Download PDF
Endoscopy 1999; 31(9): 761-767
DOI: 10.1055/s-1999-75
Review
Georg Thieme Verlag Stuttgart ·New York

Adverse Effects of Nonsteroidal Anti-Inflammatory Drugs on the Small and Large Bowel

A. R. J. Schneider 1 , C. Benz 1 , C. Beermann 2 , A. Schiebeler 3 , J. F. Riemann 1
  • Medical Department C, Gastroenterology, Hepatology and Diabetes Care, Klinikum Ludwigshafen, Academic Hospital of the University of Mainz, Germany
Further Information

Publication History

Publication Date:
31 December 1999 (online)

Also available at
    Permissions and Reprints

Nonsteroidal anti-inflammatory drugs (NSAID) account for a large part of prescriptions and self-administered medication worldwide. The adverse effects on the upper gastrointestinal tract are well documented. However, in an increasing number of publications adverse effects in the small and large intestine distal to the duodenum are being reported. This paper provides an updated review of current as well as earlier literature on the pathogenesis of such adverse effects and the potential damage to the small and large bowel caused by NSAID. In addition, suggestions for an appropriate diagnostic workup of NSAID damage are discussed.

References

  • 1 Barrier C H, Hirschowitz B I. Controversies in the detection and management of nonsteroidal anti-inflammatory drug-induced side-effects of the upper gastrointestinal tract.  Arthritis Rheum. 1989;  32 926-932
    PubMedGoogle Scholar
  • 2 Bloom B S. Risk and cost of gastrointestinal side-effects associated with nonsteroidal anti-inflammatory drugs.  Arch Intern Med. 1989;  149 1019-1022
    CrossrefPubMedGoogle Scholar
  • 3 Langman M J. Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use.  Gastroenterology. 1989;  96 640-646
    PubMedGoogle Scholar
  • 4 Griffin M R. Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury.  Am J Med. 1998;  104 23-29S
    PubMedGoogle Scholar
  • 5 Griffin M R, Piper J M, Daugherty J R, et al. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.  Ann Intern Med. 1991;  114 257-263
    CrossrefPubMedGoogle Scholar
  • 6 Osnes M, Larsen S, Eidsaunet W, et al. Effect of diclofenac and naproxen on gastroduodenal mucosa.  Clin Pharmacol Ther. 1979;  26 399-405
    PubMedGoogle Scholar
  • 7 Larkai E N, Smith J L, Lidsky M D, et al. Gastroduodenal mucosa and dyspeptic symptoms in arthritic patients during chronic nonsteroidal anti-inflammatory drug use.  Am J Gastroenterol. 1987;  82 1153-1158
    PubMedGoogle Scholar
  • 8 Duggan J M, Dobson A J, Johnson H, Fahey P. Peptic ulcer and nonsteroidal anti-inflammatory agents.  Gut. 1986;  27 929-933
    PubMedGoogle Scholar
  • 9 Traversa G, Walker A M, Ippolito F M, et al. Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs.  Epidemiology. 1995;  6 49-54
    PubMedGoogle Scholar
  • 10 Waye J D. Enteroscopy.  Gastrointest Endosc. 1997;  46 247-256
    PubMedGoogle Scholar
  • 11 Larkai E N, Smith J L, Lidsky M D, et al. Gastroduodenal mucosa and dyspeptic symptoms in arthritic patients during chronic nonsteroidal anti-inflammatory drug use.  Am J Gastroenterol. 1987;  82 1153-1158
    PubMedGoogle Scholar
  • 12 Bellary S V, Isaacs P E, Lee F I. Upper gastrointestinal lesions in elderly patients presenting for endoscopy; relevance of nonsteroidal anti-inflammatory drug usage.  Am J Gastroenterol. 1991;  86 961-964
    PubMedGoogle Scholar
