Fentanyl, a powerful opioid pain reliever, is the leading cause of overdose death in the United States. In order to improve the drug’s safety profile to make it less lethal and addictive without eliminating its ability to relieve pain, a team of researchers, led by scientists from the Center for Clinical Pharmacology at Washington University School of Medicine in St. University of Health Sciences and Pharmacy in St. Louis, changed the chemical properties of the drug and the way it binds to opioid receptors on nerve cells.
Their studies, conducted in mice and in cell lines that express the opioid receptor, show that the modified drug is still an effective pain reliever, but likely without as many potentially deadly side effects. The research was published on November 30 in the journal Nature.
Although more studies in additional animal models and humans are needed to evaluate the fentanyl modification strategy, the research holds promise for the development of safer opioid drugs that also relieve pain.
“Opioids, including fentanyl, are among the most effective pain relievers we have, but they have also led to too many accidental deaths, a situation that is simply tragic,” said the paper’s corresponding author, Dr. Susruta Majumdar, an associate. professor of anesthesiology at the University of Washington and associate professor of medicinal chemistry and pharmacology at the University of Health Sciences and Pharmacy. “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 are excited about its potential to lead to safer pain relief drugs.
Fentanyl is commonly used to treat severe pain in cancer patients and in patients undergoing major surgery. It is up to 50 times stronger than heroin and 100 times stronger than morphine, and designer fentanyl is often sold on the street mixed with other drugs, such as heroin and oxycodone. More than 150 people die in the US every day from overdoses related to opioid drugs such as fentanyl.
Like heroin and oxycodone, fentanyl binds to the mu-opioid receptor on nerve cells. Once lodged in the receptor, drugs such as fentanyl relieve pain, but they can also lower blood pressure and slow breathing, potentially leading to respiratory distress and even death. Other side effects include euphoria, dizziness, confusion and sedation. Because of its potency, fentanyl is particularly lethal, even in very small amounts.
In replacing fentanyl, researchers have developed a variation of the drug that still binds to the mu-opioid receptor, but also engages the sodium ion binding site present in the receptor. Majumdar said the research showed that by targeting the sodium binding site, the pathway through which fentanyl works to fight pain was slightly altered, allowing the drug to retain most of its analgesic effects while reducing adverse effects.
When the modified drug was tested in mice exposed to a painful stimulus or in a mouse model of chronic pain, the drug retained its ability to relieve pain. In addition, mice were less likely to experience respiratory depression than mice given a standard formulation of fentanyl, and behavioral studies in mice suggested less abuse potential. While the findings are encouraging, Majumdar cautioned that more research is needed to understand the potential risks and benefits of modified fentanyl.
The mu-opioid receptor belongs to a family of cell receptors called G-protein-coupled receptors, which are able to bind hormones and signaling molecules, in addition to opioid drugs.
“The idea that sodium ion, something we find in table salt, could modulate the activity of G-protein-coupled receptors like these opioid receptors is not new, but our group appears to be the first to successfully alter the chemistry of fentanyl so that interacts with the sodium site on the receptor,” Majumdar said.
And it turns out that many other drugs also target G-protein coupled receptors, suggesting that such drugs could also be modified to reduce their side effects by modulating the sodium binding sites present in these targets.
“Nearly one-third of all drugs currently on the market—from blood pressure drugs to diabetes drugs to analgesics such as fentanyl—bind to various G-protein-coupled receptors, so it is possible to make many drugs more effective and limit their side effects, by changing the way they bind to such receptors,” he said.
Others involved in the new research include 2012 Nobel laureate Brian Kobilka, MD, professor of molecular and cellular physiology at Stanford Medicine, who trained as a resident at Barnes-Jewish Hospital and the University of Washington School of Medicine in the early 1980s; Dr. Vsevolod Katrich, Associate Professor of Quantitative and Computational Biology and Chemistry at the University of Southern California; Georgios Skiniotis, Ph.D., Professor of Molecular and Cellular Physiology and Structural Biology at Stanford; and Jai P. McLaughlin, PhD, professor of pharmacodynamics at the University of Florida.
Most of the work was done at the Center for Clinical Pharmacology, a collaboration between the University of Washington and the University of Health Sciences and Pharmacy. Center researchers hold academic appointments at both institutions. The center’s focus is on finding better, safer and more effective ways to use prescription drugs to improve health. The initial focus was on better understanding and improving pain management.
In future studies, the researchers plan to test their chemically altered fentanyl in other lab animals and create a form of the drug that will work systemically, like a pill, instead of the current injectable version.