A RANDOMIZED, DOUBLE-BLIND COMPARISON OF PLACEBO, ETODOLAC, AND NAPROXEN ON GASTROINTESTINAL INJURY AND PROSTAGLANDIN PRODUCTION

Background: NSAIDs frequently cause gastrointestinal injury and increase the risk of ulcer complications. We compared an NSAID suggested to cause less gastric injury (etodolac) with a standard NSAID (naproxen) and a placebo in a 4-week double-blind trial assessing the effects on gastroduodenal injury, symptoms, and prostaglandin production in healthy volunteers. Methods: Fifty-two healthy volunteers not taking NSAIDs, alcohol, antibiotics, bismuth, or anti-ulcer drugs and with a normal endoscopic examination were randomly assigned to identical drugs: placebo, etodolac 400 mg, or naproxen 500 mg b.i.d. for 4 weeks. Endoscopies with biopsies were repeated at weeks 1 and 4. The number and dimensions of ulcers and erosions were recorded to quantitate injury. Results: At week 1 the mean number and area of gastric ulcers per subject were greater with naproxen than placebo or etodolac (area: naproxen, 7.4 mm(2); placebo, 0.6 mm(2), p = 0.02 vs naproxen; etodolac, 2.1 mm(2), p = 0.06 vs naproxen). Ulcer scores at week 4 were low and comparable in the three groups. The mean number and area of gastric erosions per subject were greatest with naproxen at both weeks 1 and 4 (week 4 area: naproxen, 58.3 mm(2); placebo, 29.0 mm(2); etodolac, 13.9 mm(2), p < 0.02, naproxen vs placebo and vs etodolac). Placebo injury was presumably due to biopsies at prior endoscopy. Gastric mucosal prostaglandin E(2) production did not change significantly from baseline after 1 or 4 weeks of treatment with placebo or etodolac, but did decrease significantly with naproxen (week 0, 1689; week 1, 479; week 4, 577 pg/mg protein). Gastrointestinal symptoms were present in only 1 (5%) of 20 visits in which endoscopy showed no erosions or ulcers vs 21 (26%) of 82 visits in which a mucosal defect was identified (p = 0.066). Conclusions: Gastric injury with 4 weeks of etodolac is comparable to that seen with placebo and significantly less than that occurring with naproxen, presumably due to the fact that etodolac does not suppress gastric mucosal prostaglandin production, whereas naproxen leads to a significant reduction.