Pain Drugs

The first sign of trouble came last fall when a large trial involving the popular pain-killer Vioxx was halted two months early because some patients had developed serious heart problems. The results were so disturbing that Merck, which manufactures Vioxx, pulled its billion-dollar blockbuster off the market.

That left two drugs in the same family, Pfizer’s Celebrex and Bextra, on pharmacy shelves, along with lingering questions about whether they too could cause heart attacks and strokes.

Those concerns were answered last week by a series of studies that showed an increased risk of heart problems in users of not just Vioxx but Celebrex and Bextra as well, and by FDA advisory panels that recommended stronger warnings for the whole class of pain relievers known as COX-2 inhibitors. “The cardiovascular problems appear to be a class effect,” says Dr. Eric Topol, director of cardiovascular medicine at the Cleveland Clinic. “But the magnitude of risk does seem to differ from drug to drug.” It’s now up to the FDA to decide whether the dangers, which in some drugs start to appear only at high doses, warrant its strongest, black-box warning, which would halt direct-to- consumer advertising and restrict use of the drugs to patients with the greatest medical need.

The findings–which confirmed what many scientists have long suspected but that drug companies desperately tried to deny–make sense, given the way that the drugs work. COX-2 inhibitors were designed to bypass the side effects of aspirin and other nonsteroidal anti-inflammatory agents, which can rip through the stomach lining. In the 1990s, researchers discovered that COX appears in the body in two different forms. COX-2 inhibitors, as their name implies, were designed to block just the inflammatory functions of the COX-2 enzyme, leaving the stomach-protecting functions of the COX-1 form intact.

Or so scientists thought. Animal studies suggest that COX-2 also promotes chemical reactions that churn out prostacyclin, a protein that keeps blood vessels dilated and keeps platelets from clumping together to form blood clots. Doctors believe a drop in prostacyclin may also be behind the increased incidence of heart attacks and strokes in COX-2 users. In separate studies published in the New England Journal of Medicine last week, researchers found that high-dose Celebrex users were three times as likely as nonusers to die from a heart or stroke event, while those taking Vioxx had twice the chance of suffering a heart attack or stroke. It’s too early to say whether these studies mean one drug is more dangerous than another.

The FDA will be looking closely for similar risks when the next three COX-2 inhibitors in the pipeline–Merck’s Arcoxia, Pfizer’s Dynastat and Novartis’ Prexige–come up for review in a few years. This time they hope to discover potential problems before the drugs are approved, not after. –By Alice Park