Epidemiologic Evidence on the Association Between Peptic Ulceration and Antiinflammatory Drug Use

GASTROENTEROLOGY 1989;96:640-6 Epidemiologic Evidence on the Association Between Peptic Ulceration and Antiinflammatory Drug Use M. J. S. LANGMAN Department of Medicine, Queen Elizabeth Hospital, Birmingham, United Kingdom Adverse effects associated with nonsteroidal antiinflammatory drug treatment are reported more commonly to regulatory authorities than the adverse effects of any other form of treatment. Epidemiologic evidence in general suggests a doubling or quadrupling of the risk of ulcer complications or death in recipients of such treatment. The risk appears to be related to increasing age, but no other associated factor has yet been identified. It is uncertain whether individuals with preexisting ulcer are at special risk or whether treatment predisposed equally to ulcer and ulcer complications, and there is no clear evidence that the nature of the disability leading to nonsteroidal antiinflammatory drug treatment influences the risk of, gastrointestinal complications. Six years ago Kurata et al. (1) criticized the literature associating nonsteroidal antiinflammatory drug (NSAID) use with peptic ulceration and its complications. Amongst other problems, they referred to inadequacies of study design, frequent lack of control data, failure to distinguish new from existing disease, and small size of studies, which did not allow confident conclusions. Since that time a large body of fresh data has been accumulated that describes associations between treatment and the development of endoscopic erosions or frank ulceration, and the frequent association of NSAID use with ulcer perforation, bleeding, and death. In this article the association between exposure to NSAID therapy and peptic ulcer is reviewed. Experimental Data Ulcerative or erosive damage is easily produced by NSAIDs in experimental animals but the doses required tend to be high, and the frequency with which lesions are detected and their site may depend on the circumstances under which experiments are conducted. Thus, if animals are fasted lesions may be proximal, whereas they tend to be distal if animals are fed (2). Experimental studies of gastrointestinal toxicity conducted with NSAIDs generally have included aspirin as a comparator, and damage associated with aspirin has been considerably more extensive, with the implication that nonaspirin NSAIDs are likely to be safer (3). Whether such a conclusion is fair is uncertain. A variety of controlled endoscopic studies conducted in humans have also demonstrated that NSAID use is associated with gastroduodenal erosive change or frank ulceration. These studies demonstrate that gastroduodenal damage can be produced, but the findings, usually obtained in younger individuals, may not necessarily illuminate the risks of treatment in elderly people, who appear the group at increased risk for the major ulcer complications of bleeding and perforation. Furthermore, unless studies involve direct comparisons, it would be unwise to draw conclusions about the comparative toxicity of nonaspirin NSAIDs. The critical evidence about the safety of nonaspirin NSAIDs must therefore be obtained during their clinical use. Methods of Investigating the Association Between Nonsteroidal Antiinflammatory Drug Use and Ulcer Complications Coherent clinical evidence about the possible risks of NSAID treatment can generally be obtained from four sources: (a) adverse reaction reports to national agencies, (b) sets of data collected concern- Abbreviation used in this paper: NSAID, nonsteroidal antiinflammatory drug. 1989 by the American Gastroenterological Association 0016-5085/89/$3.50

February 1989 ANTIINFLAMMATORY DRUGS AND PEPTIC ULCER 641 Table 1. Nonsteroidal Antiinflammatory Drugs Included in the 10 Drugs Most Frequently Reported to Cause Adverse Drug Reactions in 1982 Australia Denmark Finland France Germany Ireland Italy Japan New Zealand Sweden United Kingdom a Reference 4. Indomethacin, naproxen, sulindac Benoxaprofen, fenbufen, ibuprofen Piroxicam, tolfenamic acid Acetylsalicylic acid Benoxaprofen, diclofenac, piroxicam Indomethacin, piroxicam Diclofenac, diflunisal, zomepirac Indomethacin, mefanamic acid, piroxicam, sulindac Naproxen, sulindac Piroxicam Benoxaprofen, fenbufen, piroxicam, zomepirac ing adverse reactions during clinical trials of NSAID therapy, (c) retrospective comparisons of prior NSAID use in patients with ulcer