  • 13 Baker P N, Williamson J G, Louden K A. Possible low-dose-aspirin-induced gastropathy.  Lancet. 1992;  339 550
    PubMedGoogle Scholar
  • 14 Wallace J L, Bak A, McKnight W, et al. Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity.  Gastroenterology. 1998;  115 101-109
    PubMedGoogle Scholar
  • 15 Hawkey C, Kahan A, Steinbruck K, et al. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. International MELISSA study group. Meloxicam large-scale international study safety assessment.  Br J Rheumatol. 1998;  37 937-945
    CrossrefPubMedGoogle Scholar
  • 16 Gabriel S E, Jaakimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis.  Ann Intern Med. 1991;  15 787-796
    PubMedGoogle Scholar
  • 17 Griffin M R, Ray W A, Schaffner W. Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly patients.  Ann Intern Med. 1988;  109 359-363
    PubMedGoogle Scholar
  • 18 Ivey K J. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Actions of therapeutic agents.  Am J Med. 1988;  84 41-48
    CrossrefPubMedGoogle Scholar
  • 19 McCormack K, Brune K. Classical absorption theory and the development of gastric mucosal damage associated with the nonsteroidal anti-inflammatory drugs.  Arch Toxicol. 1987;  60 261-269
    PubMedGoogle Scholar
  • 20 Yeomans N D, Skeljo M V, Giraud A S. The role of acid regulation in the treatment of NSAID-induced mucosal damage.  Digestion. 1992;  51 3-10
    PubMedGoogle Scholar
  • 21 Scheiman J M. NSAID-induced peptic ulcer disease: a critical review of pathogenesis and management.  Dig Dis Sci. 1994;  12 210-222
    PubMedGoogle Scholar
  • 22 Schoen R T, Vender R J. Mechanisms of nonsteroidal anit-inflammatory drug-induced gastric damage.  Am J Med. 1989;  86 449-458
    CrossrefPubMedGoogle Scholar
  • 23 Lanza F L. A guideline for the treatment and prevention of NSAID-induced ulcers.  Am J Gastroenterol. 1998;  93 2037-2046
    CrossrefPubMedGoogle Scholar
  • 24 Reuter B K, Davies N M, Wallace J L. Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria and enterohepatic circulation.  Gastroenterology. 1997;  112 109-117
    PubMedGoogle Scholar
  • 25 Bjarnason I, Hayllar J, MacPherson A J, et al. Sice-effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans.  Gastroenterology. 1993;  104 1832-1847
    CrossrefPubMedGoogle Scholar
  • 26 Wallace J L. Nonsteroidal anti-inflammatory drugs and gastroenteropahty: the second hundred years.  Gastroenterology. 1997;  112 1000-1016
    PubMedGoogle Scholar
  • 27 Allison M C, Howatson A G, Torrance C J, et al. Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs.  N Engl J Med. 1992;  327 749-754
    CrossrefPubMedGoogle Scholar
  • 28 Bjarnason I, Zanelli G, Smith T, et al. Nonsteroidal anti-inflammatory drug induced inflammation in humans.  Gastroenterology. 1987;  93 480-489
    PubMedGoogle Scholar
  • 29 Lang J, Price A B, Levi A J. Diaphragm disease: pathology of disease of the small intestine induced by nonsteroidal anit-inflammatory drugs.  J Clin Pathol. 1988;  41 516-526
    CrossrefPubMedGoogle Scholar
  • 30 Speed C A, Bramble M G, Corbett W A, et al. Nonsteroidal anti-inflammatory induced diaphragm disease of the small intestine: complexities of diagnosis and management.  Br J Rheumatol. 1994;  33 778-780
    PubMedGoogle Scholar
  • 31 Bjarnason I, Price A B, Zanelli G, et al. Clinicopathological features of nonsteroidal anti-inflammatory drug-induced small intestinal strictures.  Gastroenterology. 1988;  94 1070-1074
