Surprising new findings about pain relievers taken by 'everyone on the planet'

In 2004, when drugmaker Merck voluntarily pulled the pain-reliever Vioxx off the market amid evidence that it increased the risk of heart attacks, concern naturally turned to its nearly identical rival, Celebrex.

The medication works the same way, by inhibiting production of an enzyme that causes pain and inflammation - as do naproxen, ibuprofen and others in the class of widely used analgesics known as non-steroidal anti-inflammatory drugs (NSAIDS).

Now the first large-scale study of the three drugs finds that Celebrex poses no greater risk of heart attack, stroke, other cardiovascular problems or death than naproxen or ibuprofen. More surprisingly, says Steven E. Nissen of the Cleveland Clinic, who led the nearly decade-long international research, there is evidence that Celebrex is less likely than the other two to cause kidney and gastrointestinal problems associated with NSAIDS.

"Do I think there's a difference between these three drugs?" Nissen asked. "The answer is yes."

That statement may be more controversial than it sounds, because so many people take NSAIDS by prescription and via over-the-counter products such as Advil and Motrin. "Everyone on the planet takes these drugs," he said.

In the United States, about 70 percent of people ages 65 and older take NSAIDS once a week, with half of them taking at least seven doses each week, according to a 2013 study in the American Journal of Managed Care. More than 100 million prescriptions are written for the drugs each year in this country.

But Nissen and other experts were quick to point out that the new findings are not easily applied to people using over-the-counter pain relief. The more than 24,000 participants in the study all had painful arthritis and elevated risk for cardiovascular problems. More importantly, they were given significantly higher doses of the three drugs than are found in over-the-counter versions.

Nevertheless, the results may cause some people to reconsider NSAID pain relievers, especially those who take them frequently and in doses larger than the amounts recommended in over-the-counter formulations, Nissen said.

"If you have pain that is sufficiently severe that you need these drugs to function, you should weigh the benefits of relieving pain versus the potential hazards," he said. He and others said that users should take the lowest possible dose for the shortest possible time to avoid side effects.

The study had a number of shortcomings. More than 27 percent of the participants left the trial before researchers could determine whether they had suffered any side effect, and more than 68 percent at some point discontinued their use of celecoxib, the generic version of Celebrex that was tested.

Both developments are to be expected in research that involves people in pain, but the proportions are very large, said Colin Baigent, director of the Medical Research Council population health research unit at England's Oxford University.

In addition, Baigent said, the daily 200-milligram dose of celecoxib given to participants because of some countries' health regulations is lower than the amount many people in other studies have received - which would tend to limit cardiovascular side effects. Previous research has shown that complications increase along with dosage, he said.

Yet Baigent and Carlo Patrono, a professor of pharmacology at the Catholic University School of Medicine in Rome, said the study confirms conclusions they reached in an analysis of previous research and adds some significant new data. "It does not provide any surprises," Patrono said.

The study, which was mandated by the Food and Drug Administration after Vioxx's withdrawal, was released Sunday at a meeting of the American Heart Association and in the New England Journal of Medicine. It was funded by Pfizer, which makes Celebrex and other NSAIDs, but numerous precautions were taken to preserve the researchers' independence, Nissen said.

An FDA spokeswoman said the agency would not comment on the results. Milton Pressler, vice president and head of clinical affairs for Pfizer, said the company is "pleased to have these results after many years" of waiting for the trial to conclude.

The company also makes the Advil brand of over-the-counter ibuprofen, but Pressler said the results cannot be applied to that product because of the study's much higher doses of ibuprofen, which were given for an average of 20 months.

Similarly, Johnson & Johnson, which makes Motrin, said in a statement that "the study evaluated ibuprofen at doses and duration greater than the over-the-counter Motrin products sold in the U.S. ... Consumers should always read and follow the label and talk to their health care professional if they have questions or health concerns."

The research looked at 24,081 people with osteoarthritis or rheumatoid arthritis at 926 medical centers in 13 countries between 2006 and 2014. About a third were given 100 milligrams of celecoxib twice a day, a third took 600 milligrams of ibuprofen three times a day and the rest took 375 milligrams of naproxen twice a day. Some patients with rheumatoid arthritis received higher doses. All had risks such as previous heart attacks or diabetes.

Patients on celecoxib fared no worse than those taking naproxen or ibuprofen when most cardiovascular complications were tallied. And they suffered significantly fewer serious kidney problems and hospitalizations for hypertension than those taking ibuprofen. They also experienced fewer gastrointestinal complications than patients in the other two groups.