Dr. Wright is with the Departments of Pharmacology and

THE LAUNCH OF THE CYCLOOXYGENASE-2 (COX-2) selective NSAIDs was based on 2 hypotheses: (1) the major adverse effects limiting the usefulness of nonselective NSAIDs are gastrointestinal in nature and (2) COX-2 selective NSAIDs are associ-ated with fewer gastrointestinal adverse effects than nonselective NSAIDs. At the time of the launch, neither of these hypotheses had been proven and, as docu-mented in this review, both remain uncertain. The increased incidence of total and nongastrointestinal serious adverse events, with the COX-2 selective NSAIDs as compared with nonselective NSAIDs, in the Celecoxib Long-term Arthritis Safety Study (CLASS) and the Vioxx Gastrointestinal Outcomes Research (VIGOR) study remains a major concern. The increased morbidity associated with the COX-2 se-lective NSAIDs may be a manifestation of the COX-2 selectivity of rofecoxib and celecoxib or the supramaximal doses of these drugs used in the trials. Proof that the increased harm was not caused by the COX-2 selectivity of the drugs depends on demonstration in a randomized controlled trial that COX-2 selective NSAIDs a