Antiinflammatory drugs and gastric mucosal damage

Antiinflammatory

Drugs and Gastric Mucosal ByElliott L. Semble

N

ONSTEROIDAL antiinflammatory drugs (NSAIDs) are among the most often used medications in the United States and throughout the world. Fifteen to 20 billion aspirin tablets are consumed each year in the United States.’ Prescriptions for nonsalicylate NSAIDs represented over 4% of the total prescription market in 1983, with consumers spending over a billion dollars for these medications.’ Approximately 3% of the United States population requires treatment for a rheumatic disorder, and NSAIDs are prescribed in most types of noninfectious arthritis.3,4 NSAIDs may cause gastrointestinal (GI) symptoms, erosions and/or ulcers, and upper GI tract bleeding. Therefore, gastric mucosal damage resulting from NSAID use is potentially a major health problem. Corticosteroids are used in a wide variety of medical conditions, including rheumatoid arthritis (RA), bronchial asthma, allergic disorders, and dermatologic diseases. The relationship of corticosteroids to gastric mucosal damage is controversial. Corticosteroids may increase the incidence of peptic ulcer disease and GI hemorrhage’ and potentiate gastric mucosal injury when used in combination with NSAIDs such as aspirin.6*7 This review is divided into two sections. The first part surveys data regarding NSAID induced gastric mucosal injury, and the second portion discusses the role of corticosteroids in causing gastric mucosal damage. NSAID INDUCED GASTRIC MUCOSAL DAMAGE Gastric mucosal injury occurring after the administration of NSAIDs has been studied in various ways. Investigators have evaluated GI symptoms, upper GI bleeding, and endoscopic findings in patients receiving NSAIDs. Gastrointestinal Symptoms The percentages of patients reporting adverse effects in clinical trials of NSAIDs represent the major source of data regarding upper GI symptoms with these agents. Complaints relating to the upper GI tract in these studies include nausea, vomiting, heartburn, dyspepsia, indigestion, epigastric pain, and abdominal distress.

Damage

and Wallace C. Wu Comparisons of the relative incidence of NSAID associated upper GI symptoms noted in clinical trials are difficult due to the variability in individual studies. Entry criteria for admission to studies may affect the frequency of complaints since patients may be excluded with active ulcer(s) or a past history of peptic ulcer disease. Methods of compiling data also differ among studies. The type and frequency of upper GI symptoms may vary depending on whether complaints were elicited specifically, by written questionnaire, or a general question was asked.’ A recent survey of the literature reported GI side effects in 8% to 61% of patients in clinical trials of NSAIDS.~ Our report includes only those studies that involved at least 50 patients per investigational group and is summarized in Table 1. This data has been compiled from double-blind trials and surveys of extensive clinical experience with NSAIDs. Several of the studies are discussed in greater detail below. In a l-year, double-blind, multicenter trial, Blechman et al” evaluated aspirin (3,000 to 6,000 mg/d) and ibuprofen (800 to 1,000 mg/d) in 885 RA patients. The most common GI symptoms for both groups were nausea, heartburn, epigastric pain, and abdominal distress. Thirtyone percent of the 447 aspirin treated patients and 17% of the ibuprofen group (438 patients) reported GI complaints. Aspirin (4,000 mg/d) and fenoprofen (1,600 mg/d) were compared in a 16-week, doubleblind, crossover, multicenter study in RA.” Forty percent of 113 patients receiving aspirin noted nausea and 30% complained of dyspepsia.

From the Department of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC. Elliott L. Semble, MD: Assistant Professor of Medicine (Rheumatology), Bowman Gray School of Medicine, Winston-Salem, NC; Wallace C Wu, MD: Associate Professor of Medicine (Gastroenterology). Bowman Gray School of Medicine, Winston-Salem, NC. Address reprint requests to Elliott L. Semble, MD, Section on Rheumatology, Department of Medicine, Bowman Gray School of Medicine, 300 S Hawthorne Rd. WinstonSalem, NC 27103. 0 1987 by Grune & Stratton, Inc. 0049-0172/87/l 6OC0005%5.00/0

Seminars in Arthritis and Rheumatism, Vol 16, No 4 (May), 1987: pp 27 l-286

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Table 1. Percentages

of Patients

Nausea

Drug Aspirin (unbuffered)

and Vomiting

Reporting

Dyspepsiaand Indigestion

GI Symptoms Abdominal Pain

in Clinical Trials of NSAIDs* Total GI Complaints

Dosage (meld)

No. of Patients Reference

3

9

16

31

3.000-6.000

447

10

40

30

NR

NR

4,000

113

11

9

6

3

21

2,400

935

12

8

NR

8

NR

3.900-5.200

74

13

NR

NR

NR

25

3,000

68

14

7

4

2

16

Fenoprofen

20

23

NR

NR

lndomethacin

12

NR

3

28

9

1

8

32

2

4

7

17

NR

NR

NR

23

4

4

6

20

NR

NR

NR

27

Ketoprofen

6

NR

48

NR

150-300

Naproxen

3

2

5

NR

200- 1,000

Piroxicam

2

3

9

NR NR

Aspirin lenteric-coated) Choline magnesium trisalicylate Diflunisal

Ibuprofen

6

NR

9

Sulindac

2

9

10

29

Tolmetin

NR

NR

NR

35

967

12

111

11

50-300

2,647

15

75-150

115

16

600- 1,600

438

10

66

17

500- 1,000 1,600

1,600 900- 1,800 2,400

20 20 200-400 1,200

117

16

52

14

52

18

415

19

909

20

71

13

1,865

21

52

17

Abbreviation: NR, not recorded. *The data were compiled from studies in which there were more than 50 patients per investigational group.

