Nonsteroidal anti-inflammatory drug-induced gastrointestinal injury

Nonsteroidal Anti-inflammatory Drug-Induced Gastrointestinal Injury David J. Bjorkman, MD, Salt Lake City, Utah

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, are the most commonly used medications worldwide. They are effective analgesic and anti-inflammatory agents. A major drawback to their use is a high frequency of adverse gastrointestinal (GI) effects that cause significant morbidity, occasional mortality, and substantial increases in cost of therapy. In this review, mechanisms of NSAID-induced GI injury are presented, and a clinical approach to diagnosis, treatment, and prevention of these adverse GI effects is provided. Am J Med. 1996;101(suppl 1A):25S-32S.

From the Division of Gastroenterology, University of Utah School of Medicine, Salt Lake City, Utah.

Requests for reprints should be addressed to David J. Bjorkman, MD, Division of Gastroenterology, University of Utah Medical Center, 50 North Medical Drive, Room 4Rl18, Salt Lake City, Utah 84132.

N 'onsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medications in the

world. More than 99 million prescriptions for NSAIDs are filled in the United States each yearJ Additionally, >40 billion aspirin tablets are con- sumed annually throughout the world. 2 A major dis- advantage of NSAID therapy is the potential for adverse gastrointestinal (GI) effects. NSAID therapy is associated with upper GI symptoms in 25% of patients, causes ulcers or erosions in 40% of patients, increases risk of ulcer bleeding or perforation three- to fourfold, and increases rate of hospitalization or death from a GI complication fivefoldJ -5 If one es- timates that there are 17 million NSAID users in the United States, this translates to 100,000-200,000 complicated ulcers and 10,000-20,000 deaths each year because of NSAID use./-9 NSAID therapy also is associated with lower GI complications: 10-15% of NSAID users experience diarrhea. Moreover, the risk of intestinal ulceration, erosion, perforation, and stricture formation increases in patients taking NSAIDsj0-~2 Treatment and prevention of these adverse GI effects dramatically increase the cost of NSAID therapy. 3

PATHOGENESIS OF NSAID-INDUCED INJURY Normal Protective Mechanisms

Normal GI function relies on a balance between protective mechanisms and damaging ac id-pep t ic secretions. Gastric surface cells produce an adher- ent layer of mucus that lines the stomach. These same cells secrete bicarbonate that neutralizes acid as it diffuses through the mucous layer. 13 The surface mucous layer of the s tomach is, in hun, covered by a thin film of hydrophobic phospholipids that repel aqueous acid) 4 All of these protective mechanisms, as well as the microcirculation that supports them, are influenced by local product ion of prostaglandins (e.g., PGE.0J a-~v If prostaglandin product ion is impaired, as occurs with NSAID ingestion, this so- called "gastric mucosal barrier" breaks down, the protective balance is disrupted, and mucosal injury may occur.

Mechanisms of NSAID Injury NSAIDs damage the gastroduodenal mucosa by

two distinct mechanisms, an acute local effect that is pH-dependent and varies greatly between NSAID

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prepara t ions and a systemic effect that is less drug specific and occurs without NSAIDs directly con- tacting the mucos a (Tab l e I).

Loca l in jury . Most NSAIDs are weak acids. At a low pH, they are lipid-soluble and diffuse across cell membranes into gastric surface cells. Once inside the cells, they are no longer lipid soluble and cannot escape. NSAIDs damage the m ucos a by a variety of mechanisms, including inhibition of prostaglandin synthesis. Damage to the surface cells breaks down the normal protect ive ihechanisms and allows dif- fusion of acid into the submucosa, resulting in mucosal injury. '7

Endoscopically, this local damage appears as superficial gastritis and submucosal hemorrhage. This pat tern of injury is not predictive of symptoms, is rarely clinically significant, and may resolve with continued NSAID use. 18,19 Because local injury requires contact with the mucosa, it may be avoided by administering NSAIDs in an enteric-coated form or as a prodrug (e.g., sulindac), which requires con- version to an active form. Reducing gastric acid with an histanfine-2 (H2)-receptor antagonist (e.g., cimetidine, ranitidine) or proton-pump inhibitor (e.g., omeprazole) nfinimizes or eliminates acute injury. ~s