    PubMedGoogle Scholar
  • 32 Day T K. Intestinal perforation associated with slow release indomethacin capsules.  Br Med J. 1983;  287 1671-1672
    PubMedGoogle Scholar
  • 33 Laidler P, Maslin S C, Gilhome R W. What's new in Osmosin and intestinal perforation?.  Path Res Pract. 1985;  180 74-76
    PubMedGoogle Scholar
  • 34 Saw K C, Quick C RG, Higgins A F. Ileocaecal perforation and bleeding are NSAID responsible?.  J R Sic Med. 1990;  83 114-115
    PubMedGoogle Scholar
  • 35 Langman M JS, Morgan L, Worrall A. Use of anti-inflammatory drugs by patients with small or large bowel perforation and haemorrhage.  Br Med J. 1985;  290 347-349
    CrossrefPubMedGoogle Scholar
  • 36 Wilcox C M, Alexander L N, Cotsonis G, et al. Nonsteroidal anti-inflammatory drugs are associated with both upper and lower gastrointestinal bleeding.  Dig Dis Sci. 1997;  42 990-997
    CrossrefPubMedGoogle Scholar
  • 37 Wilson R G, Smith A N, MacIntyre I MC. Complications of diverticular disease and nonsteroidal anti-inflammatory drugs. A prospective study.  Br J Surg. 1990;  77 1103-1104
    CrossrefPubMedGoogle Scholar
  • 38 Campbell K, Steele R JC. Nonsteroidal anti-inflammatory drugs and complicated diverticular disease: a case-control study.  Br J Surg. 1991;  78 190-191
    PubMedGoogle Scholar
  • 39 Aldoori W H, Goivannucci E L, Rimm E B, et al. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men.  Arch Fam Med. 1998;  7 255-260
    CrossrefPubMedGoogle Scholar
  • 40 Hall R I, Petty A H, Cobden I. Enteritis and colitis associated with mefenamic acid.  Br Med J. 1983;  287 1182
    PubMedGoogle Scholar
  • 41 Doman D B, Goldberg H J. A case of meclofenamate sodium-induced colitis.  Am J Gastroenterol. 1986;  81 1220-1221
    PubMedGoogle Scholar
  • 42 Carson J, Notis W M, Orris E S. Colonic ulceration and bleeding during diclofenac therapy.  N Engl J Med. 1990;  323 135
    PubMedGoogle Scholar
  • 43 Tanner A R, Raghunat H. Colonic inflammation and NSAID administration. An assessment of the frequency of the problem.  Digestion. 1988;  41 116-120
    PubMedGoogle Scholar
  • 44 Rampton D S, Sladen G E. Relapse of ulcerative protocolitis during treatment with NSAID.  Postgrad Med J. 1981;  57 297-299
    PubMedGoogle Scholar
  • 45 Evans J MM, McMahon A D, Murray F E, et al. Nonsteroidal anti-inflammatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease.  Gut. 1997;  40 619-622
    PubMedGoogle Scholar
  • 46 Benz C, Martin W R, Arnold J, et al. Endoscopic study of the small intestine with push enteroscopy. A prospective study.  Dtsch Med Wochenschr. 1997;  27 391-395
    PubMedGoogle Scholar
  • 47 Morris A J, Madhok R, Sturrock R D. Enteroscopic diagnosis of small bowel ulceration in patients receiving nonsteroidal anti-inflammatory drugs.  Lancet. 1991;  337 520
    CrossrefPubMedGoogle Scholar
  • 48 Morris A J, Wasson L A, MacKenzie J F. Small bowel enteroscopy in undiagnosed gastrointestinal blood loss.  Gut. 1992;  33 887-889
    PubMedGoogle Scholar
  • 49 Abrahamian G A, Polhamus C D, Muskat P, et al. Diaphragm-like strictures of the ileum associated with NSAID use: a rare complication.  South Med J. 1998;  91 395-397
    PubMedGoogle Scholar
  • 50 Achanta K K, Petros J G, Cave D R, et al. Use of intraoperative enteroscopy to diagnose nonsteroidal anti-inflammatory drug injury to the small intestine.  Gastrointest Endosc. 1999;  49 544-546
