WASHINGTON — Doctors are bracing for a flood of confused patients after sales of the popular arthritis drug Bextra were halted and the government ordered tougher warning labels on other nonnarcotic prescription painkillers yesterday.

The issue: whether anti-inflammatory medicines called NSAIDs or Cox-2 inhibitors — the backbone of U.S. pain treatment — increase the risk of heart attacks, strokes and stomach bleeding, particularly when taken at high doses or for long periods of time.

Pfizer reluctantly pulled its blockbuster Bextra off U.S. and European markets at the behest of the Food and Drug Administration (FDA), which also ordered its toughest warning about cardiovascular risks on 19 competitors, from Celebrex to Mobic to high-dose naproxen.

The warnings don't say which drug is safer. The FDA insists there's not enough research to rank them, although many drug specialists caution that there are indeed differences — and that some older standbys, such as naproxen, shouldn't be causing new concern.

The FDA also will strengthen warnings on over-the-counter NSAIDs — naproxen, ketoprofen and versions of ibuprofen such as Motrin and Advil, which consumers have long popped like candy. The warnings will note that the pills are for short-term use at low doses to avoid their prescription competitors' risks.

For millions of pain sufferers, especially people with chronic arthritis, the FDA action was the latest twist in six months of misfortune that began with Merck's withdrawal of the popular painkiller Vioxx. Drugs such as Vioxx, Celebrex and Bextra, hailed not long ago as near-miracle therapies, now are either gone or under a cloud, along with dozens of other anti-inflammatory drugs.

In a statement, New York-based Pfizer said it disagreed with the FDA's finding on Bextra, and the company promised to explore ways to return the drug to the market. "For now, patients should stop taking Bextra and contact their physicians about appropriate treatment options," the company said.

The withdrawal of Bextra, which had sales of $1.4 billion last year, leaves Pfizer's Celebrex as the only Cox-2 inhibitor on the market. The FDA, however, wants a tough new alert known as a "black box" warning added to that drug's labeling. It would warn consumers of Celebrex's link to heart attacks and strokes.

Similar cautions apply to the entire family of NSAIDs, prescription and nonprescription, said Dr. Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research. "All of these drugs should be used in the lowest-effective dose that works for that patient for the shortest period of time."

FDA officials said they asked drug companies to comply voluntarily to avoid lengthy legal wrangling. Drug companies seldom contest FDA actions on issues of public safety.

FDA officials said their actions yesterday were consistent with the recommendations of an advisory panel that met in February to consider the future of the Cox-2 variants. The panel voted 31-1 to keep Celebrex on the market but was split on Vioxx (17-15) and Bextra (17-13 with two abstaining).

The panel concluded that Vioxx posed the greatest heart risks among the Cox-2s while Celebrex appeared to pose the least risk. The reported advantage of Cox-2s over traditional painkillers has been that they're easier on the stomach.

Galson said life-threatening skin reactions were more common with Bextra than with Celebrex. In addition, "there isn't a demonstrated advantage [with Bextra] compared to the other [pain relievers]. So no added advantage and a special risk is what led us to the change with Bextra," Galson said.

The FDA moves brought mixed reviews.

Dr. Bruce Psaty, a University of Washington pharmacology professor and frequent FDA critic, said the agency "has done a good job of trying to clarify things for people ... of taking the available information, using the recommendations of the advisory committees, and, in this instance, taking regulatory action that makes sense."

The agency's decision to remove Bextra but keep Celebrex on the market with stronger labeling requirements was "enormously rational," considering that many people need a painkiller that's easier on the stomach than traditional ones, said Dr. Brian Strom, chairman of the Department of Biostatistics and Epidemiology at the University of Pennsylvania School of Medicine.

Consumer-advocate Jeannine Kenney, senior policy analyst for Consumers Union, was less impressed.

"Consumers shouldn't have to wait until millions of Americans are put at risk before the FDA takes action," Kenney said. "The FDA badly needs reform of its reactive, passive drug-safety system into one which proactively investigates safety concerns and takes action before Americans are harmed."

With Bextra's removal from the market and requirements for serious warnings on all other medications in the class, the agency will significantly affect the lives of tens of millions of patients. The only major nonnarcotic painkillers not included in the warning are aspirin and acetaminophen (widely sold as Tylenol), which are not NSAIDs but carry risks of their own.

The speed at which the field of arthritis pain treatment has been transformed left many patients confused and dismayed.

"I don't think that anyone imagined we would be sitting here in April with Vioxx and Bextra gone, with a black-box warning for Celebrex and talking about the safety of NSAIDs that have been used for decades," said John Klippel, president of the Arthritis Foundation.

Klippel said the foundation, which believes authorities sometimes have undervalued the benefits of the painkillers, is emphasizing lifestyle changes, injectable medications and some food supplements for arthritis sufferers worried about doing without the pills that gave them relief.

Compiled from The Associated Press, Knight Ridder Newspapers and The Washington Post.