The primary effect of nonsteroidal antiinflammatory drugs (NSAIDs) is to inhibit cyclooxygenase (prostaglandin H synthase, or PGHS), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Two related isoforms of the cyclooxygenase (COX) enzyme have been described: COX-1 (PGHS-1) and COX-2 (PGHS-2). COX-1 is involved in gastric cytoprotection. It had been proposed that the ideal NSAID would inhibit the inducible COX-2 isoform (thereby decreasing inflammation) without having any effect on the constitutive COX-l isoform (thereby minimizing gastric toxicity) . (See "NSAIDs: Mechanism of action".)
One NSAID that selectively inhibits COX-2, celecoxib, is currently approved by the US Food and Drug Administration (FDA) (table 1). Rofecoxib is a COX-2 inhibitor that was removed due to an increased risk of stroke and myocardial infarctions with long-term use. Valdecoxib was removed because of concerns of cardiovascular risk and reports of Stevens-Johnson syndrome. An increased risk of cardiovascular events has also been observed with celecoxib, especially in higher doses, although it continues to be available. These observations led the FDA to issue warnings regarding the use of these drugs. (See "COX-2 selective inhibitors: Adverse cardiovascular effects".)
Other COX-2 inhibitors are available in some countries. Parecoxib is a water soluble prodrug that is converted to valdecoxib. Etoricoxib and lumiracoxib are available in some countries. These drugs have at least a 200- to 300-fold selectivity for inhibition of COX-2 over COX-1. (See "Overview of selective COX-2 inhibitors".)
This topic review will summarize the major clinical trials that have focused on the gastroduodenal protective effects of the COX-2 inhibitors. An approach to patients at risk for gastroduodenal toxicity is presented separately. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".) An overview of COX-2 inhibitors is also available. (See "Overview of selective COX-2 inhibitors".)
Celecoxib was approved based upon the results of five clinical trials (some of which have been published only in preliminary form) involving more than 5200 patients with osteoarthritis or rheumatoid arthritis in which its efficacy and toxicity were compared to nonselective nonsteroidal antiinflammatory drugs (NSAIDs) and placebo. These data demonstrate that celecoxib produced comparable analgesia and antiinflammatory effects to nonselective NSAIDs.