Researchers Identify Genetic Factor That May Explain Individual Responses to Opioids

Researchers of a recently published study identified a genetic factor, runt-related transcription factor 1 (RUNX1), that could explain why certain individuals respond differently to opioid pain medications and why some face greater risk of adverse events (AEs), such as dependency.¹

In mice, RUNX1 deletion in microglia produces distinct ultrastructural and transcriptomic signatures, which, according to the investigators, reduces morphine potency despite no prior exposure to opioids. The observed mice also required greater postoperative morphine and displayed exacerbated hyperalgesia and withdrawal to morphine. Single-cell RNA sequencing and chromatin immunoprecipitation sequencing analyses revealed there was a unique microglial state, with RUNX1 regulating inflammatory signaling and key microglial functions.¹

“Our work highlights the importance of taking each patient’s genetic make-up into account when making medical decisions,” first study author Heather Leduc-Pessah, MD, PhD, explained in the news release. “This has been especially relevant for my work in pediatric neurology, where personalized medicine and gene therapies are at the forefront.”²

In humans, the researchers identified significant associations between RUNX1 polymorphisms and both greater post-operative opioid analgesic requirements and more severe opioid withdrawal symptoms. They noted that, although these associations cannot be specifically attributed to RUNX1 function in microglia, the data confirm that human microglia express RUNX1 and that pharmacological RUNX1 inhibition shifts microglia toward a proinflammatory and reactive profile similar to that demonstrated in mice. Although RUNX1 has not been implicated in opioid-related traits in large-scale genome-wide association study (GWAS) or phenome-wide association study (PheWAS) analyses, this does not preclude the relevance of our findings. The authors explained that their study used a conditional, microglia-specific RUNX1 knockout model that resulted in targeted gene ablation in a defined cellular context.¹

“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,” Paul Salo, MD, orthopedic surgeon and clinical professor at Cumming School of Medicine, said in the news release. “This can lead to a host of AEs, 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.”²

The authors explained that, although there are no current approved therapies that exist to directly modulate RUNX1 activity, future strategies could include pharmacogenomics screening that identifies individuals who are less likely to benefit from opioid analgesics, enabling personalized treatment that incorporates alternatives to analgesics. They emphasized that further studies are needed to clarify the cellular impact of RUNX1 variants and to assess the safety and feasibility of these interventions.¹

“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. That might mean alternative pain management strategies, closer monitoring, or adjusting dosing decisions from the outset,” principal investigator Tuan Trang, PhD, professor from the Faculty of Veterinary Medicine and Cumming School of Medicine, said in a news release. “This work shows how basic research can inform clinical understanding. 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.”²

REFERENCES

1. Leduc-Pessah H, McAllister BB, Sinha S, et al. Runx1 transcription factor modulates opioid analgesia and withdrawal in humans and rodents. Neuron. 2026;114(5):903–921.e13. doi:10.1016/j.neuron.2025.11.018

2. UCalgary led study reveals a genetic factor behind who may and may not benefit from opioids prescribed for pain. University of Calgary. News release. February 3, 2026. Accessed March 16, 2026. https://www.eurekalert.org/news-releases/1115109