    PubMedGoogle Scholar
  • 51 Ress A M, Benacci J C, Sarr M G. Efficacy of intraoperative enteroscopy in diagnosis and prevention of recurrent, occult gastrointestinal bleeding.  Am J Surg. 1992;  163 94-98
    CrossrefPubMedGoogle Scholar
  • 52 Madhok R, MacKenzie J A, Lee F D, et al. Small bowel ulceration in patients receiving nonsteroidal anti-inflammatory drugs for rheumatoid arthritis.  Q J Med. 1986;  58 53-58
    PubMedGoogle Scholar
  • 53 Bielecki J W, Gebbers J O, Filippini L. Segmental small intestine lesions after taking nonsteroidal antirheumatic drugs.  Dtsch Med Wochenschr. 1995;  120 436-441
    PubMedGoogle Scholar
  • 54 Matsuhashi N, Yamada A, Hiraishi M, et al. Multiple strictures of the small intestine after long-term nonsteroidal anti-inflammatory drug therapy.  Am J Gastroenterol. 1992;  87 1183-1186
    PubMedGoogle Scholar
  • 55 Kwo P Y, Tremaine W J. Nonsteroidal anti-inflammatory drug-induced enteropathy: case discussion and review of the literature.  Mayo Clin Proc. 1995;  70 55-61
    PubMedGoogle Scholar
  • 56 Zalev A H, Gardiner G W, Warren R E. NSAID injury to the small intestine.  Abdom Imaging. 1998;  23 40-44
    CrossrefPubMedGoogle Scholar
  • 57 Bernsdorff K R, Agrawal R M, Brodmerkel G J. Nonsteroidal anti-inflammatory drugs: gastroduodenal injury and beyond.  Digest Dis. 1995;  13 251-266
    PubMedGoogle Scholar
  • 58 Hirschowitz B I. Nonsteroidal anti-inflammatory drugs and the gut.  South Med J. 1996;  89 259-263
    PubMedGoogle Scholar
  • 59 Bjorkman D. Nonsteroidal anti-inflammatory drug-associated toxicity of the liver, lower gastrointestinal tract, and esophagus.  Am J Med. 1998;  105 17-21S
    CrossrefPubMedGoogle Scholar
  • 60 Davies N M, Jamali F, Skeith K J. Nonsteroidal anti-inflammatory drug-induced enteropathy and severe chronic anemia in a patient with rheumatoid arthritis.  Arthritis Rheum. 1996;  39 321-324
    PubMedGoogle Scholar
  • 61 Davies N M, Wallace J L. Nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: new insights into an old problem.  J Gastroenterol. 1997;  32 127-133
    CrossrefPubMedGoogle Scholar
  • 62 Morris A J. Nonsteroidal anti-inflammatory drug enteropathy.  Gastrointest Endosc Clin N Am. 1999;  9 125-133
    PubMedGoogle Scholar
  • 63 Bjarnason I, Peters T J. Influence of anti-rheumatic drugs on gut permeability and on the gut associated lymphoid tissue.  Baillieres Clin Rheumatol. 1996;  10 165-176
    PubMedGoogle Scholar
  • 64 Davies N M. Review article: nonsteroidal anti-inflammatory drug-induced gastrointestinal permeability.  Aliment Pharmacol Ther. 1998;  12 303-320
    CrossrefPubMedGoogle Scholar
  • 65 Kessler W F, Shires G T, Fahey T J. Surgical complications of nonsteroidal anti-inflammatory drug-induced small bowel ulceration.  J Am Coll Surg. 1997;  185 250-254
    CrossrefPubMedGoogle Scholar
  • 66 Bjarnason I, Zanelli G, Prouse P, et al. Blood and protein loss via small-intestinal inflammation induced by nonsteroidal anti-inflammatory drugs.  Lancet. 1987;  2 711-714
    PubMedGoogle Scholar
  • 67 Sigthorsson G, Tibble J, Hayllar J, et al. Intestinal permeability and inflammation in patients on NSAID.  Gut. 1998;  43 506-511
    CrossrefPubMedGoogle Scholar
