Skip to main content
Log in

NSAID-Induced Peptic Ulcers and Helicobacter pylori Infection

Implications for Patient Management

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

The conflicting data about the influence of Helicobacter pylori infection on the ulcer risk in patients receiving NSAIDs can be accounted for by the heterogeneity of study designs and the diversified host response to H. pylori. Factors that will affect the outcome include the choice of H. pylori diagnostic tests, previous ulcer complications, concurrent use of acid suppressants, NSAID-naive versus long-term users, low-dose aspirin (acetylsalicylic acid) versus non-aspirin NSAIDs and whether the result was derived from a pre-specified endpoint or post hoc subgroup analysis. Current evidence suggests that H. pylori eradication reduces the ulcer risk for patients who are about to start receiving NSAIDs but not for those who are already on long-term NSAID therapy. Since treatment with a proton pump inhibitor (PPI) worsens H. pylori-associated corpus gastritis, H. pylori should be tested for, and eradicated if present, before starting long-term prophylaxis with PPIs. Patients with H. pylori infection and a history of ulcer complications who require NSAIDs should receive concomitant PPIs or misoprostol after curing the infection. Among patients receiving low-dose aspirin, who have H. pylori infection and previous ulcer complications, long-term treatment with a PPI further reduces the risk of complicated ulcers if H. pylori eradication fails or if patients use concomitant non-aspirin NSAIDs. Current data on the gastric safety of COX-2 selective NSAIDs in H. pylori-infected patients are conflicting. Limited data suggest that the gastroduodenal sparing effect of rofecoxib is negated by H. pylori infection in patients who have had prior upper gastrointestinal events. In light of potential cardiovascular risk with COX-2 selective NSAIDs, it is important to weigh the potential adverse effects against the benefits for an individual patient.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Table I
Table II

Similar content being viewed by others

References

  1. Wallace JL, Tigley AW. New insights into prostaglandins and mucosal defence. Aliment Phalmacol Ther 1995; 9: 227–35

    Article  CAS  Google Scholar 

  2. Takahashi S, Fujita T, Yamamoto A. Nonsteloidal anti-inflammatory drug-induced acute gastric injury in Helicobacter pylori gastritis in Mongolian gerbils. Eur J Phalmacol 2000; 406: 461–8

    Article  CAS  Google Scholar 

  3. Futagami S, Hiratsuka T, Wada K, et al. Inhibition of Helicobacter pylori-induced cyclo-oxygenase-2 aggravates NSAIB-caused gastric damage in Mongolian gerbils. Aliment Pharmacol Ther 2002; 16: 847–55

    Article  PubMed  CAS  Google Scholar 

  4. Keto Y, Ebata M, Tomita K, et al. Influence of Helicobacter pylori infection on healing and relapse of acetic acid ulcers in Mongolian gerbils. Dig Dis Sci 2002; 47: 837–49

    Article  PubMed  Google Scholar 

  5. Kontunek PC, Brzozowski T, Kwiecien S, et al. Effect of Helicobacter pylori on delay in ulcer healing induced by aspirin in rats. Eur J Pharmacol 2002; 451: 191–202

    Article  Google Scholar 

  6. Jackson LM, Wu KC, Mahlda YR, et al. Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa. Gut 2000; 47: 762–70

    Article  PubMed  CAS  Google Scholar 

  7. Chan FK. COX-2 inhibition, H. pylori infection and the risk of gastlointestinal complications. Curr Pharm Des 2003; 9(27): 2213–9

    Article  PubMed  CAS  Google Scholar 

  8. Laine L, Cominelli F, Sloane R, et al. Interaction of NSAIDs and Helicobacter pylori on gastroduodenal injury and prostaglandin production: a controlled double-blind trial. Aliment Pharmacol Ther 1995; 9: 127–35

    Article  PubMed  CAS  Google Scholar 

  9. Kontunek JW, Bembinski A, Kontunek SJ, et al. Infection of Helicobacter pylori in gastric adaptation to continued administration of aspirin in humans. Gastroenterology 1998; 114: 245–55

    Article  Google Scholar 

  10. Wallace JL, Keenan CM, Granger BN. Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophildependent process. Am J Physiol 1990; 259: G462–7

    PubMed  CAS  Google Scholar 

  11. Lee M, Lee AK, Feldman M. Aspirin-induced acute gastric mucosal injury is a neutrophil-dependent process in rats. Am J Physiol 1992; 263: G920–6

