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Findings on the Effect of COX-2 Inhibitors on Gastrointestinal Events

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs developed to treat inflammation and pain. NSAIDs work by inhibiting cyclo-oxygenase activity, which in turn is responsible for generating prostaglandins at the site of tissue injury. While they effectively reduce inflammation and pain, the widespread use of traditional NSAIDs has been associated with various adverse events, including serious gastrointestinal (GI) toxic effects (eg, ulceration, hemorrhage, and perforation). Utilization of traditional NSAIDs has reportedly resulted in a 2% to 4% annualized incidence rate of symptomatic GI ulcers and ulcer complications that subsequently resulted in approximately 107,000 hospitalizations and 16,500 deaths in the United States. Recent pharmaceutical findings have encouraged the development of a new class of medications (ie, COX-2 inhibitors, such as rofecoxib and celecoxib). This new family of NSAIDs is designed to provide the beneficial reduction of inflammation and pain, with a better GI safety profile.

All NSAIDs inhibit cyclo-oxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities, as well as their GI side effects. Two distinctive forms of cyclo-oxygenase have been identified. Cyclo-oxygenase-1 (COX-1) exists in every organ system, including the stomach, intestines, kidneys, and platelets. Cyclo-oxygenase-2 (COX-2) is not expressed under baseline conditions (except in the kidneys and brain, where it is constitutive), but is rapidly unregulated during inflammation. The therapeutic effects of NSAIDs are largely the result of inhibition of the enzyme COX-2, whereas effects on GI cytoprotection activity and platelet activity are primarily due to the inhibition of COX-1. Inhibition of COX-1 results in reduced cytoprotective prostaglandins (PGE2 and PG12). Selective inhibitors of COX-2 subsequently result in reduced incidence of gastrointestinal, renal, and platelet side effects (Figure 1). Rofecoxib is indicated for relief of the signs and symptoms of osteoarthritis, management of acute pain in adults, and the treatment of primary dysmenorrheal. Celecoxib is indicated for relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis, and to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP) as an adjunct to usual care.

Since serious GI events have been associated with NSAID treatment, these medications should be avoided in patients who present with various pre-existing conditions (Table). Extreme caution should be practiced when prescribing NSAIDs for patients with a prior history of peptic ulcer disease of GI bleeding. These patients have an increased risk for developing a GI event (eg, perforation, obstruction, bleed) compared to patients without these risk factors.



Patients who may be at higher risk for serious gastrointestinal events while taking NSAIDs includes those:

  • With a history of ulcer disease
  • Receiving therapy with anticoagulants
  • Older in age
  • Using oral corticosteroids
  • With poor general health status


A prospective study presented at the American College of Rheumatology (ACR) 64th Annual Scientific Meeting compared the rates of GI protective agents (eg, proton pump inhibitors, cytoprotective agents, and H2 blockers), GI diagnostic procedures (eg, UGI series and endoscopy), and hospitalizations for upper GI perforation, ulcer, or bleeding following treatment with rofecoxib and naproxen. Approximately 82% of these patients were treated with NSAIDs at baseline and 56% used concomitant steroids. The results of this investigation indicated that patients treated with rofecoxib required a significantly reduced amount of treatment with new GI protective agents (11.2% with rofecoxib versus 14.5% with naproxen, P<0.001). Fewer gastrointestinal procedures were required for patients treated with rofecoxib (5.6% versus 6.9%, p=0.02), and the subjects treated with this medication were hospitalized less frequently for GI perforation, ulcer, or bleeding (0.4% versus 0.9%, p=0.01). A double-blind investigation presented at the same symposium indicated that patients treated with rofecoxib had a significantly decreased incidence of clinically important and complicated gastrointestinal events compared to patients treated with a nonselective NSAID. A recent randomized controlled investigation (the CLASS study) also determined that utilization of a COX-2 specific inhibitor was associated with a lower incidence of combined clinical upper GI events than comparator NSAIDs.

Severe pain as a result of arthritic, dental, or other inflammatory related events is extremely uncomfortable for the patient. While the proven efficacy and pain management provided by nonselective NSAIDS is undeniable, COX-1 inhibition can result in serious negative side effects and even death. Selective inhibition of COX-2 provided by both rofecoxib and celecoxib facilitates the successful achievement of pain suppression, with a significantly lower rate of adverse gastrointestinal events. Reduced stomach ulceration and GI bleeding are only some of the benefits associated with this new class of medications, and the clinical efficacy of COX-2 inhibitors continues to be evaluated.

*Senior Scientist and Head of the Division of Clinical Decision-making & Health Care, Toronto General Research Institute, Toronto, Ontario



Bombardier C, Laine L, Hochberg M. A prospective double-blind Gi outcome study of rofecoxib versus naproxen. Paper presented at: The ACR 64th Annual Scientific Meeting, Philadelphia, PA; October 31, 2000.

Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343(21): 1520-1528.

Kalgutkar AS, Crews BS, Rowlinson SW, et al. Biochemically based design of cyclo-oxygenase-2 (COX-2) inhibitors: Facile conversion of non-steroidal anti-inflammatory drugs to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci USA 2000;97(2):925-930.

Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. J Am Med Assoc 1999;282(20):1929-1933.

Lichtenstein DR, Wolfe MM. COX-2-Selective NSAIDs. New and improved? J Am Med Assoc 2000;284(10):1297-1299.

Morrison BW, Christensen S, Yuan W, et al. Analgesic efficacy of the cyclo-oxygenase-2-Specific inhibitor rofecoxib in postdental surgery pain: A randomized, controlled trial. Clin Ther 1999;21(6):943-953.

Sharma S, Prasad A, Anand KS. Non-steriodal anti-inflammatory drugs in the management of pain and inflammation: A basis for drug selection. AM J Ther 1999;6(1):3-11.

Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteriodal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. J Am Med Assoc 2000;284(10):1247-1255.

Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999;340:1888-1899.

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