S y s t e m i c in ju ry . In contrast to acute superficial injury produced by local effects of NSAIDs, long- te rm use may produce deep, chronic gastroduodenal ulcers that may bleed or perforate. '~° These chronic ulcers appear to result f rom systemic inhibition of prostaglandin synthesis. H-17'z° As outlined above, many of the norn~al protect ive mechanisms of the gastroduodenal mucosa are prostaglandin-dependent. Systemic inhibition of prostaglandin synthesis reduces gastric mucus production, b icarbonate secretion, and mucosal blood flow. z° Impai rment of this protect ive barrier allows chronic injury to occur.

Another systemic prostaglandin-dependent effect of NSAIDs is impaired platelet aggregation. This effect contributes to the risk of bleeding f rom NSAID- induced ulcers and may explain the increased risk of bleeding f rom preexist ing lesions early in the course of NSAID therapy. The relationship between NSAID-induced platelet dysfunction and GI bleeding has been demonst ra ted by measuring platelet prostaglandin product ion at the t ime of a bleeding episode. Eighty percent of patients with upper or lower GI bleeding have evidence of impaired platelet prostaglandin synthesis, suggesting recent use of NSAIDs. zl In 20% of these patients, NSAID use would have been missed by history alone.

Chronic GI injury also may occur by prostaglandin-independent mechanisms. Damage to both the upper and lower GI t ract is associated with an in- f lammatory response and leukocyte margination in mucosa l vessels that can be inhibited by immuno-

suppressive agents. ~222-25 The exact nature and relative contribution of these effects to NSAID-induced symptoms and injury are currently under study.

The systemic effect of NSAIDs is sufficient to cause ulcerations and complicat ions without the local effects. This is demonst ra ted by the fact that rec- tal or parenteral NSAID formulat ions produce the same GI complicat ions as oral formulations. 26'',7 Fur- thermore, prodrugs and enteric-coated drugs do not reduce the incidence of GI ulceration.

Ulcerations induced by NSAIDs appear to occur by a different mechanism than do ulcers caused by Helicobacter pylori infection. NSAID-induced ulcers occur with equal frequency in patients with and without H. pylori, suggesting that the presence of the organism is not a predisposing factor. '~s-3~ However, the precise interaction be tween H. pylori infection, NSAID use, and presence of recurrent or refractory NSAID-induced ulcers has not been defined.

SPECTRUM OF NSAID-INDUCED GASTROINTESTINAL TOXICITY Gastrointestinal Symptoms

Upper GI symptoms associated with NSAID use, including dyspepsia (defined as ulcerlike pain), heartburn, bloating, or cran~ping, occur in up to 25% of patients taking NSAIDs. 32'33 These symptoms are sufficient to p rompt a change in therapy in 10% of patients. Unfortunately, symptoms produced by NSAIDs have little relationship to erosions or ulcerations seen endoscopically. Patients with endoscop- icaUy visible lesions are usually asymptomat ic , and patients with symptoms often have no identifiable lesions. 5 Although the mechanism responsible for GI symptoms is not known, results f rom multiple studies show that symptoms are reduced with s tandard ulcer therapy. 5,~'35 The t rea tment of choice for NSAID-induced GI symptoms is discontinuation of the NSAID. Some patients will tolerate a lower dose or a change to a different class of NSAID. If symptoms persis t ( > 2 weeks) or if pat ients have evidence of a complication, such as iron deficiency anemia, GI bleeding, dysphagia, or weight loss, endoscopic evaluation is indicated. 2'9

In addition to upper GI symptoms , diarrhea occurs in 10-15% of pat ients taking NSAIDs. The cause of the diarrhea appears to be multifactorial. NSAIDs increase intestinal permeabil i ty , allow pas- sage of toxins and bac te r ia through the intestinal wall, and cause nonspecif ic erosions and ulcerations. I0-12'21'36'37 NSAIDs also may unmask or exac- erbate idiopathic inf lammatory bowel disease. ~0.38.39 As with upper GI symptoms , t r ea tment of choice is discont inuat ion of the NSAID; however , some pa- t ients will tolerate a different NSAID or a lower dose.

