Aspirin Without Ulcers

By Christine Gorman

Some days the arthritis pain would get so bad that Sylvia Zebroski, 51, of Stamford, Conn., couldn't sleep. Aspirin worked for a while, but then she developed stabbing pains in her stomach. She switched to naproxen, which, like aspirin, is a so-called nonsteroidal anti-inflammatory drug, or NSAID. Same story. "I took myself off naproxen and went to my doctor in tears," she recalls. He put her on a new experimental drug, and this time, no arthritis pain--and no stomach pain. Says Zebroski: "It's made all the difference in the world."

The drug that changed Zebroski's life is just one of a new class of medications that could radically alter the way in which pain is treated in the U.S. Each year 7,600 Americans die from internal bleeding caused by long-term use of NSAIDs. The new drugs, called COX-2 inhibitors, relieve pain just about as well as aspirin and its cousins but seem to have no serious side effects. With visions of $5 billion or more in potential sales over the first five years, drug companies are racing to get their own versions of these superaspirins to market first--a race that Monsanto's Celebra is likely to win. If approved by the FDA, Celebra could be available as early as next year.

Just in time too. The recall two weeks ago of Duract, a potent painkiller that also killed a number of patients by causing liver failure, shows just how hard it is to develop an analgesic that's both effective and safe. But the demand for new pain medications is growing. Baby boomers are just starting to hit their arthritis-prone 50s. While the disorder currently afflicts 40 million Americans, the number could reach 60 million in the next two decades.

The new drugs work pretty much the way the old ones do. Aspirin and other NSAIDs block production of substances called prostaglandins, which are among the most versatile molecules in the body. Among other things, prostaglandins trigger uterine contractions during birth; generate a layer of mucus that protects the stomach from its acids; and cause blood particles called platelets to form clots--a mixed blessing, since the clots that help a wound heal can also lead to a heart attack.

But prostaglandins trigger pain and inflammation, and when the body is injured or irritated--as it is in arthritic joints--they are released in huge quantities. That's why arthritis is accompanied by stiffness, swelling and pain.

In the 1970s, researchers discovered that aspirin reduces that pain and inflammation by lowering prostaglandin levels. It does so by blocking an enzyme called cyclooxygenase, or COX, that's involved in the manufacture of prostaglandins. What scientists didn't know until the early 1990s, however, was that cyclooxygenase comes in at least two versions: COX-1, ultimately responsible for protecting the stomach and making platelets sticky; and COX-2, which triggers pain and inflammation. The obvious goal, at least as far as pain relief is concerned: develop a drug that blocks COX-2 and not COX-1.

COX-2 inhibitors may not just control pain; they may also one day prevent some types of cancer. Researchers have learned that malignant cells in the intestines manufacture COX-2 enzymes to accelerate their growth. (That may help explain why consuming fruits and vegetables, which block COX-2 enzymes naturally, seems to protect against colon cancer.) Clinical trials are under way in England to see if superaspirins can prevent colon cancer. Other scientists, meanwhile, have determined that COX-2 inhibitors could conceivably lessen some of the brain damage in Alzheimer's disease.

Is there anything superaspirins can't do? Unfortunately, COX-2 inhibitors, unlike aspirin, have little or no effect on heart disease, since it's the COX-1 enzymes that cause blood clotting. But so far, no one knows how to block the COX-1 enzymes in the bloodstream without also affecting the ones that help protect the stomach.

And there's always a possibility that superaspirins could provoke some unforeseen side effects. Although clinical trials haven't yet revealed any problems, in many ways the real experiment doesn't begin until doctors start writing prescriptions for hundreds of thousands of people. The trouble with Duract, for example, showed up only after patients took the painkiller for several weeks--much longer than most subjects in the clinical trial. Researchers don't expect the same sort of trouble from COX-2 inhibitors. But they won't know for sure until long after the first million arthritis sufferers reach for a bottle.

--Reported by Alice Park/New York and Dick Thompson/Washington

With reporting by Alice Park/New York and Dick Thompson/Washington