    PubMed  CAS  Google Scholar 

  12. Yoshida N, Sugimoto N, Hirayama F, et al. Helicobacter pylori infection potentiates aspirin induced gastric mucosal injury in Mongolian gerbils. Gut 2002; 50: 594–8

    Article  PubMed  CAS  Google Scholar 

  13. Yoshida N, Sugimoto N, Ochiai J, et al. Role of elastase and active oxygen species in gastric mucosal injury induced by aspirin administration in Helicobacter pylori-infected Mongolian gerbils. Aliment Pharmacol Ther 2002; 16Suppl. 2: 191–7

    Article  PubMed  CAS  Google Scholar 

  14. Taha AS, Banhill S, Morran C, et al. Neutrophils, Helicobacter pylori, and nonsteroidal anti-inflammatory drug users. Gastroenterology 1999; 116: 1–7

    Article  Google Scholar 

  15. Rowe PH, Stallingel MU, Kasdon E, et al. Palentelal aspirin and sodium salicylate area equally injurious to the rat gastric mucosa. Gastroenterology 1987; 93: 863–7

    PubMed  CAS  Google Scholar 

  16. Elliott SL, Ferris RJ, Ginaud AS, et al. Indomethacin damage to rat gastric mucosa is markedly dependent on luminal pH. Clin Exp Pharmacol Physiol 1996; 23: 432–4

    Article  PubMed  CAS  Google Scholar 

  17. Wallace JL, McKnight GW. The mucoid cap over superficial gastric damage in the rat: a high-pH microenvironment dissipated by nonsteroidal antiinflammatory drugs and endothelin. Gastroenterology 1990; 99: 295–304

    PubMed  CAS  Google Scholar 

  18. Green Jr FW, Kaplan MM, Curtis LE, et al. Effect of acid and pepsin on blood coagulation and platelet aggregation: a possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978; 74: 38–43

    PubMed  CAS  Google Scholar 

  19. Schmassmann A, Tarnawski A, Peskar BM, et al. Influence of acid and angiogenesis on kinetics of gastric ulcer healing in rats: interaction with indomethacin. Am J Physiol 1995; 268: G276–85

    PubMed  CAS  Google Scholar 

  20. de Witte TJ, Geendink PJ, Lamels CB, et al. Hypochlorhydria and hypergastrinaemia in rheumatoid arthritis. Ann Rheum Bis 1979; 38: 14–7

    Article  Google Scholar 

  21. Labenz J, Tillenburg B, Peitz U, et al. Helicobacter pylori augments the pH-increasing effect of omeprazole in patients with duodenal ulcer. Gastroenterology 1996; 100: 725–32

    Article  Google Scholar 

  22. Gillen B, Wirz AA, Neithercut WD, et al. Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by omeprazole. Gut 1999; 44: 468–75

    Article  PubMed  CAS  Google Scholar 

  23. Yeomans ND, Tulassay Z, Juhasz L, et al. Omeprazole compared with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998; 338: 719–26

    Article  PubMed  CAS  Google Scholar 

  24. Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engi J Med 1998; 338: 727–34

    Article  CAS  Google Scholar 

  25. Ekstrom P, Carling L, Wetterhus S, et al. Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving continuous non-steroidal anti-inflammatory drug therapy: a Nordic multicentre study. Scand J Gastroenterol 1996; 31: 753–8

    Article  PubMed  CAS  Google Scholar 

  26. Graham DY, Lacey SJ, Spjut HJ, et al. Gastric adaptation: studies in humans during continuous aspirin administration. Gastroenterology 1988; 95: 327–33

    PubMed  CAS  Google Scholar 

  27. Konturek JW, Dopinsky A, Stoll R, et al. Mucosal adaptation to aspirin induced gastric damage in humans: studies on blood flow, gastric mucosal growth, and neutrophil activation. Gut 1994; 35: 1197–204

    Article  PubMed  CAS  Google Scholar 

  28. Griffin MR, Piper JM, Daugherty JR, et al. Nonsteroidal antiinflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991; 114: 257–63

    PubMed  CAS  Google Scholar 

  29. Gabriel SE, Jaakkimainen L, Bombardier C. Risks for serious gastrointestinal complications related to the use of non-steroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med 1991; 115: 787–96

    PubMed  CAS  Google Scholar 

  30. Langman MJS, 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 

  31. Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996; 312: 1563–6

    Article  PubMed  CAS  Google Scholar 

  32. Kelly SM, Jenner JR, Dickinson RJ, et al. Increased gastric juice epidermal growth factor after non-steroidal anti-inflammatory drug ingestion. Gut 1994; 35: 611–4

