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Non-Steroidal Anti-Inflammatory Agents and the Gastrointestinal Tract

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Non-Steroidal Anti-Inflammatory Agents and the Gastrointestinal Tract Postgrad Med J: first published as 10.1136/pgmj.62.723.23 on 1 January 1986. Downloaded from Postgraduate Medical Journal (1986) 62, 23-28 At our mother's knee - an occasional review Non-steroidal anti-inflammatory agents and the gastrointestinal tract K.W. Somerville and C.J. Hawkey Department ofTherapeutics, University Hospital, Nottingham NG7 2UH, UK. Non-steroidal anti-inflammatory drugs (NSAIDs) pattern with gastritis, mucosal erosions and/or occult have had a bad press recently. The proliferation of bleeding (Roth et al., 1963; Hurley & Crandall, 1964). these widely used agents has attracted the derogatory Similar changes are seen in some animals given high appellation 'me too'. Some, such as benoxaprofen, doses of other NSAIDs but there is wide interspecies zomepirac, indoprofen and a controlled delivery in- variation: unlike rats, domestic pigs have minimal domethacin formulation ('Osmosin'), have been with- duodenal mucosal changes after 15 mg/kg indometh- drawn because of concern about adverse drug effects acin (Rainsford & Willis, 1982). including gastrointestinal bleeding (benoxaprofen) Acute gastro-duodenal changes are described in (Editorial, 1982) and bowel perforation ('Osmosin') man with many NSAIDs and aspirin in particular. For (Day, 1983). Concern has been expressed for as long as example Caruso & Bianchi Porro (1980) compared 10 NSAIDs have been available and there is little doubt NSAIDs plus corticosteroids given to 249 patients that acute administration of many of them causes with arthritis; 78 (31 %) developed lesions in the upper gastric erosions in animals and provokes microscopic gastrointestinal tract identified at gastroscopy during by copyright. bleeding in man. What remains controversial is a 12 month follow-up, more with multiple (51 %) than whether there is a causative link between NSAID single (23%) drug treatment. However, deciding on ingestion and peptic ulceration or important upper the relative merits of the NSAIDs used is difficult; gastrointestinal haemorrhage. despite long-term treatment with these agents, During the last two decades admissions to hospital apparently none of the 249 had mucosal lesions at the and mortality rates for peptic ulcer have fallen in the start of the study and the allocation was not random. UK (Coggon et al., 1981). This is mostly accounted for by changes among the young with little change in the mortality rate for women over 75 years ofage. Aspirin And is it damage or impaired defence? http://pmj.bmj.com/ consumption and smoking have declined and this may be a partial explanation of the overall trend but the What is the precise effect of NSAIDs upon the gastric elderly are major users of other NSAIDs and this mucosa? In many instances, significant damage (gas- might explain the differential ulcer mortality rate tric erosions and petechiae) only occurs when the between old and young. However, the situation is gastric mucosa of NSAID-treated animals is exposed complex. The elderly often have other diseases and to topically injurious or irritant agents such as bile, take other drugs, more prescriptions are issued for ethanol, chillis, or salicylates (Whittle, 1977; Robert et NSAIDs to those under 65 years ofage than those over al., 1983). In the absence ofNSAIDs such agents cause on September 28, 2021 by guest. Protected 65 and the number of prescriptions written has been mucosal reddening, vasodilatation and shedding of steadily increasing in all age groups. There is therefore surface epithelial cells, but few overt breaks in the a need to question our fundamental assumptions mucosa. These studies suggest the NSAIDs do not about NSAIDs. necessarily inflict mucosal damage themselves but rather impair mucosal defence mechanisms. An in- teresting example of this phenomenon is the develop- Do NSAIDs damage the gastro-duodenal mucosa? ment of gastric antral erosions in indomethacin- treated rats after feeding solid food (Satoh et al., Aspirin causes gastric mucosal damage and 1982). The extent of the damage is directly pro- microbleeding. Studies in animals show a consistent portional to the amount of food eaten. Damage does not occur with isocaloric liquid feeds (which Correspondence: K.W. Somerville, M.B., F.R.A.C.P. may even be protective) suggesting that indo- Accepted: 4 July 1985 methacin blocks a mechanism capable of protect- © The Fellowship of Postgraduate Medicine, 1986 Postgrad Med J: first published as 10.1136/pgmj.62.723.23 on 1 January 1986. Downloaded from 24 K.W. SOMERVILLE & C.J. HAWKEY ing the mucosa against direct physical trauma. Continued ingestion It is, of course, widely assumed that this defence mechanism is prostaglandin mediated, and