Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to relieve pain related to headaches, menstrual cramps, and arthritis. About 20 percent of Canadians older than 65 years use prescription NSAIDs, but many others use over-the-counter forms of these medications. The major adverse effects of NSAIDs are gastrointestinal complications, including gastrointestinal bleeding, symptomatic peptic ulcer disease, and gastric outlet obstruction. About 1 to 2 percent of NSAID users develop gastrointestinal complications every year; however, for many patients, NSAIDs provide effective pain relief without the adverse effects of opiates. Targownik and Thomson reviewed a variety of strategies to provide gastroprotection during NSAID use.

The Study: They reviewed the three current strategies: prostaglandin E₁ analogues, cyclooxygenase-2 (COX-2) inhibitors, and proton pump inhibitors (PPIs). Multiple randomized controlled trials using these agents were identified; however, no trials or observational studies were found that used combinations of two or more of these gastroprotective medications.

Endoscopy studies of NSAID users have shown that misoprostol (Cytotec), a synthetic analogue of prostaglandin E₁, decreases the development of gastric erosions and peptic ulcers. Patients using NSAIDs who were given misoprostol 200 mcg four times daily were 40 percent less likely to develop gastrointestinal complications compared with patients who only used NSAIDs. Nevertheless, misoprostol is not highly efficient—266 average-risk NSAID users would have to be given misoprostol to prevent one gastrointestinal complication. Additionally, more than 20 percent of misoprostol users have experienced diarrhea, which often leads to the discontinuation of therapy. It can be prescribed in twice-daily doses to reduce diarrhea, but this method provides substantially less gastrointestinal protection, so it is not recommended as a gastroprotective regimen.

Results: COX-2 inhibitors were not found to affect the production of gastroprotective prostaglandins and are believed to relieve pain without inducing gastrointestinal complications. In several clinical trials of patients with osteoarthritis or rheumatoid arthritis, COX-2 inhibitors provided pain relief equivalent to NSAIDs. In some studies, the risk of serious gastrointestinal complications was 50 to 60 percent lower with COX-2 inhibitors than with NSAIDs. COX-2 inhibitors have been associated with an increased risk of myocardial infarction or stroke. Although the risk of myocardial infarction was only 0.4 percent over 13 months in one study, this was significantly greater than the 0.1 percent seen in patients using naproxen (Naprosyn). Larger studies with longer follow-up periods have indicated that valdecoxib (Bextra [not available in the United States]) and rofecoxib (Vioxx [withdrawn from the market]) might have a higher risk than celecoxib (Celebrex). Recent guidelines, however, have restricted celecoxib use to patients without cardiovascular risk and have recommended a maximal daily dose of 200 mg.

Several studies support the use of PPIs to prevent gastrointestinal bleeding during NSAID use. An endoscopy study showed a lower rate of peptic ulceration and a better tolerance profile than misoprostol. Use of PPIs also was shown to reduce recurrent gastrointestinal hemorrhage by 90 percent in patients who require low-dose aspirin or continued NSAID therapy and have a history of drug-induced gastrointestinal bleeding.

Conclusion: The authors stress that selecting a gastroprotective strategy for patients using NSAIDs varies greatly. Those who are younger than 76 years, have no significant comorbidities or a history of NSAID-related gastrointestinal complications, and are not taking warfarin (Coumadin) are at low risk and do not need gastroprotection. Moderate- risk patients 76 years or older who have a substantial comorbidity or a history of NSAID-related gastrointestinal complications, and use warfarin or more than 10 mg of prednisone daily, require gastroprotection. For patients at high risk because of multiple risk factors, a combination of gastroprotective strategies is recommended.

editor's note: Two studies recently published have focused on the renal and cardiac risks of COX-2 agents, specifically rofecoxib.^1,2 An editorial, also addressing the safety of COX-2 inhibitors, noted that the safest and most cost-effective therapy for patients who have chronic pain and are at high risk for gastrointestinal complications may be a combination of naproxen and a PPI.³ The editorial notes that more research needs to be done to clarify the most effective, safest, and least-costly regimen to provide long-term pain relief for the large number of patients who currently depend on NSAIDs.—a.d.w.