Recommendations for the clinical use of cyclooxygenase-2-specific inhibitors.

During the past decade, intensive research has revealed that two separate cyclooxygenase (COX) isoforms, COX-1 and COX-2, initiate the metabolism of arachidonic acid to prostaglandins and related lipid mediators. COX-1 is constitutively expressed in most tissues and governs the production of arachidonic acid metabolites that are necessary for the maintenance of physiologic homeostasis. In contrast, COX-2 is induced locally in response to inflammatory stimuli or physiologic stress, resulting in increased production of the eicosanoid mediators that are characteristic of these situations. All of the conventional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 to varying degrees; therefore, they may all be considered “nonspecific” COX inhibitors. The discovery of the two COX gene products led to the development of compounds that were especially designed to inhibit COX-2 while sparing COX-1 at therapeutic doses. Clinical trials in patients with osteoarthritis, rheumatoid arthritis, and dental pain have demonstrated that COX-2–specific inhibitors are as therapeutically effective as conventional NSAIDs, – 8 while endoscopic studies have shown a significant reduction in gastric ulcers and mucosal damage compared with the conventional agents. Moreover, COX-2–specific inhibitors have no measurable effect on platelet aggregation, and they do not prolong bleeding time. Because serious upper gastrointestinal (GI) side effects are the most frequent concerning adverse effects associated with conventional NSAID therapy, the COX-2–specific inhibitors may be expected to provide a significantly improved risk– benefit ratio compared with conventional NSAIDs. Thus, current evidence indicates that COX-2–specific inhibitors should be considered whenever conventional NSAID therapy is required. In a recent consensus statement published in the Journal of Rheumatology, a panel of experts convened by the International COX-2 Study Group (see Appendix) provided recommendations for the use of COX-2–specific inhibitors in clinical practice. The panel thought there was emerging evidence to support the conclusion that the use of COX-2–specific inhibitors rather than conventional NSAIDs would be preferred in patients at increased risk of serious upper GI complications. These patients include individuals older than 65 years; those with a history of peptic ulcer disease; those taking glucocorticoids (with a high-dose NSAID), anticoagulants, or aspirin; and those requiring high doses of NSAIDs (Table 1). Current clinical evidence and expert opinion suggest that the COX-2–specific inhibitors will impose less of a risk in these individuals than conventional nonspecific NSAIDs. Furthermore, COX-2–specific inhibitors may be considered for use in patients with multiple medical problems or taking multiple medications, those with excessive alcohol intake, and those with active bleeding or a bleeding tendency, because the use of a conventional NSAID may increase their already elevated GI risk (Table 1). Figure 1 presents a proposed treatment approach based on the recommendations of the panel. If a patient is using a conventional NSAID that has shown clinical efficacy without apparent adverse effects, then the need to switch to a COX-2–specific inhibitor is a matter of clinical judgment. Physicians must keep in mind, however, that a large proportion of serious NSAID-induced GI complications can be asymptomatic. Patients currently using conventional NSAIDs should therefore be considered for treatment with a COX-2–specific inhibitor based on the GI risk factors mentioned above, as well as on the patient’s need for ongoing analgesic and/or anti-inflammatory therapy. Alternatively, consideration could be given to the use of a conventional NSAID along with an effective gastroprotective agent. To date, no studies have examined the relative safety of COX-2–specific inhibitors