National Institutes of Health scientists have achieved a significant breakthrough in cancer pain management with the first-in-human clinical trial of resiniferatoxin (RTX), a plant-derived therapy that demonstrated remarkable efficacy in patients with intractable cancer pain. The study showed that a single injection of RTX into the lumbar cerebrospinal fluid reduced patients' worst pain intensity by 38% and decreased their opioid use by 57%.
Targeting the Most Vulnerable Cancer Patients
The trial enrolled research participants with terminal end-stage cancer who represented the 15% of cancer patients unable to find pain relief from standard care interventions, including vast quantities of opiates. These patients experienced immediate and durable relief following a single RTX injection, with significant improvements in quality of life.
"The effects are immediate," said Andrew Mannes, M.D., lead study author and chief of the NIH Clinical Center Department of Perioperative Medicine. "This is a potential new therapy from a new family of drugs that gives people with severe cancer pain an opportunity to return some normality to their lives."
Following treatment, patients no longer needed to spend significant periods being sedated with opioids and were able to reengage with their family, friends and communities.
Selective Mechanism of Action
RTX operates through a highly selective mechanism that distinguishes it from existing pain management approaches. The therapy prevents pain signals from reaching the brain by inactivating a specific sub-group of nerve fibers that transmit heat and pain signals from damaged tissue. RTX functions as an activator of the transient receptor potential vanilloid 1 (TRPV1) ion channel and represents a super-potent equivalent of capsaicin, the active molecule in hot peppers.
"Basically, RTX cuts the pain-specific wires connecting the body to the spinal cord, but leaves many other sensations intact," explained senior study author Michael Iadarola, PhD, a senior research scientist in the NIH Clinical Center Department of Perioperative Medicine. "These TRPV1 neurons are really the most important population of neurons that you want to target for effective pain relief."
The ability of RTX to open the channel pore in TRPV1 allows an overload of calcium to flood into the nerve fiber and block its ability to transmit pain signals. Unlike other current approaches that use heat, cold, chemicals, or surgery to non-selectively interrupt nerves, RTX targets specific sensory pathways while preserving touch, pin prick, pressure, muscle position sense (proprioception), and motor function.
Non-Addictive Alternative
RTX offers a crucial advantage over current pain management strategies as it is not addictive and doesn't cause a high. "What makes this unique from all the other things that are out there is this is so highly selective," Mannes said. "The only thing it seems to take out is heat sensation and pain."
Plant Origins and Development
RTX is derived from the Euphorbia resinifera plant, a cactus-like plant native to North Africa. Euphorbia extract has been known for 2,000 years to contain an "irritant" substance. NIH scientists identified how to use this compound for patients through basic research on living cells observed through a microscope. Adding RTX to TRPV1-containing cells caused a visible calcium overload, which Iadarola and Mannes eventually translated into the early-stage human clinical trial.
Broader Therapeutic Potential
The NIH scientists believe RTX has potential to treat many other pain conditions beyond cancer pain, including chronic pain from nerve injuries called neuromas, post-surgical pain, trigeminal neuralgia (a facial pain condition), and chronic oral inflammatory problems following head and neck radiation therapy.
"Targeting specific nerves brings many pain disorders into range of RTX and allows physicians to tailor the treatment to the patient's pain problem. This interventional approach is a simple path to personalized pain medicine," Iadarola said.
Next Steps
The research team plans additional, larger clinical trials to move RTX toward eventual approval by the U.S. Food and Drug Administration and clinical availability. This research was supported by the Intramural Research Program of the NIH Clinical Center and NIH's National Institute of Neurological Disorders and Stroke.
