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Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality?

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Abstract

Background

Nonsteroidal anti-inflammatory drugs (NSAIDs), conventional and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely used medications for the treatment of various inflammatory conditions. There is strong evidence of a possible association between the use of these drugs and the relapse of inflammatory bowel diseases (IBD).

Objective

Our objective was to examine the literature regarding the exacerbation of IBD associated with the use of conventional NSAIDs and selective COX-2 inhibitors and the underlying pathogenetic mechanisms.

Study design

We reviewed articles, including original papers, controlled trials, case reports, reviews, and editorials published in English at the PubMed, Scopus Database, and Science Direct database, searching with the following keywords: nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, Coxibs, inflammatory bowel diseases (IBD), ulcerative colitis (UC), Crohn’s disease (CD).

Results

There is substantial evidence that exacerbation of IBD happens after treatment with NSAIDs, but the available data remain conflicting, and it is not clear whether selective COX-2 inhibitors are safer than traditional NSAIDs. However, there is some evidence that selective COX-2 inhibition and COX-1 inhibition (with low-dose aspirin) appear to be well-tolerated in the short term. Regarding the mechanisms of relapse, the reduction of prostaglandins appears to be the hallmark of the NSAIDs adverse effects.

Conclusions

Further randomized, double-blind, controlled trials should be performed to address this issue, and more in vitro studies to identify the pathways involved are required.

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References

  1. Lanas A, Sopena F (2009) Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications. Gastroenterol Clin North Am 38(2):333–352

    Article  PubMed  Google Scholar 

  2. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347(6):417–429

    Article  PubMed  CAS  Google Scholar 

  3. Korzenik JR, Podolsky DK (2006) Selective use of selective nonsteroidal anti-inflammatory drugs in inflammatory bowel disease. Clin Gastroenterol Hepatol 4(2):157–159

    Article  PubMed  Google Scholar 

  4. Takeuchi K, Smale S, Premchand P, Maiden L, Sherwood R, Thjodleifsson B, Bjornsson E, Bjarnason I (2006) Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 4(2):196–202

    Article  PubMed  CAS  Google Scholar 

  5. Generini S, Fiori G, Matucci CM (2002) Therapy of spondyolarthropathy in inflammatory bowel disease. Clin Exp Rheumatol 20(6 Suppl 28):S88–S94

    PubMed  CAS  Google Scholar 

  6. Meyer AM, Ramzan NN, Heigh RI, Leighton JA (2006) Relapse of inflammatory bowel disease associated with use of nonsteroidal anti-inflammatory drugs. Dig Dis Sci 51(1):168–172

    Article  PubMed  CAS  Google Scholar 

  7. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, Lipsky PE (1998) Cyclooxygenase in biology and disease. FASEB J 12(12):1063–1073

    PubMed  CAS  Google Scholar 

  8. Rampton DS, Sladen GE (1981) Relapse of ulcerative proctocolitis during treatment with non-steroidal anti-inflammatory drugs. Postgrad Med J 57(667):297–299

    Article  PubMed  CAS  Google Scholar 

  9. Fries JF, Miller SR, Spitz PW, Williams CA, Hubert HB, Bloch DA (1989) Toward an epidemiology of gastropathy associated with nonsteroidal antiinflammatory drug use. Gastroenterology 96(2 Pt 2 Suppl):647–655

    PubMed  CAS  Google Scholar 

  10. Bonner GF (2001) Exacerbation of inflammatory bowel disease associated with use of celecoxib. Am J Gastroenterol 96(4):1306–1308

    Article  PubMed  CAS  Google Scholar 

  11. Wallace JL (1997) Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 112(3):1000–1016

    Article  PubMed  CAS  Google Scholar 

  12. Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, Verburg KM, Isakson PC, Hubbard RC, Geis GS (1999) Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 354(9196):2106–2111

    Article  PubMed  CAS  Google Scholar 

  13. Gornet JM, Hassani Z, Modiglian R, Lemann M (2002) Exacerbation of Crohn's colitis with severe colonic hemorrhage in a patient on rofecoxib. Am J Gastroenterol 97(12):3209–3210

