Summary
Aspirin and paracetamol (acetaminophen) are the most commonly used minor analgesics, but their effects on the gastrointestinal tract differ widely. The effects of other non-steroidal anti-inflammatory drugs (NSAIDs), including phenylbutazone, are intermediate. Aspirin is significantly associated with major upper gastrointestinal haemorrhage, whereas paracetamol is not. Short term use of aspirin produces erythema, erosions and occasionally ulcers; paracetamol does not, while other NSAIDs do so to varying degrees. Chronic gastric ulcer is linked to aspirin intake in patients with rheumatic disease, and epidemiologically in all heavy aspirin users. In only one epidemiological study was a paradoxical significant association reported between paracetamol intake and chronic gastric ulcer. Faecal occult blood loss is increased in most regular aspirin users but not in those taking paracetamol. Although formal studies in children have apparently not been made, in isolated small clinical series it has been reported that gastrointestinal bleeding and anaemia do occur in the paediatric age group after the use of aspirin. Pathophysiologically, aspirin alters the gastric mucosal barrier to hydrogen ions and lowers gastric potential difference; paracetamol has no effect on these parameters. Such changes correlate ultrastructurally with damage in surface epithelial cells and microerosions after the use of aspirin, but not after the use of paracetamol. Aspirin and other NSAIDs cause a dramatic reduction in the ability of gastric mucosa to generate protective prostaglandins; however, paracetamol also reduces prostaglandins. Other postulated mechanisms of aspirin damage include reduction in gastric mucosal secretion, reduction in bicarbonate output, and alteration of cell turnover. Because damage to gastric mucosa by aspirin and NSAIDs is often ‘silent’, the clinician needs a high level of suspicion and awareness regarding this problem. In patients prone to gastric damage, or in those with a past history of aspirin-induced gastric damage, paracetamol is the drug of choice when a minor, non-inflammatory problem requires an analgesic.
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References
Alvarez, A.S. and Summerskill, W.H.J.: Gastrointestinal haemorrhage and salicylates. Lancet 2: 920–923 (1958).
Ameer, B. and Greenblatt, D.J.: Paracetamol. Annals of Internal Medicine 87: 202–209 (1977).
Barbour, H.G. and Dickerson, C.: Gastric ulceration produced in rats by oral and subcutaneous aspirin. Archives Internationales de Pharmacodynamie et de Thérapie 58: 78–82 (1938).
Baskin, W.; Ivey, K.J.; Krause, W. and Jeffrey, G.E.: Aspirin-induced ultrastructural changes in human gastric mucosa. Correlation with potential differences. Annals of Internal Medicine 85: 299–303 (1976).
Bowen, B.K.; Krause, W.J. and Ivey, K.J.: Effect of sodium bicarbonate on aspirin-induced damage and potential difference changes in human gastric mucosa. British Medical Journal 2: 1052–1055 (1977).
Brodie, D.A. and Chase, B.J.: Role of gastric acid in aspirin-induced gastric irritation in the rat. Gastroenterology 53: 604–607 (1967).
Chapman, B.B. and Duggan, J.M.: Aspirin and uncomplicated ulcer. Gut 10: 433–437 (1969).
Chvasta, T.E. and Cooke, A.R.: The effect of several ulcerogenic drugs on the canine gastric mucosal barrier. Journal of Laboratory and Clinical Medicine 79: 302–315 (1972).
Coggon, D.; Langman, M.J.S. and Spiegelhalter, D.: Aspirin, paracetamol and haematemesis and melaena. Gut 23: 340–344 (1982).
Cohen, M.M.; McCready, D.; Clark, L. and Sevilius, H.: Prostaglandin analogue averts gastric mucosal injury. Gastroenterology 3: 1–2 (1984).
Croft, D.M.: Aspirin and the exfoliation of gastric epithelial cells. Cytological and biochemical observations. British Medical Journal 1: 137–139 (1967).