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Ulcers and Ulcer Complications Gastroduodenal ulcerations and erosions occur

with increased frequency in patients taking NSAIDs. The majority of patients with these lesions have n o symptoms unless bleeding or perforat ion occurs. '~ Results from several endoscopic studies suggest a point prevalence of 40% for gastric erosions, 15% for gastric ulcers, 15% for duodenal erosions, and 5% for duodenal ulcers after 12 weeks of NSAID therapy, s'4°

Although NSAID-induced, asymptomatic ulcers alone are of limited clinical significance, it is clear that these ulcers predispose patients to complications. Risk of developing a bleeding ulcer increases three- to fourfold in patients taking NSAIDs. 4"6 There also appears to be an increased risk of GI perforation 6'44 and a five- fold increased risk of hospitalization or death from adverse GI effects in patients taldng NSAlDs.~5

Because NSAID-induced ulcers often occur without warning symptoms, it is important to identify subgroups of patients who are more likely to develop a complication. Although nun]erous risk factors have been suggested, there is epidemiologic support for only a few conditions. 9'~'45-~7 The best-defined risk factors are history of an NSAID-induced ulcer complication, prior ulcer disease, advanced age, and concomitant cort icosteroid or anticoagulant ther- apyJ 1'4s-5° Some studies have suggested that women and patients with heart disease have a greater risk for NSAID-induced GI complications. 4'45'4s NSAID use, however, is also greatest in women, making it difficult to differentiate increased susceptibility to adverse GI effects from increased NSAID use. ~

Injury to the Esophagus, Small Bowel, and Colon

As previously noted, NSAIDs can produce injury or bleeding from any part of the GI tract.'°-12 Some bleeding has been attributed to platelet inhibition in patients with underlying lesions, such as esophagitis, vascular malfommtions, diverticula, and Mallory- Weiss tears. 21'5z Local effects of NSAIDs also may produce esophagitis and benign esophageal stric- tures. 52'53 NSAIDs also produce ulcerations and erosions of the small bowel and colon. ~°'11'3~ These ulcers are usually asymptomatic but occasionally may cause acute lower GI bleeding and occult blood loss in patients taking NSAIDs. The mechanism for this effect appears multifactorial, includi.n, g increased intestinal permeability, mucosal cell damage, and neutrophil chemotaxis.10 Lastly, NSAID use is associated with development of characteristic weblike stric- tures of the small bowel. ' 2'37 As discussed above, idiopathic inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, may be un- masked or exacerbated by NSAID nseJ °'~'39

TABLE I Local and Systemic Effects of NSAIDs on the Upper

Gastrointestinal Tract Local Effects Systemic Effects

• Local chemical injury • Systemic inhibition of prostaglandin synthesis Occur with any route of administration pH independent independent of pKa of drug Occur independent of form of administration Occur with chronic therapy (weeks)

• Deep ulcerations • May lead to severe bleeding

or perforation

• Require topical contact •

• pH dependent • • Vary with pKa of drug • • Avoided with enteric coating •

or use of inactive precursors • Occur acutely (within hours) •

• Superficial injury • Rarely cause significant

bleeding or perforation

NSAID = nonsteroidal anti-inflammatory drug.

