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Prostanoids that mediate inflammation, pain, and fever are synthesized through the action of cyclooxygenase-2 (COX-2), an enzyme that is constitutively expressed in the brain but can be induced in other tissues by cytokines. In both osteoarthritis and rheumatoid arthritis, COX-2 inhibitors have been shown to be superior in pain relief to acetaminophen and placebo, and equivalent to nonselective nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and naproxen. In rheumatoid arthritis, COX-2 inhibitors are not disease-modifying drugs. Because nonselective NSAIDs inhibit not only COX-2 but also inhibit COX-1, which plays a role in platelet aggregation and gastric mucosal protection, their use is associated with a higher risk of gastrointestinal bleeding than that of selective COX-2 inhibitors. Like NSAIDs, however, the selective agents can cause liver and kidney toxicity, fluid retention, and hypertension. One of them (rofecoxib) was withdrawn by the manufacturer after 5 years on the market because of an unacceptably high incidence of heart attack and thrombotic stroke in patients receiving it for 18 months or more. For these reasons and because they are more expensive than NSAIDs, COX-2 inhibitors are indicated chiefly in patients who are at increased risk of gastrointestinal bleeding.