Davenport, H.W.: Gastric mucosal injury by fatty and acetylsalicylic acids. Gastroenterology 46: 245–250 (1964).
Davenport, H.W.: Salicylate damage to gastric mucosal barrier. New England Journal of Medicine 276: 1307 (1967).
Davenport, H.W.: Gastric mucosal hemorrhage in dogs. Effects of acid, aspirin and alcohol. Gastroenterology 56: 439–443 (1969).
Djahanguiri, B.: The production of acute gastric ulceration by indomethacin in the rat. Scandinavian Journal of Gastroenterology 4: 265–267 (1969).
Douglas, R.A. and Johnston, E.D.: Aspirin and chronic gastric ulcer. Medical Journal of Australia 2: 893–897 (1961).
Duggan, J.M.: Aspirin ingestion and perforated peptic ulcer. Gut 13: 631–635 (1972).
Eastwood, G.L. and Quimby, G.F.: Effect of chronic aspirin ingestion on epithelial proliferation in rat fundus, antrum and duodenum. Gastroenterology 82: 852–856 (1982).
Goodman, M.J.; Kent, P.W. and Truelove, S.C.: Inhibition of glucosamine synthesis by salicylates, hydrocortisone and two non-ulcerogenic drugs. Archives Internationales de Pharmacodynamie et de Thérapie 226: 4–10 (1977).
Gordon, M.J.; Skillman, J.J.; Edwards, B.G. and Silen, W.: Effect of ethanol, acetylsalicylic acid, paracetamol and ferrous sulphate on gastric mucosal permeability in man. Surgery 76: 405–412 (1974).
Goulston, K. and Cooke, A.R.: Alcohol, aspirin and gastrointestinal bleeding. British Medical Journal 4: 664 (1968).
Goulston, K. and Skyring, A.: Effect of paracetamol on gastrointestinal bleeding. Gut 5: 463–466 (1964).
Graham, D.Y. and Smith, J.L.: Effects of aspirin and an aspirin-acetaminophen combination on the gastric mucosa in normal subjects. Gastroenterology 88: 1922–1925 (1985).
Grossman, M.I.; Matsomoto, K.K. and Lichter, R.S.: Fecal blood loss produced by oral and intravenous administration of various salicylates. Gastroenterology 40: 383 (1961).
Hoftiezer, J.W.; Burks, M.; Silvoso, G.F. and Ivey, K.J.: Comparison of the effects of regular and enteric-coated aspirin on gastroduodenal mucosa of man. Lancet 2: 609–612 (1980).
Hoftiezer, J.W.; O’Laughlin, J.C. and Ivey, K.J.: Comparison of acute effects of regular aspirin, bufferin, and paracetamol on human gastroduodenal mucosa. Gut 23: 692–697 (1982).
Holt, P.R.: Measurement of gastrointestinal blood loss in patients taking aspirin. Journal of Laboratory and Clinical Medicine 56: 717–721 (1943).
Huskisson, E.C.: Anti-inflammatory drugs. Seminars in Arthritis and Rheumatism 7(1): 1–20 (1977).
Ivey, K.J.: Gastric mucosal barrier. Gastroenterology 61: 247–257 (1971).
Ivey, K.J.: Drugs, gastritis and peptic ulcer. Journal of Clinical Gastroenterology 3: 29–34 (1981).
Ivey, K.J. and Roth, J.: Drug and chemical-induced injuries of the stomach; in Berk (Ed.), Brockus Gastroenterology (4th ed. Vol. 2) pp. 975–1003 (W.B. Saunders Company, Philadelphia 1985).
Ivey, K.J. and Settree, P.: Effect of paracetamol (acetaminophen) on gastric ionic fluxes and potential difference in man. Gut 17: 916–919 (1976).
Ivey, K.J.; Morrison, S. and Gray, C.: Effect of oral and intravenous salicylates on the gastric mucosal barrier. Australian and New Zealand Journal of Medicine 1: 301–305 (1971).