or its complications in matched controls, and (d) the outcome of surveillance studies. The latter may be conducted as formal postmarketing surveillance studies or as a by-product of data generated through schemes, such as prepayment insurance programs, where drug prescriptions can be linked to succeeding events. Spontaneous Reports to Agencies The biases inherent in such data are well known, they are not random samples of events, the rates of reporting are unknown but generally low, and there is a tendency, actively encouraged by the agencies themselves, to collect information about newly released treatments rather than those that are standard. As a consequence, cross-comparisons of frequencies cannot be made between drugs marketed at different times. Even if marketing has taken place in the same time period, differences in approved indications and in marketing strategies, which change the target population, could greatly influence the recorded frequency of adverse events, and these interpretations have to be made with caution. Nevertheless, NSAID-associated adverse events are reported to registration authorities in general and to the Food and Drug Administration in the United States and the Committee on Safety of Medicines in the United Kingdom more frequently than adverse responses for any other drug group (Table 1) (4-6). However, reporting rates are low, being expressed as rates per million, and other evidence suggests that <10% of events are in fact reported. Consideration of individual data sets indicates that most reports concern the elderly and that serious events, including ulcer perforation or bleeding, and subsequent death are frequently described. Differences between reporting rates in individual countries do not necessarily indicate varying risks; they are at least as likely to indicate differences in reporting processes. Thus, a high proportion of reports in the United Kingdom come from individual medical practitioners, whereas there are few such reports in the United States (4). Table 2 contrasts data collected in the United Kingdom and the United States for drugs released in roughly comparable time periods. The figures indicate two general trends: (a) the ordering of drugs in relation to the reporting of adverse effects differed little between the countries and (b) perhaps more importantly, adverse effects were reported with much greater frequency in the United Kingdom than in the United States. The reasons for this difference are unclear. They may relate to the greater frequency with which medical practitioners in the United Kingdom are prepared to report the adverse effects of drugs or they may be due to inherent differences, for unknown reasons, in the propensity of NSAIDs to be associated with gastrointestinal adverse events. Adverse Effects Recorded in Case-Control Studies of the Effectiveness of Nonsteroidal Antiinflammatory Drug Therapy Dyspepsia is commonly reported in trials of NSAID therapy, usually more often in those receiving active treatment than in controls. Such comparative data are valuable because they are obtained' in controlled circumstances, so that any differences in adverse event rates could reasonably be attributed to the treatment and not to confounding extraneous factors. However, the data have the disadvantage that findings may not generalize to the population at large, and particularly to the sick, elderly population who may be at special risk for adverse events. In addition, studies have generally been too small to produce compelling sets of data. One investigation Table 2. Spontaneous Reports of Nonsteroidal Antiinflammatory Drug Side Effects United Kingdom a United States a Piroxicam 58.7 6.5 Tolmetin 41.7 5.9 Diflunisal 33.5 2.8 Naproxen 32.8 3.1 Fenoprofen 32.3 3.0 Sulindac 23.9 3.6 Ibuprofen 6.6 1.8 Figures are rates per million prescriptions in the United Kingdom for the first 5 yr of drug marketing and in the United States for the first 3 yr of drug marketing, adjusted also for secular trends in prescribing. a Reference 5.