TABLE II Indications for Endoscopy

• Refractory pain • Gastrointestinal bleeding • Iron deficiency anemia • Dysphagia • Unexplained weight loss

From Arthritis Rheum 2 and from Br J RheumatoL 55

NSAID-INDUCED ULCER DIAGNOSIS AND TREATMENT

The majority of NSAID-induced ulcers are asymptomatic, making their diagnosis difficult. Often the initial symptom of an NSAID-induced ulcer is bleeding or perforation. When an ulcer is suspected, the most accurate diagnostic test is endoscopy. Al- though barium contrast studies can detect large ulcers, they are less effective in identifying shallow ulcers and erosions. Endoscopy has the additional benefit of therapeutic or diagnostic interventions during acute bleeding or when tissue is needed for diagnosis. 54

Endoscopy is not indicated for dyspeptic symptoms that respond to therapy. It should be reserved for patients who have symptoms suggestive of a complicated ulcer or other possible abnormality (Table II). 2'55

NSAID therapy is associated with positive fecal occult blood tests for a variety of reasons. Erosions and ulcerations can occur throughout the G! tract, and the antiplatelet effect can increase blood loss from preexisting lesions. Because of the high frequency of positive tests, fecal occult blood testing is not helpful in the diagnosis of NSAID-induced ulcers. 56 However, a positive occult blood test should be t reated like any positive test in screening because

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NSAIDs can increase blood loss from colon polyps or malignancy. Evaluation of the lower GI tract is indicated, particularly in patients older than 40 years and in those with a personal or family history of colon cancerP 6 In patients with a persistently positive fecal occult blood test and iron deficiency anemia, a negative evaluation of the lower GI tract should prompt endoscopic evaluation of the s tomach and duodenum for lesions.

The t reatment of choice for NSAID-induced ulcers is discontinuation of the offending medication. Most ulcers will heal after the NSAID has been stopped. During this period, other analgesic or anti-inflammatory medications can be utilized. For example, patients with osteoarthritis can take ace t aminopheny and patients with inflammatory disorders may respond to low-dose corticosteroids. In patients taking NSAIDs for analgesia, non-NSAID medications should be considered. It is presumed, but not proven, that antiulcer therapy speeds ulcer healing and usually is recommended. In patients requiring continued NSAID therapy, initial ulcer t reatment is similar to that for peptic ulcer disease. Acid reduction therapy with an He-receptor antagonist (e.g., cimetidine, ranitidine) or proton-pump inhibitor (e.g., omeprazole) is effective for NSAID-induced duodenal ulcers. ~-6° Treatment of gastric ulcers may require more inten- sive or prolonged acid-reduction therapyP 9'6° Duo- denal ulcers respond to sucralfate when the NSAID is stopped but not when NSAlDs are continuedP s Misoprostol, a prostaglandin analogue, speeds healing of aspirin-induced gastric lesions but has not been studied extensively in ulcers caused by other NSAIDs and appears less effective than acid-reduction therapyP ~ Another prostaglandin analogue, enprostil, has recently been shown to promote healing of gastric ulcers during continued NSAlD use but is associated with a high incidence of diarrheaY

ULCER PREVENTION NSAID Selection

In spite of the high frequency of ulceration, risk of developing a GI complication while taking an NSAID remains relatively low (1-5°/dyear). 9'~ It is clear that systemic prostaglandin inhibition plays a major role in the development of ulcers and complications. 13-~6 Because all NSAIDs inhibit systemic prostaglandin synthesis, it has been presumed that all carry a similar risk for GI complications. However, retrospective epidemiologic studies have demonstrated that different NSAIDs carry different risks for producing serious GI complications. 41'6z Griffin and colleagues 41 have shown considerable variation in the number of GI complications seen with long-term use of different NSAIDs. In their retrospective study, risk of developing peptic ulcer disease was four times greater

in patients taking meclofenamate or tolmetin than in patients taking ibuprofen. Other studies have demonstrated that some NSAIDs are associated with a lower frequency of GI complications. Nonacetylated salicylates are associated with a lower incidence of ulceration than other NSAIDs. ~'65

Variability Among NSAIDs Postmarketing data suggest that two newer

NSAIDs, nabumetone and etodolac, may have a lower risk of producing GI complications (<0.1%). 66 Initial results from small comparative studies between nabumetone, naproxen, aspirin, and ibuprofen indicate fewer endoscopic lesions with chronic nabumetone useY Findings from similar studies comparing etodolac, naproxen, ibuprofen, and indomethacin demonstrate a lower frequency of injury and preservation of gastric prostaglandin levels with etodolac. 6~'es'69 Although these results are promising, more studies are needed to compare these agents with other NSAIDs for longer periods of time. Avail- able data suggest a decrease in the number of ulcers; however, it has yet to be proven that fewer ulcers translate into fewer complications.

