Post-COX-2, pain relief strategies present new challenges

Heart protection has become more important than safeguarding the GI tract, but this, in turn, can make regimens more difficult and more expensive.

By Victoria Stagg Elliott — Posted June 6, 2005

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When physicians make choices about how to treat pain, preventing gastrointestinal bleeding is no longer a priority on the list of factors they consider. Protecting the heart is, according to an expert panel at Digestive Disease Week held in Chicago last month. This event is an annual joint meeting of the American Assn. for the Study of Liver Diseases, the American Gastroenterological Assn., the American Society of Gastrointestinal Endoscopy, and the Society for Surgery of the Alimentary Tract.

"When physicians are selecting an NSAID [consults with gastroenterologists] are not as important because it's not about protecting the GI any more," said James Scheiman, MD, a gastroenterologist and director of the Endoscopic Ultrasound Program at the University of Michigan Medical School, Ann Arbor. "In 2005, the heart has got to come first."

This mind-set is the result of the controversy over the use of COX-2 inhibitors. Since both Vioxx (rofecoxib) and Bextra (valdecoxib) have been withdrawn from the market and stronger warnings have been placed on Celebrex (celecoxib) -- all because of increased cardiovascular risks associated with long-term use -- physicians and patients are returning to the older nonsteroidal anti-inflammatory drugs.

"We're seeing less and less use of COX-2s except for highly selected patients," said Dr. Scheiman.

Guidelines are soon expected to start reflecting this change.

For the moment, though, experts are wrestling with how to ensure the greatest pain relief while providing the fewest risks.

"We can't forget efficacy because if these patients don't have the NSAID, they'll have pain," said Dr. Angel Lanas, professor of medicine at the University of Zaragoza, Spain, who presented a study looking at the rates of upper GI bleeding linked to the use of COX-2s, NSAIDs and aspirin.

But with less long-term data on the more traditional NSAIDs than is available on the newer COX-2s and little new data expected, deciding what to do is a challenge.

"We have a mess here," said Dr. Scheiman. "There's no placebo-controlled studies for the traditional NSAIDs, but who's going to do these studies?"

Experts say that COX-2 inhibitors at the lowest dose possible still have an important, albeit smaller, role to play for those patients at low risk of a cardiac event but high risk of gastrointestinal trouble.

"A low dose is good enough for most arthritis patients," said Dr. Francis Chan, associate professor at the Dept. of Medicine and Therapeutics at the Chinese University of Hong Kong.

For everyone else, things are more complicated. Most experts are recommending that NSAIDs be prescribed in combination with a proton pump inhibitor in order to address a patient's pain without adding to the risk of adverse events. This strategy is not new, but it's never been overly popular because of the increased cost.

"My patients are elderly and can't afford this," said Howard Monsour Jr., MD, a gastroenterologist from Granbury, Texas.

Even if patients can afford it, evidence suggests that many are less than eager to take one more pill. One study presented at DDW found about a third of patients prescribed this combination regimen did not adhere to it. Researchers at the University of Illinois, Chicago, gleaned this finding from a managed care database. Thus, the cost of the drugs was probably less of an issue.

But the noncompliant patients did pay a price in the long term by increasing their risks for complications. Those who only took the PPIs 20% to 40% of the time were four times more likely to have a gastrointestinal event than those who took the meds at least 80% of the time.

"I don't think they're purposely trying to hurt themselves," said Jay L. Goldstein, MD, lead author and co-director for clinical affairs. "They looked at the two pills. One is there to help them today. The other is there for prevention. There's less appeal."

Some physicians also are concerned about the risks that may be associated with PPIs.

A University of Pennsylvania Health System study found that the chronic use of PPIs was associated with an increased risk of hip fracture. The authors said this information was not a reason to stop prescribing the drugs, although it may be a reason to consider calcium supplementation for these patients.

"It's not a surprise, and it probably is safe," said Yu-Xiao Yang, MD, lead author and assistant professor of medicine. "We just have to be aware of this impact on bone health."

But for some patients, combining the two drugs may not be the only option. A paper presented by Dr. Chan suggested that, for those who test positive for Helicobacter pylori, eradication of the bug may be sufficient to significantly reduce the risk of a gastrointestinal event associated with the use of NSAIDs.

"If they have no other risk factors, just eradication will be enough for them," he said.

Other evidence suggests that when it comes to this type of adverse drug event, NSAIDs may not be the only pharmaceutical class requiring attention. According to preliminary data presented by researchers at the Northwestern University Medical School in Chicago, selective serotonin reuptake inhibitors may also increase the risk of gastrointestinal bleeding by 50%.

This increased risk is similar to that incurred with NSAIDs. But a solution has yet to be determined.

"If you have a patient who is taking their aspirin and their SSRI and their ibuprofen, the risk is real," said Michael P. Jones, MD, lead author and associate professor of medicine. "The true magnitude of risk and how to manage it needs to be determined."

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A PPI with an NSAID

Objective: To determine if patient adherence to taking a proton pump inhibitor along with a nonsteroidal anti-inflammatory drug makes a difference in the rate of developing upper gastrointestinal ulcers or bleeding.

Methods: Researchers analyzed a large managed care claims database looking at rates of prescriptions filled for non-selective NSAIDs, COX-2 inhibitors and PPIs and correlated them with diagnostic codes for peptic ulcer disease and upper GI bleeds.

Results: Patients prescribed a non-selective NSAID who took PPIs at least 80% of the time had a 60% reduction in the rate of adverse events when compared to those who took PPIs less often. Those who took PPIs with NSAIDs less than 20% of the time were six times more likely to develop an adverse event. Adherence to PPI therapy made no impact in patients on the COX-2 drugs.

Conclusion: Patients on non-selective NSAIDs who don't take their acid-suppression drugs are more likely to have a gastrointestinal event.

Source: Digestive Disease Week, May

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External links

Digestive Disease Week (link)

Food and Drug Administration on COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs (link)

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