Opioids remain the gold standard for managing severe oral cancer pain, but growing concerns about tolerance and side effects are prompting researchers to explore alternative approaches.
A new study suggests that inhibitors of the epidermal growth factor receptor (EGFR)—already used in cancer treatment—may help reduce oral cancer–related pain while restoring the effectiveness of opioid analgesics.
Oral cancer pain can be severe and debilitating, often interfering with eating, drinking and speaking. Pain intensity also tends to increase as tumours grow, pointing to shared molecular pathways that may drive both cancer progression and pain signalling.
EGFR, a protein found on the surface of certain cells and involved in regulating cell growth and division, is overexpressed in most oral cancers. Several U.S. Food and Drug Administration–approved drugs that block or inhibit EGFR are already used to treat lung, breast, colorectal, pancreatic and oral cancers.
Researchers from NYU Dentistry, The University of Texas MD Anderson Cancer Center and Loma Linda University School of Dentistry investigated whether EGFR signalling also plays a role in oral cancer pain and opioid tolerance. Their findings were published in Science Signaling.
EGFR ligands secreted
Using tissue samples from patients with oral cancer and mouse models of the disease, the team found that cancer cells and nearby glial cells secreted EGFR ligands—molecules that activate the receptor. EGFR was overexpressed in nerves associated with oral cancer tumours, including the trigeminal ganglia, which contain the main sensory nerve cells for the face and mouth.
The researchers also observed that EGFR activation drove hyperactivity of the glutamate N-methyl-D-aspartate receptor (NMDAR), a key pain-signalling receptor implicated in the development of opioid tolerance, in both the trigeminal ganglia and the brainstem.
In additional mouse experiments, EGFR ligands that activated the receptor in the trigeminal system increased pain and reduced the analgesic effectiveness of morphine. By contrast, treatment with an EGFR inhibitor reduced pain and restored morphine’s analgesic effects.
“These results are clinically significant and reveal a link between EGFR signalling and NMDAR hyperactivity, a mechanism that heightens pain signalling and reduces the effectiveness of opioid analgesics,” said Hui-Lin Pan, MD, PhD, professor of anesthesiology and perioperative medicine at MD Anderson.
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Repurposing cancer drugs
The findings suggest that EGFR inhibitors could offer a dual benefit in oral cancer care—helping control tumour growth while reducing pain and limiting the need for escalating opioid doses.
“This study provides a rationale for repurposing FDA-approved EGFR inhibitors already used to treat oral cancers, shifting from symptomatic suppression to mechanistic intervention,” said Moran Amit, MD, PhD, assistant professor of head and neck surgery at MD Anderson. “This approach may offer dual benefits, controlling cancer while addressing pain through a non-opioid, biologically rational strategy that could dramatically improve quality of life.”
Yi Ye, PhD, associate professor at NYU College of Dentistry and associate director of clinical research operations at NYU Dentistry’s Translational Research Center, said the work addresses a longstanding challenge in pain management.
“In the field of pain research, we struggle with the fact that—even after all these decades of research—the best drug on the market is often still opioids, which come with many risks,” Ye said.
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Next steps
The researchers plan to further evaluate the role of EGFR signalling in oral cancer pain by analyzing patients’ tumour and blood samples alongside self-reported pain scores and opioid use. They also intend to retrospectively assess the impact of EGFR inhibitors on pain relief using clinical records from an existing oral cancer trial.
“In drug development, it can take decades for a new compound to reach the market,” Ye said. “If our mechanism holds true in future studies, repurposing EGFR inhibitors is appealing because it could lead to rapid translation and quickly help patients.”
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Chi Viet, DDS, MD, PhD, associate professor of oral and maxillofacial surgery at Loma Linda University School of Dentistry, said the findings could reshape how cancer pain is treated.
“These findings could significantly impact the way we manage cancer pain, providing a targeted approach that mitigates the detrimental side effects seen with opioids,” Viet said. “This new treatment strategy offers hope to both patients and clinicians treating oral cancer.”
The study was supported by the U.S. National Institute of Dental and Craniofacial Research.