Studies Could Revolutionize Cancer Pain Treatment

The intense, debilitating pain of bone cancer can be relieved by blocking the growth of cells that eat away at the bone, scientists at the University of Minnesota say.

The cancer “hijacks the bone into destroying itself,” but a naturally occurring protein, called osteoprotegerin, can stop that process, says Patrick Mantyh, a neurosystems professor in the university’s Department of Preventive Sciences.

In mice, the protein appeared to stop bone destruction and relieve the pain within two days, Mantyh said. Amgen Inc. began human safety tests with a few patients in late 1999 but cannot say when they will be completed, spokesman David Kaye said.

Mantyh was among thousands of scientists who recently presented their work to the Society for Neuroscience. More than 400 studies were submitted on pain alone.

More than 1.2 million people a year are diagnosed with cancer in the United States. Hundreds of thousands will face agonizing pain.

Bone cancer causes two kinds of pain: a dull ache that grows over time and intense pain brought on by movement. If it has spread to the spine, even breathing hurts.

The vast majority of bone cancers have spread from the breast, prostate, lung, colon or other areas into bones. Only 2% start in the bone, Mantyh said.

Bone-destroying cells, called osteoclasts, usually work in balance with cells that create bone. But something secreted by the tumor cells--scientists don’t know just what, but are working to find out--kicks the osteoclasts into “hyperdrive,” Mantyh said.

“If a normal person would have, say, 10 osteoclasts, these patients have a thousand. They’re bigger and more active than you’d ever find in a normal person,” he said.

Osteoprotegerin does nothing to the tumor cells, but cancels their effect on osteoclasts, he said.

Mantyh said the osteoclasts also seem to hypersensitize nerves that carry pain stimuli to the brain. Even a gentle touch can cause excruciating pain.

In mice, that extreme sensitivity can be tested by stroking a foot with the end of a very thin fishing line, or by shining a lamp on the floor of the animal’s cage to heat it slightly.

The osteoprotegerin studies are very exciting, said Dr. Richard Payne, chief of pain and palliative care services at Memorial-Sloan Kettering Cancer Center and a professor of neurology and pharmacology at Cornell Medical College.

“This is the kind of data that will get oncologists and clinicians excited about taking this work from the laboratory to the clinic as soon as possible,” said Payne, who was not connected with the studies.

Drugs often do little to relieve bone cancer pain and can cause such problems as drowsiness, difficulty thinking and severe constipation.

One study looked at two of those drugs.

George Wilcox, also of the University of Minnesota, said studies in mice suggest that clonidine and morphine work much better when taken together by mouth than when injected into the spine, either alone or together.

If people have the same response as mice, he said, it might be possible to give one-tenth the current dose of either if they were given together.

Payne said that might be worth studying.

Yet another study by Dr. Aaron Filler, a neurosurgeon at the University of Cambridge in the United Kingdom, and colleagues at UCLA used the nerves themselves to deliver drugs. Nerve cells carry messages from one cell to another by moving molecules along fibers called axons, which can be from a fraction of an inch to 4 feet long.

The way they do this has been the topic of 20,000 to 30,000 papers over the last few decades. But they haven’t been used to deliver medicine before, said Filler, who created a British company that holds rights to his delivery system.

He and other researchers hooked up an “axonal transport facilitator” to a long molecule and then attached drug molecules to the long tail. The complex of molecules can be injected under the skin or into muscle of an area that hurts, and the nerves carry it where it is needed, Filler said.

Just what happens in the nerves after that is still being studied.

Filler said one injection of gabapentin--a drug used both as an anticonvulsant and to alleviate pain arising from the nerves themselves--reduced hypersensitivity by half for several days.

“Using one thousand times less than the usual dose, a single injection gave very significant pain relief for four days,” he said.

It is an exciting approach, Payne said.

Claire Hulsebosch and her colleagues at the University of Texas Medical Branch at Galveston looked at the hypersensitivity caused by spinal cord injuries.

The study conducted by Hulsebosch, Mary Eaton of the Miami Project and graduate student Bryan Hains used bioengineered cells that produce serotonin to treat such pain, transplanting them into the injured area.

The cells were designed to multiply only at temperatures lower than a rat’s body temperature so they could not create tumors.

The cells survived and secreted serotonin. The animals were less likely to flinch when touched by thin fishing line or to lick their paws when the floor of their cage was heated.

“And the rats walk better,” she said.

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University of Minnesota:

https://www.umn.edu

The Society for Neuroscience:

https://www.sfn.org

Memorial-Sloan Kettering Cancer Center: https://www.mskcc.org