Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

COX-2 inhibitors and gastroduodenal toxicity: Major clinical trials

Mark Feldman, MD, MACP, AGAF, FACG
Section Editor
J Thomas Lamont, MD
Deputy Editor
Shilpa Grover, MD, MPH, AGAF


The primary effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is to inhibit cyclo-oxygenase (prostaglandin H synthase, or PGHS), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Two related isoforms of the cyclo-oxygenase (COX) enzyme have been described: COX-1 (PGHS-1) and COX-2 (PGHS-2). COX-1 is involved in gastric cytoprotection. It had been proposed that the ideal NSAID would inhibit the inducible COX-2 isoform (thereby decreasing inflammation) without having any effect on the constitutive COX-l isoform (thereby minimizing gastric toxicity) [1]. (See "NSAIDs: Pharmacology and mechanism of action".)

One NSAID that selectively inhibits COX-2, celecoxib, is currently approved by the US Food and Drug Administration (FDA). Rofecoxib is a COX-2 inhibitor that was removed due to an increased risk of stroke and myocardial infarction with long-term use. Valdecoxib was removed because of concerns of cardiovascular risk and reports of Stevens-Johnson syndrome. An increased risk of cardiovascular events has also been observed with celecoxib, especially in higher doses. These observations led the FDA to issue warnings regarding the use of these drugs. (See "COX-2 selective inhibitors: Adverse cardiovascular effects".)

Other COX-2 inhibitors are available in some countries. Parecoxib is a prodrug that is converted to valdecoxib. Etoricoxib and lumiracoxib are available in some countries. These drugs have at least a 200- to 300-fold selectivity for inhibition of COX-2 over COX-1. (See "Overview of selective COX-2 inhibitors".)

This topic review will summarize the major clinical trials that have focused on the gastroduodenal protective effects of the COX-2 inhibitors as compared to nonselective NSAIDs. An approach to patients at risk for gastroduodenal toxicity is presented separately. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".) An overview of COX-2 inhibitors is also available. (See "Overview of selective COX-2 inhibitors".)


Celecoxib was approved by the FDA based upon the results of clinical trials involving more than 5200 patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in which its efficacy and toxicity were compared with that of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and placebo. These data demonstrate that celecoxib produced comparable analgesia and anti-inflammatory effects to nonselective NSAIDs.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jul 05, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353:307.
  2. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999; 282:1921.
  3. Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999; 354:2106.
  4. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284:1247.
  5. Jüni P, Rutjes AW, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ 2002; 324:1287.
  6. Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med 2006; 119:255.
  7. Chan FK, Lanas A, Scheiman J, et al. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376:173.
  8. Goldstein JL, Eisen GM, Agrawal N, et al. Reduced incidence of upper gastrointestinal ulcer complications with the COX-2 selective inhibitor, valdecoxib. Aliment Pharmacol Ther 2004; 20:527.
  9. Stoltz RR, Harris SI, Kuss ME, et al. Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects. Am J Gastroenterol 2002; 97:65.
  10. Laine L, Curtis SP, Cryer B, et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2007; 369:465.
  11. Hunt RH, Harper S, Watson DJ, et al. The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events. Am J Gastroenterol 2003; 98:1725.
  12. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004; 364:665.
  13. Topol EJ, Falk GW. A coxib a day won't keep the doctor away. Lancet 2004; 364:639.
  14. Hawkey CC, Svoboda P, Fiedorowicz-Fabrycy IF, et al. Gastroduodenal safety and tolerability of lumiracoxib compared with Ibuprofen and celecoxib in patients with osteoarthritis. J Rheumatol 2004; 31:1804.
  15. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343:1520.
  16. Lanas A, Baron JA, Sandler RS, et al. Peptic ulcer and bleeding events associated with rofecoxib in a 3-year colorectal adenoma chemoprevention trial. Gastroenterology 2007; 132:490.
  17. Cryer B, Feldman M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology 1999; 117:17.
  18. Fiorucci S, Santucci L, Gresele P, et al. Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study. Gastroenterology 2003; 124:600.
  19. Laine L, Maller ES, Yu C, et al. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology 2004; 127:395.
  20. Combe B, Swergold G, McLay J, et al. Cardiovascular safety and gastrointestinal tolerability of etoricoxib vs diclofenac in a randomized controlled clinical trial (The MEDAL study). Rheumatology (Oxford) 2009; 48:425.
  21. Goldstein JL, Lowry SC, Lanza FL, et al. The impact of low-dose aspirin on endoscopic gastric and duodenal ulcer rates in users of a non-selective non-steroidal anti-inflammatory drug or a cyclo-oxygenase-2-selective inhibitor. Aliment Pharmacol Ther 2006; 23:1489.
  22. Goldstein JL, Aisenberg J, Zakko SF, et al. Endoscopic ulcer rates in healthy subjects associated with use of aspirin (81 mg q.d.) alone or coadministered with celecoxib or naproxen: a randomized, 1-week trial. Dig Dis Sci 2008; 53:647.
  23. Rostom A, Muir K, Dubé C, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol 2007; 5:818.
  24. Chan FK, Wong VW, Suen BY, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet 2007; 369:1621.
  25. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med 2016; 375:2519.
  26. Chan FKL, Ching JYL, Tse YK, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet 2017; 389:2375.