Twenty percent of 111 patients receiving fenoprofen experienced nausea and 23% had dyspepsia. Diflunisal (500 to 1,000 mg/d) and aspirin (2,400 mg/d) were evaluated in a double-blind study in patients with acute musculoskeletal pain.” Nine hundred sixty-seven patients received diflunisal, with 6.5% reporting nausea, 3.1% experiencing indigestion, and 1.9% noting abdominal pain. Nine hundred thirty-five patients used aspirin, with 9.3% reporting nausea, 6.1% experiencing indigestion and gastric upset, and 2.6% noting abdominal pain. Bower et al*’ reviewed clinical trials involving 1,865 patients treated with sulindac (200 to 400 mg/d). GI complaints included 2.4% with nausea and vomiting, 9.1% with dyspepsia, and 10.2% with abdominal pain. Clinical trials of indomethacin were reviewed by O’Brien.” He evaluated data from 35 papers reporting indomethacin use in 2,847 patients. Twelve percent had nausea and 3.2% noted abdominal pain. Indomethacin (75 to 150 mg/d) and ibuprofen (900 to 1,800 mg/d) were compared in a 6-month, double-blind, multiclinic trial in 232 osteoarthritis (OA) patients.16 Nine percent of 115 patients receiving indomethacin complained of nausea and vomiting, 1% had

indigestion, and 8% noted abdominal distress or epigastric pain. Four percent of 117 patients receiving ibuprofen noted nausea and vomiting, 4% experienced dyspepsia, and 6% had abdominal or epigastric pain. Ibuprofen (1,200 to 2,400 mg/d) and ketoprofen (150 to 300 mg/d) were evaluated in a 3-month, double-blind, multicenter study in 102 RA patients.“’ Fifty patients received ibuprofen, with 10% complaining of nausea and vomiting and 44% noting abdominal pain. Fifty-two patients used ketoprofen, with 8% complaining of nausea and vomiting and 48% experiencing abdominal pain. Katona” reviewed clinical trials with naproxen (200 to 1,000 mg/d) in 415 patients. Nausea was noted in 3%, dyspepsia in 2%, and abdominal pain in 5%. Clinical studies with piroxicam (20 mg/d) were reported by Pitts and Proctor*’ in 909 patients. Two percent of patients had nausea and vomiting, 3% complained of indigestion, and 9% experienced epigastric distress. Piroxicam (20 mg/d) was compared with enteric-coated aspirin (3,900 to 5,200 mg/d) in 145 RA patients.13 Six percent of 71 piroxicam treated patients noted nausea, 11% had heartburn, and 9% complained of epigastric distress. Eight percent of 74 patients

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using enteric-coated aspirin reported nausea, 1% noted heartburn, and 8% had epigastric distress. Tolmetin (1,200 mg/d) and ibuprofen (1,600 mg/d) were evaluated in a 12-week, double-blind study in 104 RA patients.” Fifty-two patients received tolmetin, with 35% reporting GI symptoms. Twenty-seven percent of 52 patients using ibuprofen noted GI complaints. A 7-week, double-blind, multicenter study carried out by Ehrlich et all4 compared choline magnesium trisalicylate (3,000 mg/d) and ibuprofen (2,400 mg/d) in 134 RA patients. Sixty-eight patients received choline magnesium trisalicylate, with 25% noting GI complaints. Twenty-three percent of 66 patients using ibuprofen reported GI symptoms. The data regarding the incidence of GI symptoms varies widely among clinical studies of NSAIDs. Aspirin is generally associated with the highest frequency of complaints in most clinical trials comparing NSAIDs. Differences between other NSAIDs are usually small, and probably clinically insignificant. Although the incidence of complaints reported in clinical trials of NSAIDs may be helpful in assessing toxicity with these agents, investigators have observed a lack of correlation between symptoms and endoscopic findings in NSAID treated arthritic patients.22*23 Patients with GI complaints may have lesions on endoscopy or may have normal endoscopies. Furthermore, placebo treated arthritic patients often have GI symptoms in clinical trials evaluating NSAIDs. 24,25This high “background” frequency of complaints makes interpretation of NSAID associated GI symptoms difficult. In conclusion, the evaluation of GI complaints in clinical trials of NSAIDs is of limited use in determining the comparative toxicity of these agents. Upper Gastrointestinal Bleeding Gastric mucosal injury associated with NSAIDs may result in increased gastric RBC shedding and thus, fecal blood loss. Bleeding occurring with these agents is usually mild and occult, but may be considerable. Gastric microbleeding may be detected by the erythrocyte-5’Chromium labeling technique, an accurate and sensitive method of quantitating

fecal blood loss. “Normal” blood loss is approximately 0.5 to 2 mL/d,26 but even losses up to 3 mL/d may be clinically insignificant. However, patients losing more than 10 mL/d are at risk for iron deficiency anemia.’ Daily blood loss in arthritic patients and normal volunteers is generally increased with high dose aspirin (>4 mL/d).25 A bimodal pattern of bleeding in aspirin users has been described, with some patients losing more than 10 mL/d.27 Blood loss may be quite variable among individuals, but a single person will lose similar quantities of blood when rechallenged with aspirin on two separate occasions.28*2g Enteric-coated aspirin3’ and nonacetylated salicylates, including choline magnesium trisalicylate,” salsalate,32 and sodium salicylate,33 cause less blood loss than high dose unbuffered aspirin. Indomethacin may result in increases in fecal blood loss, but less than is seen with aspirin. 34-36Daily blood loss within or near the “normal” range and significantly less than high dose aspirin has been demonstrated with naproxen,37 ibuprofen,38 tolmetin,36 fenoprofen,3g ketoprofen40 piroxicam,4’ and sulindac42 in clinical trials involving arthritic patients and normal volunteers. Although aspirin is the major offender causing microbleeding, certain individuals may lose blood from their upper GI tracts with other NSAIDs. Gastric mucosal damage should be suspected if fecal blood is detected in arthritic patients receiving NSAIDs. Massive hemorrhage originating from the gastric mucosa may be potentially life threatening in patients on NSAIDs. The United Kingdom Committee on Safety of Medicine maintains a system for collecting reports of adverse reactions to drugs by practicing physicians in Great Britain. The number of reported cases of upper GI bleeding, number of reported deaths due to upper GI hemorrhage, and estimated number of reported cases of hemorrhage per million prescriptions collected by the committee from 1963 to 1979 is listed in Table 2. This summary of NSAID associated gastric mucosal injury indicates that naproxen has been implicated as a cause of hemorrhage in a relatively large number of cases reported to the Committee of Safety of Medicines. In contrast,