    Article  PubMed  Google Scholar 

  14. Kurahara K, Matsumoto T, Iida M, Honda K, Yao T, Fujishima M (2001) Clinical and endoscopic features of nonsteroidal anti-inflammatory drug-induced colonic ulcerations. Am J Gastroenterol 96(2):473–480

    Article  PubMed  CAS  Google Scholar 

  15. Bonner GF, Walczak M, Kitchen L, Bayona M (2000) Tolerance of nonsteroidal antiinflammatory drugs in patients with inflammatory bowel disease. Am J Gastroenterol 95(8):1946–1948

    Article  PubMed  CAS  Google Scholar 

  16. Bonner GF, Fakhri A, Vennamaneni SR (2004) A long-term cohort study of nonsteroidal anti-inflammatory drug use and disease activity in outpatients with inflammatory bowel disease. Inflamm Bowel Dis 10(6):751–757

    Article  PubMed  Google Scholar 

  17. Rahme E, Marentette MA, Kong SX, Lelorier J (2002) Use of NSAIDs, COX-2 inhibitors, and acetaminophen and associated coprescriptions of gastroprotective agents in an elderly population. Arthritis Rheum 47(6):595–602

    Article  PubMed  CAS  Google Scholar 

  18. Puspok A, Kiener HP, Oberhuber G (2000) Clinical, endoscopic, and histologic spectrum of nonsteroidal anti-inflammatory drug-induced lesions in the colon. Dis Colon Rectum 43(5):685–691

    Article  PubMed  CAS  Google Scholar 

  19. Bjarnason I, Hayllar J, Macpherson AJ, Russell AS (1993) Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 104(6):1832–1847

    PubMed  CAS  Google Scholar 

  20. Wallace JL, McKnight W, Reuter BK, Vergnolle N (2000) NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 119(3):706–714

    Article  PubMed  CAS  Google Scholar 

  21. Darling RL, Romero JJ, Dial EJ, Akunda JK, Langenbach R, Lichtenberger LM (2004) The effects of aspirin on gastric mucosal integrity, surface hydrophobicity, and prostaglandin metabolism in cyclooxygenase knockout mice. Gastroenterology 127(1):94–104

    Article  PubMed  CAS  Google Scholar 

  22. Tibble J, Teahon K, Thjodleifsson B, Roseth A, Sigthorsson G, Bridger S, Foster R, Sherwood R, Fagerhol M, Bjarnason I (2000) A simple method for assessing intestinal inflammation in Crohn's disease. Gut 47(4):506–513

    Article  PubMed  CAS  Google Scholar 

  23. Roseth AG, Schmidt PN, Fagerhol MK (1999) Correlation between faecal excretion of indium-111-labelled granulocytes and calprotectin, a granulocyte marker protein, in patients with inflammatory bowel disease. Scand J Gastroenterol 34(1):50–54

    Article  PubMed  CAS  Google Scholar 

  24. Newberry RD, Stenson WF, Lorenz RG (1999) Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med 5(8):900–906

    Article  PubMed  CAS  Google Scholar 

  25. Evans JM, McMahon AD, Murray FE, McDevitt DG, MacDonald TM (1997) Non-steroidal anti-inflammatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease. Gut 40(5):619–622

    PubMed  CAS  Google Scholar 

  26. Felder JB, Korelitz BI, Rajapakse R, Schwarz S, Horatagis AP, Gleim G (2000) Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study. Am J Gastroenterol 95(8):1949–1954

    Article  PubMed  CAS  Google Scholar 

  27. Bonner GF, Fakhri A, Vennamaneni SR (2004) A long-term cohort study of nonsteroidal anti-inflammatory drug use and disease activity in outpatients with inflammatory bowel disease. Inflamm Bowel Dis 10(6):751–757

    Article  PubMed  Google Scholar 

  28. Guslandi M (2006) Exacerbation of inflammatory bowel disease by nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors: fact or fiction? World J Gastroenterol 12(10):1509–1510

    PubMed  CAS  Google Scholar 

  29. Mahadevan U, Loftus EV Jr, Tremaine WJ, Sandborn WJ (2002) Safety of selective cyclooxygenase-2 inhibitors in inflammatory bowel disease. Am J Gastroenterol 97(4):910–914

