Abstract
Nonsteroidal anti-inflammatory drugs are widely used for the treatment of chronic arthropathies, but their gastrointestinal damage remains a significant limitation to their use. In this review, the pathogenic mechanisms through which these drugs are believed to cause gastrointestinal damage are outlined. A better understanding of the pathogenesis of gastric and intestinal injury has resulted in novel strategies that are being employed to develop nonsteroidal anti-inflammatory drugs that do not have significant adverse effects on the gastrointestinal tract.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Blower PR. Nonsteroidal anti-inflammatory drugs. Br J Rheumatol 1993;32(Suppl 4):35–38.
Baum C, Kennedy DL, Forbes MB. Utilization of nonsteroidal antiinflammatory drugs. Arth Rheum 1985;28:686–692.
Epstein AM, Read JL, Winickoff R. Physician beliefs, attitudes, and prescribing behavior for anti-inflammatory drugs. Am J Med 1984;77:313–318.
Wilkens RF. The selection of a nonsteroidal antiinflammatory drug. Is there a difference? J Rheumatol 1992;19(Suppl 36):9–12.
Myers ABR. Salicin in acute rheumatism. Lancet 1876;II:676–677.
Fries JF. NSAID gastropathy: Epidemiology. J Musculoskeletal Med 1991;8:21–28.
Rainsford KD. Introduction and historical aspects of the side-effects of anti-inflammatory analgesic drugs. In: Rainsford KD, Velo JP (eds) Side effects of anti-inflammatory drugs. Part 1: Clinical and epidemiological aspects. Lancaster: MTP Press, 1987;3–26.
Rampton DS. Non-steroidal anti-inflammatory drugs and the lower gastrointestinal tract. Scand J Gastoenterol 1987;22:1–4.
Silvoso G, Ivey KJ, Butt J. Incidence of gastric lesions in patients with rheumatic disease on chronic aspirin therapy. Ann Intern Med 1979;91:517–520.
Upadhyay R, Torley HI, McKinley AW, et al. Iron deficiency anemia in patients with rheumatic disease receiving non-steroidal anti-inflammatory drugs: The role of upper gastrointestinal lesions. Ann Rheum Dis 1990;26:359–362.
Madok R, Mackenzie JA, Lee FD, et al. Small bowel ulceration in patients receiving NSAIDs for rheumatoid arthritis. Q J Med 1986;58:53–58.
Day TK. Intestinal perforation associated with osmotic slow release indomethacin capsules. BMJ 1983;287:1672–1672.
Going J, Canvin J, Sturrock R. Possible precursor of diaphragm disease in the small intestine. Lancet 1993;341:638–639.
Bjarnason I. Hayllar J, Macpherson AJ, et al. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine. Gastroenterology 1993;104:1832–1847.
Morris AJ, Wasson LA, Mackenzie JF. Small bowel enteroscopy in undiagnosed gastrointestinal blood loss. Gut 1992;33:887–889.
Bjarnason I, Zanelli G, Smith T, et al. Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans. Gastroenterology 1987;93:480–489.
Bjarnason I, Zanelli G, Prouse P, et al. Effect of non-steroidal anti-inflammatory drugs on the human small intestine. Drugs 1986;32:35–41.
Langman MJS, Morgan L, Worall A. Use of inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage. BMJ 1985;290:347–349.
Allison MC, Howatson AG, Torrance CJ, et al. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992:327(11):751–756.
Davies NM. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis Col Rec 1995;38(12):1311–1321.
Kaufmann HJ, Taubin HL. Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 1987;107:513–515.
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol 1971;231:232–235.
Whittle BJR, Vane JR. A biochemical basis for the gastrointestinal toxicity of non-steroid anti-rheumatoid drugs. Arch Toxicol 1984;7:315–322.
Vane JR. Mitchell JA, Appleton I, et al. Inducible isoforms of cyclooxygenase and nitric oxide synthetase in inflammation. Proc Natl Acad Sci USA 1994;91:2046–2050.
Kitahhora T, Guth PH. Effect of aspirin plus hydrochloric acid on the gastric microcirculation. Gastroenterology 1987;93:810–817.
Asako H, Kubes P, Wallace JL, et al. Indomethacin-induced leukocyte adherence in mesenteric venules: Role of lipoxygenase products. Am J Physiol 1992;262:G903-G908.
Kitahora T, Guth PH. Effect of aspirin plus hydrochloric acid on the gastric mucosal microcirculation. Gastroenterology 1987;93:810–817.
Andrews FJ, Malcontenti-Wilson C, O'Brien PE. Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa. Am J Physiol 1994;266:G657-G664.
Wallace JL, Keenan CM, Granger DN. Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophildependent process. Am J Physiol 1990;259:G462-G467.
Lee M, Lee AK, Feldman M. Aspirin-induced acute gastric mucosal injury is a neutrophil-dependent process in rats. Am J Physiol 1992;263:G290-G926.
Wallace JL, Arfors K-E, McKnight GW. A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in rabbits. Gastroenterology 1991;100:878–883.
