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Unmet Needs in Non-steroidal Anti-inflammatory Drug-induced Upper Gastrointestinal Diseases

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Abstract

The use of traditional and cyclooxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs (NSAID) for the relief of pain and inflammation increases the risk of gastrointestinal side-effects ranging from dyspepsia to symptomatic and complicated ulcers. The COX-2-selective agents were designed to provide comparable pain relief to traditional NSAID, with a reduced rate of adverse gastrointestinal events. However, there appears to be little clinically significant difference between COX-2 and traditional NSAID in terms of dyspepsia, a common cause of the discontinuation of a traditional NSAID. Furthermore, concomitant aspirin use substantially reduces the gastrointestinal safety advantage of COX-2-selective drugs.

An increase in the numbers of people taking low-dose aspirin for cardioprotection, an aging population and potential chemoprevention benefits are resulting in the rising consumption of NSAID. Proton pump inhibitors have a demonstrated role in the treatment and prevention of both non-selective NSAID and selective COX-2 inhibitor-related upper gastrointestinal damage. However, the use of gastroprotective agents is far from optimal, and many high-risk patients are not being clearly identified. At the same time, inappropriate low-dose aspirin use is placing low cardiovascular risk patients at risk of gastrointestinal bleeding.

Combined with the recent withdrawal of rofecoxib and valdecoxib from the market because of excess cardiovascular adverse events, and concerns about the safety of other COX-2 inhibitors, a review of strategies to reduce the overall risks in users of anti-inflammatory drugs is timely. This article examines the current issues of understanding and managing NSAID-induced upper gastrointestinal diseases.

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References

  1. Larkai EN, Smith JL, Lidsky MD, et al. Dyspepsia in NSAID users: the size of the problem. J Clin Gastroenterol 1989; 11: 158–62

    Article  PubMed  CAS  Google Scholar 

  2. Ofman JJ, Maclean CH, Straus WL, et al. Meta-analysis of dyspepsia and nonsteroidal antiinflammatory drugs. Arthritis Rheum 2003; 49: 508–18

    Article  PubMed  CAS  Google Scholar 

  3. Graham DY, White RH, Moreland LW, et al. Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs. Misoprostol Study Group. Ann Intern Med 1993; 119: 257–62

    PubMed  CAS  Google Scholar 

  4. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 1075–8

    Article  PubMed  CAS  Google Scholar 

  5. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123: 241–9

    PubMed  CAS  Google Scholar 

  6. Hawkey C, Talley NJ, Yeomans ND, et al. Improvements with esomeprazole in patients with upper gastrointestinal symptoms taking non-steroidal antiinflammatory drugs, including selective COX-2 inhibitors. Am J Gastroenterol 2005; 100: 1028–36

    Article  PubMed  CAS  Google Scholar 

  7. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999; 282: 1929–33

    Article  PubMed  CAS  Google Scholar 

  8. Lisse JR, Perlman M, Johansson G, et al. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med 2003; 139: 539–46

    PubMed  CAS  Google Scholar 

  9. Tanaka A, Araki H, Hase S, et al. Up-regulation of COX-2 by inhibition of COX-1 in the rat: a key to NSAID-induced gastric injury. Aliment Pharmacol Ther 2002; 16 suppl. 2: 90–101

    Article  PubMed  CAS  Google Scholar 

  10. Wallace JL, McKnight W, Reuter BK, et al. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 2000; 119: 706–14

    Article  PubMed  CAS  Google Scholar 

  11. Scheiman JM. Gastroduodenal safety of cyclooxygenase-2 inhibitors. Curr Pharm Des 2003; 9: 2197–206

    Article  PubMed  CAS  Google Scholar 

  12. 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: 1520–8

    Article  PubMed  CAS  Google Scholar 

  13. 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: 1247–55

    Article  PubMed  CAS  Google Scholar 

  14. Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995; 310: 827–30

    Article  PubMed  CAS  Google Scholar 

  15. Kelly JP, Kaufman DW, Jurgelon JM, et al. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996; 348: 1413–6

    Article  PubMed  CAS  Google Scholar 

  16. Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998; 338: 727–34

    Article  PubMed  CAS  Google Scholar 

  17. Bensen W, Weaver A, Espinoza L, et al. Efficacy and safety of valdecoxib in treating the signs and symptoms of rheumatoid arthritis: a randomized, controlled comparison with placebo and naproxen. Rheumatology (Oxford) 2002; 41: 1008–16

