make naloxone more potent and longer lasting, capable of reversing the effects of opioids in mice at low doses without worsening withdrawal symptoms. The study is published July 3 in Nature.

“Naloxone is a lifesaver, but it’s not a miracle drug; it has limitations,” said co-senior author Susruta Majumdar, PhD, a professor of anesthesiology at Washington University. “Many people who overdose on opioids need more than one dose of naloxone before they are out of danger. This study is a proof of concept that we can make naloxone work better — last longer and be more potent — by giving it in combination with a molecule that influences the responses of the opioid receptor.”

Opioids such as oxycodone and fentanyl work by slipping inside a pocket on the opioid receptor, which is found primarily on neurons in the brain. The presence of opioids activates the receptor, setting off a cascade of molecular events that temporarily alters how the brain functions: reducing the perception of pain, inducing a sense of euphoria and slowing down breathing. It is this suppression of breathing that makes opioids so deadly.

The molecular compound described in the paper is a so-called negative allosteric modulator (NAM) of the opioid receptor. Allosteric modulators are a hot area of research in pharmacology, because they offer a way to influence how the body responds to drugs by fine-tuning the activity of drug receptors rather than the drugs themselves. Co-author Vipin Rangari, PhD, a postdoctoral fellow in the Majumdar lab, did the experiments to chemically characterize the compound.

Naloxone is an opioid, but unlike other opioids, its presence in the binding pocket doesn’t activate the receptor. This unique feature gives naloxone the power to reverse overdoses by displacing problematic opioids from the pocket, thereby deactivating the opioid receptor. The problem is that naloxone wears off before other opioids do. For example, naloxone works for about two hours, while fentanyl can stay in the bloodstream for eight hours. Once naloxone falls out of the binding pocket, any fentanyl molecules that are still circulating can re-attach to and re-activate the receptor, causing the overdose symptoms to return.

The research team — led by co-senior authors Majumdar; Brian K. Kobilka, PhD, a professor of molecular and cellular physiology at Stanford University; and Jay P. McLaughlin, PhD, a professor of pharmacodynamics at the University of Florida — set out to find NAMs that strengthen naloxone by helping it stay in the binding pocket longer and suppress the activation of the opioid receptor more effectively.

To do so, they screened a library of 4.5 billion molecules in the lab in search of molecules that bound to the opioid receptor with naloxone already tucked into the receptor’s pocket. Compounds representing several molecular families passed the initial screen, with one of the most promising dubbed compound 368. Further experiments in cells revealed that, in the presence of compound 368, naloxone was 7.6 times more effective at inhibiting the activation of the opioid receptor, partly because naloxone stayed in the binding pocket at least 10 times longer.

“The compound itself doesn’t bind well without naloxone,” said Evan O’Brien, PhD, the lead author on the study and a postdoctoral scholar in Kobilka’s lab at Stanford. “We think naloxone has to bind first, and then compound 368 is able to come in and cap it in place.”

Even better, compound 368 improved naloxone’s ability to counteract opioid overdoses in mice and enabled naloxone to reverse the effects of fentanyl and morphine at 1/10th the usual doses.

However, people who overdose on opioids and are revived with naloxone can experience withdrawal symptoms such as pain, chills, vomiting and irritability. In this study, while the addition of compound 368 boosted naloxone’s potency, it did not worsen the mice’s withdrawal symptoms.

“We have a long way to go, but these results are really exciting,” McLaughlin said. “Opioid withdrawal likely won’t kill you, but they’re so severe that users often resume taking opioids within a day or two to stop the symptoms. The idea that we can rescue patients from overdose with reduced withdrawal might just help a lot of people.”

Compound 368 is just one of several molecules that show potential as NAMs of the opioid receptor. The researchers have filed a patent on the NAMs, and are working on narrowing down and characterizing the most promising candidates. Majumdar estimates that it will be 10 to 15 years before a naloxone-enhancing NAM is brought to market.

“Developing a new drug is a very long process, and in the meantime new synthetic opioids are just going to keep on coming and getting more and more potent, which means more and more deadly,” Majumdar said. “Our hope is that by developing a NAM, we can preserve naloxone’s power to serve as an antidote, no matter what kind of opioids emerge in the future.”

