Volume 99, Issue 11

The clinical utility of nonsteroidal anti-inflammatory drugs (NSAIDs) to manage pain and inflammation is limited by adverse side effects. Although effective analgesic and anti-inflammatory agents, NSAIDs are associated with side effects that. are a consequence of nonspecific inhibition of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).The primary adverse events associated with NSAID therapy are upper gastrointestinal (GI) ulceration, pedoration, or bleeding, all of which involve mucosal damage of varying severity and can be asymptomatic and occur with little warning. Clinicians who prescribe NSAIDs should be able to identify patients who are at risk of an NSAID-induced GI adverse event and to detect and manage the event should one occur. The use of COX-2-specific inhibitors to I manage pain and inflammation may minimize the risks of NSAID-associated toxicities.

Nearly 30 years ago, cyclooxygenase (COX) was identified as an enzyme that initiates the biotransformation of arachidonic acid to prostanoids. It is now known that COX exists as two distinct but similar isozymes, COX-1 and COX-2. Prostaglandins (PGs) formed by the enzymatic activity of COX-1 are primarily involved in the regulation of homeostatic functions throughout the body, whereas PGs formed by COX-2 primarily mediate pain and inflammation. Based on structural differences in the active sites of COX-1 and COX-2, a new class of drugs has been developed that specifically inhibits COX-2 but not COX-1 activity. By preserving the synthesis of homeostatic PGs, these specific inhibitors of COX-2 provide the clinical benefits of nonsteroidal anti-inflammatory drugs and minimize the consequences of nonspecific inhibition of PG synthesis.

Inflammation and pain, the principal signs and symptoms of arthritis along with swelling and stiffness, are routinely controlled by treatment with a nonsteroidal antiinflammatory drug (NSAID). Celecoxib, an anti-inflammatory and analgesic agent indicated for the treatment of osteoarthritis and rheumatoid arthritis, is the first cyclooxygenase (COX) inhibitor with well-defined cyclooxygenase-2 (COX-2) specificity. Preclinical studies of celecoxib in vitro and in vivo support the COX-2 hypothesis that the therapeutic effects of NSAIDs are due to the inhibition of COX-2, and the adverse events associated with NSAID therapy are due to the inhibition of cyclooxygenase-1 (COX-1), the constitutively expressed isoform of COX. Clinical trials in patients with osteoarthritis or rheumatoid arthritis found that the efficacy of celecoxib is superior to that of placebo and comparable to that of naproxen, a conventional NSAID. Clinical studies also found celecoxib to be safe and well tolerated, with no evidence of alteration in platelet aggregation or gastrointestinal ulceration.

Although conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have long been a major therapeutic choice for the management of arthritic conditions, the potential adverse effects of these agents sometimes compromise their clinical utility. New modes of therapy have recently been introduced, and data on the cyclooxygenase-2 (COX72)-specific inhibitors celecoxib and rofecoxib suggest that these agents will meet the need for safe and effective therapeutic alternatives to conventional NSAIDs.