A large study has produced reassuring evidence about a drug that millions of people use to alleviate pain from arthritis and other ailments.
The study found no evidence that the drug Celebrex, or generically, celecoxib, poses any greater risk for causing heart attacks and strokes than two other widely used pain relievers.
Doctors have been concerned about Celebrex for more than a decade because it is very similar to another pain reliever, Vioxx, which was pulled from the market in 2004 after being linked to heart attacks and strokes.
Celebrex "didn't share the risks that were seen with Vioxx," says Nissen, whose findings were also published online by the New England Journal of Medicine.
Nissen and other heart specialists cautioned that Celebrex can increase the chance of cardiovascular complications. But it doesn't appear to boost those odds nearly as much as Vioxx, or even as much as other painkillers thought to be safer. Both Vioxx and Celebrex are so-called Cox-2 inhibitors, which act by blocking an enzyme involved in inflammation.
Moreover, the study suggests Celebrex may be less risky than other so-called nonsteroidal anti-inflammatory drugs, or NSAIDs, in other ways. For example, Celebrex appears to pose less of a risk of causing kidney problems.
"It is very reassuring," says Milton Packer, a cardiologist at Baylor University who was not involved in the study. "I think what we'll see is a greater confidence in the use of drugs like Celebrex. I think people will turn to it now more frequently."
But others cautioned that all the drugs tested remain risky, especially for people with heart disease. "It's reassuring that it's not as bad as Vioxx, but it's not a recommendation to take the medication," says Dr. Mary Norine Walsh, the president-elect of the American College of Cardiology.
After Vioxx came on the market in 1999, it quickly became a blockbuster used by millions of people because it was designed to cause fewer gastrointestinal complications than existing NSAIDs.
The Food and Drug Administration allowed continued sales of Celebrex even though it was very similar. But the agency ordered Pfizer Inc., the company marketing Celebrex, to study the drug's safety. In 2005, however, Pfizer withdrew Bextra, another Cox-2 inhibitor, at the FDA's request.
Celebrex is used by an estimated 2 million Americans each year for arthritis, menstrual cramps and other aches and pains.
The new study involved 24,081 patients with osteoarthritis or rheumatoid arthritis. One-third of the patients took Celebrex. One-third took prescription doses of ibuprofen. The remaining third took prescription naproxen.
Ibuprofen is sold over the counter in much lower doses as a generic and under a variety of brand names, including Advil and Motrin. Naproxen, also generic, is sold over the counter with various names, like Aleve and Naprosyn.
Higher, prescription doses of ibuprofen and naproxen were more likely than Celebrex to cause digestive system problems, such as ulcers and bleeding, the researchers found.
Specifically, naproxen had a 1.5 percent risk of gastrointestinal complications, ibuprofen had a 1.6 percent risk, and Celebrex had a 1.1 percent risk in a 30-month period.
That wasn't a surprise. Celebrex and Vioxx were designed to be easier on the digestive system than the existing NSAIDs. But some other risks were surprising, Nissen says.
Compared with Celebrex, patients taking ibuprofen were more likely to experience kidney problems, including kidney failure and the need for dialysis.
Specifically, there was a 1.1 percent risk of kidney complications among those taking ibuprofen for 30 months, versus a 0.7 percent risk among those taking Celebrex and a 0.9 percent risk among those taking naproxen, the researchers report.
All these drugs are known to carry some risks to kidney function, but the risk from ibuprofen was higher than expected, Nissen says.
There was also a hint that naproxen and ibuprofen may pose more of a risk of causing cardiovascular complications that Celebrex. Nissen stresses, however, that that finding was only borderline-statistically significant for ibuprofen.
In addition, there was an even weaker hint that naproxen might increase the risk for death for any reason, compared with Celebrex. But that wasn't statistically significant either.
It means those risks could have been statistical flukes. But they do warrant further investigation, he says.
"What is so surprising about it is that most authorities have believed that if there was a drug that was the safest, it was naproxen," Nissen says. "So we were pretty surprised that there was this borderline significant increase in all-cause mortality with naproxen."
Celebrex turned out to be the least likely of the three drugs to increase the risk for cardiovascular complications. The risk of dying, suffering a stroke or having a heart attack among patients taking Celebrex was 2.3 percent during a 30-month period, compared to 2.5 percent for naproxen and 2.7 percent for ibuprofen.
Nissen stresses that all the patients in the study took doses of these drugs available in the prescription formulation — not the much lower doses most people take when they buy them without a prescription and use them occasionally.
The maximum recommended over-the-counter dose of ibuprofen is typically 1,200 milligrams daily. The study used 600 milligrams of ibuprofen three times a day, or 1,800 milligrams daily. Naproxen tablets are sold over the counter at a dose of 220 milligrams, and are taken twice a day. The study used doses between 375 and 500 milligrams taken twice a day.