642 LANGMAN GASTROENTEROLOGY Vol. 96, No.2, Part 2 was, however, sufficiently large to merit individual attention (7). Two thousand thirty-five individuals were randomly assigned treatment with naproxen (1014) or pirclxicam (1021). Three hundred eightyone and 321 of these, respectively, suffered from at least one gastrointestinal event. Of these, nine and eight events, respectively, were considered s e v ~ e r e However, the authors give little additional detail. Moreover, the lack of double-blind, placebo comparison limits the usefulness of the information. Chalmers et al. (8) attempted to combine data from all placebo-controlled trials of NSAID treatment. Table 3 summarizes the data. The authors had difficulty in combining the symptom categories to obtain a coherent set. Symptoms were, nevertheless, generally common irrespective of categorical method. The data on ulcer occurrence and on hemorrhage are hard to interpret. The recorded frequency of ulcer was low, but possibly because ulcer was seldom sought formally. The. information about the frequency of bleeding also poses problems. Thus, although hemorrhage was recorded in 1 in.50 of all NSAID recipients, it was also noted in 1 in 140 of all placebo recipients. Perforation was not noted. It seems likely that bleeding was usually. trivial., - ~ Retrospective Case-Control Inquiries Into Adverse Effects of Treatment Classical retrospective case-,control studies are open to criticism that bias can arise because questioners inevitably tend to be aware of the diagnoses made in individuals questioned, and so may tend to question one group of subjects more intensively than another. Furthermore, patients themselves, in seeking to rationalize about the occurrence of their illness, may be more likely to remember antecedent factors than controls. Moreover, drug intake varies with age and sex, so that careful matching has to be undertaken. Generally, however, if studies are designed sensibly, the information obtained seems to be reliable; thus retrospectively gathered results tend to match those obtained when data are collected prospectively. Table 3. Meta-analysis of Adverse Events Recorded During 100 Trials of Nonsteroidal Antiinflammatory Drug Therapyo Proven ulcer Hemorrhage Abdominal pain Dyspepsia Unspecified gastric events Placebo 0/758 8/1103 118/2817 64/2148 381/3274 NSAID 2/821 24/1157 175/2856 116/2206 556/3325 NSAID, nonsteroidal antiinflammatory drug. a Reference 5. Table 4. Risk of Gastric Ulcer Associated With Drug Intake Patients Controls Relative risk 95% CI Duggan et al. (9) Total 95 95 Regular a NSAIDs 20 11 5.0 1.4-26.9 Regular a aspirin b 17 6 3.0 0.7-21.3 Mc[ntosh et al. (10) Total 104 208 Dailyc NSAIDs 7 7 4.7 1.3-16.6 Dailyc analgesics 14 5 16.4 5.2-51.6 CI, confidence interval; NSAID, nonsteroidal antiinflammatory drug. a Two or more doses each week in the 3 mo before symptom onset. b Includes compound mixtures, excludes acetaminophen. C In the 1 yr preceding symptom onset. Ulcer occurrence. Duggan et al. (9) conducted a retrospective case-control study in 95 patients with gastric ulcer and 85 patients with duodenal ulcer in Australia and in 180 hospital inpatient and outpatient controls without ulcer. A statistically significant association was found between gastric ulcer and NSAID intake, but none with duodenal ulcer. These results are in agreement with those of Piper and colleagues (10) who found, also in Australia, a significant association of gastric ulcer with NSAID intake and also with smoking. Duodenal ulcer was not studied. The authors calculated that up to fourfifths of gastric ulcer disease might be attributed to smoking, and the daily ingestion of analgesic agents and antiinflammatory drugs. Both investigations used similar methodology with standardiz'ed questionnaires and trained interviewers, which should have minimized bills. Nevertheless, the numbers of elderly subjects would have been small, so that conclusions would not necessarily apply to individuals of all ages. Furthermore, confidence intervals for these risk estimates were often wide (Table 4). In the United Kingdom; Clinch et al. (11) compared the antecedent histories of NSAID intake in a group of patients with an average age of 75 yr who underwent endoscopy because of upper gastrointestinal symptoms and who subsequently proved to have, or not have, peptic ulceration. There was a highly significant association between the detection of lesions and previous NSAID use. No material difference's were, however, detected between the groups when age, smoking habits, and alcohol intake were considered. This study had methodolcigic weaknesses. Endoscopists were unaware of whether there had been prior NSAID intake, but the NSAID histories themselves do not seem to have been collected in a planned manner using a standard questionnaire from the patients but rather were obtained from referring doctors' information and other case records.