Ivey, K.J.; Silvoso, G. and Krause, W.J.: Effect of paracetamol on human gastric mucosa. British Medical Journal 1: 1586–1588 (1978).
Ivey, K.J.; Baskin, W.N.; Krause, W.J. and Terry, B.: The effect of aspirin and acid on human jejunal mucosa: An ultrastructural study. Gastroenterology 76: 50–56 (1979).
Jennings, G.H.: Causal influences in haematemesis and melaena. Gut 6: 1–4 (1965).
Jick, H.L.: Effects of aspirin and paracetamol in gastrointestinal hemorrhage. Results from the Boston Collaborative Drug Surveillance Program. Archives of Internal Medicine 141: 316–321 (1981).
Johnson, L.R. and Overholt, B.F.: Release of histamine into gastric venous blood following injury by acetic and salicylic acid. Gastroenterology 52: 505–509 (1967).
Johnson, P.C. and Driscoll, T.: Comparison of plain and buffered aspirin with paracetamol in regard to gastrointestinal bleeding. Current Therapeutic Research 30: 78–84 (1981).
Katz, A.M.; Pearson, C.M. and Kennedy, J.M.: A clinical trial of indomethacin in rheumatoid arthritis. Clinical Pharmacology and Therapeutics 6: 25–29 (1965).
Kauffman Jr, G.L.: Gastric mucus and bicarbonate secretion in relation to mucosal protection. Journal of Clinical Gastroenterology 3: 45–50 (1981).
Kelly, J.J.: Salicylate ingestion. A frequent cause of gastric hemorrhage. American Journal of the Medical Sciences 232: 119–128 (1956).
Kent, T.H.; Cardelli, R.M. and Stamler, F.W.: Small intestinal ulcers and intestinal flora in rats given indomethacin. American Journal of Pathology 54: 237–245 (1969).
Konturek, S.J.; Obtulowicz, W.; Sito, E.; Oleksy, J.; Wilkin, S. and Kiec-Dembinski, A.: Distribution of prostaglandins in gastric and duodenal mucosa of healthy subjects and duodenal ulcer patients: effect of aspirin and paracetamol. Gut 22: 283–289 (1981).
Langman, M.J.S.: Epidemiologic evidence for the association of aspirin and acute gastrointestinal bleeding. Gut 11: 726–730 (1970).
Lanza, F.; Royer, G.L. and Nelson, R.S.: An endoscopic evaluation of the effects of nonsteroidal anti-inflammatory drugs on the gastric mucosa. Gastrointestinal Endoscopy 21: 103–105 (1975).
Lanza, F.; Royer, G.L.; Nelson, R.S.; Chen, T.T.; Seckman, C.E. and Rack, M.F.: The effects of ibuprofen, indomethacin, aspirin, naproxen and placebo on the gastric mucosa of normal volunteers. A gastroscopic and photographic study. Digestive Diseases and Sciences 24: 823–828 (1979).
Lanza, F.L.; Royer, G.L. and Nelson, R.S.: Endoscopic evaluation of the effects of aspirin, buffered aspirin and enteric-coated aspirin in gastric and duodenal mucosa. New England Journal of Medicine 303: 136–138 (1980).
Lanza, F.; Royer, G.L.; Nelson, R.S.; Chen, T.T.; Seckman, C.E. and Rack, M.F.: A comparative endoscopic evaluation of the damaging effects of non-steroidal anti-inflammatory agents on the gastric and duodenal mucosa. American Journal of Gastroenterology 75: 17–21 (1981).
Leeling, J.L.; Johnson Jr, N. and Helms, R.J.: Effect of paracetamol co-administration on aspirin-induced gastrointestinal bleeding in dogs. Journal of Pharmacy and Pharmacology 33: 61–62 (1981).
Leonards, J.R.: Absence of gastrointestinal bleeding following administration of salicylic acid. Journal of Laboratory and Clinical Medicine 74: 911–915 (1969).