    Article  CAS  Google Scholar 

  18. Desjardins PJ, Mehlisch DR, Chang DJ, et al. The time to onset and overall analgesic efficacy of rofecoxib 50 mg: a meta-analysis of 13 randomized clinical trials. Clin J Pain 2005; 21: 241–50

    Article  PubMed  Google Scholar 

  19. 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: 2106–11

    Article  PubMed  CAS  Google Scholar 

  20. Makarowski W, Zhao WW, Bevirt T, et al. Efficacy and safety of the COX-2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized, double-blind, placebo-controlled comparison with naproxen. Osteoarthritis Cartilage 2002; 10: 290–6

    Article  PubMed  CAS  Google Scholar 

  21. 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: 395–402

    Article  PubMed  CAS  Google Scholar 

  22. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115: 787–96

    PubMed  CAS  Google Scholar 

  23. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet 1994; 343: 769–72

    Article  PubMed  CAS  Google Scholar 

  24. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002; 359: 14–22

    Article  PubMed  CAS  Google Scholar 

  25. Cox ER, Frisse M, Behm A, et al. Over-the-counter pain reliever and aspirin use within a sample of long-term cyclooxygenase 2 users. Arch Intern Med 2004; 164: 1243–6

    Article  PubMed  Google Scholar 

  26. Battistella M, Mamdami MM, Juurlink DN, et al. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med 2005; 165: 189–92

    Article  PubMed  CAS  Google Scholar 

  27. Dai C, Stafford RS, Alexander GC. National trends in cyclooxygenase-2 inhibitor use since market release: nonselective diffusion of a selectively cost-effective innovation. Arch Intern Med 2005; 165: 171–7

    Article  PubMed  Google Scholar 

  28. Mamdani M, Juurlink DN, Kopp A, et al. Gastrointestinal bleeding after the introduction of COX 2 inhibitors: ecological study. BMJ 2004; 328: 1415–6

    Article  PubMed  Google Scholar 

  29. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102

    Article  PubMed  CAS  Google Scholar 

  30. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005; 365: 475–81

    PubMed  CAS  Google Scholar 

  31. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352: 1081–91

    Article  PubMed  CAS  Google Scholar 

  32. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071–80

    Article  PubMed  CAS  Google Scholar 

  33. US Food and Drug Administration Advisory Committee. COX-2 cardio risk is class effect, but varies by drug and dose, Cmte. Available from: http://www.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Arthritis+Drugs/021805_cox2day3/0216-1805_Cox-2R2.htm. 18 February 2005. Cited: 18 October 2005.

  34. Hayden M, Pignone M, Phillips C, et al. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002; 136: 161–72

    PubMed  CAS  Google Scholar 

  35. Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002; 106: 388–91

    Article  PubMed  Google Scholar 

  36. US Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med 2002; 136: 157–160.

    Google Scholar 

  37. Kim C, Beckles GL. Cardiovascular disease risk reduction in the Behavioral Risk Factor Surveillance System. Am J Prev Med 2004; 27: 1–7

    Article  PubMed  CAS  Google Scholar 

  38. Fries JF, Murtagh KN, Bennett M, et al. The rise and decline of nonsteroidal antiinflammatory drug-associated gastropathy in rheumatoid arthritis. Arthritis Rheum 2004; 50: 2433–40

    Article  PubMed  Google Scholar 

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Correspondence to James M. Scheiman.

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Dr Scheiman has or has had in the recent past relationships (consulting, speakers’ bureau, grant/research support) with the following companies: AstraZeneca, Boehringer Ingelheim, Boston Scientific, McNeil, Merck, Nitromed, Novartis, Pfizer, Pozen, Proctor and Gamble, Santarus, Sirna, TAP Pharmaceuticals, and The GI Company.

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Scheiman, J.M. Unmet Needs in Non-steroidal Anti-inflammatory Drug-induced Upper Gastrointestinal Diseases. Drugs 66 (Suppl 1), 15–21 (2006). https://doi.org/10.2165/00003495-200666001-00004

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