February 1989 ANTIINFLAMMATORY DRUGS AND PEPTIC ULCER 643 None of these studies has the ability to discriminate between NSAID use that might exacerbate preexisting ulcer and drug use that caused ulcer to develop de novo. Clinically, it is well known that ulcers that have every indication of chronicity in their histologic appearance may present with acute bleeding or perforation in individuals who deny antecedent symptoms. Ulceration must be assumed to have been present, though silent. McIntosh et al. (10) did take particular pains to study exposure variables before the onset of symptoms, but this approach still cannot be used to determine whether NSAID intake exacerbates silent ulcer or causes ulcer to develop de novo. Complications. Although a number of investigators have drawn attention to the high frequency with which previous NSAID use had taken place in individuais with ulcer complications, there are few controlied sets of data. Collier. and Pain (12) in the United Kingdom compared the antecedent drug intake of 269 patients with perforated ulcer and 269 inpatient controls matched for age and sex. They found that in those 2=:65 yr old there was a highly significant association between NSAID intake and ulcer perforation, either gastric or duodenal. They also drew attention to the parallel between the increasing numbers of patients with NSAID-associated perforation and the increasing number of prescriptions for NSAIDs being issued to the population at large (though not' in the same specific population). They suggested that the association was causal. Again in the United Kingdom, Armstrong and Blower (13) considered 235 patients with life-threatening complications of peptic ulcer who either died or underwent emergency surgery. Seventy-eight of these died, 25 at home and the remainder in hospital. One hundred thirty-seven patients had perforated ulcers, five associated with bleeding, and 98 had bleeding ulcers. The unusually high ratio of perforated to bleeding ulcer reflects the authors' exclusive concentration in the hospital study on patients operated upon. Sixty percent of the total group were recorded as NSAID users, and in 58% of these a life-threatening complication was the first sign of an ulcer. Nearly 80% of the deaths occurred in the patients with ulcer who were NSAID users. The paper by Armstrong and Blower (13) contains unsatisfactory features. An inpatient nonulcer control group was questioned for comparative purposes, but the value of this control is doubtful. Cases and controls were not matched, the groups were not paired, and questioning took place over different time periods and was done by different groups of people. The tendency of the NSAID group in partic- ular to include a high proportion of those dying could reflect the greater average age of these patients. In a third study based in the United Kingdom (14) we questioned all patients admitted with bleeding gastric and duodenal ulcer to two hospitals serving a single city over a 2-yr period. Those 2=:60 yr old were matched for both age and sex with a hospital inpatient control and a community control who received the same questionnaire. Thirty-five percent of those with bleeding ulcers had been NSAID users at the time of admission compared with 14% and 16%, respectively, of hospital and community controls. The control data showing relative uniformity of NSAID exposure in hospital and community groups validates the use of either, at least in the United Kingdom. The relative risks associated with NSAID use were 3.8 and 2.7, respectively, according to the control used; confidence intervals overlapped between control groups but not with the study group. The result did not differ maferially for gastric or duodenal ulcer. We further calculated that the etiologic fraction, the amount of disease directly attributable to NSAID use, assuming causality, was 22%. The general uniformity of United Kingdom casecontrol data suggesting an association between NSAID use and ulcer complications can be contrasted with data obtained in the United States and with the outcome of surveillance studies in the United Kingdom. Surveillance Studies Surveillance studies, in essence, compare the frequency of adverse events in individuals prescribed treatment under ordinary prevailing clinical circumstances with a comparator. This may be the outcome in a group who do not receive such treatment or the outcome in a succeeding period of time in the same treated individuals. They are not, therefore, equivalent to controlled clinical trials in that random allocation has not taken place and cannot therefore be assumed to take account of extraneous confounding influences. As a consequence, NSAID users and nonusers may differ so substantially that data interpretation becomes extremely difficult (15). On the other hand, the studies have the advantage that they mirror the outcome of ordinary treatment. In the United Kingdom Inman (16) found that perforated peptic ulcer and upper gastrointestinal bleeding were recorded about once for every 200 patient-years of treatment with any of five NSAIDs (benoxaprofen, fenbufen, osmotically delivered indomethacin "Osmosin," piroxicam, and zomepirac). Table 5 gives the data obtained in 55,642 courses of treatment and shows that, although dyspepsia and