  • 68 Buchman A L, Schwartz M R. Colonic ulceration associated with the systemic use of nonsteroidal anti-inflammatory medication.  J Clin Gastroenterol. 1996;  22 224-226
    CrossrefPubMedGoogle Scholar
  • 69 Kirsch M. Nonsteroidal anti-inflammatory drug colopathy: mimicry of Crohn's disease and colon carcinoma.  J Clin Gastroenterol. 1997;  24 121-123
    CrossrefPubMedGoogle Scholar
  • 70 Stamm C, Bukhalter C E, Pearce W, et al. Benign colonic ulcers associated with nonsteroidal anti-inflammatory drug ingestion.  Am J Gastroenterol. 1994;  89 2230-2233
    PubMedGoogle Scholar
  • 71 Davies N M. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine.  Dis Colon Rectum. 1995;  38 1311-1321
    CrossrefPubMedGoogle Scholar
  • 72 Faucheron J L, Parc R. Non-steroidal anti-inflammatory drug-induced colitis.  Int J Colorectal Dis. 1996;  11 99-101
    CrossrefPubMedGoogle Scholar
  • 73 Goff J S, Barnett J L, Pelke T, et al. Collagenous colitis: histopathology and clinical course.  Am J Gastroenterol. 1997;  92 57-60
    PubMedGoogle Scholar
  • 74 Gentric A, Pennec Y L. Diclofenac-induced pseudomembraneous colitis.  Lancet. 1992;  340 126-127
    PubMedGoogle Scholar
  • 75 Romero-Gomez M, Suarez Garcia E, Castro Fernandez M. Pseudomembranous colitis induced by diclofenac.  J Clin Gastroenterol. 1998;  26 228
    PubMedGoogle Scholar
  • 76 Baert F, Hart J, Blackstone M O. A case of diclofenac-induced colitis with focal granulomatous change.  Am J Gastroenterol. 1995;  90 1871-1873
    PubMedGoogle Scholar
  • 77 Sacanella E, Munoz F, Cardellach F, et al. Massive haemorrhage due to colitis secondary to nonsteroidal anti-inflammatory drugs.  Postgrad Med J. 1996;  72 57-58
    PubMedGoogle Scholar
  • 78 Holt S, Rigoglioso V, Sidhu M, et al. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal bleeding.  Dig Dis Sci. 1993;  38 1619-1623
    CrossrefPubMedGoogle Scholar
  • 79 Foutch P G. Diverticular bleeding: are nonsteroidal anti-inflammatory drugs risk factors for hemorrhage and can colonoscopy predict outcome for patients?.  Am J Gastroenterol. 1995;  90 1779-1784
    PubMedGoogle Scholar
  • 80 Peura D A, Lanza F L, Gostout C J, et al. The America College of Gastroenterology bleeding registry: preliminary findings.  Am J Gastroenterol. 1997;  92 924-928
    PubMedGoogle Scholar
  • 81 Lanas A, Serrano P, Bajador E, et al. Evidence of aspirin use in both upper and lower gastrointestinal perforation.  Gastroenterology. 1997;  112 683-689
    CrossrefPubMedGoogle Scholar
  • 82 Gargot D, Chaussade S, d'Alteroche L, et al. Nonsteroidal anti-inflammatory drug-induced colonic strictures: two cases and literature review.  Am J Gastroenterol. 1995;  90 2035-2038
    PubMedGoogle Scholar
  • 83 Eis M F, Watkins B M, Philip A, et al. Nonsteroidal-induced benign strictures of the colon: a case report and review of the literature.  Am J Gastroenterol. 1998;  93 120-121
    CrossrefPubMedGoogle Scholar
  • 84 Miner P B. Factors influencing the relapse of patients with inflammatory bowel disease.  Am J Gastroenterol. 1997;  92 1-4S
    PubMedGoogle Scholar
  • 85 Gut A, Halter F, Ruchti C. Nonsteroidal antirheumatic drugs and acetylsalicylic acid: adverse effects distal to the duodenum.  Schweiz Med Wochenschr. 1996;  126 616-625
    PubMedGoogle Scholar

A.R. J. Schneider

Medical Department C

Klinikum Ludwigshafen

Bremserstrasse 79

67063 Ludwigshafen

Germany

Phone: + 49-621-503-4114

      >