Leonards, J.R. and Levy, G.: The role of dosage form in aspirin-induced gastrointestinal bleeding. Clinical Pharmacology and Therapeutics 8: 400–404 (1969).
Levy, M.: Aspirin use in patients with massive upper gastrointestinal bleeding and peptic ulcer disease: A report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. New England Journal of Medicine 290: 1158–1162 (1974).
Loebl, D.H.; Craig, R.M.; Curie, D.D.; Ridolfo, A.S.; Falk, J. and Schmid, F.R.: Gastrointestinal blood loss: effect of aspirin, fenoprofen, and paracetamol in rheumatoid arthritis as determined by sequential gastroscopy and radioactive fecal markers. Journal of the American Medical Association 237: 976–981 (1977).
Lovgren, O. and Allander, E.: Side effects of indomethacin. British Journal of Medicine 1: 118–122 (1964).
MacDonald, W.C.: Correlation of mucosal histology and aspirin intake in chronic gastric ulcer. Gastroenterology 65: 381–389 (1973).
MacKercher, P.; Ivey, K.J.; Baskin, W.; Krause, W. and Jeffrey, G.: Effect of cimetidine on aspirin-induced human gastric mucosal damage. Gastroenterology 70: 912–916 (1976).
Max, M. and Menguy, R.: Influence of adrenocorticotropin, cortisone, aspirin, and phenylbutazone on the rate of exfoliation and the rate of renewal of gastric mucosal cells. Gastroenterology 58: 329–333 (1970).
Menguy, R.B.: Effects of aspirin on gastric mucus secretion. Surgery, Gynecology and Obstetrics 120: 92–96 (1965).
Moyersolm, M.; Thow, M.S.; Kasterbauder, H.B. and Rowland, M.: Aspirin. Journal of the American Pharmaceutical Association 17: 107–112 (1977).
Muir, A. and Cossa, I.A.: Aspirin and ulcer. British Medical Journal 2: 7–11 (1955).
Murray, H.S.; Strottman, M.P. and Cooke, A.R.: Effect of several drugs on gastric potential difference in man. British Medical Journal 1: 19 (1974).
Nicoloff, D.: The effect of Indocin (indomethacin) on gastric secretion, parietal cell population and ulcer provocation in the dog. Gastroenterology 52: 1111–1115 (1967).
Norcross, B.M.: Treatment of connective tissue disease with a new non-steroidal compound (indomethacin). Arthritis and Rheumatism 6: 290–294 (1963).
Okabe, S.; Tabata, K. and Ishihara, Y.: Indomethacin. Its irritative activity on the gastrointestinal tract of experimental animals; in Pfeiffer (Ed.) Drugs and Peptic Ulcer (Vol. II) pp. 24–25 (CRC Press, Boca Raton, Florida 1982).
O’Laughlin, J.C.; Hoftiezer, J.W. and Ivey, K.J.: Effect of aspirin on the human stomach in normals: Endoscopie comparison of damage produced one hour, 24 hours, and 2 weeks after administration. Scandinavian Journal of Gastroenterology 16(Suppl. 67): 211–214 (1981a).
O’Laughlin, J.C.; Hoftiezer, J.W. and Ivey, K.J.: Healing of aspirin associated peptic ulcer disease despite continued salicylate ingestion. Archives of Internal Medicine 141: 781–783 (1981b).
O’Laughlin, J.C.; Hoftiezer, J.W.; Mahoney, J. and Ivey, K.J.: Does aspirin prolong bleeding from gastric biopsies in man? Gastrointestinal Endoscopy 27(1): 1–5 (1981c).
O’Laughlin, J.C.; Silvoso, G.K. and Ivey, K.J.: Resistance to medical therapy of gastric ulcers in rheumatic disease patients taking aspirin: a double-blind study with cimetidine and follow-up. Digestive Diseases and Sciences 27: 980–997 (1982).