644 LANGMAN GASTROENTEROLOGY Vol. 96, No.2, Part 2 Table 5. Outcome of Surveillance: Event and Death Rates Associated with Nonsteroidal Antiinflammatory Drug Intake During and After TreatmentO Benoxaprofen Fenbufen "Osmosin" Piroxicam Zomepirac Event rates per 1000 On Off On Off On Off On Off On Off Dyspepsia and gastritis 77 30 83 All peptic ulcer + 8 10 7 complications 41 10 110 64 52 26 50 22 9 11 12 8 11 9 Deaths from ulcer (No.) 1 2 0 a Reference 15. Total courses = 55,642. 1 2 1 4 6 1 2 gastritis were noted more commonly during than after treatment, peptic ulcer, its complications, and ulcer death were not. Inman concluded that significaht serious risks were not apparent. In assessing the study from Inman it should be noted that responses to questionnaires were elicited some months after treatment was given, which could reduce accuracy; that the response rate was just over 50%; and that another NSAID could well have been prescribed in the "off" period. Nevertheless, dyspepsia did emerge as a risk. A reasonable interpretation would be that if significant risk of serious adverse events did exist, then the rate would have to be relatively low, perhaps of the order of one event in every 10,000 courses of treatment. The study would not be large enough to detect this. Jick and his colleagues in the United States examined data collected routinely by the Group Health Cooperative in Puget Sound. They initially reported (17) the outcome in NSAID recipients ::565 yr old, concentrating on upper gastrointestinal bleeding but excluding all bleeding due to duodenal ulcer. In the period under review, 265,339 prescriptions were filed and 301 patients were admitted to hospital with bleeding. Fourteen of these had filed a prescription within the previous 90 days. After review of case records they concluded that the chances of an etiologic connection were remote in four instances, and possible in seven, although aspirin use and coincident alcoholism complicated assessment. Only 3 subjects remained in whom an etiologic connection seemed probable. In their second study patients of all ages with perforated ulcer were considered (18). One hundred three cases were initially found, but 49 were excluded because of coding and other errors. Drug use in the remaining 54 was compared with that in an age- and sex-matched group with six controls for each patient. Interpretation of data was hindered because increasing age was strongly associated both with NSAID use and hospital admission. Nevertheless, adjusted for age and sex, the rate ratio of upper gastrointestinal bleeding for NSAID users compared with nonusers was 1.6, although 95% confidence intervals overlapped unity (0.68-3.7). However, the relative risk is similar to that found by Carson et al. (19). These investigators working in Michigan and Minnesota compared the chances of upper gastrointestinal bleeding in 47,136 Medicaid patients who received prescriptions for NSAIDs with 44,634 unexposed patients. Rates of bleeding were, respectively, 1.27 and 0.83 per 10,000 patientmonths of treatment; the adjusted relative risk was 1.5 with 95% confidence intervals of 1.1-1.9. Two further studies considered the chances of death. In the first study, residents of Saskatchewan (134,060 subjects) who filed an NSAID prescription in 1983 were studied (20) and no significant risk was detected except in women over the age of 75 yr. Risk appeared to be concentrated in those without a recent history of upper gastrointestinal disease (relative risk, 4.7; 95% confidence interval, 1.7-13.6). The second study concentrated on Medicaid enrollees aged ~ 6in 0 Tennessee (21). One hundred twenty-two individuals died between 1976 and 1984 with peptic ulceration or gastrointestinal hemorrhage. These were matched with 3897 population controls. Thirty-four percent of cases had filed an NSAID prescription in the previous 30 days, compared with 11 % of controls (relative risk, 4.7; 95% confidence interval,3.1-7.2). Overall Interpretation of Risks of Nonsteroidal Antiinflammatory Drug Use At first sight the conclusions reached by individual investigators, which vary from no significant risk to very substantial risks, seem irreconcilable. Table 6 displays the odds ratios and confidence intervals for NSAID use given by investigators in the studies reviewed. Figures vary from just above unity to a quintupling of risk. Confidence intervals are wide and plainly overlap, and a reasonable synthesis suggests that risk is perceptibly increased by a factor of between 2 and 4 for gastric ulcer occurrence, for