O’Brien ES, Rangari VA, El Daibani A, Eans SO, Hammond HR, White E, Wang H, Shiimura Y, Kumar KK, Jiang Q, Appourchaux K, Huang W, Zhang C, Kennedy BJ, Mathiesen JM, Che T, McLaughlin JP, Majumdar S, Kobilka BK. Negative allosteric modulation of the μ-opioid receptor. Nature. July 3, 2024. DOI: 10.1038/s41586-024-07587-7

Newswise — The U.S. Supreme Court has blocked the Sackler family’s bid for immunity from opioid-related lawsuits in a landmark decision. This ruling marks a pivotal moment in the ongoing opioid crisis, potentially reshaping how litigation against pharmaceutical companies is handled nationwide. It underscores the accountability of the Sacklers for their role in the epidemic and ensures that settlement funds are directed to support affected communities. This decision highlights the importance of justice and reparations for those impacted by opioid addiction.

The Supreme Court’s decision is crucial as it sets a precedent for future opioid litigation and the distribution of settlement funds.

The media is actively covering this significant decision, reflecting the widespread interest and its potential impact. Notable coverage includes:

Newswise Research

Cost may not keep many people from filling opioid addiction treatment prescriptions

Exploitation of supply chain monitoring loopholes fueled US opioid epidemic, study finds

Newswise Experts

Deborah A. Pasko, PharmD, MHA

Cheryl Healton, DrPH, 

Stephen Crystal, PhD

Larissa Mooney, MD

Dr. Ty Schepis, Ph.D., Clinical Psychology

Call for Experts

If you have comments or research to contribute to Newswise, please email us at [email protected].

Newswise — CHAPEL HILL, N.C. – Christian Hendershot, PhD, associate professor of psychiatry and director of the Clinical and Translational Addiction Research Program at the UNC School of Medicine, recently presented early findings from the first completed randomized controlled trial of semaglutide in participants with alcohol use disorder (AUD).

The preliminary and unpublished findings, which were presented at the Research Society on Alcohol’s Annual Meeting, showed a reduction in heavy drinking and drinking quantity among those who were given semaglutide versus the placebo group.

“We believe these findings are promising and warrant further trials of GLP-1 receptor agonists in treatment-seeking participants with alcohol use disorder,” said Hendershot, who is also a member of the Bowles Center for Alcohols Studies at the UNC School of Medicine.

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) was originally formulated to treat diabetes and has emerged as a weight loss drug. Anecdotal observations from patients have suggested the drug may also reduce alcohol and other substance cravings. This possibility is also consistent with numerous preclinical studies over the past decade, which led Hendershot and other groups to design early randomized clinical trials of GLP-1RAs in participants with AUD.

Participants in the Phase II randomized controlled trial were non-treatment-seeking volunteers who reported symptoms of alcohol use disorder. A total of 48 participants were randomized to medication or placebo groups. Participants assigned to the medication arm received the lower two clinical doses of semaglutide (0.25mg/week, 0.5mg/week) over approximately 2 months. The study was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Preliminary results from the trial indicate that those taking the medication experienced greater reductions in drinking quantity and heavy drinking more than those in the placebo group. Given the magnitude of the effects at relatively lower doses, it appears that semaglutide could have the potential to reduce drinking to a greater extent than existing medications. With 96% of those in the medication group finishing the study, researchers concluded that the drug was safe and well tolerated in this population.

Replication studies will be needed to further confirm the safety, tolerability, and efficacy of semaglutide at higher doses in this population, and to identify patient subgroups that are more or less responsive to GLP-1RAs.

Other UNC-based co-investigators on the study include Klara Klein, MD, PhD, assistant professor at the Department of Medicine’s Division of Endocrinology and Metabolism; Amanda Tow, MD, PhD, assistant professor in the Department of Psychiatry; and Robyn Jordan, MD, PhD, associate professor in the Department of Psychiatry and medical director of the UNC Addiction Medicine Program.

FOR IMMEDIATE RELEASE:

Newswise — BLOOMINGTON, Ind. — New research from the Indiana University Kelley School of Business explains how pharmaceutical companies were able to saturate the country with massive quantities of opioids, despite efforts by the Drug Enforcement Administration to regulate their supply.

The research identifies a loophole in the DEA’s monitoring system exploited by some pharmaceutical companies, leading to an oversupply of opioid drugs in communities. The hallmark of this activity was high supply chain complexity, such as pharmacies with dozens of distributors across the country.