Olson, C.; Guth, P.; Paulsen, G. and Soll, A.H.: Diurnal variation of sensitivity to gastric mucosal injury by ASA/HCl or ethanol in the rat. Gastroenterology 88: 1523 (1985).
Parry, D.J. and Wood, P.N.H.: Relationship between aspirin taking and gastroduodenal haemorrhage. Gut 8: 301–305 (1967).
Phillips, S.F.: Gastric and duodenal ulceration associated with aspirin ingestion. Gastrointestinal Endoscopy 19: 160–163 (1973).
Pierson, R.N.: Aspirin and gastrointestinal bleeding. American Journal of Medicine 31: 259–263 (1961).
Piper, D.W.; Mclntosh, J.H.; Arvotti, D.E.; Fenton, B.H. and McLennan, R.: Analgesic ingestion and chronic peptic ulcer. Gastroenterology 80: 427–432 (1981).
Quick, A.J.: Acetylsalicylic acid as a diagnostic aid in hemostasis. American Journal of the Medical Sciences 254: 392–396 (1967).
Roth, J.L.A.: Report of symposium on salicylates. Gastroenterology 44: 389–391 (1963).
Roth, J.L.A.; Valdez-Dapena, A.; Pieses, P. et al.: Topical action of salicylates in gastrointestinal erosion and hemorrhage. Gastroenterology 44: 146–150 (1963).
Rothermich, N.O.: An extended study of indomethacin. Journal of the American Medical Association 195: 123–127 (1966).
Salter, R.H.: Aspirin and gastrointestinal bleeding. Digestive Diseases and Sciences 13: 38–42 (1968).
Sarfeh, I.J.; Malki, A.; Mason, G.R.; Tarnawski, A.; Mach, T. and Ivey, K.J.: Influence of portal hypertension on ethanol-in-duced gastric mucosal damage. Gastroenterology 82: 1243–1246 (1982).
Satoh, H.; Inada, I.; Hirata, T. and Maki, Y.: Indomethacin produces gastric antral ulcers in the refed rat. Gastroenterology 81: 719–725 (1981a).
Satoh, H.; Inada, I.; Hirata, T. and Maki, Y.: Gastric antral ulcers produced by indomethacin in the rat. I. Method and factors influencing their evolution. Gastroenterology 80: 1271 (1981b).
Satoh, H. and Guth, P.H.: Gastric antral ulcers produced by indomethacin in the rat. III. Role of acid and prostaglandins. Gastroenterology 80: 1271 (1981c).
Satoh, H.; Guth, P.H. and Grossman, M.I.: Gastric antral ulcers produced by indomethacin in the rat. IV. Role of bacteria. Gastroenterology 80: 1272 (1981d).
Satoh, H.; Guth, P.H. and Grossman, M.I.: The role of bacteria in gastrointestinal ulcers produced by indomethacin in the rat. Clinical Research 29: 35A (1981e).
Satoh, H.; Guth, P.H. and Grossman, M.I.: Role of food in gastrointestinal ulceration produced by indomethacin in the rat. Gastroenterology 83: 10–15 (1982).
Seegers, A.J.M.; Jager, I.P. and Van Noordwijk, J.: Effects of phenacetin, paracetamol and caffeine on the erosive activity of acetylsalicylic acid in the rat stomach: dose-response relationship, time course of erosion development and effects on acid secretion. Journal of Pharmacy and Pharmacology 31: 840–848 (1979).
Silvoso, G.; Ivey, K.J.; Butt, J.; Lockard, O.O.; Holt, S.D.; Sisk, C.; Baskin, W.N.; MacKercher, P.A. and Hewett, J.: Incidence of gastric lesions in patients with rheumatic disease on chronic aspirin therapy. Annals of Internal Medicine 91: 517–520 (1979).