February 1989 ANTIINFLAMMATORY DRUGS AND PEPTIC ULCER 645 Table 6. Calculated Relative Risks of Ulcer and Its Complications Relative risk 95% CI Ulcer occurrence Gastric Duggan et al. (9) 5.0 1.4-26.9 McIntosh et al. (10) 4.7 1.3-16.6 Duodenal Duggan et al. (9) 1.1 0.4-3.7 Ulcer complications Bleeding Somerville et al. (14)0 3.8 2.2-6.4 Carson et al. (19)b 1.5 1.1-4.9 Perforation Jick et al. (18) 1.6 0.7-3.7 Death Griffin et al. (21) 4.7 3.1-7.2 CI, confidence interval. 0 Hospital controls. b Community controls. ulcer complications (particularly bleeding), and for ulcer death. Differences between data may be accounted for largely by the size of the study and by the varying inclusion of elderly subjects, who appear at greatest risk. Studies of small size lack power. Relative risk does not give a measure of individual risk, which may be quite low. Thus Carson et al. (19) found an excess of 0.44 episodes of bleeding over the expected rate for every 10,000 person-months of treatment. This figure is broadly compatible with our suggestion for the United Kingdom of about 2000 cases of bleeding per year in individuals aged ;;:::60 yr in association with an estimated 11 million prescriptions (14,22). These figures yield an estimated 2 cases of hemorrhage for every 11,000 person-months of NSAID treatment, assuming an average prescription duration of 1 mo. If the overall risk can be considered in terms of single episodes for 10,000 courses of treatment, then individual risk is obviously low and would be undetectable by conventional surveillance of cohorts of tens of thousands of prescription recipients. Suggestions about the proportion of peptic ulcer deaths attributable to set factors have also varied widely. Thus, Cocke I (23) argued that in the United Kingdom some 4000 ulcer deaths annually (about 90% of total ulcer deaths) might be associated with NSAID intake, whereas Kurata et al. (24) drewattention to the parallels in the United States between national tobacco consumption patterns and duodenal ulcer deaths. Sonnenberg (25) associated dietary salt intake with gastric ulcer deaths. Walt et al. (22) drew attention to the rising ulcer mortality in older people in the United Kingdom, a pattern also observed in Holland (26) and the Federal Republic of Germany (27), but not in the United States. This pattern was not associated with tobacco consumption, as the elderly were not the prime users. These authors noted that, although a minor proportion of the increased death rate was explained by NSAID use, the greater proportion was unexplained. If individual risk is low, it is necessary to consider whether risk is in fact concentrated in any specific group. Age emerges as a risk factor from several sources (5,11-14,20,21). Furthermore, in a high proportion of complications there appears no previous significant ulcer history (13,20). Epidemiologic data available are inadequate to determine whether there was preexisting silent ulcer. It has been suggested that not only are the elderly at particular risk of complicated, often silent ulcer but that NSAID use especially increases the chances of dying (13). However, a carefully conducted study in Australia contradicts this hypothesis (29). Any association of NSAID use with death beyond the risk from the ulcer itself probably represents confounding by general illness, age, and serious complications. Other potential risk factors may be particularly important within selected subgroups of patients. These factors include the musculoskeletal disease for which NSAIDs were used, the nature of the NSAID itself, and potential differences in the rate of drug metabolism. Consideration of individual patient characteristics has shown no evidence that disease, such as rheumatoid arthritis or osteoarthritis, is a marker for drug-induced damage (14). Data concerning individual NSAIDs are fragmentary. We found a suggestive increase in the frequency of bleeding in association with all NSAIDs except ibuprofen, but the data were too few for confident conclusions to be possible (14). Carson et al. (29) used ibuprofen as a reference agent and found differences between NSAIDs, notably a raised frequency with sulindac (adjusted relative risk, 1.4; 95% confidence interval, 1.1-1.9, compared with ibuprofen). Relative risks for five other drugs all ranged between 0.7 and 1.4, with confidence intervals overlapping with those for sulindac. Nevertheless, consideration of a second set of data suggested a marginally greater risk associated with sulindac than other agents. It has to be remembered that data have not been obtained after randomization as in a controlled trial and, therefore, selection bias is possible and even likely. Considerably larger data sets will be required and must be carefully analyzed for confounding variables before one drug is accepted as more dangerous than another. Examination of pharmacokinetic parameters has been limited. The elderly are well known to metabolize drugs slowly; however, in a single, unconfirmed study no evidence was found that slow metabolizers were prone to drug side effects (30). Adverse reactions reported by regulatory authorities are subject to the vagaries of reporting trends and