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Table 2. Number of Cases of NSAID Associated Committee

Drug

GI Bleeding Reported

on Safety of Medicines

No. of RepcrtedCasesof Upper GI Bleeding

Between

to the United Kingdom

1963 to 1979

No. of ReportedDeaths Due tc Upper GI Bleeding

EstimatedNo. of ReportedCasesof Hemorrhageper MillionPrescriptions*

Aspirin

236

92

Ibuprofen

116

12

3.20

lndomethacin

229

69

4.27

3.21t

Ketoprofen

110

5

11.01

Naproxen

158

21

11.72

Phenylbutazone

220

61

4.29

95

16

0.32T

Paracetamol

*Based on 1975 prescription figures. TThese drugs may also be sold without prescription so the quoted figures for frequency of hemorrhage per million prescriptions are likely to be over-estimated.“3 Adapted from the United Kingdom Safety and Medicine Committee

naproxen has not been shown in clinical trials to be associated with any increased risk of hemorrhage as compared with other NSAIDS.~‘*~’ Furthermore, an appreciable number of cases of hemorrhage have been associated with paracetamol (acetaminophen), which is considered nonulcerogenic.44 Although the reports of adverse drug reactions by practicing physicians to such committees are an important source of information on the serious side effects of drugs, causality cannot be inferred from such data, nor can a reliable estimate of comparative frequencies of untoward events be calculated.*’ The major reason for this is that the system of reporting adverse events is voluntary, and therefore, there is underreporting for different drugs. An increased number of reports is seen with new agents, which declines as experience with the drug declines. Clinical trials have demonstrated an incidence of upper GI tract bleeding that ranges from 0.7% with indomethacini4 to 5.5% with aspirin4’ However, the risk of major GI bleeding in patients who regularly receive aspirin or other NSAIDs is unknown. Several investigators have indicated that despite studies showing patients with hemorrhage have a higher aspirin intake,46v47 massive bleeding occurs rarely, namely in 15 per year out of 100,000 habitual aspirin users.46 Close monitoring of patients receiving NSAIDs for bleeding is necessary. Massive hemorrhage may occur in arthritic patients who are often elderly and frail with catastrophic consequences. Bleeding may not be associated with GI complaints in patients on NSAID therapy, and endoscopy should be performed if a decrease in

hemoglobin or positive demonstrated.

hemoccult

reaction

is

Gastroscopic Studies The toxic effects of NSAIDs on gastric mucosa have been evaluated in endoscopic studies. Placebo treated subjects have low gastric injury scores in these studies,48 but the recent demonstration of gastric lesions in 17% of “normal” asymptomatic volunteers on screening endoscopies before entry into clinical trials makes the interpretation of gastroscopic data more difficult.49 Furthermore, endoscopic findings in NSAID treated arthritic patients may be related to factors other than antiinflammatory drug use, such as alcohol, smoking, or emotional stress. We will discuss endoscopic studies of short duration (less than 2 weeks) involving NSAIDs, and then summarize endoscopic investigations of arthritic patients on NSAIDs for 3 or more months. Ibuprofen (1,200 mg/d), aspirin (3,600 mg/d), indomethacin (100 mg/d), phenylbutazone (400 mg/d), and placebo were compared in a 7-day, double-blind, crossover study in 20 normal volunteers.” Varying deg rees of gastric mucosal injury were seen with all four drugs, including hemorrhages and erosions. The most severe abnormalities were observed with aspirin and indomethacin, while those with phenylbutazone and ibuprofen were much less marked. Aspirin (4,000 mg/d) and fenoprofen (2,400 mg/d) were evaluated in a 7-day, double-blind trial in 14 RA patients.5’ Gastroscopy before and after treatment demonstrated mucosal damage

DRUGS AND GASTRIC MUCOSAL DAMAGE

in seven of 13 patients after aspirin and one of 14 receiving fenoprofen. Sixteen normal subjects receiving either aspirin (3,900 mg/d), fenoprofen (2,400 mg/d), or placebo were evaluated by Chernish et al” in a 7-day, double-blind, crossover trial. Fenoprofen was associated with significantly more erosions than placebo, but significantly less erosions and hemorrhages than aspirin. Twenty-five normal volunteers received either ibuprofen (2,400 mg/d), tolmetin (2,000 mg/d), indomethacin (150 mg/d), naproxen (750 mg/ d), or placebo in a 7-day trials3 The greatest degree of gastric mucosal injury was observed with tolmetin and naproxen. A lesser degree was seen with ibuprofen and indomethacin. A poor correlation was noted between GI symptoms and endoscopic findings. Sulindac (300 to 400 mg/d), naproxen (500 to 750 mg/d), aspirin (2,600 to 3,900 mg/d), or placebo were compared in a 14-day study in 60 normal subjects.54 Gastric mucosal injury was greatest with aspirin, less severe with naproxen, and least frequent with sulindac. However, all three drugs had significantly greater gastric mucosal damage than placebo. Lanza et alSS studied aspirin (3,600 mg/d), indomethacin (100 or 150 mg/d), naproxen (500 or 750 mg/d), ibuprofen (1,600 or 2,400 mg/d) or placebo in 40 normal volunteers randomly assigned to eight groups of five each for 1 week. Severe gastric mucosal damage consisting of widespread submucosal hemorrhages was seen with aspirin. Subjects receiving naproxen (750 mg/d), or either dose of indomethacin showed damage similar to aspirin, but fewer abnormalities. One volunteer receiving naproxen (750 mg/ d) and another using indomethacin (100 mg/d) developed antral ulcers. Lesser injury was demonstrated with both doses of ibuprofen and naproxen (500 mg/d). GI symptoms generally correlated with the degree of gastric mucosal damage. However, in nine of the subjects, severe injury was present in the absence of virtually any clinical symptomatology. Rahbek compared aspirin (3,000 mg/d) to ketoprofen (100 mg/d) in healthy volunteers during a 2-week trial.56 Aspirin showed gastric mucosal injury in 77% of subjects, while damage was seen in 38% of ketoprofen treated volunteers. Erosions were observed in subjects receiving both

