Arthrotec

With safety concerns about the two remaining cyclooxygenase-2 inhibitors on the market, more patients may be turning to an option that fell by the wayside in the onslaught of direct-to-consumer advertising of COX-2s: conventional NSAIDs with proton pump inhibitor cotherapy.

As if on cue, the Food and Drug Administration in November approved the proton pump inhibitor esomeprazole (Nexium) for reducing the risk of gastric ulcers associated with continuous NSAID therapy. Lansoprazole (Prevacid) had been approved for reducing the risk of NSAID-associated gastric ulcers in 2000, making two proton pump inhibitor (PPI) therapies specifically approved for the indication.

Although some experts assert that PPI cotherapy has been an underutilized option, it's clear that it's going to take time and data to address the variety of patients in the post-Vioxx era.

A nonselective NSAID with a PPI is "a reasonable" approach in a patient at high risk, but for patients on Coumadin (warfarin) who can't take a nonselective NSAID because of their effects on platelets, the selective COX-2 inhibitors were a welcome choice, noted Elizabeth Tindall, M.D., president of the American College of Rheumatology.

Dr. Tindall added that the ACR's guidelines on the treatment of osteoarthritis (published in 2000) and rheumatoid arthritis (published in 2002) include comments on the use of concomitant PPIs with NSAIDs in high-risk patient populations. More physicians may be turning to these recommendations for reference. But, she admits, right now "there are not enough data to tell us exactly what to do in all patients. Everyone is trying to get through this as best they can." And that means taking a case-by-case approach, weighing the benefits and risks of available options for each individual patient.

Dr. Tindall said that a PPI cotherapy approach was initially underutilized because health plans refused to pay for these drugs before they were specifically approved for this indication.

Another "very good option," if a patient can tolerate it, is to take a conventional NSAID with misoprostol. For some patients this works very well. But it's trial and error. Arthrotec, which is a combination of diclofenac and misoprostol (Cytotec) in one pill is also an option, said Dr. Tindall, of the division of arthritis and rheumatology at Oregon Health and Science University, Portland.

With the huge marketing campaigns for COX-2-specific inhibitors, physicians and the public lost sight of the fact that the whole point of developing COX-2s was for improved GI safety. Instead, people inferred that COX-2s were more effective pain relievers--despite the lack of proof. And in the process, the PPI cotherapy strategy was sidelined, said Byron Cryer, M.D., associate professor of medicine at the University of Texas, Dallas.

If there's a silver lining to the adverse events associated with Vioxx, Celebrex, Bextra, and naproxen, it's the fact that physicians now are probably more thoughtfully considering all a patient's options before writing prescriptions for treating pain, said Eric Matteson, M.D., a consultant in rheumatology and professor of medicine at Mayo Medical School, Rochester, Minn.

Motivated by the fact that no study has ever shown selective COX-2s to be more effective than conventional NSAIDs, Dr. Matteson's group at the Mayo Clinic began tightly restricting the use of selective COX-2 inhibitors a few years ago. After those restrictions were implemented, utilization of COX-2s was cut in half, and yet the rate of GI events didn't increase, he said.

About 15%-20% of the population seeking arthritis pain treatment met the criteria for receiving a selective COX-2, which included having a history of GI bleeding, major ulcerative disease, major inflammatory bowel disease, current use of warfarin, or a history of aspirin-induced asthma, which is a contraindication for conventional NSAID use. With the market withdrawal of Vioxx, Mayo has tightened its restrictions even further: No longer are patients over the age of 60 years considered automatic candidates for selective COX-2 therapy. Now, regardless of their age, patients must have at least one of the contraindications listed above.

As with any medication regimen, compliance with PPI cotherapy will be an issue.

Having to take two drugs is less practical from a patient perspective, "but our options have been decreased," said Dr. Cryer who has conducted several NSAID-associated ulcer research studies. But from the physician's perspective, dosing and prescribing the drugs is pretty straightforward, Dr. Mattesoa said.

The use of PPI cotherapy is an "absolutely underutilized" approach, but since the strategy only covers the stomach and duodenum, it won't reduce NSAID-related complications in the lower GI tract, which recent studies suggest account for about 12.5% of all NSAID-related GI complications, noted Dr. Cryer, also of Dallas Veterans Affairs Medical Center.

For most indications where the PPIs have been compared with each other, they "all seem to have comparable efficacy," he added. For the indication of preventing ulcers in continuous NSAID users, only omeprazole, esomeprazole, and lansoprazole have been studied, and two have been approved. However, if the appropriate studies were done with the other three PPIs. Dr. Cryer said he would expect that they would have similar benefits in regards to the GI risk reduction.

Dr. Cryer said he has received grants from Wyeth Consumer Health Care, manufacturer of another PPI, pantoprazole (Protonix), and has received consulting fees from lansoprazole's manufacturer, TAP Pharmaceuticals, and esomeprazole's manufacturer, AstraZeneca.

BY ELIZABETH MECHCATIE AND KATHRYN DEMOTT

Senior Writer and Senior Editor

COPYRIGHT 2005 International Medical News Group
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