Wallace JL, McKnight W, Miyasaka M, et al. Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury. Am J Physiol 1993;265:G993-G998.
Wallace JL, Granger DN, The pathogenesis of NSAI-Dgastropathy-are neutrophils the culprits? TIPS 1992;13:129–131.
Vaananen PM, Meddings JB, Wallace JL. Role of oxygen-derived free radicals in indomethacin-induced gastric injury. Am J Physiol 1991;261:G470-G475.
Gryglewski RJ, Szczeklik A, Wandzilak M. The effect of six prostaglandins, prostacyclin and iloprost on generation of superoxide anions by human polymorphonuclear leukocytes stimulated by zymosan or fromyl-methionyl-leucyl-phenyl-alanine. Biochem Pharmacol 1987;36:4209–4212.
Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunological inducible TNF/cachectin. Nature 1990:346:274–276.
Kunkel SL, Wiggins RC, Chensue SW, et al. Regulation of macrophage tumor necrosis factor production by prostaglandin E2. Biochem Biophys Res Commun 1986;137:404–410.
Santucci L, Fiorucci S, Giansanti M, et al. Pentoxifylline prevents indomethacin-induced acute mucosal damage in rats: Role of tumour necrosis factor alpha. Gut 1994;35:909–915.
Rothlein R, Czaijkowski M, Kishimoto TK. Intercellular adhesion molecule-1 in inflammatory response. Chem Immunol 1994;50:135–142.
Appleyard CB, McCafferty DM, Tigley AW, et al. Tumor necrosis factor mediation of NSAID-induced gastric damage: Role of leukocyte adherence. Am J Physiol 1996;269:G119-G125.
Wallace JL, Keenan CM, Mugridge KG, et al. Reduction of the severity of experimental gastric and duodenal ulceration by interleukin-1β. Eur J Pharmacol 1990;186:279–284.
Wallace JL, Keenan CM, Cucula M, et al. Mechanisms underlying the protective effects of interleukin 1 in experimental nonsteroidal anti-inflammatory drug gastrogathy. Gastroenterology 1992; 102:1176–1185.
Kubes P, Suzuki M, Granger DN. Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88:4651–4655.
Rubanyi GM, Ho EH, Cantor EH, et al. Cytoprotective function of nitric oxide: Inactivation of superoxide radicals produced by human leukocytes. Biochem Biophys Res Commun 1991; 181:1392–1397.
MacNaughton WK, Cirino G, Wallace JL. Endothelium-derived relaxation factor (nitric oxide) has protective acions in the stomach. Life Sci 1989;45:1869–1876.
Wallace JL, Reuter BK, Cirino G. Nitric oxide-releasing nonsteroidal anti-inflammatory drugs: A novel approach for reducing gastrointestinal toxicity. J Gastroenterol Hepatol 1994;9:S40-S44.
Lopez-Belmonte J, Whittle BJR, Moncada S. The actions of nitric oxide donors in the prevention or induction of injury to the rat gastric mucosa. Br J Pharmacol 1993;108:73–78.
Asako H, Kubes P, Wallace JL, et al. Modulation of leukocyte adhesion in rat mesenteric venules by aspirin and salicylate. Gastroenterology 1992;103:146–152.
Tepperman BL, Whittle BJR. Endogenous nitric oxide and sensory neuropeptides interact in the modulation of the rat gastric microcirculation. Br J Pharmacol 1992;105:171–175.
Brody TM. The uncoupling of oxidative phosphorylation as a mechanism of drug action. Pharmacol Rev 1956;7:335–365.
Glaborg-Jorgensen T, Weis-Fogh US, Neilsen NH, et al. Salicylate and aspirin-induced uncoupling of oxidative phosphorylation in mitochondria isolated from the mucosal membrane of stomach. Scand J Lab Invest 1976;36:649–653.
Somasundarum S, Hayllar H, Rafi S, et al. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: A review and a hypothesis. Scand J Gastroenterol 1995;30:289–299.
Bjarnason I, Smethurst P. Macpherson A, et al. Glucose and citrate reduce the permeability changes caused by indomethacin in humans. Gastroenterology 1992;102:1546–1550.
Rainsford KD. Prevention of indomethacin-induced gastrointestinal ulceration in rats by glucose-citrate formulations: Role of ATP in mucosal defenses. Br J Rheumatol 1987;26(Suppl 2):81.
Hayllar J, Somasandarum S, Sarathchandra P, et al. The synthetic prostaglandins, a glucose and citrate formulation of indomethacin and other agents in preventing NSAID enteropathy in the rat (abstract). Gastroenterology 1991;100(Suppl 1):586.
Davies NM, Wright MR, Jamali F. Glucose/citrate (G/C) gastrointestinal cytoprotective effect: A physiochemical G/C-NSAIDs interaction (abstract). Pharm Res 1995;12(Suppl 357): 8122.
Wallace JL, Cirino G. The development of gastrointestinal sparing nonsteroidal anti-inflammatory drugs. TIPS 1994;15:405–406.
Whittle BJR. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 1981;80:94–98.
Davies GR, Wilkie ME, Rampton DS. Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability. Dig Dis Sci 1993;38:417–425.