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drugs, but were more common in aspirin treated subjects. Twenty healthy volunteers were studied during a seven-day trial comparing unbuffered aspirin (3,900 mg/d), buffered aspirin (3,900 mg/ d), enteric-coated aspirin (3,900 mg/d), and placebo.57 Unbuffered and buffered aspirin produced significantly greater gastric mucosal damage than did enteric-coated aspirin or placebo. Kilander and Doterall” evaluated the effects of aspirin (3,000 mg/d) and choline magnesium trisalicylate (3,000 mg/d) in a five-day, doubleblind, crossover trial in ten normal volunteers. Nine of the ten subjects receiving aspirin developed gastric erosions, while only one volunteer had erosions on choline magnesium trisalicylate. A review of short-term endoscopic studies indicates that aspirin is associated with greater gastric mucosal damage than other NSAIDs. Enteric-coated aspirin and nonacetylated salicylates appear to result in less mucosal injury than unbuffered aspirin. Larger doses of NSAIDs (eg, ibuprofen, 2,400 mg/d; indomethacin, 100 to 150 mg/d; naproxen, 750 to 1,500 mg/d) cause varying degrees of mucosal damage. Differences among non-aspirin NSAIDs are probably minimal, but these agents require further study before their comparative effects on the gastric mucosa are determined. There are two major endoscopic studies examining the gastric mucosa in arthritic patients receiving NSAIDs for at least 3 months. Silvoso et al’* evaluated 82 patients with arthritic disorders who received at least 2,400 to 2,600 mg of aspirin daily for more than 3 months; 24 were also receiving one other NSAID (eg, ibuprofen, indomethacin, naproxen, or phenylbutazone). Patients were excluded from the study if they had a history of peptic ulcer disease or major GI symptoms. Endoscopy revealed gastric ulcers in 17% and erosions in 40% of patients. Gastric ulcers were defined as sharply circumscribed, three-dimensional lesions with a white base, while erosions were represented by superficial, white, twodimensional defects in the gastric mucosa. The incidence of ulcers and erosions was much less in those receiving enteric-coated aspirin than in those receiving unbuffered or buffered aspirin. Thirty-three percent of patients with gastric ulcers did not complain of GI symptoms.

276

The second study reporting the effects of at least 3 months of NSAID therapy on the gastric mucosa was performed by Caruso and Porro.23 They evaluated 249 patients, 164 with RA and 85 with OA, in whom endoscopy showed no active lesions before treatment. Thirty-six patients had a history of ulcer and/or erosions, of whom 24 had signs of healed peptic ulcers on pretreatment endoscopy. After 3 months of receiving one of 12 NSAIDs or combinations of these, 31% had gastric erosions. Erosions occurred in 23% receiving a single drug and 5 1% using combination therapy. All of the NSAIDs caused gastric erosions, the greatest offender being aspirin (13 of 26 patients [50%], and the least being sulindac and difluninsal (two of 19 [ 1 l%] and two of 20 [lo%] patients, respectively). Two new gastric ulcers were observed in this study, both occurring in patients with a history of ulcer and/or erosions. A recurrence of peptic ulcer was detected in 11 of the 24 patients (46%) with healed peptic ulcers at pretreatment endoscopy. The endoscopic criteria used to distinguish ulcers from erosions was not provided by the investigators. Clinical symptoms and endoscopic findings did not correlate in this study. Forty-one percent of patients with erosions had no GI complaints, while 21% with symptoms had normal endoscopies. These long-term endoscopic studies indicate that objective evidence of gastric mucosal damage is frequent in arthritis patients receiving NSAIDs. Gastric mucosal injury is more common in patients receiving unbuffered or even buffered aspirin and in those receiving multiple NSAIDs. A lack of correlation between GI complaints and endoscopic findings was noted in both studies. Therefore, NSAIDs should be used cautiously in arthritic patients with a history of gastric mucosal damage. Acute and Chronic NSAID Induced Gastric Mucosal Damage Acute aspirin administration has been associated with gastric mucosal damage in nearly 100% of patients.59-60 Disruption of the surface epithelium occurs within minutes of aspirin administration6’ Submucosal hemorrhages, endoscopically visible as petechiae, occur next. Erosions initially appear several hours after aspirin is taken.59 Petechiae spontaneously resolve

