Final word still out on popular pain medications

Independent studies that sort through the risks posed by COX-2 inhibitors and the older NSAIDS are needed, physicians say.

By Susan J. Landers — Posted Jan. 31, 2005

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Washington -- Is the bottom line in sight for physicians and patients puzzling over recent news about COX-2 inhibitors, NSAIDS and the risks they carry?

Not yet. And one may be a long time in coming. But perhaps the risk versus benefit calculation is becoming a bit clearer.

News of the withdrawal of the COX-2 inhibitor Vioxx because of cardiovascular risks was quickly followed by findings that cast doubt on other drugs prescribed for and taken by millions for long-term, non-narcotic pain relief, often for arthritis.

As they have in the recent past, physicians once again were fielding queries from dozens of nervous patients who wondered if they should stop taking the popular drugs. Placed under a cloud of suspicion were Celebrex, Bextra, and the older nonsteroidal anti-inflammatory drug, Aleve, or naproxen.

"I think it's going to take a long time to settle down," said Mary Frank, MD, president of the American Academy of Family Physicians, of the ensuing controversy. "Some of the unsettled environment has to do at this point with a rising awareness that no medication is absolutely safe and no new medication has been studied for very long."

There has also been some "jump-the-gun" thinking going on, said Dr. Frank. Although preliminary results of a trial on naproxen, which was approved for over-the-counter sales a decade ago, showed a possible increased risk of heart attacks among participants in an Alzheimer's disease study, some physicians believe the risk to be small.

But reaching solid conclusions is important. "The problem is if you can't use anti-inflammatories and Tylenol and a heating pad don't work, what do you have to offer patients beyond saying, 'Gosh, I guess you'll have to tough it out,' " said Dr. Frank.

While it hasn't come to that yet, the Food and Drug Administration has issued warnings on the use of all of these drugs. The agency plans to hold an advisory committee meeting next month to discuss the medications.

The naproxen trial that was halted on Dec. 20, 2004, was the Alzheimer's Disease Anti-Inflammatory Prevention trial, which was designed to assess whether naproxen and Celebrex (celecoxib) could affect the onset of Alzheimer's disease. The study enrolled subjects 70 and older who were considered to be at increased risk of the disease because of family history. Whether the results pertain to younger people is being questioned by many.

Before the preliminary results of that trial were released, naproxen, also marketed under the brand name Aleve by Bayer Pharmaceuticals Corp., was thought to be a relatively heart-healthy medication.

It may still prove to be so. Roger S. Blumenthal, MD, who is director of the Ciccarone Preventive Cardiology Center at Johns Hopkins University in Baltimore, points out that the doubts were cast by just one study. "You have to be aware that sometimes you can be fooled by one study and small numbers."

Dr. Blumenthal is also not as concerned about the risks of COX-2 inhibitors as are some other doctors. "Unfortunately, there are a lot of people in the medical profession who tend to overexaggerate benefits and risks."

He cited the Women's Health Initiative as an example of the "mass hysteria" that can affect the public and the medical field before all the data are available. News in 2002 that the estrogen replacement therapy Prempro was associated with an increased risk for breast cancer caused many women and their physicians to shy away from the medication.

"We found out subsequently that there was absolutely no increased risk in those women in the WHI who were within 10 years of menopause," said Dr. Blumenthal.

An aspirin a day

Dr. Blumenthal would also like the National Institutes of Health to examine whether a daily low-dose aspirin would attenuate the increased risk of heart attack among those who take Celebrex, manufactured by G.D. Searle & Co., or Bextra (valdecoxib), manufactured by Pfizer Inc.

"The American Heart Assn. has guidelines for aspirin use. I think many physicians forget there are a lot of older individuals who probably have a burden of some clinical atherosclerosis and should be given aspirin," he said.

Dr. Blumenthal said he had requested that the NIH examine the data from the now discontinued Celebrex studies to see if aspirin use made a difference.

James D. Katz, MD, associate professor of medicine at George Washington University and acting director of the university's rheumatology division, would welcome some peer-reviewed, double-blinded studies. He has responded to numerous calls from anxious patients who had been taking a COX-2 inhibitor or naproxen for arthritis pain and finds the calls are fraught with emotion.

"They deal with that scary topic of cardiovascular risk, which is on everyone's mind these days. With worrying about your cholesterol, your blood pressure and all that, the last thing you need to worry about is anti-inflammatory agents aggravating that risk.

"My personal bias is -- and I can't give hard and fast data -- that patients with increased cardiovascular risk factors may want to shy away from the COX-2 inhibitors until all this is sorted out."

However, the data on naproxen are less convincing, Dr. Katz said. "I still find it a useful agent, so I think it's not necessarily a crisis for naproxen."

Dr. Katz likened the current situation to a pendulum swinging from overenthusiastic acceptance of a new drug to absolute rejection. "We must understand the pros and cons and weigh [the drugs] for each individual situation."

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A cascade of doubts

September 2004: Vioxx (rofecoxib), was withdrawn from the market when a pharmaceutical company trial examining the drug's effectiveness at preventing colon cancer revealed that Vioxx was twice as likely to cause heart attacks and strokes as was the placebo among patients taking the drug for longer than 18 months.

December 2004: The National Cancer Institute halted a trial testing whether Celebrex (celecoxib), could prevent colon polyps when an increased risk of cardiovascular events was noted. The average duration of treatment in that trial was 33 months.

December 2004: The Food and Drug Administration strengthened warnings on the label of Bextra (valdecoxib), for cardiovascular risks and serious skin reactions.

December 2004: The National Institutes of Health halted a clinical trial of the nonsteroidal anti-inflammatory drug naproxen in patients at risk of developing Alzheimer's disease when some evidence of increased cardiovascular risk emerged from preliminary data.

February 2005: An FDA advisory committee meeting is planned to review COX-2 inhibitors and nonsteroidal anti-inflammatory drugs.

Sources: Food and Drug Administration and National Institutes of Health

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External links

Food and Drug Administration on Vioxx (link)

FDA on naproxen (link)

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