Miura S, Suematsu M, Tanaka S. Microcirculatory disturbance in indomethacin-induced intestinal ulcer. Am J Physiol 1991;261: G213-G219.
Akamatsu H, Oguchi M, Nishijima S, et al. The inhibition of free radical generation by human neutrophils through the synergistic effects of metronidazole with palmitoleic acid: A possible mechanism of action of metronidazole in rosacea and acne. Arch Dermatol Res 1991;282:449–454.
Bjarnason I, Hayllar J, Smethurst P, et al. Metronidazole reduces intestinal inflammation and blood loss in non-steroidal antiinflammatory drug-induced enteropathy. Gut 1992;33:1204–1208.
Yamada T, Deitch E, Specian RD, et al. Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation 1993;17:641–662.
Collins AJ, Reid J, Soper CJ, et al. Characteristics of ulcers of the small bowel induced by non-steroidal anti-inflammatory drugs in the rat: Implications for clinical practice. Br J Rheumatol 1995;34:727–731.
Robert A, Asano T. Resistance of germfree rats to indomethacininduced intestinal lesions. Prostaglandins 1977;14:333.
Melarange R, Moore G. Blower PR, et al. A comparison of indomethacin with ibuprofen on gastrointestinal mucosal integrity in conventional and germ-free rats. Aliment Pharmacol Ther 1992;6:67–77.
Kent TH, Cardelli RM, Stamler FW. Small intestinal ulcers and intestinal flora in rats given indomethacin. Am J Pathol 1969;54:237–245.
Satoh H, Guth PH, Grossman MI. Role of bacteria in gastric ulceration produced by indomethacin in the rat: Cytoprotective action of antibiotics. Gastroenterology 1983;84:483–489.
Wax J, Clinger A, Varner P. et al. Relationship of the enterohepatic cycle to ulcerogenesis in the rat small bowel with flufenamic acid. Gastroenterology 1970;58:772–779.
Bjarnason I, Williams, P, Smethurst P, et al. Effect of nonsteroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine. Gut 1986;27:1292–1297.
Davies NM, Wright MR, Jamali F. Antiinflammatory-induced intestinal permeability: Rat is a suitable model. Pharm Res1994;11:1652–1654.
Giercksky K-E, Huseby G, Rugstad H-E. Epidemiology of NSAID-related gastrointestinal side effects. Scand J Gastroenterol 1989;24(Suppl 163):3–8.
Committee on the Safety of Medicines. Non-steroidal antiinflammatory drugs and serious gastrointestinal adverse reactions-2. BMJ 1986;292:1190–1191.
Boyce S, Chan CC, Gordon R, et al. L-745,337: A selective inhibitor of cyclooxygenase-2 elicits antinociception but not gastric ulceration in rats. Neuropharmacology 1994;33:1609–1611.
Masferrer JL, Zweifel BS, Manning PT, et al. Selective inhibition of inducible cyclooxygenase in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad Sci USA 1994;91:3228–3232.
Morham SG, Langenbach RL, Loftin CD, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 1995;83:473–482.
Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 1995;378:406–409.
Lagenbach R, Morham SG, Tiano HF, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995;83:483–492.
Appleton I, Tomlinson A, Willoughby DA. Inducible cyclooxygenase (COX-2): A safer therapeutic target? Brit J Rheumatol 1994;33:410–411.
Reuter BK, Cirino G, Wallace JL. Markedly reduced intestinal toxicity of a diclofenac derivative. Life Sci 1994;55:1–8.
Wallace JL, Reuter B, Cicala C, et al. A diclofenac derivative without ulcerogenic properties. Eur J Pharm 1994;257:249–255.
Wallace JL, Reuter B, Cicala C, et al. Novel nonsteroidal antiinflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology 1994;107:173–179.
Cuzzolin L, Conforti A, Adami A, et al. Anti-inflammatory potency and gastrointestinal toxicity of a new compound, nitronaproxen. Pharmacol Res 1995;31:61–65.
Wallace JL, McKnight W, Del Soldato P, et al. Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative. J Clin Invest 1995;96:2711–2718.
Takeuchi K, Ohuchi T, Miyake H, et al. Endogenous nitric oxide in gastric alkaline response in the rat stomach after damage. Gastroenterology 1990;106:367–374.
Brown JF, Hanson PJ, Whittle BJR. Nitric oxide donors increase mucus gel thickness in rat stomach. Eur J Pharmacol 1992;223:10–104.
Brown JF, Keates AC, Hanson PJ, et al. Nitric oxide generators and cGMP stimulate mucus secretion by rat gastric mucosal cells. Am J Physiol 1993;265:G418-G422.
Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 1991;43:109–141.
Elliot SN, McKnight W, Cirino G, et al. A nitric oxide-releasing NSAID accelerates gastric ulcer healing in rats. Gastroenterology 1995;109:524–530.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Davies, N.M., Wallace, J.L. Nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: New insights into an old problem. J Gastroenterol 32, 127–133 (1997). https://doi.org/10.1007/BF01213310
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01213310