there is In both man and laboratory animals mucosal changes critical evidence in favour of this proposition. can be detected within an hour of a single dose of NSAIDs inhibit gastric mucosal prostaglandin synth- aspirin (O'Laughlin et al., 1981). As judged endos- esis and the enhancement of damage caused by copically and by bleeding into the lumen there is injurious stimuli in their presence is mirrored by a greater damage when further doses are given over 24 greater resistance to damage when prostaglandin and 48 hours (O'Laughlin et al., 1981; Graham et al., levels are increased (whether from endogenous or 1983; Hunt & Franz, 1981). Subsequently, the mucosa exogenous sources) (Robert et al., 1983). seems to adapt and the pattern of injury changes and its extent probably declines: dogs given aspirin over 10 days initially developed erosions but these disap- Salicylates: a special case? peared with continued ingestion (Hurley & Crandall, 1964). At this stage the mucosa remains resistant to Salicylates are different from many other NSAIDs in further aspirin challenge for 48 hours after cessation of acting as topical irritants to the gastric mucosa. The chronic dosing. In man two endoscopic studies have basis ofthis property is ill understood but it is separate agreed that adaptation occurs with continued aspirin from the ability to inhibit prostaglandin synthesis ingestion though the results have been less dramatic (Ligumsky et al., 1982). Sodium salicylate is not an than in the dog. In one study, there were fewer inhibitor ofprostaglandin synthesis in gastric mucosa petechiae (though no fewer erosions) after 7 days than but is a topical irritant: this normally results in trivial after one day of aspirin ingestion (O'Laughlin et al., mucosal damage followed by beneficial adaptive chan- 1981). More recently, the number oferosions has also ges which enhance resistance to further gastric damage been reported to diminish with continued ingestion (Robert, 1981). However, where prostaglandin synth- (Graham et al., 1983). esis is inhibited (as with aspirin, or when sodium salicylate is given after pretreatment with indometh- Do erosions become chronic ulcers? acin) greater damage results than with either inhibitors by copyright. of prostaglandin synthesis or topical irritants alone It is sometimes assumed that erosions represent ulcers (Ligumsky et al., 1982; Steele & Whittle, 1984). at an early stage. There is no evidence that this is so. Indomethacin probably also has topical irritant The evidence of adaptation to aspirin suggests that properties (Chvasta & Cooke, 1972) but the extent to such a progression is at least unusual. It is also which this is true of other NSAIDs and whether assumed that acute gastric mucosal damage assessed topical irritancy amounts to the same as electro- by microbleeding correlates with the chronic physiological breakdown of the gastric mucosal ulcerogenicity of the drug. This too is unproven. In 'barrier' is not known. their endoscopic survey, Caruso & Bianchi Porro Whether the dyspepsia experienced by some (1980) found only two new ulcers and 46% (11/24) hadhttp://pmj.bmj.com/ patients taking some NSAIDs might relate to topical an ulcer recurrence, results little different from those irritancy, or some other property, is also unknown but expected in such patients not given NSAIDs. This there seems no reason necessarily to attribute it to contrasts with the 31% (78/249) who developed other inhibition of prostaglandin synthesis. For NSAIDs more trivial 'gastric lesions'. which are topical irritants gastro-duodenal mucosal damage may be reduced by altering the formulation or mode ofadministration. This mucosal change assessed Is there a NSAID - chronic ulcer association? endoscopically may be obviated by enteric coating of on September 28, 2021 by guest. Protected aspirin but not by buffering (Lanza et al., 1980). Most data come from case-control studies. Given that the association may be weak, the patients are usually taking other drugs and have other illnesses and that Does acute gastric mucosal damage matter? the widely believed NSAID-ulcer link may provide impetus for referral and investigation of a dyspeptic Most animal studies involve acute administration of patient, these studies are often bedevilled by confoun- NSAIDs and observe the development of gastric ding, spurious associations and bias (Kurata et al., erosions. This begs two questions: (1) Do NSAIDs 1982). remain injurious to the gastric mucosa (human or Corticosteroids perhaps are a good example of this animal) with continued ingestion or does adaptation difficulty. Cooke (1967) reviewed the available data occur? (2) Is the relatively trivial damage of a gastric and concluded that there was no evidence of an erosion the first step in the development of chronic association with peptic ulcer. In a widely quoted study
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