    Article  PubMed  CAS  Google Scholar 

  30. Sandborn WJ, Stenson WF, Brynskov J, Lorenz RG, Steidle GM, Robbins JL, Kent JD, Bloom BJ (2006) Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study. Clin Gastroenterol Hepatol 4(2):203–211

    Article  PubMed  CAS  Google Scholar 

  31. El Miedany Y, Youssef S, Ahmed I, El Gaafary M (2006) The gastrointestinal safety and effect on disease activity of etoricoxib, a selective cox-2 inhibitor in inflammatory bowel diseases. Am J Gastroenterol 101(2):311–317

    Article  PubMed  CAS  Google Scholar 

  32. Reinisch W, Miehsler W, Dejaco C, Harrer M, Waldhoer T, Lichtenberger C, Vogelsang H (2003) An open-label trial of the selective cyclo-oxygenase-2 inhibitor, rofecoxib, in inflammatory bowel disease-associated peripheral arthritis and arthralgia. Aliment Pharmacol Ther 17(11):1371–1380

    Article  PubMed  CAS  Google Scholar 

  33. Wilcox GM, Mattia AR (2005) Rofecoxib and inflammatory bowel disease: clinical and pathologic observations. J Clin Gastroenterol 39(2):142–143

    PubMed  Google Scholar 

  34. Singer II, Kawka DW, Schloemann S, Tessner T, Riehl T, Stenson WF (1998) Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease. Gastroenterology 115:297–306

    Article  PubMed  CAS  Google Scholar 

  35. Weaver SA, Russo MP, Wright KL, Kolios G, Jobin C, Robertson DA, Ward SG (2001) Regulatory role of phosphatidylinositol 3-kinase on TNF-alpha-induced cyclooxygenase 2 expression in colonic epithelial cells. Gastroenterology 120(5):1117–1127

    Article  PubMed  CAS  Google Scholar 

  36. Biancone L, Tosti C, Geremia A, Fina D, Petruzziello C, Emerenziani S, Pallone F (2004) Rofecoxib and early relapse of inflammatory bowel disease: an open-label trial. Aliment Pharmacol Ther 19(7):755–764

    Article  PubMed  CAS  Google Scholar 

  37. Goh J, Wight D, Parkes M, Middleton SJ, Hunter JO (2002) Rofecoxib and cytomegalovirus in acute flare-up of ulcerative colitis: coprecipitants or coincidence? Am J Gastroenterol 97(4):1061–1062

    Article  PubMed  Google Scholar 

  38. Terhaar Sive Droste JS, Tuynman JB, Van Dullemen HM, Mulder CJ (2006) Chemoprevention for colon cancer: new opportunities, fact or fiction? Scand J Gastroenterol Suppl 243:158–164

    Article  PubMed  CAS  Google Scholar 

  39. Thiefin G, Beaugerie L (2005) Toxic effects of nonsteroidal antiinflammatory drugs on the small bowel, colon, and rectum. Joint Bone Spine 72(4):286–294

    Article  PubMed  Google Scholar 

  40. Rainsford KD (1999) Profile and mechanisms of gastrointestinal and other side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Am J Med 107(6A):27S–35S

    Article  PubMed  CAS  Google Scholar 

  41. Redfern JS, Feldman M (1989) Role of endogenous prostaglandins in preventing gastrointestinal ulceration: induction of ulcers by antibodies to prostaglandins. Gastroenterology 96(2 Pt 2 Suppl):596–605

    PubMed  CAS  Google Scholar 

  42. Tanaka K, Suemasu S, Ishihara T, Tasaka Y, Arai Y, Mizushima T (2009) Inhibition of both COX-1 and COX-2 and resulting decrease in the level of prostaglandins E2 is responsible for non-steroidal anti-inflammatory drug (NSAID)-dependent exacerbation of colitis. Eur J Pharmacol 603(1–3):120–132

    Article  PubMed  CAS  Google Scholar 

  43. Wallace JL (2001) Prostaglandin biology in inflammatory bowel disease. Gastroenterol Clin North Am 30(4):971–980

    Article  PubMed  CAS  Google Scholar 

  44. Dubois RN, Eberhart CF, Williams CS (1996) Introduction to eicosanoids and the gastroenteric tract. Gastroenterol Clin North Am 25(2):267–277