SEMBLE AND VW

within a few days of aspirin administration,59-60 but erosions may last more than 1 week.59 Although many patients will develop gastric mucosal injury with long-term aspirin therapy, continued aspirin ingestion in normal individuals may result in resistance of the gastric mucosa to further damage.27~48~59This increased tolerance for aspirin has been called gastric mucosal adaptation. Smith et al62 found that it could take up to several weeks (maximum, 9 weeks) in normal subjects until adaptation was completed. The mechanism of increased gastric mucosal tolerance to continued aspirin ingestion is unknown, but may be related to increased mucosal turnover and the emergence of younger epithelial cell populations.63 It may partially explain why a certain percentage of RA patients are able to tolerate large doses of aspirin.48 Chronic aspirin intake has been associated with gastric ulcers in epidemiologic studies.46,64 Duggan64 reported data from eastern Australia suggesting a link between heavy aspirin ingestion and the incidence of gastric ulcer, particularly in women. Hospitalized patients in Boston using aspirin for at least four days per week for at least 3 months had an increased frequency of gastric ulcers.46 The development of a chronic gastric ulcer with long-term aspirin administration may reflect a failure of mucosal adaptation, a locally susceptible area of mucosa, or both.27 Short-term endoscopic studies (three to 14 days) in normal subjects and arthritic populations evaluating the potential of non-aspirin NSAIDs to cause acute gastric mucosal damage have demonstrated varying degrees of injury.*’ Most trials comparing aspirin and other NSAIDs have indicated greater injury in aspirin treated normal volunteers and arthritic paIt is difficult to draw conclusions regardtients.*j ing the relative toxicities of non-aspirin NSAIDs in acute endoscopic studies due to differences in entry requirements and methodologies, but it appears that indomethacin and tolmetin are associated with increased acute gastric mucosal injury.*’ Although the chronic administration of nonaspirin NSAIDs has been reported to be associated with peptic ulcers in individual cases, their ulcerogenic potential appears to be less than with aspirin. In animal studies, indomethacin and phenylbutazone may cause ulcers,65 but no well-

DRUGS AND GASTRIC MUCOSAL

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controlled prospective epidemiologic or clinical trial exists in humans that prove the ulcerogenicity of indomethacin, phenylbutazone, or other nonaspirin NSAIDs. Endoscopic and histologic examination may be helpful in differentiating NSAID induced gastric ulcers from typical benign gastric ulcers. NSAID associated gastric ulcers often appear in typical areas such as the antrum, and are frequently surrounded by histologically normal gastric mucosa.27.66367Benign gastric ulcers usually occur in the body of the stomach in mucosa affected by gastritis.27366 Furthermore, sex and age distribution differ significantly for NSAID induced gastric ulcers, as opposed to gastric ulcers in the genera1 population. NSAID associated gastric ulcers approximate the female predominance and the older age patterns seen in arthritic patients, while gastric ulcers unrelated to NSAIDs usually affect young ma1es.68 NSAID Dosage and Gastric Mucosal Damage NSAID dosage may be related to the degree of gastric mucosal injury. Cameronj9 found that radiologically defined gastric ulcers were more frequent in regular aspirin users (ie, those who received more than 15 aspirin-containing tablets or capsules each week) than controls. Animal studies have also suggested that the amount of aspirin was important in the development of chronic gastric ulcers. Rats receiving variable doses of aspirin ranging from 120 to 500 mg/kg body weight for 6 months all showed acute gastric erosions, while only rats receiving 250 or 500 mg/kg had chronic gastric u1cers.70 Although the beneficial effects of lowering the dose of NSAIDs in patients who have developed gastric mucosal injury on higher doses has not been systematically investigated, clinical, microbleeding, and endoscopic studies suggest that smaller doses of some of these agents (eg, aspirin, indomethacin, naproxen) are associated with less GI side effects.25327*35.55*7’ Further investigation is necessary to evaluate the relationship between adverse GI effects and NSAID dosage. Physiology of the Gastric Mucosa The healthy gastric mucosa is capable of withstanding high concentrations of intraluminal acid. Mucosal defense mechanisms that prevent acid injury include specialized secretions by the

277

surface epithelium (ie, mucus, bicarbonate) and physiologic events taking place below the basement membrane (ie, mucosal blood flow). The concept of the gastric mucosa as a barrier to ion diffusion developed from an understanding that the electrolyte concentration in gastric juice varied with the rate of secretion. At high secretory rates, gastric juice had a high hydrogen ion concentration and a low sodium ion concentration, while at low secretory rates the reverse the gastric was true.72 Teore1173 considered mucosa a diffusion barrier and explained events at the surface of the gastric mucosa in relation to an exchange diffusion between hydrogen ion in the lumen and sodium ion in the mucosa. Ho11ander’s74 conception of the mucosal barrier was different. He proposed a two-component system consisting of a layer of mucus covering the wall of the gastric cavity and the layer of epithelial cells beneath it. He suggested that the reduction in hydrogen ion concentration resulted from dilution and neutralization by a sodium ion containing non-acid secretion or leakage of interstitial fluid. Davenport7’ further expanded Hollander’s mode1 system by postulating that the gastric mucosal barrier was formed by the apical membrane of the surface epithelial cells together with the tight junctions linking adjacent cells. The tight junctions functioned as an ion barrier to prevent entry of hydrogen ion into the gastric mucosa. Heat1ey76 proposed a more important role for the mucus layer in gastric mucosal defense. He suggested that mucus could provide an unstirred layer (ie, a zone of low turbulence) on the mucosal surface, allowing the development of pH gradients for bicarbonate secreted by the surface epithelium and hydrogen ion diffusing from the lumen. Bicarbonate could protect surface epithelial cells against acid by neutralizing hydrogen ions diffusing toward the mucosa through the mucus layer. Experimental data supporting the concept of gastric mucosal protection by a mucus-bicarbonate barrier system have been reported by several investigators.77-80 These studies have demonstrated that gastric mucosal epithelium actively secretes bicarbonate77 and that mucus can delay the transfer of hydrogen ion across it.78 Furthermore, the existence of pH gradients across the mucus layer in the gastric mucosa of rat and