    Article  PubMed  CAS  Google Scholar 

  33. Polk WH, Dempsey PJ, Russell WF. Increased production of transforming growth factor alpha following acute gastric injury. Gastroenterology 1992; 102: 1467–74

    PubMed  CAS  Google Scholar 

  34. Konturek JW, Fischer H, Konturek PC, et al. Heat shock protein 70 (HSP70) in gastric adaptation to aspirin in Helicobacter pylori infection. J Physiol Pharmacol 2001; 52: 153–64

    PubMed  CAS  Google Scholar 

  35. Khoda K, Tanaka K, Aiba Y, et al. Role of apoptosis induced by Helicobacter pylori infection in the development of duodenal ulcer. Gut 1999; 44: 456–62

    Article  Google Scholar 

  36. Moss SF, Calam J, Agarwal B, et al. Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 1996; 38: 498–501

    Article  PubMed  CAS  Google Scholar 

  37. Jones NL, Shannon PT, Cutz E, et al. Increase in proliferation and apoptosis of gastric epithelial cells early in the natural history of Helicobacter pylori infection. Am J Pathol 1997; 151: 1695–703

    PubMed  CAS  Google Scholar 

  38. Leung WK, To KF, Chan FK, et al. Interaction between Helicobacter pylori infection and non-steroidal anti-inflammatory drugs on gastric epithelial cell apoptosis and proliferation: implication on ulcerogenesis. Aliment Pharmacol Ther 2000; 14: 879–85

    Article  PubMed  CAS  Google Scholar 

  39. Zhu GH, Yang XL, Lai KC, et al. Nonsteroidal antiinflammatory drugs could reverse Helicobacter pylori-induced apoptosis and proliferation in gastric epithelial cells. Dig Dis Sci 1998; 43(9): 1957–63

    Article  PubMed  CAS  Google Scholar 

  40. Watanabe K, Hoshiya S, Tokunaga K, et al. Helicobacter pylori and acetylsalicylic acid synergistically accelerate apoptosis via Fas antigen pathway in rabbit gastric epithelial cells. Dig Dis Sci 2002; 47: 809–17

    Article  PubMed  CAS  Google Scholar 

  41. Chan FK. Helicobacter pylori and nonsteroidal anti-inflammatory drugs. Gastroenterol Clin North Am 2001; 30: 937–52

    Article  PubMed  CAS  Google Scholar 

  42. Cullen DJ, Hawkey GM, Greenwood DC, et al. Peptic ulcer bleeding in the elderly: relative roles of Helicobacter pylori and non-steroidal anti-inflammatory drugs. Gut 1997; 41: 459–62

    Article  PubMed  CAS  Google Scholar 

  43. Stack WA, Atherton JC, Hawkey GM, et al. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Aliment Pharmacol Thel 2002; 16: 497–506

    Article  CAS  Google Scholar 

  44. Pilotto A, Franceschi M, Leandro G, et al. The effect of Helicobacter pylori infection on NSAID-related gastroduodenal damage in the elderly. Eur J Gastroenterol Hepatol 1997; 9: 951–6

    Article  PubMed  CAS  Google Scholar 

  45. Pilotto A, Leandro G, Di Mario F, et al. Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the elderly: a case-control study. Dig Dis Sci 1997; 42: 586–91

    Article  PubMed  CAS  Google Scholar 

  46. 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 

  47. Tu TC, Lee CL, Wu CH, et al. Comparison of invasive and noninvasive tests for detecting Helicobacter pylori infection in bleeding peptic ulcers. Gastrointest Endosc 1999; 49: 302–6

    Article  PubMed  CAS  Google Scholar 

  48. Colin R, Czernichow P, Baty V, et al. Low sensitivity of invasive tests for the detection of Helicobacter pylori infection in patients with bleeding ulcer. Gastroenterol Clin Biol 2000; 24: 31–5

    PubMed  CAS  Google Scholar 

  49. Leung WK, Sung JJ, Siu KL, et al. False-negative biopsy urease test in bleeding ulcers caused by the buffering effects of blood. Am J Gastroenterol 1998; 93: 1914–8

    Article  PubMed  CAS  Google Scholar 

  50. Houghton J, Ramamoorthy R, Pandya H, et al. Human plasma is directly bacteriocidal against Helicobacter pylori in vitro, potentially explaining the decreased detection of Helicobacter pylori during acute upper GI bleeding. Gastrointest Endosc 2002; 55: 11–6

    Article  PubMed  Google Scholar 

  51. Taha AS, Sturrock RD, Russell RI. Mucosal erosions in long-term non-steroidal anti-inflammatory drug users: predisposition to ulceration and relation to Helicobacter pylori. Gut 1995; 36: 334–6

    Article  PubMed  CAS  Google Scholar 

  52. Kim JG, Graham DY, The Misoprostol Study Group. Helicobacter pylori infection and the development of gastric or duodenal ulcer in arthritic patients receiving chronic NSAID therapy. Am J Gastroenterol 1994; 89: 203–7

    PubMed  CAS  Google Scholar 

  53. Bianchi Porro G, Parente F, Imbesi V, et al. Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in longterm NSAID users: response to omeprazole dual therapy. Gut 1996; 59: 22–6

    Article  Google Scholar 

  54. Hawkey CJ, Tulassay Z, Szczepanski L, et al. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs Study. Lancet 1998; 352: 1016–21

    Article  PubMed  CAS  Google Scholar 

  55. Lai KC, Lau CS, Ip WY, et al. Effect of treatment of Helicobacter pylori on the prevention of gastroduodenal ulcers in patients receiving long-term NSAIDs: a double-blind, placebo-controlled trial Aliment Pharmacol Ther 2003; 17: 799–805

    Article  PubMed  CAS  Google Scholar 

  56. Chan FK, Chung SC, Suen BY, et al. Prevention of recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking non-steroidal anti-inflammatory drugs. N Engl J Med 2001; 344: 967–73

    Article  PubMed  CAS  Google Scholar 

  57. Chan FK, Sung JY, Chung SC, et al. Randomised trial of eradication of Helicobacter pylori before starting non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997; 350: 975–9

    Article  PubMed  CAS  Google Scholar 

  58. Chan FK, To KF, Wu JC, et al. Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet 2002; 359: 9–13

    Article  PubMed  CAS  Google Scholar 

  59. Labenz J, Blum AL, Bolten WW, et al. Primary prevention of diclofenac associated ulcers and dyspepsia by omeprazole or triple therapy in Helicobacter pylori positive patients: a randomised, double blind, placebo controlled, clinical trial. Gut 2002; 51: 329–35

    Article  PubMed  CAS  Google Scholar 

  60. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002; 346: 2033–8

    Article  PubMed  CAS  Google Scholar 

  61. Chan FK, Sung JY, Suen R, et al. Does eradication of H. pylori impair healing of nonsteroidal anti-inflammatory drug associated bleeding peptic ulcers?: a prospective randomized study. Aliment Pharmacol Ther 1998; 12: 1201–5

    Article  PubMed  CAS  Google Scholar 

  62. Scheiman JM, Bandekar RR, Chernew ME, et al. H. pylori screening for individuals requiring chronic NSAID therapy: a decision analysis. Aliment Pharmacol Ther 2001; 15: 63–71

    Article  PubMed  CAS  Google Scholar 

  63. Goldstein JL, Cornea P, Zhao WW, et al. Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis. Am J Gastroenterol 2001; 96: 1019–27

    Article  PubMed  CAS  Google Scholar 

  64. Goldstein JL, Agrawal NM, Silvenstein FE, et al. Influence of H. pylori infection and/or low-dose aspirin on gastnoduodenal ulceration in patients treated with placebo, celecoxib, or NSAIDs [abstract]. Gastroenterology 1999; 116: A174

    Google Scholar 

  65. Laine L, Bombardier C, Hawkey CJ, et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterology 2002; 123: 1006–12

    Article  PubMed  CAS  Google Scholar 

  66. 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: 1520–8

    Article  PubMed  CAS  Google Scholar 

  67. Graham BY, Agrawal NM, Campbell DR, et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002; 162: 169–75

    Article  PubMed  CAS  Google Scholar 

  68. Graham BY, Opekun AR, Yamaoka Y, et al. Early events in proton pump inhibitor-associated exacerbation of corpus gasiritis. Aliment Pharmacol Ther 2003; 17:193–200

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The author did not receive any financial support in preparing this article and does not have any potential conflicts of interest that are relevant to the contents of the article.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chan, F.K. NSAID-Induced Peptic Ulcers and Helicobacter pylori Infection. Drug-Safety 28, 287–300 (2005). https://doi.org/10.2165/00002018-200528040-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200528040-00002

Keywords

Navigation