Recognizing that the risk of GI complications varies among NSAIDs has prompted the question of why these differences occur. Although local effects of NSAIDs vary with acidity of the drug, frequency of dosing, and whether the drug is enteric coated or metabolized to an active form, differences in these local effects do not correlate with relative risk of GI injury. Variations in dosing and compliance may explain differences seen in retrospective studies. Many NSAIDs, including indomethacin, diclofenac, naproxen, piroxicam, and sulindac, undergo biliary ex- cretion of active metabolites that may provide longer contact with the GI mucosa and increase the degree of local damage. Relative contribution of biliary ex- cretion to long-term GI injury is not known.

New laboratory evidence suggests that there are differences in systemic effects of NSAIDs on prostaglandin synthesis. Meade and colleagues v° have demonstrated that NSAIDs produce different relative effects on two mouse prostaglandin synthase enzymes (also called cyclooxygenase). Flurbiprofen, ibuprofen, and meclofenamate inhibited both enzymes equally. Piroxicam, indomethacin, and sulindac preferentially inhibited the type 1 isoenzyme (PGHS-1 or COX-l) that is produced in most tissues, including platelets, kidneys, joint synovium, and gastric mucosa. 71 Nabumetone showed relatively greater inhibition of the type 2 isoenzyme (PGHS-2 or COX-2) than other compounds studied. T° This en- zyme i s -expressed in inflamed tissue, activated monocytes, and macrophages. ~' Data using human enzymes also indicate that etodolac and nabumetone

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have a greater relative effect on the type 2 isoenzyme than other NSAIDs. However, no agent is totally selective for inhibiting human COX-2. 72 It is possible that differences in cyclooxygenase inhibitory effects may contribute to the differences in adverse GI effects observed with various NSAIDs.

Although assuming that selective inhibitors of the type 2 isoenzyme are safer is still premature, differences in systemic effects may lead to identification or development of NSAIDs that have fewer GI effects. Until truly selective COX-2 inhibitors are avail- able, it will be difficult to determine the efficacy and safety of these agents.

Preliminary studies suggest that NSAIDs linked to a nitric oxide donor molecule also may decrease the risk of ulceration. ~3'74 NSAID selection for a specific patient may be guided by our current knowledge of differences in both local and systemic effects on the GI tract.

Assessing the Need for Prophylactic Therapy Just as NSAIDs may have different relative risks

of GI injury, some patients appear to be at higher risk when treated with an NSAID. Healthy young patients without prior GI problems have a low risk of NSAID-induced compl ica t ions . 4'6'9'43'45-47 Under these circumstances, the cost of drug prophylaxis outweighs potential therapeutic gain. For other patients, the risk of an NSAID-induced complication is much higher; therefore, prophylactic therapy is indicated. Identification of patients who should re- ceive prophylactic therapy has been at tempted in nu- merous epidemiologic studies. Results indicate that selected groups of patients may be at increased risk for developing adverse GI effects from NSAIDs. Pa- tients at an increased risk of developing a GI complication include those with a prior NSAID-induced ulcer, a history of ulcer disease (particularly a prior ulcer complication), elderly patients (>75 years), and those taking corticosteroids or anticoagulants. 9'4~-'~° Other factors that may warrant prophylactic therapy are high NSAID doses, a history of car- diac disease, and a history of rheumatoid arthritis. 9'47 Patients with other severe comorbid conditions, who would be unlikely to tolerate a GI complication, also may require prophylactic therapy. Smoking, in the absence of other risk factors, does not appear to increase the risk of NSAID-induced ulceration or bleeding. 9

Selecting a Prophylactic Regimen Upon determining that an NSAID user requires

prophylactic therapy, a t reatment plan must be de- veloped. A variety of approaches have been suggested. The only medication shown to prevent both NSAID-induced gastric and duodenal ulcers is mis-

oprostol. It is also the only medication approved by the U.S. Food and Drug Administration for this in- dication.

Misoprostol is an analogue of prostaglandin E. By increasing prostaglandin levels, it restores the protective fimction of the gastric mucosal barrier; at higher doses, it inhibits gastric acid secretion. Mis- oprostol ingestion increases gastric mucosal blood flow, mucous secretion, and bicarbonate secretion. 13-'6 Misoprostol decreases the incidence of both gastric and duodenal ulcers to <1.5% after 3 months of NSAID therapy. 7'~'~6 Until recently, this decrease in ulcers had not been shown to translate into decreased complications. In a large, prospective, multicenter study, patients taldng an NSAID for 6 months demonstrated a 40% reduction in GI complications when taking concomitant misoprostol as compared with placebo, a8

Misoprostol therapy, however, is not without problems. Diarrhea is a frequent side effect with high doses of the drug (39% incidence in patients taking 200 #g 4 times daily)75 Fortunately, diarrhea is less common with lower doses. Initiating therapy with small doses and increasing the dose gradually can circumvent the development of diarrhea in many patients. 9 Lower doses of misoprostol (e.g., 100 #g 4 times daily) are only slightly less effective in ulcer prevention than higher doses. 7~w Misoprostol should be avoided in pregnant women because it may induce spontaneous abortions.

Unfortunately, prophylactic therapy is not always successful and is costly. The risk of an NSAID-induced complication can be reduced but not elimi- nated. Up to 10% of patients may develop ulcers in spite of misoprostol therapy. TM Because of potential adverse effects and frequent dosing of misoprostol, other approaches to ulcer prevention have been ad- vocated. Concomitant use of an Hz-receptor antagonist in standard doses is effective in preventing duodenal ulcers but not gastric ulcers. ~9-a' However, preliminary data suggest that higher doses of He-receptor antagonists also may decrease gastric ulcers. 82 Preliminary data also suggest that omeprazole prevents development of duodenal ulcers, but there are conflicting data for the efficacy of omeprazole in prevention of NSAID-induced gastric ulcers. 8z-s5 There are not sufficient data to recommend sucralfate for prophylactic therapy. 86 Likewise, data are unavailable to support use of antacids to prevent NSAID-induced ulcers.

IMPLICATIONS FOR MANAGED CARE In the managed care environment, high priority is

placed on disease prevention and cost-effective care. This is particularly important with NSAID use. Al- though NSAIDs are effective anti-inflammatory and

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TABLE III Cost of NSAID-induced Ulcer Prophylaxis with Misoprostol

Cost Per Year of Life Population Saved (US$)

Universal prophylaxis $667,400 Elderly patients (>60 yr) $186,700 Rheumatoid arthritis $95,600 History of NSAID-induced

gastrointestinal bleeding $40,000

NSAID = nonsteroidal anti.inflammatory drug. From JAMA. 3

analgesic agents, their widespread use is associated with additional costs. GI symptoms associated with NSAIDs increase the number of physician visits and may prompt concomitant therapy with acid-reduction medications, such as an He-receptor antagonist. In a retrospective study of arthritis patients, NSAID- induced adverse GI effects increased cost of therapy by an average of 46%. 87 Annual cost for treating a GI complication, including diagnosis and hospitalization, was $3.9 billion in the same population.

The cost of preventing NSAID-induced ulcers is significant. Edelson and colleagues 3 evaluated the cost effectiveness of misoprostol therapy under different circumstances. They determined cost of therapy to be $667,400 per year of life saved if all patients taking NSAIDs received misoprostol. Careful evaluation of risk factors significantly reduced this cost. When prophylactic t reatment was limited to selected populations, reductions in the cost of therapy per year of life saved were observed (Tab le III). 3 Simi- lar results were calculated by Levine 8a for ulcer prevention. These numbers suggest that alternative approaches to treating patients with chronic pain or inflammatory disorders may be more cost effective than NSAID therapy.