278

humans as hypothesized by Heatley, has been shown experimentally by pH microelectrode studies.799*0 However, the theory of a mucus-bicarbonate barrier to luminal acid has recently been disputed. Morphologic studies indicate that there may be no continuous mucus layer in the undamaged stomach. ” Instead, the mucosa appears to be only partly covered by a discontinuous network of mucus that originates, not from surface epithelial cells, but from the gastric glands deep in the mucosa.” Other experimental evidence challenging the mucus-bicarbonate barrier concept of mucosal protection indicates that the amount of bicarbonate secreted by the stomach is much less than necessary to neutralize luminal acid, and that the pH gradient disappears during maximal acid secretion.a3 More recent studies have demonstrated the presence of an adsorbed layer of phospholipids on the gastric surface.a43a5 This layer of phospholipids may provide a barrier to luminal acid, protecting both the surface epithelium and mucosal glands from acid injury.a23a4*a5However, further investigation must be performed before any conclusions can be reached regarding the role of this putative phospholipid barrier in mucosal injury. In addition to pre-epithelial protection by mucus, bicarbonate, and possibly phospholipid, post-epithelial mucosal protection against acid aggression occurs. Several studies have demonstrated that gastric mucosal blood flow plays an important role in protecting the gastric mucosa from acid injury. a6 When disruption of the gastric mucosal barrier to acid occurs and hydrogen ions enter the interstitial tissue, a compensatory increase in mucosal blood flow occurs, permitting removal of excess acid and resulting in little or no damage. If, under the same conditions, mucosal blood flow is decreased (eg, by hemorrhagic shock, vasoconstrictor agents, etc), marked lesion formation results.a6 The mucosal microvasculature may also assist gastric mucosal defense against luminal acid by transporting bicarbonate, released interstitially from secreting parietal cell deep within the mucosa, toward the surface epithelium.a7 Thus, the ability of gastric mucosa to defend itself against acid injury is incompletely understood. Further study of the properties of surface

SEMELE AND WU

epithelial cells, structure of the mucus layer, mechanism of bicarbonate secretion, function of phospholipids, and role of gastric mucosal blood flow is important in order to expand our knowledge regarding the physiologic mechanisms of gastric mucosal protection. Pathophysiology of NSAID Induced Gastric Mucosal Damage NSAID induced gastric mucosal damage is probably multifactorial. These agents have effects on mucosal defense mechanisms, including mucus and bicarbonate secretion and mucosal blood flow, and on acid secretion. Aspirin causes a breakdown of gastric mucosal defense. Increased mucosal permeability occurs, as reflected by a decrease in transmucosal potential difference.6’ There is an efflux of sodium from the mucosal epithelium into the lumen and a loss of hydrogen ion from the lumen (backdiffusion).‘* Significant denudation of surface epithelial cells occurs within ten minutes of ingestion of two aspirin tablets.** The disruption of the surface epitheiium by aspirin is followed rapidly (within one to two hours) by emigration of mucosal gland cells completely restoring the integrity of the epithelium.a9 However, in contrast to the reversible surface damaging effects of aspirin, severe vascular damage may occur with this drug, preventing the restoration of epithelial integrity by cell migration and resulting in hemorrhagic erosions.‘* The integrity of gastric mucosal defenses are adversely affected by NSAIDs. Aspirin decreases the thickness of mucus,9o inhibits mucus secretion,” and reduces the pH gradient across the mucus layer.” Aspirin also prevents the incorporation of radiolabeled precursors into the glycoprotein component of mucus and inhibits the activity of enzymes necessary for mucus biosynthesis.9’V92 Aspirin and indomethacin inhibit bicarbonate secretion,93’94 reduce mucosal blood flo~,~’ and decrease protective mucosal phospholipids.a4.96 NSAID induced gastric mucosal damage may also be related to effects on gastric acid output. Recent studies have indicated that acid secretion may be stimulated by aspirin and indomethacin.95997 Aspirin and indomethacin increased basal and pentagastrin-stimulated acid secretion

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in dogs,95 and in human studies, indomethacin enhanced basal and histamine-stimulated acid output? The Role of Prostaglandins in Gastric Mucosal Defenses Against NSAIDs

In 197 1, Vane proposed that aspirin damaged the gastric mucosa by inhibiting prostaglandin synthesis.98 Since then, the role of prostaglandins in preventing gastric mucosal injury has been extensively studied. Prostaglandins have been theorized to be cytoprotective in the stomach. This property indicates that they cause a general enhancement of mucosal resistance to damage.99 Morphologic observations of rat gastric mucosa have shown that both natural and synthetic prostaglandins can reduce the damage caused by aspirin and indomethacin.96~‘00~‘0’ Synthetic oral prostaglandin E2 analogues (eg, 16,16-dimethyl PGE,) can significantly reduce the rate of rat gastric mucosal epithelial cell shedding resulting from aspirin and indomethatin.“’ In human studies, pretreatment with PGE, prevented the shedding of mucosal epithelial cells after exposure to acidified aspirin.“’ Furthermore, Terano et allo have reported that aspirin induced damage to rat gastric epithelial cells cultured in vitro was significantly inhibited by 16,16-dimethyl PGE,. The mechanisms of cytoprotection remain to be determined. Most animal studies show that prostaglandins of the E class prevent or reduce alterations in hydrogen ion permeability or transmucosal potential difference associated with mucosal barrier disruption.‘04 Investigations in humans have demonstrated that 16, 16-dimethyl PGEz prevented the decrease in potential difference caused by aspirinlo and indomethatin. '05,106 Mucus and bicarbonate secretion may maintain pH neutrality at the surface of the gastric epithelial cell. Prostaglandins have been demonstrated to stimulate,‘07~‘08and NSAIDs to inhibit, lo7bicarbonate secretion in human and animal studies.93 Prostaglandins of the E class have also been shown to stimulate, and NSAIDs to inhibit, mucus synthesis and secretion.‘W-“O E and I prostaglandins increase, while NSAIDs can decrease, gastric mucosal blood flow. This may be of clinical significance in gastric mucosal

