UCalgary-led study reveals a genetic factor behind who may and may not benefit from opioids prescribed for pain

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 acute, short-term pain conditions.

“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) that 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 makeup into account when making medical decisions,” says Dr. Heather Leduc-Pessah, MD’20, PhD’20, a paediatric neurology resident and first author on the study. “This has been especially relevant for my work in paediatric neurology, where personalized medicine and gene therapies are at the forefront.” 

Understanding unique personal responses to pain treatment

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, orthopaedic surgeon and clinical professor at CSM. “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.”

Research highlights the power of collaboration  

At its core, the study bridges basic science and clinical medicine. Using both human genetic data and advanced cellular tools, the team uncovered genetic and biological causes that explain why opioid responses can vary dramatically between individuals.

The scale and complexity of the work reflect what Trang calls a “truly multi-institutional effort,” involving trainees, clinicians, basic scientists and international partners.

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 results matched what the team saw in a laboratory setting in mice. In those experiments, turning off the protein reduced morphine’s effectiveness, changed patterns of gene activity, and was linked to more severe withdrawal symptoms. Together with real-world patient outcomes, these findings offer a clearer biological explanation for why people respond differently to opioids and point toward safer, more personalized prescribing in the future.

“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.”

Discovery supported by community

Breakthroughs like this one do not happen overnight, nor do they come without risk.

Trang’s research falls into a category often described as “high-risk, high-reward” science. While the potential impact is significant, the outcomes are not guaranteed, and securing funding for this type of fundamental research can be challenging. Support from Calgary philanthropists Rod and Donna Evans helped advance the project at a critical stage, enabling the team to pursue bold questions about how genetics influence pain management for those struggling with chronic pain.

In addition to community philanthropy, the research was supported by grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. Additional acknowledgements are included in the published paper.