646 LANGMAN GASTROENTEROLOGY Vol. 96, No.2, Part 2 thus must be considered with extreme caution. Therefore, the data given in Table 2 cannot be assumed to define real differences in toxicity. Determining the etiologic factors that best accord with ulcer morbidity and mortality is difficult. The same factors may not apply in all regions, nor for duodenal as well as gastric ulcer. The suggestion that ulcer deaths are mainly due to NSAID exposure seems exaggerated. However, even though the risk of complications and death may be low in individual terms, the number of cases becomes large when the widespread use of NSAIDs is taken into account. References 1. Kurata JH, Elashoff JD, Grossman MI. Inadequacy of the literature on the relationship between drugs, ulcers, and gastrointestinal bleeding. Gastroenterology 1982;82:373-82. 2. Sato H, Guth PH, Grossman MI. Role of food in gastrointestinal ulceration produced by indomethacin in the rat. Gastroenterology 1982;83:210-5. 3. Ivey KJ. Gastrointestinal intolerance and bleeding with nonnarcotic analgesics. Drugs 1986;Suppl 32:71-89. 4. Griffin JP. Survey of the spontaneous adverse drug reaction reporting schemes in fifteen countries. Br J Clin Pharmacol 1986;22(SuppI1):83S-100S. 5. Committee on the Safety of Medicine Update 1. Non-steroidal anti-inflammatory drugs and serious gastrointestinal adverse reactions. Br Med J 1986;292:614. 6. Rossi AC, Hsu JP, Faich GA. Ulcerogenicity of piroxicam: an analysis of spontaneously reported data. Br Med J 1987;294: 147-50. 7. Husby G, Holme I, Rugstad HG, et al. A double-blind multicentre trial of piroxicam and naproxen in osteoarthritis. Clin Rheumatol 1986;5:84-91. 8. Chalmers TC, Berrier J, Hewitt P, et al. Meta-analysis of randomized controlled trials as a method of estimating rare complications of non-steroidal anti-inflammatory drug therapy. Aliment Pharm Therap 1988;2(Suppl 1):9-26. 9. Duggan JM, Dobson AJ, Johnson H, et al. Peptic ulcer and non-steroidal anti-inflammatory agents. Gut 1986;27:929-33. 10. McIntosh JH, Byth K, Piper DW. Environmental factors in aetiology of chronic gastric ulcer: A case control study of exposure variables before the first symptoms. Gut 1985;26: 789-98. 11. Clinch D, Banerjee AK, Ostick G, et al. Non-steroidal antiinflammatory drugs and gastrointestinal adverse effects. J R Coli Physicians Lond 1983;17:228-30. 12. Collier DS, Pain JA. Non-steroidal anti-inflammatory drugs and peptic ulcer perforation. Gut 1985;26:359-63. 13. Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut 1987;28:527-32. 14. Somerville K, Faulkner G, Langman M. Non-steroidal antiinflammatory drugs and bleeding peptic ulcer. Lancet 1986;i: 462-4. 15. Colin-Jones DG, Langman MJS, Lawson DH, et al. Review of post-marketing surveillance of the safety of cimetidine-the problems of data interpretation. Aliment Pharm Therap 1987; 1:167-78. 16. Inman WHW. Comparative study of five NSAIDs. PEM News 1985;3:3-13. 17. Jick H, Feld AD, Perera DR. Certain non-steroidal anti-inflammatory drugs and hospitalization for upper gastrointestinal bleeding. Pharmacotherapy 1985;5:280-4. 18. Jick SS, Perera DR, Walker AM, et al. Non-steroidal antiinflammatory drugs and hospital admission for perforated peptic ulcer. Lancet 1987;ii:380-2. 19. Carson JL, Strom BL, Soper KA, et al. The association of non-steroidal anti-inflammatory drugs with upper gastrointestinal bleeding. Arch Intern Med 1987;147:85-8. 20. Guess HA, West R, Strand LM, et al. Fatal upper gastrointestinal hemorrhage or perforation among users and non-users of non-steroidal anti-inflammatory drugs in Saskatchewan, Canada, 1983. J Clin EpidemioI1988;41:35-45. 21. Griffin MR, Ray WA, Schaffner W. Non-steroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med 1988;109:359-63. 22. Walt R, Katschinski B, Logan R, et al. Rising frequency of ulcer perforation in elderly people in the United Kingdom. Lancet 1986;i:489-92. 23. Cockel R. NSAIDs-should every prescription carry a government health warning? Gut 1987;28:515-8. 24. Kurata JH, Elashoff JD, Nogawa AN, et al. Sex and smoking differences in duodenal ulcer mortality. Am J Public Health 1986;76:700-2. 25. Sonnenberg A. Dietary salt and gastric ulcer. Gut 1986;27: 1138-42. 26. Hagedoorn D. Opmekelijke verschuivingen inhet epidemiologische patroon van het ulcus pepticum. Ned Tijdschr Geneeskd 1984;128:484-91. 27. Sonnenberg A, Muller H, Pace F. Cohort analysis of peptic ulcer mortality in Europe. J Chronic Dis 1984;88:309-17. 28. Henry DA, Johnston A, Dobson A, Duggan J. Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs, aspirin and corticosteroids. Br Med J 1987;295:1227-9. 29. Carson JL, Strom BL, Morse LM, et al. The relative gastrointestinal toxicity of the non-steroidal anti-inflammatory drugs. Arch Intern Med 1987;147:1054-9. 30. Rugstad HE, Hundal 0, Holme I, et al. Piroxicam and naproxen plasma concentrations in patients with osteoarthritis relative to age, sex, efficacy and adverse events. Clin RheumatoI1986;5:389-98. Received October 24, 1988. Accepted December 1, 1988. Address requests for reprints to: M. J. S. Langman, Department of Medicine, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom.