nsaid--induced gastric ulcers: exploring the silent...

INTRODUCTION

NSAID--induced gastric ulcers: Exploring the silent diletntna

RICI IARJ) H I IUNT. FRCP, FACG, FRCPC

T his specia l issue ofTheCanadian}ournalofGastroenrerology is devoted to the proceedings of a sate llite symposium

he ld at the t ime of the Fourth International Course in Therapeut ic Endoscopy which took place in Toronto in October 1989. The symposium , spon~ored hy Searle Canada, took advantage of the large gathering of Canadian and overseas gast roemerologists to d iscuss some of the current controversies surrounding NSAIDs and gastroduodenal damage. T he presen tat ions, given by an in ternational panel of experts, focused on the fo llowing issues: the risk of developing gastric and duodenal les ions and the extent of th is risk with regard ro complicatio ns of bleeding and perfora t ion ; how symptoms should be managed and ulcers Lreated depending upon the ir locat ion ; and prophylaxis, particularly regard ing the problems related tO iden tify ing who should receive prophylactic trc;icment and with what medication .

Studies reporting symptoms in patients taking NSA IDs show a considerable range from l O to 60% with a mean of about one-third of patien ts experienc ing problems at t hree mon ths. But do all symptomat ic patients require investigation and trcatmem ? In many cases severi ty will decline over the first few weeks as 1o lerance develops, and loss of symptoms may coincide wi th a change in the cho ice of NSAID which is often c redited with the improvement. Other a lternatives inc lude red uc ing the dose or giving the

Dr Hant is the I lead of che Dit1ision of Gascroentcrology, De/>arrment of Medicine , Mc Master University, Hamilton , Ontario

Correspondence : Dr Richard /-1 Hunt , McMascer University Medical Centre, I lamilton, Onrariu L8N 325. T elcphone ( 4 16)52 1-2100 ext 6404

CAN J GASTROENTEROL VOL 4 No 3 MAY 1990

NSA ID with food or antac ids, although these approache~ have not been well studied . Few t reatments are effective in cont roll ing the symptoms associated with NSAID inge~tion , although some have suggested tha t the Hz receptor an Lagonists arc effective ( I ) and chat sucra lfatc may he he lpful (2).

At what point should investigation he undertaken ? It seems wise to undertake fu ll investigatio n with endoscopy for patien ts whose symptoms persist, or who experience anemia, weight loss or other symptoms. I lowever, it is clear thm symptoms arc a poor predictor of the presence of an ulcer or subsequen t complica tions. Endoscopy is much better to leraLed in the e lderl y arth ritic pa tient than the double con trast barium meal, as patients can lie comfortably unde r ligh t sedation rathe r than be subjected to extensive maneuvering on the x- ray table.

W h ile there is a general acceptance that NSA!Ds can cause damage to the gast roduodcnal mucosa , the extent of th is risk has been controversia l (1 ). Most studies indicate a relative risk for Lhe prevalence of NSAID-associated gast ric ulcer of 46 t imes the risk of the genera l population , and for duodenal ulcer 8 times (2).

Since the risk of developing a gastric ulcer is considerably greater than for d uodenal ulcer, a causal re lat ionship has been suggested between NSA!Ds and gastric ulceration . In the case of duodenal ulce r, NSAIDs appear to be associated with the exacerbation of a pre-exist ing ulce r diathesis.

T he presence of an ulcer is assoc iated with a significant increase in the risk of complicmions. T he relative risk of complications ranges from 1.4 to 4. 7 in the most reli able studies. T h i:. risk is clearly related to increasing age, and epidem iological evidence suggests as much as a quadrupling

89

lNTROOUC'TION

of the risk of complications o r death in patients taking NSAIDs (3 ). The most recent evidence suggests that the risk of a significant gastrointest inal bleed in an indiv idua l taking an NSAID is between 5 and 6% by the enJ of one year of treatment.

It is thus important to ascertain a history of NSA!D treatment before initiating treatment of symptoms of peptic ulce r. But how should this be undertaken ?

Palients who develop an NSAID-associared ulcer should have the NSAI D stoppcJ, if possible. For those without joint inflamma tion, analgesics provi<le a safer alternative. For patients with persisting inflammatory disease it may be possible to reduce the dose, o r co consider using n onacetylated salicylatcs or perhaps low dose corticosteroids, although these should not be combined with NSAIDs.

T rcatment of the ulcer can be underraken with a variety of ulcer therapies. Full dose H z receptor antagonists or misoprostol can be used to treat gastric ulcer, and a recent study has suggested rapid hea ling in a subset of prepyloric and ga5tric ulce r patients continuing to take NSA IDs and created with omeprazole (4).

For NSAID-associated duoJenal ulcer, Hz receptor antagonists and sucralfate have been shown to heal the ulce r whether or not the NSAID is continued. The results of trials with misoprostol in this situatio n will shortly he available.

H owever, it is the discrepancy between results for gastric and duodenal ulcer in trials of prophylaxis which confound rational prescription. For example, data c urrently show that the PGE, analogue misoprosto l significantly prevents the development of gast ric ulceration in anhritis patients rak ing NSAIDs, and that the H z receptor an tagonist, ranitidine, prevents d uodena l but not gastric ulceration. It is important to point out that whi le these agents have been shown to prevent gastric and duodenal ulcers, respectively, neither has yet been shown to prevent complications. lt is reasonable to

expect, however, that if the incidence ofNSAID-associated ulcers can be signi ficantly reduced , complications may be prevented.

How should we translate this informat ion to clinical practice? S ince the overall risk of complications is about on e in 5500 NSAID prescriptions, and t here were 10.7 millio n prescriptions for NSAIDs in Canada in 1989, the costs o f co-the rapy would be considerable, and prophylaxis is clearly no t appropriate for all pat ients taking an NSAID. Prophylax is should be considered, howeve r, for patients with a previous history of peptic ulce r, especia lly with complications; any elderly patient whose genera l medical condition could no t to lerate an ulcer complication ; and patien ts who con tinue to smoke cigarettes and are thus at significantly greater risk of ulcer recurrence.

90

lf the location of a previous ulcer is known; misoprostol should be chosen for a gastric ulcer and an Hz receptor antagonist for a duodenal ulcer. If the site of previous ulcer is not known, it could be argued tha t since the risk of gastric ulcer is s ignificantly greater while taking NSA!D~ that misoprostol should he given. About one-half of all NSAIDassociated complications occur, however, wi th duodenal ulcers and one might comider an Hz receptor antagonist appropriate. S ince there a re no c lear stud ies w guide us in this instance, e ither d rug would seem an appropriate c hoice until fu rther evidence becomes available.

Ma ny of these controversial issues arc addrcs~cd more fully and e loquently in the contributions to th is symposium. They serve to highligh t the extent of the research which has been undertaken in this perplexing condition, but more importantly, they point the way to further important stud ies which are necessary for better management of this problem in the future. For example, how should patients at risk be identified? Are there risk factors ocher than age? ls rhe sex of the patient important or do more women seem w get thi.s problem simply because more are t reated? Arc patients who are se lected for prophylactic treatment on the basis of previous ulcer or symptoms any different from those who present with complications? While short term, three month studies show that treatments can reduce the incidence of NSAID-associated ulcer, will they pred ictably reduce complications? Finally, what a re the real costs of prophylaxis? These a nd many other questions are likely to he answered in the n ear future, and t he recommendations made here and at the symposium may well c hange as our knowledge evolves. For the time being, however, rhe conclusions of this symposium should serve as a valuable guide.

REFERENCES 1. Bij lsma JWJ. Treacmenc of endoscopy-negative

NSAlD-inJuced upper gastrointestinal symptoms with cimetidine: An international mulricentre collaborative ,tudy. Aliment Pharmacol Thcr 1988;5 I :75-84.

2. Caldwell JR, Roth SH, Wu WL, er al. Sucralface treatment of non-steroidal anti-inflammatory drug-induced gastrointestinal sympcoms and mucosa! damage. Am j Med 1987;83(Suppl 38):74-82.

3. Hawkey CJ. Non-steroidal anti-inflammatory Jrugs and pepuc ulcer. Br Med J l 990;300:278-83.

4. McCarthy DM. Non-steroidal anti -inflammatory drug-induced ulcers: Management by trad itional therapies. Gastroenrerology l 989;96:662-74.

5. Langman MJS. Epidemiologic evidence on che association between peptic ulceration anJ anti-inflammatory drug use. Gastroenterology l 989;96:640-6.

6. Walan A, Gader JP, Classen M, et al. Effect of omeprazole and ranitidine on ulcer healing and relapse races in patients with benign gastric ulcer. N Engl J Med J 989;320:69-75.

CAN J GASTROENTEROL VOL 4 No 3 MAY 1990

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nsaid--induced gastric ulcers: exploring the silent...

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