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Pain relievers

Taking the bite out of pain. (Illustrations: Dave Cutler)

U researchers take the bite out of a formidable foe—chronic pain

“The worst pain a man can suffer: to have insight into much and power over nothing.” — Herodotus

If Herodotus was right about the connection between pain and power, research into chronic pain has been hurting until recently. We’ve long known much about the nervous system’s mechanisms that communicate and register pain, but we have lacked the power to treat and end chronic pain in many patients. This shortcoming produces sobering consequences: About 30 percent of Americans experience chronic pain from a variety of causes, leaving them in continual distress and handing our economy an annual loss of nearly $100 billion.

There’s no denying that pain makes a devious opponent. It often appears and persists for unknown reasons. “It makes me cringe to imagine having pain when you don’t know the cause,” says Christopher Honda, Ph.D., a professor and pain researcher in the University of Minnesota’s Department of Neuroscience. “Besides suffering from the pain, these patients wonder and worry about what’s behind it. Unfortunately, there’s no consistent course of treatment—no common path to wellness. Many people have to find out what works just for them, which can become very frustrating.”

Such a wily foe deserves determined adversaries, which the University can claim in abundance. “We have one of the largest collection of pain researchers in the world working on all aspects of the problem, from determining how people sense and perceive pain to studying new drugs for controlling it,” says Timothy Ebner, M.D., Ph.D., professor and head of the Department of Neuroscience.

By pooling their expertise, University of Minnesota scientists from a variety of disciplines are taking on pain in the laboratory, where they are steadily gaining on humanity’s longtime enemy. Cancer pain is a prime example: Scientists specializing in such wide-ranging fields as neuroscience, pharmacology, hematology/oncology, orthopaedic surgery, dentistry, and veterinary medicine are discovering new approaches to outwitting the chronic pain that often accompanies cancer.

The promise and pitfalls of opioids

Leading the way is George Wilcox, Ph.D., a professor of neuroscience, pharmacology, and dermatology and program director of the Minnesota Center for Pain Research, which fosters cross-disciplinary research and education. For decades, he has focused his attention on opioids, the drugs that have long offered the best hope for sufferers of chronic pain. These medications come with serious disadvantages; patients can develop a tolerance or addiction to them, requiring ever-growing doses to ease the pain, as well as other side effects, including nausea and vomiting, constipation, dizziness, and impaired cognition.

“Sometimes people with chronic pain from a disease like cancer will be taking very large doses of morphine for years and years,” says Wilcox. “They get to the point where the side effects begin to appear.”

Wilcox’s lab has devised a way of avoiding the undesirable consequences of opioids by administering drugs near the spinal cord, lessening the amount needed to reduce pain and bypassing many of the side effects. His lab has also investigated the use of chlonidine—a drug normally used to treat hypertension—in tandem with morphine. The two drugs seem to have a synergistic relationship, with the combination easing pain while reducing the amount of morphine needed by 10 to 15 times. As the dose of morphine declines, so does the incidence of side effects. In addition, Wilcox has found that chlonidine, when administered alone, can control types of pain that are resistant to morphine.

Kalpna Gupta, Ph.D., an assistant professor in the Division of Hematology, Oncology, and Transplantation, approaches opioids from a different angle. She asks a previously unexplored question: If morphine and related drugs lose their ability to control cancer pain over time, could the reason be that the opiates are actually making the cancer worse?

“We found that in mice, the drugs do increase the growth of vessels in cancerous tumors over time,” Gupta explains. “That suggests a relationship with the disease process. The ineffectiveness of opiates is not only due to the effect of the drugs on the central nervous system. We have to consider their effect on the disease. The more rapid the growth of a tumor, the greater the increase in pain.”

