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Studies on painkillers in jeopardy

From coast to coast, warnings about several popular anti-inflammatory painkillers are triggering confusion and anxiety.
/ Source: a href="" linktype="External" resizable="true" status="true" scrollbars="true">The Washington Post</a

The spate of bad news about painkillers has dealt a major setback to what had been a highly promising effort to use the drugs to prevent a host of leading killers, including many types of cancer, Alzheimer's and other forms of dementia.

Since concerns emerged that drugs such as Vioxx and Celebrex might cause heart attacks and strokes, researchers testing the drugs in dozens of studies have been frantically scouring whatever data they have gathered so far for signs of danger, urgently debating whether the trials should continue, and quickly informing participants of possible risks.

Studies halted amid concerns
Several large studies have shut down fully or partially, including trials for preventing colon cancer, prostate cancer, Alzheimer's and, just last week, two large international studies evaluating Celebrex to cut the risk of getting breast cancer or suffering a recurrence. Other studies have been temporarily suspended until all participants could be warned of the possible danger.

Overall, the startling new concerns about the drugs' safety have cast a pall over what had been one of the most exciting fields of biomedical research, which was trying to harness important new insights into the underlying cause of a wide spectrum of illnesses.

"It's definitely been a big setback," said Raymond N. DuBois of Vanderbilt University School of Medicine in Nashville. "It's really disappointing because there had been a lot of enthusiasm in this area, and a lot of trials were underway. I think this is going to slow things down considerably. It's really unfortunate."

The developments are particularly distressing because a large body of evidence indicates the drugs could provide significant benefits aside from relieving pain. Even the studies that revealed the possible heart disease and stroke risks produced evidence that the approach could be highly effective for reducing the risk for cancer.

"We have produced evidence for the proof-of-principle that agents like these could be effective for preventing cancer," said Robert Bresalier of the University of Texas M.D. Anderson Cancer Center in Houston, who led the study that raised the first alarm. "There's a great deal of data suggesting that these drugs might be beneficial in terms of preventing or treating a large number of cancers. It would be a major mistake not to go forward with this line of research."

Prudence or overreaction?
Several researchers said they believed the response to revelations of what are potential risks was an overreaction. It may turn out that Celebrex and similar drugs pose less of a danger than initially suspected, or that the drugs could prove useful at lower doses or for certain patients, they said.

"I think we have created a situation of mass hysteria that's completely unwarranted," said Carol Fabian, director of breast cancer prevention at the University of Kansas Medical Center in Kansas City, who decided to continue two breast cancer studies after warning participants of the possible risk. "I don't think we have all the data yet, and we may be prematurely drawing conclusions."

The drugs were developed to relieve pain with fewer side effects than existing painkillers, but researchers began testing them to treat or prevent a variety of diseases because of their ability to reduce inflammation, limit cell growth, inhibit the growth of blood vessels that nourish tumors and, in the case of breast cancer, lower estrogen levels.

A cascade of panic began in September when Merck & Co. pulled its blockbuster arthritis drug Vioxx from the market because Bresalier's study indicated the drug doubled the risk for heart attacks and strokes. Bresalier was testing whether Vioxx reduced the risk for colon polyps, which can lead to cancer. Merck then shut down another colorectal cancer-prevention trial, as well as one for prostate cancer prevention.

That prompted the National Institutes of Health to begin scrutinizing other trials using similar drugs, especially Pfizer Inc.'s popular Celebrex. On Dec. 17, the NIH announced that another cancer prevention trial had found evidence of a similarly increased risk for heart problems for Celebrex, and shut down that trial.

Snowball effect derails studies
Although another study contradicted that finding, the announcement caused patients in many studies testing Celebrex to stop taking their drugs, including those in a large Alzheimer's prevention trial. That trial also raised concern about the over-the-counter pain reliever naproxen, sold as Aleve.

