A University of Calgary-led international research team has identified a genetic factor that may explain why people respond so differently to opioid pain medications, and why some individuals face greater risk of side effects including dependency.
The study, published in Neuron , involved researchers from the Faculty of Veterinary Medicine (UCVM), Cumming School of Medicine (CSM), and Hotchkiss Brain Institute (HBI), and provides new clinical insight that could lead to personalized strategies to optimize pain management.
Opioid medications are widely used to treat pain and are particularly effective in managing people with acute, short-term pain.
"If we can identify individuals who are unlikely to benefit from opioid pain relief or who are genetically predisposed to dependence, we can tailor their care accordingly." says Dr. Tuan Trang, PhD, principal investigator on the study and a professor with both CSM and UCVM. "That might mean alternative pain management strategies, closer monitoring, or adjusting dosing decisions from the outset."
The discovery centres on a gene called runt-related transcription factor 1 (RUNX1). RUNX1 provides the instructions for making a specific protein that helps control other genes involved in key biological processes like pain. People carry different variants of the gene, and this can influence how one responds to opioid medications. This could include their effectiveness in managing pain, dose requirements, and possible side-effects, including the risk of dependence.
"Our work highlights the importance of taking each patient's genetic make-up into account when making medical decisions," says Dr. Heather, Leduc-Pessah, MD '20, PhD '20, first author on the study. "This has been especially relevant for my work in pediatric neurology, where personalized medicine and gene therapies are at the forefront."
Researchers reviewed genetic data from patients who had undergone jaw and abdominal surgeries.
People carrying the genetic RUNX1 variant required higher opioid doses to achieve pain relief, while others with different variants experienced more intense withdrawal symptoms.
"Pain management is fundamental to medical and surgical practice and clinicians have long known that the responses to opioid analgesics can be quite surprising and unpredictable from patient to patient," says Dr. Paul Salo, MD, orthopedic surgeon and clinical professor at the Cumming School of Medicine. "This can lead to a host of adverse effects, ranging from nausea, vomiting, and inadequate pain relief to oversedation, respiratory depression, and of course, dependency. We would welcome the ability to screen patients so that these important medications can be used more safely and appropriately."
In addition to HBI, UCVM and CSM, collaborators included experts from other Canadian universities including McGill, Laval and Victoria, and international teams at Washington University in St. Louis, the University of Sydney in Australia and the University of Tokyo.
The clinical findings aligned with results from the team's advanced preclinical research in mice. The scale and complexity of the work reflect what Trang calls a "truly multi-institutional effort," involving trainees, clinicians, basic scientists and international partners.
"This work shows how basic research can inform clinical understanding," says Trang. "By identifying the cellular and genetic pathways involved, we can start thinking differently about how pain medications are prescribed and monitored. This is an important step toward personalized pain medicine."
Researchers are now exploring how Runx1 interacts with other genetic factors linked to chronic pain, opioid sensitivity and neuroimmune function.
The study was supported by Calgary philanthropists Donna and Rod Evans, as well as the Canadian Institutes Health Research (CIHR), and the Natural Sciences and Engineering Research Council of Canada (NSERC). Other acknowledgments are noted in the paper.