When Gupta’s team explored ways to prevent the opiates’ detrimental effects, they found interesting results involving an enzyme in the body called COX-2, which plays a key role in the perception of pain and cancer progression. “If you combine morphine with a drug that inhibits COX-2, you reduce the ill effect of morphine on cancer, and you also block COX-2 activity in the spinal cord,” Gupta says. “We’ve found that this combination reduces tumor growth and metastasis and increases survival, while it results in much more pain reduction than the use of each drug alone.”

Pain reduction can also result when the nervous system is “primed” to more quickly sense naturally occurring opioids before a painful incident happens. That’s been the focus of research by Honda, whose lab studies the sensory nociceptors, or pain-sensing neurons, that contain opiate receptors. His research suggests that it might be possible to prepare the body to deal with cancer pain or another trauma by medically stimulating the nociceptors in advance.

Natural cannabinoids

Neuroscience professor Virginia Seybold, Ph.D., studies the effects on pain—including cancer pain—of cannabinoids, forms of an active ingredient in marijuana and related plants. Like the opioids, cannabinoids occur naturally in our bodies and reduce the sensation of pain by binding with receptors in the nervous system.


“The compounds we’re working with are not themselves strictly cannabinoids—they’re compounds that trick the body into increasing levels of naturally occurring cannabinoids,” Seybold says. “In essence, we’re manipulating physiology to make the body generate its own chemicals to alleviate pain. It’s a highly attractive approach and it seems effective.”

Seybold’s experiments on mice suggest that her line of attack works. Increasing the levels of the body’s own cannabinoid compounds by blocking the enzymes that break them down at the site where tissue is injured alleviates pain, Seybold says. “The advantage of this strategy is that it circumvents the brain, which avoids the problems of impaired cognitive function and dependence that are associated with medical marijuana.”

Other University researchers are investigating the power of cannabinoids to fight cancer pain, including Donald Simone, Ph.D., professor in the Department of Diagnostic and Biological Sciences in the School of Dentistry. Simone’s research on mice has shown that cannabinoids can significantly reduce cancer pain and hypersensitivity that result from the growth of certain malignant tumors. That’s a hopeful prospect for cancer patients with chronic pain.

A way to block bone cancer pain

Bone cancer presents its own distinctive challenges for cancer pain therapy. “It’s a very big problem,” says Denis Clohisy, M.D., a professor of orthopaedic surgery. “Most patients who experience it are dealing with end-of-life issues, and controlling their pain is important.”

Traditionally, physicians have treated bone cancer pain like a toothache, headache, or any other kind of pain—with narcotics. “Our approach is to discover why the pain of bone cancer happens at the level of cells and molecules,” says Clohisy. In a 10-year collaboration, he and colleague Patrick Mantyh, Ph.D., now at the University of Arizona College of Medicine, found that anti-inflammatory, nerve-targeted medications are effective in easing bone cancer pain in mice. Conversely, nerve growth factor, a protein that nurtures certain nerves, makes the pain worse.

“We’re going to see less use of narcotics and more use of mechanism-based therapies,” predicts Clohisy, whose research is now focused on eliminating bone cancer entirely. “Those would be combinations that include anti-inflammatories and medications that block the effect of nerve growth factor. If it proves effective in humans, which we don’t yet know, this could start up within five years.”

Alvin Beitz, Ph.D., a professor in the Department of Veterinary and Biomedical Sciences, recently received a federal stimulus grant to study a different approach to blocking bone cancer pain at the cellular level. His laboratory has found that pain decreases when two proteins secreted by bone tumors are absent. Beitz will study the effect on pain of deactivating these proteins in mice, in hopes that his findings will lead to the development of new drugs to prevent or reduce bone cancer pain in people.

And reducing or eliminating chronic pain—whatever its cause—is the goal these University scientists and many others share.

“What I’ve valued here is that there’s an intellectual environment focused on pain, which always fuels the discussions and possibilities,” says Seybold. “My research advances because of people with expertise who can answer my questions and who contribute to a critical mass of shared interests.”

By Jack El-Hai

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