In a groundbreaking development, scientists from the Center for Clinical Pharmacology at Washington University School of Medicine in St. Louis and the University of Health Sciences & Pharmacy in St. Louis have made significant strides in altering the properties of fentanyl, a potent opioid pain reliever. Fentanyl, notorious for being a leading cause of overdose deaths in the United States, has long posed a grave threat to public health.
The researchers’ objective was clear: to enhance the safety profile of fentanyl, making it less lethal and less addictive, while preserving its vital role in pain management. Their innovative approach involved modifying the chemical composition of the drug and altering how it interacts with opioid receptors on nerve cells.
Their comprehensive studies, conducted using mice and cell lines expressing opioid receptors, yielded promising results. The modified fentanyl retained its effectiveness as a pain reliever while demonstrating a reduced likelihood of causing potentially fatal side effects. These findings, published in the prestigious journal Nature on November 30, mark a significant step toward the development of safer opioid medications that can still alleviate pain effectively.
Dr. Susruta Majumdar, the corresponding author of the research paper and an associate professor of anesthesiology at Washington University, expressed the urgency of this work, given the opioid crisis. “Opioids, including fentanyl, are among the most effective pain-relieving drugs we have, but they also have led to too many accidental deaths, a situation that is simply tragic,” Dr. Majumdar stated. “We are desperately looking for ways to maintain the analgesic effects of opioids, while avoiding dangerous side effects such as addiction and respiratory distress that too often lead to death. Our research is still in its early stages, but we’re excited about its potential for leading to safer pain-relieving drugs.”
Fentanyl, often used to manage severe pain in cancer patients and those undergoing major surgery, is exceptionally potent, being up to 50 times stronger than heroin and 100 times stronger than morphine. Illegally manufactured designer fentanyls, often mixed with other drugs like heroin and oxycodone, contribute to the alarming rise in opioid-related overdoses, claiming over 150 lives in the U.S. daily.
Like other opioids, fentanyl binds to the mu-opioid receptor on nerve cells. While it effectively relieves pain, it also poses risks, including dangerously low blood pressure and slowed breathing, potentially leading to respiratory distress and death. Additional side effects encompass euphoria, dizziness, confusion, and sedation. The potency of fentanyl makes it especially perilous, even in minute doses.
The researchers’ modification of fentanyl involved creating a variation that still binds to the mu-opioid receptor but also engages a sodium ion binding site within the receptor. This alteration shifted the pathway through which fentanyl acts to mitigate pain, thereby reducing adverse effects while retaining its analgesic properties.
Tests conducted on mice exposed to painful stimuli and a mouse model of chronic pain revealed that the altered drug remained effective in pain relief. Moreover, mice receiving the modified fentanyl exhibited a lower risk of respiratory depression, and behavioral studies suggested a reduced potential for abuse. While these findings are encouraging, Dr. Majumdar emphasized the need for further research to fully understand the risks and benefits of this modified fentanyl.
The mu-opioid receptor belongs to a family of cellular receptors known as G-protein coupled receptors. These receptors can bind to hormones, signaling molecules, and opioid drugs.
Dr. Majumdar noted, “The idea that the sodium ion, something we find in table salt, could modulate the activity of G-protein coupled receptors, such as these opioid receptors, is not new, but our group appears to be the first to successfully alter the chemistry of fentanyl so that it interacts with the sodium site on the receptor.”
This groundbreaking research opens doors to the possibility of modifying other drugs that target G-protein coupled receptors, potentially reducing their side effects and enhancing their effectiveness. Approximately one-third of all drugs on the market, from blood pressure medications to diabetes drugs to analgesics like fentanyl, bind to various G-protein coupled receptors, making this discovery highly relevant to the pharmaceutical industry.
The research involved collaboration with 2012 Nobel laureate Dr. Brian Kobilka, as well as researchers from the University of Southern California and Stanford Medicine. Most of the work was conducted at the Center for Clinical Pharmacology, a joint effort between Washington University and the University of Health Sciences & Pharmacy, focusing on improving the use of prescription medications to enhance health. Their initial emphasis has been on advancing pain treatment.
In future studies, the researchers plan to further evaluate their chemically modified fentanyl in various laboratory animals and develop a systemic form of the drug, potentially in the form of a pill, as an alternative to the current injectable version. This groundbreaking research offers hope for safer pain relief in the future.
