Procedure alleviates pain for terminally ill patients

Craig Gustafson

Denis Clohisy works with terminally ill patients at the University on a daily basis.
The associate professor of orthopedic surgery remembers a woman in her 30s dying from cancer of the pelvic and spinal bones. Doctors administered heavy doses of morphine to ease her unbearable pain.
The only thing she wanted in her final days was to be coherent and awake, not drugged-up and drowsy, so she could spend quality time with her 3-year-old daughter. Her constant, chronic pain didn’t allow her that simple luxury.
Clohisy said the woman needed something to “make the last moments of life worth living.”
With that goal in mind, University researchers finished a study this fall using a new procedure on rats that could make the last days of a terminally ill human patient more comfortable by stopping chronic pain where it begins in the spinal cord.
Two years ago, researchers followed up on a hunch that a “molecular scalpel” could be created to destroy the cells that deliver signals to the brain, allowing doctors to cut down on the use of overpowering drugs.
Patrick Mantyh, a University professor and researcher, and his colleagues conducted a study on rats to test their hypothesis.
Earlier this year, they proved their theory was more than just a hunch.
Mantyh and his team discovered how to alleviate two forms of pain — inflammatory pain and pain due to nerve injury — while leaving responsiveness to mild pain, and to therapies like morphine, intact.
Mantyh said most treatments used today are effective in slowing fatal diseases but largely ineffective in relieving the physical agony that accompanies them.
“If a person is in chronic pain, the major and sole focus of their life is the pain and how to get rid of it,” Mantyh said.
Morphine is the most common drug used by patients with cancer and severe arthritis. Although morphine reduces discomfort, it also dulls the brain, causing a patient to be incoherent and disoriented much of the time. As tolerance builds up, dosage also increases, making side effects like difficulty with speech and basic motor skills more apparent. Overall, quality of life deteriorates rapidly.
Attacking pain at its root
Mantyh’s study zeroed in on a neurotransmitter called substance P located in certain cells in the spinal cord. The neurotransmitter, found in 5 percent of cells in the lower spinal cord, transmits signals to the brain for only the most intense forms of pain.
For instance, substance P is released by everything from hot peppers to chronic discomfort caused by arthritis and certain cancers.
“The goal was to block pain before it gets to the brain,” Mantyh said, by eliminating cells in the spinal cord that relay pain signals to the brain.
To do this, researchers attach a toxin to the substance P neurotransmitter. Cells with substance P receptors then bind and internalize the poison along with substance P. The toxin kills the cell, stopping any pain signal from being sent to the brain.
In the laboratory, 200 rats were used in the study, although not all were injected with the toxin.
After 30 days, the rats were placed on a warm plate to see if the experiment was successful. Researchers measured response to pain by the number of seconds it took for the rat to lift its feet from the plate.
Mantyh said the warm plate acts in much the same way as a person placing a hand on a hot car hood. At first it’s not too hot, but after a few seconds a person lifts their hand.
The test showed that rats injected with the toxin responded more slowly to heat than normal rats.
Closer examination revealed the neurons in other parts of the brain and spinal cord remained unaffected by the toxin. Relief did not diminish during the entire 200-day observation period and no side effects were observed.
“For the first time, you can begin to focus on particular cells,” Mantyh said.
The response to morphine remained the same; an important detail, because morphine could still be used in other areas of the body if a patient has other ailments besides chronic pain, Mantyh said.
Clohisy, a physician whose patients could possibly benefit from the technique, insisted that although the procedure is promising, it is not foolproof. There are certain side effects that one can’t measure in a rat that could affect humans, such as dizziness or severe headaches, he said.
But despite his skepticism, Clohisy said the technique has merit.
“The real beauty of what Mantyh did was take the highest quality of science, and he’s applying that in a practical way to help patients,” he said.
Before it can be applied to humans, researchers need to perform tests on larger animals like pigs. Estimates suggest that within five years the procedure will be approved for humans.

Craig Gustafson covers the Medical School and welcomes comments at [email protected] He can also be reached at (612) 627-4070 x3233.