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resistance, since erosions develop when vasodilation is prevented by administering NSAIDs or by stimulating thromboxane synthesis.‘00*“‘~“3 Another possible mechanism of cytoprotection is the ability of certain prostaglandins to increase the endogenous levels of gastric mucosal phospholipids, substances which appear to be protective in gastric necrosis experiments.84 Indomethacin and aspirin reduce these phospholipids in similar studies.84 Although cytoprotection is considered to be independent of gastric acid secretion, there is experimental evidence in humans showing that endogenous prostaglandin synthesis can decrease acid production.96 Furthermore, NSAIDs, which were originally thought to have no effects on acid output, have been reevaluated and recent studies in humans have shown increased basal and histamine-stimulated acid production with indomethacin.97 Prostaglandins accelerate healing of peptic ulcers in humans.“e”s Although the mechanisms of prostaglandin protection or repair in chronic gastric mucosal injury are unknown, several investigators have found reduced prostaglandin synthesis in patients with gastric ulcers,‘16 and long-term prostaglandin treatment may result in gastric mucosal hyperplasia in both laboratory animals”’ and humans.“* Further studies are necessary to elucidate the mechanisms of cytoprotection in the healing process of acute or chronic mucosal injury due to aspirin or other NSAIDs. Gastric Mucosal Damage in Arthritic Patients

Arthritic patients may be more susceptible to gastric mucosal injury resulting from NSAIDs. A higher frequency of peptic ulcer disease has been found in patients with RA, but it is unclear whether this possible association is due to drugs or to unknown causes.“9-‘20 Rainsfordz4 has hypothesized that psychological and physical stress factors, poor nutritional status, reduced drug binding by plasma proteins, abnormal levels of some intestinal enzymes,“’ and decreased albumin metabolism”’ may contribute to a reduction in gastric mucosal resistance and/or enhancement of the injurious effects of NSAIDs in arthritic patients. Increased plasma levels of gastrin, a peptide involved in regulating gastric acid secretion, have

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been found in RA patients.‘23 Gastrin could cause increased acid secretion in these patients and may result in a predisposition to damage by NSAIDs. Additional studies need to be performed, evaluating the effects of the underlying disease state (ie, RA or other arthritides) on gastric mucosal defenses and the ability to resist NSAID injury. Management of NSAID Induced Gastric Mucosal Damage Cessation of NSAID intake is the most effective way to avoid GI side effects. Alternatives would be to lower the dosage or switch to another NSAID. The degree of mucosal damage also depends on the type of preparation used. Inasmuch as many individuals prefer to take aspirin in tablet form, patients should be warned to chew tablets thoroughly (powdered formulations are less damaging than whole tablets) and to take the medication after meals. Aspirin and other NSAIDs should be taken with meals or with liquids. Concomitant ingestion of concentrated alcoholic beverages should be avoided, as the gastric mucosal barrier-breaking capacities of aspirin and ethanol are additive.‘24 The combination of ethanol and aspirin may cause more gastric mucosal damage than aspirin alone, and several studies have shown an increased risk of bleeding when they are used together.‘259126 Modifications of aspirin may reduce the potential for gastric mucosal damage. Entericcoated aspirin is a reasonable alternative for patients who cannot tolerate aspirin, since it has been associated with less Gl complaints and results in fewer mucosal lesions and less gastric bleeding than unbuffered or buffered aspirin. Nonacetylated salicylates, such as choline magnesium trisalicylate and salsalate, cause less gastric mucosal damage and reduced gastric bleeding compared with aspirin, and may also be considered in aspirin sensitive patients. Inasmuch as NSAIDs relieve joint inflammation in arthritis patients, discontinuing these agents or modifying their dosage may impair the efficacy of therapy. Treatment or prophylaxis of NSAID induced mucosal injury may permit arthritic patients to remain on their anti-inflammatory medication.

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Cimetidine, an H,-receptor antagonist that inhibits gastric acid secretion, may be effective in the treatment of NSAID induced gastric mucosal injury. Loludice et a112’ prospectively studied a group of 70 patients with documented gastric ulcers induced by NSAIDs or prednisone. All anti-inflammatory drugs were discontinued and patients were instructed to avoid known gastric irritants. Twenty-five of the 38 patients (66%) receiving cimetidine and antacid showed endoscopic healing of ulcers within the 6-week period, while only eight of the 32 patients (25%) receiving placebo and antacid had ulcer healing within the same time period (P < .Ol). Croker et al”* demonstrated in an open study that cimetidine was associated with gastric ulcer healing in ten of 14 patients (7 1%) with arthritis in 6 weeks. Three patients who continued their anti-inflammatory drug treatment did not show gastric ulcer healing even after 3 months of cimetidine therapy. O’Laughlin et a1’29 compared cimetidine plus antacids with placebo plus antacids in a double-blind controlled study evaluating endoscopic healing of aspirin induced gastric ulcers during continued salicylate ingestion in 18 arthritic patients over 2 months. Healing occurred in only 56% of the cimetidine plus antacid group, compared with 44% of the placebo plus antacid group (ie, a nonsignificant difference). Aspirin induced gastric ulcer r 1 cm in diameter were relatively resistant to treatment, but most eventually healed with prolonged cimetidine and antacid treatment over 6 to 26 months. The Hz-receptor antagonist, ranitidine, has been shown to reduce gastric submucosal hemorrhages, but not erosions, as assessed by endoscopy in normal men after three days of receiving aspirin.13’ Ranitidine also demonstrated prevention of aspirin induced gastric bleeding in eight healthy volunteers.‘3’ Robert99 has defined cytoprotection as the protection of the gastric mucosa against injury by noxious agents (eg, NSAIDs) unrelated to the inhibition of acid secretion. Agents that may have cytoprotective properties include sucralfate,“’ prostaglandins,99*‘33,‘34 and possibly Hzreceptor antagonists.‘30s’35 Synthetic oral prostaglandin analogues (eg, PGE2) have been shown in acute endoscopic