    Article  PubMed  CAS  Google Scholar 

  45. Atchison CR, West AB, Balakumaran A, Hargus SJ, Pohl LR, Daiker DH, Aronson JF, Hoffmann WE, Shipp BK, Treinen-Moslen M (2000) Drug enterocyte adducts: possible causal factor for diclofenac enteropathy in rats. Gastroenterology 119(6):1537–1547

    Article  PubMed  CAS  Google Scholar 

  46. Bjarnason I, Takeuchi K (2009) Intestinal permeability in the pathogenesis of NSAID-induced enteropathy. J Gastroenterol 44(Suppl 19):23–29

    Article  PubMed  CAS  Google Scholar 

  47. Leite AZ, Sipahi AM, Damiao AO, Coelho AM, Garcez AT, Machado MC, Buchpiguel CA, Lopasso FP, Lordello ML, Agostinho CL, Laudanna AA (2001) Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID: a new mechanism. Gut 48(2):163–167

    Article  PubMed  CAS  Google Scholar 

  48. Bjarnason I, Zanelli G, Smith T, Prouse P, Williams P, Smethurst P, Delacey G, Gumpel MJ, Levi AJ (1987) Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans. Gastroenterology 93(3):480–489

    PubMed  CAS  Google Scholar 

  49. Somasundaram S, Rafi S, Hayllar J, Sigthorsson G, Jacob M, Price AB, MacPherson A, Mahmod T, Scott D, Wrigglesworth JM, Bjarnason I (1997) Mitochondrial damage: a possible mechanism of the "topical" phase of NSAID induced injury to the rat intestine. Gut 41(3):344–353

    Article  PubMed  CAS  Google Scholar 

  50. Fortun PJ, Hawkey CJ (2007) Nonsteroidal antiinflammatory drugs and the small intestine. Curr Opin Gastroenterol 23(2):134–141

    PubMed  CAS  Google Scholar 

  51. Hayashi Y, Yamamoto H, Taguchi H, Sunada K, Miyata T, Yano T, Arashiro M, Sugano K (2009) Nonsteroidal anti-inflammatory drug-induced small-bowel lesions identified by double-balloon endoscopy: endoscopic features of the lesions and endoscopic treatments for diaphragm disease. J Gastroenterol 44(Suppl 19):57–63

    Article  PubMed  Google Scholar 

  52. Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Mahler JF, Lee CA, Goulding EH, Kluckman KD, Kim HS, Smithies O (1995) Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 83(3):483–492

    Article  PubMed  CAS  Google Scholar 

  53. Whittle BJ (2004) Mechanisms underlying intestinal injury induced by anti-inflammatory COX inhibitors. Eur J Pharmacol 500(1–3):427–439

    Article  PubMed  CAS  Google Scholar 

  54. Smale S, Tibble J, Sigthorsson G, Bjarnason I (2001) Epidemiology and differential diagnosis of NSAID-induced injury to the mucosa of the small intestine. Best Pract Res Clin Gastroenterol 15(5):723–738

    Article  PubMed  CAS  Google Scholar 

  55. Davies NM, Skjodt NM (1999) Clinical pharmacokinetics of meloxicam. A cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug. Clin Pharmacokinet 36(2):115–126

    Article  PubMed  CAS  Google Scholar 

  56. Wallace JL (2008) Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? Physiol Rev 88(4):1547–1565

    Article  PubMed  CAS  Google Scholar 

  57. Cryer B, Feldman M (1998) Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med 104(5):413–421

    Article  PubMed  CAS  Google Scholar 

  58. Whittle BJ (2000) COX-1 and COX-2 products in the gut: therapeutic impact of COX-2 inhibitors. Gut 47(3):320–325

    Article  PubMed  CAS  Google Scholar 

  59. O'Brien J (2000) Nonsteroidal anti-inflammatory drugs in patients with inflammatory bowel disease. Am J Gastroenterol 95(8):1859–1861

    Article  PubMed  Google Scholar 

  60. Houchen CW, Stenson WF (1999) Cyclooxygenase expression in intestinal epithelial cells. Curr Opin Gastroenterol 15(2):97–99

    Article  PubMed  CAS  Google Scholar 

  61. Hendel J, Nielsen OH (1997) Expression of cyclooxygenase-2 mRNA in active inflammatory bowel disease. Am J Gastroenterol 92(7):1170–1173

    PubMed  CAS  Google Scholar 

  62. Tsubouchi R, Hayashi S, Aoi Y, Nishio H, Terashima S, Kato S, Takeuchi K (2006) Healing impairment effect of cyclooxygenase inhibitors on dextran sulfate sodium-induced colitis in rats. Digestion 74(2):91–100

    Article  PubMed  CAS  Google Scholar 

  63. Camacho-Barquero L, Villegas I, Sanchez-Calvo JM, Talero E, Sanchez-Fidalgo S, Motilva V, Alarcon dlL (2007) Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int Immunopharmacol 7(3):333–342

    Article  PubMed  CAS  Google Scholar 

  64. Williams TJ (1979) Prostaglandin E2, prostaglandin I2 and the vascular changes of inflammation. Br J Pharmacol 65(3):517–524

    PubMed  CAS  Google Scholar 

  65. Cipolla G, Crema F, Sacco S, Moro E, De Ponti F, Frigo G (2002) Nonsteroidal anti-inflammatory drugs and inflammatory bowel disease: current perspectives. Pharmacol Res 46(1):1–6

    Article  PubMed  CAS  Google Scholar 

  66. Reuter BK, Asfaha S, Buret A, Sharkey KA, Wallace JL (1996) Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. J Clin Invest 98(9):2076–2085

    Article  PubMed  CAS  Google Scholar 

  67. Lesch CA, Kraus ER, Sanchez B, Gilbertsen R, Guglietta A (1999) Lack of beneficial effect of COX-2 inhibitors in an experimental model of colitis. Methods Find Exp Clin Pharmacol 21(2):99–104

    Article  PubMed  CAS  Google Scholar 

  68. McCartney SA, Mitchell JA, Fairclough PD, Farthing MJ, Warner TD (1999) Selective COX-2 inhibitors and human inflammatory bowel disease. Aliment Pharmacol Ther 13(8):1115–1117

    Article  PubMed  CAS  Google Scholar 

  69. Sigthorsson G, Crane R, Simon T, Hoover M, Quan H, Bolognese J, Bjarnason I (2000) COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin. Gut 47(4):527–532

    Article  PubMed  CAS  Google Scholar 

  70. Hawkey CJ (2000) Nonsteroidal anti-inflammatory drug gastropathy. Gastroenterology 119(2):521–535

    Article  PubMed  CAS  Google Scholar 

  71. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 231(25):232–235

    PubMed  CAS  Google Scholar 

  72. Sigthorsson G, Jacob M, Wrigglesworth J, Somasundaram S, Tavares I, Foster R, Roseth A, Rafi S, Mahmud T, Simpson R, Bjarnason I (1998) Comparison of indomethacin and nimesulide, a selective cyclooxygenase-2 inhibitor, on key pathophysiologic steps in the pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in the rat. Scand J Gastroenterol 33(7):728–735

    Article  PubMed  CAS  Google Scholar 

  73. Page J, Henry D (2000) Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 160(6):777–784

    Article  PubMed  CAS  Google Scholar 

  74. Singh S, Graff LA, Bernstein CN (2009) Do NSAIDs, antibiotics, infections, or stress trigger flares in IBD? Am J Gastroenterol 104(5):1298–1313

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Clinical Pharmacology, Faculty of Medicine, University of Crete, Crete, Greece

    Helenie Kefalakes, Theodoros J. Stylianides & George Amanakis

  2. Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Dragana, Alexandroupolis, 68100, Greece

    George Kolios

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  1. Helenie Kefalakes
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  2. Theodoros J. Stylianides
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  3. George Amanakis
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  4. George Kolios
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Correspondence to George Kolios.

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Kefalakes, H., Stylianides, T.J., Amanakis, G. et al. Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality?. Eur J Clin Pharmacol 65, 963–970 (2009). https://doi.org/10.1007/s00228-009-0719-3

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