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Two-Drug Combo May Best Replace Bextra Vioxx

Non-cox-2 painkiller plus an acid-reducer is safer and cheaper, study finds

FRIDAY, April 15, 2005 (HealthDay News) -- In the post-Bextra, post-Vioxx age, how can arthritis patients get effective pain relief while protecting their hearts and stomachs from dangerous side effects?

The answer may have arrived in a major new study, which used computer models to determine that a combination of two drugs -- a non-cox-2 pain reliever like Aleve, Advil or Motrin and a gastro-protective medicine like Prilosec or Nexium -- may be the best solution for a majority of arthritis patients.

In fact, it may have always been the best solution, some experts say.

"For years I've been advocating a 'back to the future' combination of these two old and safe drugs," said Dr. Mark Fendrick, a long-time expert on these issues and a professor of internal medicine at the University of Michigan, Ann Arbor.

Although not involved in the current study, Fendrick agreed that, for the vast majority of patients, a traditional non-steroidal anti-inflammatory drug (NSAID) plus one of the newer generation of acid-reducers, called proton pump inhibitors (PPIs), is the safest, most effective way of easing joint pain while sparing the heart and stomach.

The furor over the cox-2 subclass of NSAID drugs began last September, when Vioxx was pulled from the market after studies linked its long-term use to increased cardiovascular risk. Then, last week, another cox-2, Bextra, was pulled because of similar fears, as well as evidence of increased risks for a rare but potentially fatal skin reaction.

The U.S. Food and Drug Administration has allowed a third cox-2, Celebrex, to remain on the market, albeit with tough labels warning of possible cardiovascular risk. And in its order April 7, the agency also mandated black-box warnings on all similar prescription drugs and labeling changes for similar over-the-counter drugs.

Bextra's demise brought up the same question, however: What now for cox-2 users?

Reporting in the April 15 issue of Arthritis Care & Research, a team led by Dr. Brennan Spiegel, of the David Geffen School of Medicine at the University of California, Los Angeles, may have provided an answer.

The study used complex computer modeling to estimate the one-year costs, both in terms of patient health outcomes and financial expenditure, of three standard treatments for chronic arthritis pain in a hypothetical group of 60-year-old patients. Those treatments included a cox-2 inhibitor drug alone; a traditional NSAID alone; or an NSAID plus a PPI drug, used to prevent the gastrointestinal damage common to all NSAIDs.

Reflecting current medical practice, all of the "patients" in the hypothetical model were also taking a heart-healthy daily aspirin.

"What we found is that, under every circumstance that we could imagine, there was no health-economic benefit to using the cox-2 inhibitors, at all," Spiegel said.

While cox-2s did reduce arthritic pain, the costs linked to their use rose considerably when researchers factored in an increased incidence of heart attacks and strokes. And while Vioxx, Bextra and Celebrex are somewhat safer on the stomach than traditional NSAIDs, they still convey some risk in that area, too.

"The most frequent thing that happens is dyspepsia -- nuisance symptoms like belly aches," Spiegel said. "Belly aches themselves cost money, and that's another reason we see quite a big difference in cost. That really hadn't been looked at before."

Use of pain-relieving traditional NSAIDs alone still left users with these added gastro risks, however, so the best therapy seems to be combining an over-the-counter NSAID like Aleve, Motrin or Advil (the latter two contain ibuprofen) with a stomach-quelling PPI like Nexium, Prevacid or Prilosec.

The study was funded by Tap Pharmaceuticals, the makers of Prevacid, but Spiegel said his team worked hard to fight any potential bias that would favor PPIs.

"We actually went through a lot of steps to try and make it as hard as possible for the PPI strategy to look good," he said. "But, like the phoenix rising from the ashes, it still came out looking good."

Spiegel advocates using any of the PPIs, in fact: "They're all the same, as far as I'm concerned. I say go with the cheapest."

He stressed that, unlike cox-2s, there's a wealth of long-term safety data on these drugs, which work by shutting down acid production in the stomach. "In general they are extremely safe," he said.

Fendrick said the study more or less validates what he's been saying for years. He believes that, for most patients, the combination of naproxen (Aleve) with a PPI may be best. That's because -- as in the Michigan model -- the majority of older patients requiring chronic pain relief are also taking daily aspirin to fight cardiovascular disease.

"If you take ibuprofen and aspirin at the same time, however, ibuprofen blocks aspirin's protective effect on the heart," he pointed out. That's why non-ibuprofen Aleve may be safer for aspirin users, as opposed to other common NSAID pain relievers such as Advil or Motrin, which contain ibuprofen.

Fendrick believes that only a small fraction of pain sufferers -- those with a very high risk for gastrointestinal bleeding -- should turn to Celebrex. "That's probably only about 10 percent of the market," he said.

He also stressed that "there's no one-size-fits-all" solution for patients, and that patients should make their decision in consultation with their doctor, based on their specific risk-benefit profile.

According to Spiegel, since traditional NSAIDs and cox-2 drugs "are equal in effectiveness" in terms of easing pain for the vast majority of arthritis sufferers, it only makes sense to go with the safest, cheapest option.

Of course, all of this begs the question of whether it was necessary for the FDA to approve cox-2s in the first place.

While he believes there may be some small role left for cox-2s, Spiegel said the FDA "was a little shortsighted in the framework that they were using" as they weighed the risks and benefits of these medications.

"That's because they were only really looking at cox-2s versus the traditional NSAID," he said. "They really hadn't thought about this combination, which many people use practically every day now -- a PPI plus an NSAID."

More information

For more on pain-relieving arthritis drugs, check out the Arthritis Foundation.

SOURCES: Brennan Spiegel, M.D., M.S.H.S., assistant professor, medicine, David Geffen School of Medicine, University of California, Los Angeles; Mark Fendrick, M.D., professor, internal medicine, University of Michigan, Ann Arbor; April 15, 2005, Arthritis Care & Research
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