John Breitner of the University of Washington in Seattle, who led the Alzheimer's trial, said the hint of risk for naproxen was far from clear from his data, and the main reason his trial shut down was because so many participants were worried about Celebrex.

"The reasons we had to suspend the treatments had less to with the perception of danger ... than with other purely practical considerations," Breitner said. "It's all very unfortunate."

Other Alzheimer's researchers expressed similar disappointment, saying they feared the developments would unnecessarily derail a promising line of research.

"We should not give up on this," said Linda Van Eldik of the Northwestern University Feinberg School of Medicine in Chicago. "Inflammation is a key player in the damage in Alzheimer's. I would hate to have something like these initial results make people stop this whole area of research, because I think it's really important."

Similarly, researchers leading the two large breast cancer trials decided to discontinue parts involving Celebrex in part because of the health concerns, but primarily because they felt the rising alarm made it impractical to continue.

"We were concerned that, because of the widespread media attention around this class of agents, the reaction of ethics review committees around the country, and the volume of telephone contacts we were having from study participants, that the entire machinery of our clinical research program would unravel if we tried to persist," said Paul Goss of the Massachusetts General Hospital in Boston, who is leading the studies.

'Caught in the eye of the storm'
The researchers are proceeding with the primary part of both studies, which will test another type of drug known as an aromatase inhibitor in thousands of patients in the United States, Canada and Spain.

"We felt we were being caught up in the eye of the storm, and it would be even more harmful to us if this decision had to be made further down the road," Goss said. "I'm very disappointed. In my heart, I don't believe that blanket withdrawal of this scientific endeavor is the most productive decision to be made."

Goss and others said that even if it turns out Celebrex and similar drugs do increase the risk of heart attacks and strokes, many patients may be willing to take that risk to cut their chances of getting cancer, especially if it runs in their families.

"For women with a very high risk of breast cancer, if there is an opportunity for them to benefit, it may strongly outweigh a cardiovascular risk," Goss said.

Other researchers agreed, saying what might emerge is a more targeted use of these drugs only for those at low risk for heart disease and high risk for other diseases.

"I hope what's going to emerge from this is that we're going to understand risk and benefits more clearly and quantify them more explicitly," said Bernard Levin of the M.D. Anderson Cancer Center.

Maligned drugs not dead yet
Elias A. Zerhouni, director of the National Institutes of Health, defended the NIH's actions, saying even a hint of risk warranted discontinuing the Alzheimer's trial because it involved healthy people. "You have to err on the side of doing no harm," he said.

But Zerhouni agreed that once the risk is better understood, it could turn out that the drugs or others like them could still be useful, either for selected patients or by taking countermeasures.

"We shouldn't shy away from this class of drugs because of Vioxx. If you can demonstrate a benefit that is non-zero, then you have to evaluate risk versus benefit," Zerhouni said. "The inflammation theory is a very valid and strong mechanistic approach."

Several researchers noted that evidence has continued to mount that cholesterol-lowering statin drugs cut the risk for heart attacks in part through their anti-inflammatory effects. Some evidence has suggested they, too, may reduce the risk for cancer.

Part of the problem for drugs such as Vioxx and Celebrex is that companies are focused on developing drugs that can be marketed to large numbers of patients, said Carl F. Nathan of the Weill Medical College of Cornell University in Ithaca, N.Y.

"We have to stop demanding that every drug be a blockbuster," Nathan said. "What we have to go back to is smaller markets for individual drugs. We have to take good drugs and market them conservatively and increase our knowledge of the settings where the risk-benefit ratio is best."

Other researchers said they were pessimistic that drugs such as Celebrex would ever reemerge as major players for disease prevention, but the underlying concept remains highly promising. As a result, the focus is likely to shift to developing drugs without the negative side effects.

"I'm really cautious now. Anything we come up with, we'll have to evaluate carefully after this," DuBois said. "There are other ways to attack this pathway, and there are other agents in early development. I think now they could be moved up now. We'll have to see what new drugs might pop out from people looking at this in a different way."