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studies to protect the gastric mucosa from aspirin induced damage in normal volunteers.‘36”37 A recent report indicated that misoprostil, a prostaglandin E’ analogue, was effective in reducing gastric mucosal injury caused by tolmetin in normal subjects.‘38 However, a therapeutic trial of 15R- 15-methyl prostaglandin E, in 13 RA patients receiving various NSAIDs with gastric lesions (erosions, ulcers) demonstrated no dramatic improvement in gastric mucosal damage after 1 month of therapy.‘39 Several studies have evaluated the effects of prostaglandins in upper Gl bleeding.‘40-‘43 Prostaglandin E’ and Ez analogues reduced blood loss into gastric washings caused by aspirin in normal subjects.‘409’4’ Gastric microbleeding, as measured by fecal blood loss, was reduced by prostaglandin E2 in aspirin and indomethacin treated volunteers and arthritic patients.359’429143 Further studies evaluating the protective effects of prostaglandins and other agents in the treatment of NSAID induced gastric mucosal injury in arthritic patients are needed before any definite recommendations can be made. In the meantime, NSAIDs should be used cautiously in patients with gastric mucosal damage or a history of such disease. CORTICOSTEROIDS

The association of corticosteroids and gastric mucosal damage has been debated by several investigators.‘,‘44 Spiro7 reported that the development or reactivation of peptic ulceration was one of the most serious side effects of prolonged corticosteroid therapy. Conn and Blitzer’44 combined data from 42 randomized, control trials and concluded that corticosteroids did not cause peptic ulcers unless they were administered for more than 30 days or in a total dose exceeding 1,000 mg of prednisone. More recently, the relationship of corticosteroids and peptic ulcer disease was reexamined by Messer et al.s They examined data from 71 controlled trials and concluded that corticosteroids increased the risk of peptic ulcers and GI hemorrhage. The incidence of ulcers was significantly increased even in patients treated for less than a month and in those receiving a total dose of less than 1,000 mg of prednisone. Patients at increased risk for corticosteroid

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induced gastric mucosal damage may include those requiring high doses of parenteral corticosteroids (up to 1,000 mg/d of prednisolone) for treatment of various medical disorders. Corticosteroids may also make the gastric mucosa more susceptible to injury by concomitant noxious agents like aspirin.6 Although sparse data is available regarding the GI complaints experienced by patients receiving corticosteroid therapy, GI symptoms were relatively common in patients treated with prednisone (25 mg/d) for 2 weeks in a doubleblind, controlled study evaluating the effects of cimetidine on gastric symptoms during corticosteroid treatment.14’ The mean number of days of epigastric pain and heartburn per patient was 6.1 and 4.3, respectively, with corticosteroids. Few studies evaluating the endoscopic findings in patients treated with corticosteroids have been performed. Gastroscopy after six days of prednisolone therapy (1,000 mg/d intravenously) did not reveal any lesions attributable to corticosteroid use.‘46 Caruso and Porro23 showed that corticosteroids caused gastric damage in three of 21 arthritic patients (14%) compared with 13 of 26 (50%) for aspirin. Gastric microbleeding is apparently not increased with corticosteroid therapy. Scott et al’47 demonstrated that patients treated with 5 to 20 mg/d of prednisolone did not have abnormal fecal blood loss. The mechanisms of corticosteroid induced gastric mucosal injury are unknown. Corticosteroids do not seem to produce significant changes in gastric acid secretion.‘46 However, they may disrupt the gastric mucosal barrier, causing an impairment in mucosal defense. Gastric mucus secretion is decreased by corticosteroids in the rat14* and in humans,‘46 and high doses in humans inhibit gastric output of N-acetylneuraminic acid containing mucus glycoproteins.146 Corticosteroids by themselves do not alter the permeability of the gastric mucosa to hydrogen ion, but enhance the back-diffusion of luminal acid in the presence of aspirin.6 Several investigators have demonstrated that corticosteroids decrease mucosal epithelial cell turnover in the rat and dog and thus may interfere with repair processes and healing in the stomach.‘49-‘50 The question of whether cortico-

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steroids affect healing of chronic peptic ulcers in humans has not been systematically studied, but several reports indicate that gastric ulcers can heal in arthritic patients despite continuation of corticosteroid therapy.679’5L Hz-receptor antagonists may be useful in the treatment of corticosteroid induced gastric mucosal damage. Loludice et alIz have shown gastric ulcer healing in a small number of prednisone treated patients with cimetidine and antacid therapy. We recommend that corticosteroids be withdrawn gradually in patients with severe gastric mucosal damage. If a complication such as bleeding or perforation occurs, the corticosteroid dose should be rapidly decreased to the equivalent of 10 to 15 mg/d of prednisone (ie, doses

that avoid precipitating acute adrenocortical insufficiency), and the patient should be considered for therapy with H,-receptor antagonists. Arthritic patients may have an exacerbation of their underlying disease with abrupt decreases in corticosteroid dose. Corticosteroid treated patients who may be at high risk for gastric mucosal injury include the following: (1) individuals with a history of peptic ulcer disease or upper GI bleeding; (2) patients requiring high dose corticosteroids or those needing long-term therapy; and (3) arthritic patients receiving prednisone and concomitant NSAIDs (especially aspirin). These patients should be considered for gastric mucosal damage prophylaxis with Hz-receptor antagonists or cytoprotective agents.

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