'Game-Changing' Arthritis Drug Blocks Pain Too Well in Some

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An experimental pain-relieving drug has yielded an unexpected finding for patients with osteoarthritis.

It's not that the drug doesn't work; indeed, it appears to be remarkably effective against pain in many with arthritic knees. But in some patients, the drug blunted joint pain so powerfully they never felt the warning signs or twinges that they were overdoing it -- and suffered joint destruction as a result.

In the quest for new pain relievers with minimal side effects, researchers have been focusing on a chemical known as nerve growth factor, which has been associated with increased pain from a variety of injuries and inflammatory conditions.

The experimental drug in this study aims to inhibit nerve growth factor. Its effect is significant, especially in light of the prevalence of osteoarthritis, a common result of excessive wear-and-tear on the joints, which plagues an estimated 27 million American adults. Many sufferers seek pain relief from non-narcotic medications.

"This is a radical notion for most people: that pain can be protective, but if you think about it, without pain signals, we would injure ourselves all the time" said Dr. Jack Choueka, chairman of orthopedics at Maimonides Medical Center in Brooklyn, N.Y., who was not involved in the study.

Doctors strive to reduce chronic pain, but they need to preserve at least some of it. It is the body's way of putting up a red flag warning about imminent tissue damage, Choueka said. "So it's important for doctors to help patients cope with pain, but not to the point where their ability to feel pain is impaired and places them in danger. Ergo: a little pain is a good thing."

The drug that worked "too well," tanezumab, is among a class of targeted treatments using monoclonal antibodies that latch onto a specific target, in this case nerve growth factor, and neutralize it.

In a clinical trial, reported in this week's New England Journal of Medicine, researchers assessed the safety and pain-relieving effect of the Pfizer drug on patients who suffered severe knee pain while walking on a flat surface. All 450 men and women were either unwilling to take non-narcotic pain relievers, hadn't gotten relief from such medications, or were facing knee surgery or injections.

The researchers, led by Dr. Nancy E. Lane, director of the Center for Healthy Aging at the University of California, Davis, randomly assigned them to receive one of five different doses of tanezumab intravenously -- on the first and 56th day of the study -- or a placebo.

Drug 'Like Novocain' Blocks Even Useful Pain in Some

Indisputably, tanezumab did a good job. Patients reported it reduced their knee pain anywhere from 45 percent to 62 percent on average, compared with a 22 percent average reduction for those getting a placebo. The drug often achieved this in the first couple of days after treatment, according to patient diary entries, Lane said. That surpassed the 30 percent reduction in pain intensity often cited as a threshold for meaningful pain relief.

The effect persisted through four months of treatment, allowing some patients to do previously unheard-of things like dance again, Lane said. The medication also reduced stiffness and improved physical function more than the placebo, with only mild to moderate side effects, which generally dissipated in a few days. The most common were headache, upper respiratory infection and pricking or tingling sensations in the hands and feet.

But tanezumab's potential as an arthritis pain reliever has been tempered by emerging evidence that use can lead to joint failure, said John N. Wood of the Wolfson Institute for Biomedical Research at University College, London, in an accompanying editorial in the New England Journal. Since the UC Davis-led study ended on May 24, 16 patients in a Phase III study of the drug in knee and hip osteoarthritis suffered joint breakdown that required total joint replacements.

At the FDA's request, Pfizer in June suspended studies of the drug for osteoarthritis. In July, it also suspended tanezumab studies for lower back pain and diabetic nerve damage, but said it would continue investigating its potential for other conditions, including cancer pain.

In an interview Wednesday, Lane called the tanezumab "a game-changing medication. We've never had an agent this potent. You get something that takes the pain away, you're bound to accelerate the disease."

She described researchers as so dazzled by tanezumab's powerful analgesic effect that they didn't warn their patients to take it easy.

"We've never had anything like this. We didn't know to counsel our patients, to say, 'This is like Novocain that the dentist gives. You're not going to feel anything...

"' Everyone got so excited by the findings, they didn't realize that everyone who has pain -- they aren't necessarily going to sit in a chair all day."

Experimental Drug May Have Advantages Over Current Treatment

Of those patients, she said: "We didn't monitor activity ... or how hard they were pushing, loading their joints. We just let them go to town. And they did."

Lane said the drug has multiple advantages over current analgesics: "It's not a narcotic, so it doesn't mess with your brain and intestines. It doesn't hurt your stomach. It has no effect at all on the kidneys and liver." With so many factors in its favor, she said it's up to the medical research community "to figure out how to use it so patients can benefit. We want to maximize the benefit and lower the risk."

Lane said she was grateful that the destructive side effects appeared while the drug was still experimental, rather than "when the drug was out. Now we can counsel patients, rather than have the drug withdrawn like the COX-2 inhibitors," which were taken off the market when they caused heart problems. "I think this is responsible drug development. Thank goodness it happened now."

While studies of the drug remain suspended at the request of the FDA, she said, "there are there other companies that have this type of a medication in development right now." Those companies have told her the FDA advised them to "go ahead cautiously. I think we will see a nerve growth factor inhibitor on the market -- whether it will be Pfizer's, I can't say."

Dr. Alton J. Stubbs, an assistant professor of orthopedic surgery at Wake Forest University Baptist Medical Center Winston-Salem, N.C., called the study "very important" and said that scientists in the last 15 to 20 years have "become very good at targeting specific proteins in the body that may be associated with chronic disease."

He, too, wasn't sure if tenazumab would ultimately win FDA approval, but said the take-home message of Lane's study was "that the science is advancing, there are some positive therapies on the horizon, and that patients should have a lot to look forward to in the next 5-10 years."

The study has several reported conflicts of interest. Rinat Neuroscience, now a subsidiary of pharmacy giant Pfizer, designed and coordinated the study. Lane, who holds an endowed chair in medicine and rheumatology, has been a paid consultant to Pfizer as well as Amgen, Merck, Aventis and NicOx.