Celecoxib-Induced Upper Gastrointestinal Hemorrhage and Ulceration

Andrew S. Crawford, DO, Joseph G. White, MD

Disclosures

South Med J. 2002;95(12) 

In This Article

Discussion

Nonselective nonsteroidal anti-inflammatory drugs are the initial treatment for rheumatoid arthritis and have, until recently, been a primary drug for the treatment of pain associated with osteoarthritis. These agents are also commonly used for the relief of pain and inflammation associated with a wide array of conditions, but they have potentially serious GI side effects. Clinical trials have shown that approximately 20% of arthritic patients who used NSAIDs had endoscopically detected erosions.[1] An estimated 17 million people in the United States take prescription NSAIDs regularly,[2] and NSAID-induced GI complications account for approximately 107,000 hospitalizations each year.[3]

Nonsteroidal anti-inflammatory drugs reduce pain and inflammation by inhibiting cyclooxegenase, an enzyme in the pathway for formation of prostaglandins, and thromboxane. Needleman et al?? demonstrated two isoforms of cyclooxygenase, COX-1 and COX-2. It has since been determined that COX-1 products are responsible for maintenance roles in GI, renal, and platelet physiology,[4] and that inhibition of COX-1 is responsible for the majority of the gastric mucosal injury noted with nonselective NSAIDs.[5] COX-2 products have been shown to be responsible for modulating pain and inflammation.[6,7] From this information, it was hypothesized that if a drug could be synthesized that would target COX-2 without inhibiting COX-1, pain and inflammation could be reduced without the GI irritation brought on by inhibition of COX-1. Such drugs have been synthesized and are now known as the COX-2 selective NSAIDs (celecoxib, rofecoxib).

The COX-2 inhibitors are an exciting new class of drugs that may give much relief to patients with inflammatory conditions such as rheumatoid arthritis, while causing less GI toxicity than conventional NSAIDs. In fact, Simon et al[8] have shown in four phase II trials that celecoxib is effective in treating the signs and symptoms of osteoarthritis and rheumatoid arthritis, as well as showing that celecoxib is statistically significantly less likely than nonselective NSAIDs to cause gastric or duodenal erosions/ulcerations,[9] without any significant effect on platelet aggregation or thromboxane B2 levels.[12]

From this information, it is clear that there is a fine balance between COX-1 and COX-2 in gastric injury. Although evidence supports COX-2 inhibitors as being less ulcerogenic than nonselective NSAIDS,[2,6,8,10,11] the COX-2 inhibitors are not completely "ulcer-proof," and in fact can cause delayed ulcer healing and worsening of a preexisting inflammatory state.[12,13,14,15]

COX-2 has been found to be an inducible isoform of cyclooxygenase that may be necessary for the production of essential prostaglandins used in the repair process in some inflammatory conditions. It is in these states that inhibition of COX-2 could be troublesome.[12,13,14,15] Evidence also supports the notion that good anti-inflammatory efficacy from COX-2 inhibitors is achieved only at doses where the COX-2 specificity is lost.[16]

Our patient was in fact taking supratherapeutic doses to control his symptoms. His dosing may have been so great as to inhibit both isoforms of cyclooxygenase, leading to the GI hemorrhage. A second postulate is that he had an underlying stress gastritis/duodenitis from his illness, in which the COX-2 should have been producing essential repair prostaglandins, and when inhibited resulted in GI hemorrhage.

Our case illustrates the concept that even though the new COX-2 inhibitors may be safer, one should remain cautious when prescribing these drugs, since they too can cause erosions and ulcerations. These lesions, like those due to nonselective NSAIDs, may be asymptomatic until a significant GI hemorrhage occurs, as seen in our patient.

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