Simmons, T.C.; Weinstein, W.M.; Shapira, M. and Grossman, M.I.: A therapeutic trial of 15 (R)-15-methyl prostaglandin E2in rheumatoid arthritis patients with gastroduodenal lesions. Prostaglandins 21 (Suppl.): 165–173 (1981).
Stern, A.I.; Hogan, D.L.; Kahn, L.H. and Isenberg, J.I.: Protective effect of acetaminophen against aspirin and ethanol-induced damage to the human gastric mucosa. Gastroenterology 86: 728–733 (1984).
St. John, D.J.B. and McDermott, F.T.: Influence of achlorhydria on aspirin-induced occult gastrointestinal blood loss studies in Addisonian pernicious anaemia. British Medical Journal 2: 450–452 (1970).
Strand, L.J.: Upper gastrointestinal effects of newer non-steroidal anti-inflammatory agents; in Pfeiffer (Ed.) Drugs and Peptic Ulcer (Vol. II) pp. 8–24 (CRC Press, Boca Raton, Florida 1982).
Stubbe, L.: Occult blood in faeces after administration of aspirin. British Medical Journal 2: 1062–1064 (1958).
Summerskill, W.H.F. and Alvarez, A.S.: Salicylate anaemia. Lancet 2: 925–928 (1958).
Sutor, A.H.; Bowie, E.J.W. and Owen, C.A.: Effect of aspirin, sodium salicylate, and acetaminophen on bleeding. Mayo Clinical Proceedings 46: 178–182 (1971).
Taylor, L.A. and Crawford, L.M.: Aspirin-induced gastrointestinal lesions in dogs. Journal of the American Veterinary Medical Association 152: 617–623 (1968).
Terano, A.; Mach, T.; Stachura, J.; Tarnawski, A. and Ivey, K.J.: Effect of 16, 16 dimethyl prostaglandin E2 on aspirin-induced damage in rat gastric cultured cells. Gastroenterology 81: 1195–1199 (1982).
Thomas, B.H.; Nera, E.A. and Zeitz, W.: Failure to observe pathology in the rat following chronic dosing with acetaminophen and acetyl salicylic acid. Research Communications in Chemical Pathology and Pharmacology 17: 663–678 (1977).
Vecchio, C.; Fontana, A. and Tavacci, L.: Effetto della soministrazone prolungata di indomethacin sulla mucosa gastrica del ratto. Reumatismo 16: 404 (1964).
Weinstein, W.M.: The diagnoses and classification of gastritis and duodenitis. Journal of Clinical Gastroenterology 3(Suppl. 2): 7–16 (1981).
Weiss, H.J.: Platelet aggregation, adhesion and adenosine diphosphate release in thrombopathia (platelet factor 3 deficiency) — a comparison with Glanzmann’s disease. American Journal of Medicine 43: 570–574 (1967).
Weiss, J.F.: Von Willebrand’s disease-diagnostic criteria. Blood 32: 668–672 (1968).
Weiss, H.J.; Aledort, L.M. and Kochwa, S.: The effect of salicylates on the hemostatic properties of platelets in man. Journal of Clinical Investigation 47: 2169–2173 (1968).
Whitehead, R. (Ed.): Mucosal biopsy of the gastrointestinal tract. Section 1, pp. 1–36 (W.B. Saunders, Philadelphia 1979).
Winawer, S.J.; Bejar, J.; McCray, R.S. and Zamcheck, N.: Aspirin and atrophic gastritis. Archives of Internal Medicine 127: 129–133 (1971).
Wood, P.H.N.: Salicylates and gastrointestinal bleeding (acetylsalicylic acid and aspirin derivatives). British Medical Journal 1: 669–671 (1962).
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Ivey, K.J. Gastrointestinal Intolerance and Bleeding with Non-Narcotic Analgesics. Drugs 32 (Suppl 4), 71–89 (1986). https://doi.org/10.2165/00003495-198600324-00007
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DOI: https://doi.org/10.2165/00003495-198600324-00007