hen Merck pulled its blockbuster painkiller, Vioxx, from the market on Sept. 30, 2004, after a large clinical trial provided evidence that the drug increased the risk of heart attack and stroke, the move cast doubts on the safety of similar Cox-2-specific inhibitors, including Pfizer's Celebrex and Bextra, Prexige, which is manufactured by Novartis, and another Merck drug, Arcoxia. In February, a panel of experts advising the US Food and Drug Administration aired those doubts, but voted against banning Celebrex, Bextra, or Vioxx. Regardless, some scientists worry that the shadow of risk could hamper future research on the entire class. "In light of the Vioxx withdrawal and the public outcry, I expect there will be fewer dollars available to do the research that we need to do to find out how these--and other--drugs work," says Matt Breyer, professor of medicine at Vanderbilt University, adding that Vioxx's cancer-prevention and disease-fighting benefits should continue to be researched.

Clinical results of the aborted Adenomatous Polyp Prevention of Vioxx (APPROVe) trial have not yet been published. But many are still interested in discovering whether Vioxx does fight cancer, something seen as overwhelmingly positive.

Many researchers worry that other studies looking for beneficial side effects from Cox-2 inhibitors might get shut down as well. Some already have. In late December of 2004, the National Cancer Institute (NCI) halted a 2000-patient test of Celebrex's efficacy in stopping the growth of colon polyps. NCI said it had reviewed the pattern of cardiovascular events in the trial, after hearing of the Vioxx withdrawal, and determined a 2.5-fold rise in heart attacks and strokes for patients taking 400 mg daily and a 3.5-fold increase in those taking 800 mg daily.

Another trial, testing Celebrex and naproxen on Alzheimer patients, was also halted. Some other trials are still going forward, albeit with heightened oversight and more stringent patient consent forms.

Janet Woodcock, acting deputy commissioner of the FDA, says that the agency will need to be more careful about approving drugs like Arcoxia and Prexige, which are currently approved in parts of Europe. But she echoed the February panel's assertion that some risk is acceptable. "As far as we're concerned, we understand there are trade-offs with any given drug," she says.

Eric Topol, chairman of cardiovascular medicine at the Cleveland Clinic and a vehement critic of Merck's and the FDA's handling of Vioxx, says that more prudent use of the painkillers could become standardized. "The future I foresee is one where you do a one-time screen of the patient, to determine likelihood of particular diseases... and then plan a treatment taking into account those predispositions. If you have risk for colon cancer, say, but low risk for heart disease, a Cox-2 inhibitor might still be a good drug for you."

That future appears a long way off, however. "There's been very little research into linking drug therapy and genomics," says Tony Yaksh, vice chairman for research in the Department of Anesthesiology at the University of California, San Diego. "And as for Vioxx and Celebrex, there have been no studies at all."

Yaksh says one study should be undertaken immediately: Find all the patients who have taken Vioxx or another Cox-2 drug for a long period of time and compare the gene sequences of those who had thrombotic events with those who did not. "That's how you come up with the chromosomal maps we need to take this to the next stage," he says.

Victor Schuster, chairman of medicine at Montefiore Medical Center and Albert Einstein College of Medicine, agrees. "Merck's got the blood samples. The tests are do-able, and the results would give us insights into the mechanisms. You could do SNP [single nucleotide polymorphism] analysis and find the correlations. That would be a good entry point to investigating the higher incidence of cardiovascular events and deciding what to do about it."