The same research also documents how the opioid epidemic — commonly regarded as a national public health crisis among white Americans — had a much deeper impact in Black communities, where overdose deaths tripled from 2014 to 2020.

“We believe we are the first to uncover insights into the supply chain mechanisms that were used to evade the DEA and fuel the opioid crisis,” said Jonathan Helm, professor of operations and decision technologies and the W.W. Grainger Inc. Faculty Fellow at the Kelley School. “Up until now, the focus has been on each of the pharmaceutical companies individually, ignoring the huge impact of the broader supply chain.”

“No one was looking at it from a supply chain perspective,” added Iman Attari, a Kelley School doctoral candidate in operations and decision technologies and the paper’s corresponding author.

Attari, Helm and Jorge Mejia, an associate professor in the Kelley School, analyzed information in the 2019 release of the DEA’s Automation of Reports and Consolidated Orders System — commonly known as the ARCOS database — which tracked each shipment in the U.S. opioid supply chain from 2006 to 2014.

Their paper, “Hiding Behind Complexity: Supply Chain, Oversight, Race, and the Opioid Crisis,” appears in the latest issue of the journal Production and Operations Management.

The researchers uncovered how supply chain complexity may have facilitated the influx of large qualities of opioids into the market, undetected by the DEA. Their research combined ARCOS data about pharmacies’ opioid dispensing and supply chain structures with county-level demographics and socioeconomic factors.

Using a fixed effect model, they found that a one-unit increase across three dimensions of supply chain complexity was associated with a 16% increase in opioid dispensing.

DEA monitoring involves using ARCOS to collect data on all shipments of controlled substances, and requiring manufacturers and distributors to report suspicious orders of unusual size and frequency.

“The issue was that pharmacies wanting to have large shipments were very smart about it,” Attari said. “Instead of placing an order for a large shipment from one single distributor, they broke down that large order across multiple distributors. They got smaller shipments from different distributors; when added up, it was a huge order. Each distributor is only going to see the data from the pharmacy that links themselves to it, and not to shipments from other distributors.”

As a result, the DEA monitoring system failed. By using more suppliers, pharmacies were able to evade detection.

Another factor they studied was the location of distributors. Because of the DEA’s structure, with 23 often independently operated field divisions spread across the U.S., the researchers found that a lack of coordination and aggregation of information among them was another factor in overlooking potentially suspicious activity.

“Even if a supplier reports a suspicious order in one division, other divisions that the pharmacy orders from are unlikely to be informed,” they wrote.

“It cannot be just ‘business,’ because when you look at it from a business standpoint, it makes more sense to work with one distributor because you benefit from economy of scale,” Attari said. “It is expected for a pharmacy to have one or two distributors, or at most three distributors of opioid drugs.

“When we saw pharmacies in the data set with 25 distributors — all over the U.S. — that was a strong indication that they were trying to mess with the monitoring system.”

The research found that supply chain complexity had a stronger association with the increase in opioid dispensing in non-white communities. A 10% increase in the non-white proportion of the population yielded a 3.39% increase in the overall dispensing by pharmacies with high supply chain complexity.

“Communities of color have been historically under-resourced and neglected by many government and social services,” the researchers wrote. “In the context of the opioid crisis, it appears that the DEA has spent more effort arresting non-White drug users than on regulating the flow of opioids from pharmaceutical companies into non-White communities.”

To be certain that their analysis was distinguishing between legitimate medical use and non-medical, recreational demand, they compared statistics for the reformulated OxyContin, which was redesigned to prevent abuse.

“In a novel approach, we leverage the fact that different pharmacies received their first shipment of reformulated OxyContin at different times and use a difference-in-differences model to estimate the heterogeneous effect of the shock on dispensing,” they wrote. “As the reformulated OxyContin stifled (non-medical) demand, high-complexity pharmacies experienced a 15.31% greater reduction in dispensing compared to lower-complexity pharmacies, suggesting that their excess dispensing was indeed satisfying non-medical/recreational demand.”

As a follow-up to this paper, the researchers are investigating the dynamics between major chain pharmacies and their distributors, and how they may facilitate the oversupply by pharmacies. Their initial findings suggest that the pharmacies’ practice of self-distribution, where they distribute opioids from their own distribution centers, combined with their close ties to large distributors, also may have led to excessive opioid dispensing without adequate oversight by the DEA.