SUMMARY NSAIDs are effective anti-inflammatory and anal-

gesic agents that are often utilized in the management of chronic painful conditions. Unfortunately, they frequently cause adverse GI effects; GI symptoms occur in >25% of patients, and ulcerations or erosions develop in 40% of patients on long-term NSAID therapy. Both local and systemic effects of NSAIDs contribute to the formation of lesions. NSAID-induced ulcers are frequently asymptomatic until they present as an acute bleeding episode or perforation.

Treatment of NSAID-induced lesions centers on discontinuation of the NSAID and healing of the ulcer with acid-reduction therapy. If an alternative medication cannot be substituted for the NSAID, t reatment with an He-receptor antagonist or proton

pump inhibitor may heal the ulcer. In patients at high risk for a GI complication, prophylactic therapy should be considered. Misoprostol decreases the incidence of ulcer formation and complications. The use of He-receptor antagonists and proton pump inhibitors to prevent ulcers and complications requires further study.

The high frequency of GI symptoms and complications and the need for prophylactic therapy signif- icantiy increase the overall cost of NSAID therapy. Development of NSAIDs with fewer adverse GI effects and nonaddictive analgesics may provide im- proved therapy for patients with chronic pain or inflammatory diseases.

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19. Graham DY, Smith JL, Dobbs SM. Gastric adaptation occurs with aspirin administration in man. Dig Dis Sci. 1983;28:1-6. 20. Wallace JL. Prostaglandins, NSAIDs, and cytoprotection. Gastroenferol Clin North Am. 1992;21:631-641. 21. Lanas A, Sekar MC, Hirschowitz BI. Objective evidence of aspirin use in both ulcer and nonulcer upper and lower gastrointestinal bleeding. Gastroen- tero/ogy 1992;103:862-869. 22. Wallace JL, Keenan CM, Granger DN. Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil-dependent process. Am J Phy- siol. 1990;259:G462-G467. 23. Wallace JL, Hogaboam CM, Kubes P. Immunopathology of NSAID-gastropathy: inhibitory effects of interleukin-I and cyclosporin A. Ann NY Acad Sci. 1992;664:400-407. 24. Hawkey CJ. Non-steroidal anti-inflammatory drugs and the gastric mucosa: mechanisms of damage and protection. Aliment Pharmacol Ther. 1988;2(Suppl 1):57-64. 25. Vaananen PM, Keenan CM, Grisham MB, Wallace JL. Pharmacological in- vestigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy. Inflammation. 1992;16:227-240. 26. Lanza FL, Karlin DA, Yee JP. A double-blind placebo-controlled endoscopic study comparing the mucosal injury seen with an orally and parenterally admin- istered new nonsteroidal analgesic ketorolac tromethamine at therapeutic and supratherapeutic doses. (Abstr.) Am J Gastroenterol. 1987;82:939. 27. Lanza FL, Umbenhauer ER, Nelson RS, Rack MF, Daurio CP, White LA. A double-blind randomized placebo-controlled gastroscopic study to compare the effects of indomethacin capsules and indomethacin suppositories on the gastric mucosa of human volunteers. J Rheumatol. 1982;9:415-419. 28. Kim JG, Graham DY. Helicobacter pylori infection and development of gastric or duodenal ulcer in arthritic patients receiving chronic NSAID therapy. The Misoprostol Study Group. Am J Gastroenterol. 1994;89:203-207. 29. Gubbins GP, Schubert l-r, Attanasio F, Lubetsky M, Perez-Perez GI, Blaser MJ. Helicobacter pylori seroprevalence in patients with rheumatoid arthritis: effect of nonsteroidal anti-inflammatory drugs and gold compounds. Am J Med. 1992;93:412-418. 30. Laine L, Marin-Sorensen M, Weinstein WM Nonsteroidal anti-inflammatory drug-associated gastric ulcers do not require Helicobacter pylori for their development. Am J Gastroenterol. 1992;87:1398-1402. 31. Graham DY, Lidsky MD, Cox AM, et al. Long-term nonsteroidal anti-inflammatory drug use and Helicobacter pylori infection. Gastroenterology. 1991;100:1653-1657. 32. Larkai EN, Smith JL, Lidsky MD, Sessoms SL, Graham DY. Dyspepsia in NSAID users: the size of the problem. J Clin Gastroenterol. 1989; 11:158-162. 33. Coles LS, Fries JF, Kraines RG, Roth SH. From experiment to experience: side effects of nonsteroidal anti-inflammatory drugs. Am J Med. 1983;74:820- 828. 34. Bijlsma JW. Treatment of endoscopy-negative NSAID-induced upper gastrointestinal symptoms with cimetidine: an international multicentre collabora- tive study. Aliment Pharmacol Ther. 1988;2(Suppl 1):75-83. 35. Caldwell JR, Roth SH, Wu WC, et al. Sucralfate treatment of nonsteroidal anti-inflammatory drug-induced gastrointestinal symptoms and mucosal damage. Am J Med. 1987;83(Suppl 3B):74-82. 36. Himal HS. Benign cecal ulcer. Surg Endosc. 1989;3:170-172. 37. Lang J, Price AB, Levi A J, Burke M, Gumpel JM, Bjarnason I. Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs. J Clin Pathol. 1988;41:516-526. 38. Kaufmann H J, Taubin HL. Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med. 1987;107:513-516. 39. Gibson GR, Whitacre EB, Ricotti CA. Colitis induced by nonsteroidal anti- inflammatory drugs: report of four cases and review of the literature. Arch Intern Med. 1992;152:625-632. 40. Silvoso GR, Ivey K J, Butt JH, et al. Incidence of gastric lesions in patients with rheumatic disease on chronic aspirin therapy. Ann Intern Med. 1979;91:517-520. 41. Griffin MR, Piper JM, Daugherty JR, Snowden M, RayWA. Nonsteroidal anti- inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med. 1991;114:257-263.

