As reported by The Hartford Courant, December 28, 2004.

Painful Predicament

By William Hathaway

As doctors and patients grow increasingly leery of the safety of prescription pain relievers and look for alternatives, experts say they need to bear in mind the downside of taking cheaper, over-the-counter medications.

People in pain who are concerned about the safety of drugs such as the Cox-2 inhibitors Vioxx, Bextra and Celebrex should not begin to gulp down aspirin and ibuprofen, which cause tens of thousands of deaths and hospitalizations annually from gastrointestinal complications, they say.

"We need to remember why [Cox-2 inhibitors] were invented in the first place," said Dr. Jay Goldstein, a professor of medicine at the University of Illinois at Chicago and a national expert on nonsteroidal anti-inflammatory drugs, or NSAIDs.

The story of Cox-2 inhibitors, which were designed to minimize stomach ailments caused by most pain relievers but have recently been implicated in the development of heart disease, is a reminder that all drugs - including those available without a prescription - carry risks.

NSAIDs are the most widely used family of drugs in the United States. They are very effective at reducing mild pain, and one - aspirin - has been shown to help prevent heart disease. The drugs are generally safe, but all have a well-known side effect: They increase the risk of gastrointestinal bleeding.

People who regularly take traditional NSAIDs have about three times the risk of developing bleeding ulcers as people who don't take the drugs. By one estimate, 16,000 Americans die and 100,000 are hospitalized each year because of gastrointestinal bleeding caused by traditional NSAIDs such as ibuprofen. A decade ago, before the advent of Cox-2 inhibitors, the leading cause of death in women over 65 in the United Kingdom was bleeding from aspirin-related ulcers, said Dr. Joel Levine, professor of medicine and director of the colon cancer center at the University of Connecticut Health Center.

The risks of gastrointestinal problems among NSAID users are highest for people over 65, people who have a history of ulcers, those who take the drugs in high doses, and people who take anti-coagulants or steroids such as prednisone or cortisone.

Those problems spurred drug companies to develop Cox-2 inhibitors in the 1990s. They found that by selectively blocking the enzyme Cox-2, which is associated with inflammation, they could retain the pain relief of NSAIDs and reduce the risk of bleeding.

The new drugs cut the rate of gastrointestinal problems caused by pain relievers in half, Goldstein said.

But in the past three months, it has been reported that Cox-2 inhibitors and naproxen - which is sold in prescription form and over-the-counter as Aleve - may increase the risk of heart attacks and strokes. And that has many people rethinking pain-relief strategies.

Some doctors say they worry that their patients will simply reach for aspirin or ibuprofen.

"I am concerned that we may see more cases of gastrointestinal bleeding than we have been seeing," said Dr. Ted Loewenthal, medical director of the gastrointestinal endoscopy unit at Hartford Hospital.

"In a practical way, most folks over 60 will not become regular NSAID users," Levine said. "Any reversion to that position is looking for trouble. That song has already been written."

So what are people who experience persistent pain supposed to do?

In some cases they should continue to take Cox-2 inhibitors like Celebrex, which unlike Vioxx has not been removed from the market. Arthritis patients with ulcers are still good candidates for Cox-2 inhibitors, said Dr. William White, chief of the division of hypertension and clinical pharmacology at the UConn Health Center.

"We cannot remove these drugs from the market," White said. "These people will be in serious, serious trouble, because there isn't anything else."

However, most doctors agree that, pending more study, Cox-2 inhibitors should not be prescribed to people with heart disease or at risk of heart disease.

One alternative to Cox-2 inhibitors and NSAIDs is acetaminophen (Tylenol), said Dr. Ralph Stocker, staff rheumatologist at Hartford Hospital. Acetaminophen in general is not as good at relieving pain, he said, but it does not cause the gastrointestinal problems that NSAIDs do.

Another option is the use of acid-reduction medicines, called proton pump inhibitors, in conjunction with NSAIDs, to help minimize stomach problems, Stocker said.

Public confusion about pain relievers shows that much more research needs to be done on the health effects of a combination of medicines, including low-dose aspirin, which many people take to prevent heart disease, experts say.

But Stocker and most doctors also say that medicines will always carry risks, because of the tremendous variation in how individuals respond to drugs. All medications will sometimes make somebody sick. Finding out which people will respond positively and negatively to certain drugs is the job for the next generation of researchers, they add.

"What we need now are tools to know who are good candidates for this medication and who can't tolerate them," Loewenthal said.