"I don't want the public to think that if you take an occasional ibuprofen or naproxen that you're going to have kidney failure or you're going to die," Nissen says. "We didn't study that. We studied daily doses in arthritis patients [taking] ... high doses of these drugs."
But the findings should encourage people who need pain relief to take the lowest dose of the drugs for the shortest time possible.
"If you twist your knee and you hurt, I want people to take medicines for pain relief," Nissen says. "But when they're better, try to get off the drugs and not take them every day and not take them in very high doses."
Other doctors agreed.
"There's probably a risk of all of these drugs, especially at high doses," Packer says. "The question is: If you need these drugs for pain, which is the safest? Right now, based on this study, it appears Celebrex has advantages."
Several experts pointed out that the study has some flaws. The dose of Celebrex tested was relatively low, for example, and a significant number of subjects dropped out of the study, which raises questions about the reliability of the findings.
DAVID GREENE, HOST:
Today In Your Health - trying to prevent peanut allergies. We'll get to that in a moment. But first, some news this morning about the safety of prescription painkilling drugs that are used by millions of people. NPR health correspondent Rob Stein joins us with the details. Hey, Rob.
ROB STEIN, BYLINE: Dave
GREENE: So what is this new research, and how worried should we be?
STEIN: So we're talking about three drugs here, and they were examined as part of a large study that was released late yesterday. Now, the focus of the study was a drug known as celecoxib. Now, some people might recognize the brand name that was originally used to sell this drug - Celebrex.
GREENE: Painkiller, right?
STEIN: It's a painkiller. It's a prescription painkiller. And people have been worried about this drug for more than a decade. And the reason is it's very similar to another drug known as Vioxx.
GREENE: Which made a lot of news.
STEIN: Yeah. That was a huge, blockbuster painkiller that came in the market. And then it was pulled off the market because doctors discovered it could sharply increase the risk for heart attacks and strokes. So ever since then, doctors have been worried about Celebrex. Is it another Vioxx or not? So the FDA let the drug stay on the market but only with the condition that researchers study it to determine how safe it might be.
GREENE: OK, so the FDA wanted Celebrex to be studied. Is that the news that we got yesterday - the study's done?
STEIN: Yeah, absolutely. They finally have the results. And this study involved more than 24,000 arthritis patients and took more than a decade to complete.
STEIN: One-third of the patients took Celebrex every day for at least more than a year. And the researchers compared them to patients who were either taking prescription doses of ibuprofen - you know, people might recognize that as Advil or Motrin - or prescription doses of another drug known as naproxen, which people might recognize as Aleve.
GREENE: Over the counter, yeah.
STEIN: Right. And when they took a look at it after analyzing all the data, they realized that, no, Celebrex is no Vioxx. It doesn't have the sharply increased risk for heart attacks and strokes that Vioxx does. Now, that doesn't mean it's completely safe. All of these drugs do have some risk for increasing the chances of having a heart attack and stroke. It just looks like Celebrex is no worse than these other drugs.
GREENE: OK, so I ask you how worried we should be. It sounds like we shouldn't be that worried, that Celebrex is safe. Is that what they're saying?
STEIN: Well, they're saying it's not as dangerous as we feared it might be. And all these drugs do carry some risks. And when they look further at some of the other side effects that are associated with these drugs, they continue to find some differences. For example, they found that Celebrex was less likely to cause complications to the stomach, like bleeding or ulcers in the digestive system that - compared to ibuprofen or compared to naproxen.
And they also found that ibuprofen was more likely to cause kidney problems that could become kind of serious in some cases, like, even kidney failure or the need for kidney dialysis. And there was also a hint - and I really have to emphasize a hint - that naproxen and ibuprofen may be a little bit more likely to cause heart problems than Celebrex and even a slighter hint that Celebrex may be less likely to cause overall death compared to naproxen.
Now, it's really important to note that these were just really hints, and they weren't statistically significant or were only borderline statistically significant. So they're really just sort of food for thought that researchers follow up to see whether or not they're real or not.
GREENE: So, Rob, I mean, the take-home here, it's sounding like, is if you're taking any of these painkillers, just some questions out there. Talk to your doctor. Be careful.
STEIN: Absolutely, talk to your doctor. And it's important to note that this study was not perfect. They did have some flaws. There were some questions about the low dose of Celebrex that was used, and a lot of patients dropped out, which always raises questions about the reliability. But the take-home message - advice I'm hearing from experts is, if you have to take these drugs, take them for the shortest period of time at the lowest dose, and talk to your doctor first to try and decide which drug to take.
GREENE: And we're talking about all of them here - the naproxen, the ibuprofen and the Celebrex.
STEIN: All of them. All of them have some risks.
GREENE: OK. That's NPR health correspondent Rob Stein. Rob, thanks.
STEIN: Sure. Nice to be here. Transcript provided by NPR, Copyright NPR.