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64. Roth S, Bennett R, Caldron P, et al. Reduced risk of NSAID gastropathy (GI mucosal toxicity) with nonacetylated salicylate (salsalate): an endoscopic study. Semin Arthritis Rheum. 1990; 19(4 Suppl 2): 11-19. 65. The Multicenter Salsalate/Aspirin Comparison Study Group. Does the ace- tyl group of aspirin contribute to the anti-inflammatory efficacy of salicylic acid in the treatment of rheumatoid arthritis? J RheumatoL 1989;16:321-327. 66. Lanza FL. Gastrointestinal toxicity of newer NSAIDs. Am J GastroenteroL 1993;88:1318-1323. 67, Roth SH, Tindall EA, Jain AK, et aL A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa. Arch Intern Med. 1993;153:2565-2571. 68. Taha AS, McLaughlin S, Sturrock RD, Russell RI. Evaluation of the efficacy and comparative effects on gastric and duodenal mucosa of etodolac and naproxen in patients with rheumatoid arthritis using endoscopy. Br J RheumatoL 1989;28:329-332. 69. Laine L, Sloane R, Ferretti M, Cominelli F. A randomized, double-blind comparison of placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production. Gastrointest Endosc. 1995;42:428-433. 70. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase {cyclooxygenase) isozymes by aspirin and other nonsteroidal anti-inflammatory drugs. J Biol Chem. 1993;268:6610-6614. 71. DeWitt DL, Meade EA, Smith WL. PGH synthase isoenzyme selectivity: the potential for safer nonsteroidal anti-inflammatory drugs. Am J Med. 1993;95(Suppl 2A):40S-44S. 72. Lanueville O, Breuer DK, DeWitt DL, Hla T, Funk CD, Smith WL. Differential inhibition of human prostaglandin endoperoxide H synthases-1 and -2 by nonsteroidal anb-inflammatory drugs. J Pharmacol Exp Ther. 1994;271:927-934. 73. Wallace JL, Reuter B, Cicala C, et aL Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gas- troenterology. 1994;107:173-179. 74. Elliott SN, McKnight W, Cirino G, Wallace JL. A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gas- troenterology. 1995;109:524-530. 75. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lan- cet. 1988;ii:1277-1280.

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