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 ad- verse gastrointestinal (GI) effects. NSAID therapy is associated with upper GI symptoms in 25% of pa- tients, 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 ad- verse 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 acid-peptic 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 stomach 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 production of prostaglandins (e.g., PGE.0J a-~v If prostaglandin production is im- paired, 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 @1996 by Excerpta Medica, Inc. 0002-9343/96/$15.00 1A-25S All rights reserved. PII S0002-9343(96)00135-0
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`SYMPOSIUM ON MANAGEMENT OF CHRONIC PAIN/BJORKMAN preparations and a systemic effect that is less drug specific and occurs without NSAIDs directly con- tacting the mucosa (Table I). Local injury. 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 mucosa by a variety of mechanisms, including inhibition of prostaglandin synthesis. Damage to the surface cells breaks down the normal protective ihechanisms and allows dif- fusion of acid into the submucosa, resulting in mu- cosal injury. '7 Endoscopically, this local damage appears as su- perficial gastritis and submucosal hemorrhage. This pattern of injury is not predictive of symptoms, is rarely clinically significant, and may resolve with continued NSAID use. 18,19 Because local injury re- quires 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., cimet- idine, ranitidine) or proton-pump inhibitor (e.g., omeprazole) nfinimizes or eliminates acute injury. ~s Systemic injury. In contrast to acute superficial injury produced by local effects of NSAIDs, long- term use may produce deep, chronic gastroduodenal ulcers that may bleed or perforate. '~° These chronic ulcers appear to result from systemic inhibition of prostaglandin synthesis. H-17'z° As outlined above, many of the norn~al protective mechanisms of the gastroduodenal mucosa are prostaglandin-depen- dent. Systemic inhibition of prostaglandin synthesis reduces gastric mucus production, bicarbonate se- cretion, and mucosal blood flow. z° Impairment of this protective barrier allows chronic injury to occur. Another systemic prostaglandin-dependent effect of NSAIDs is impaired platelet aggregation. This ef- fect contributes to the risk of bleeding from NSAID- induced ulcers and may explain the increased risk of bleeding from preexisting lesions early in the course of NSAID therapy. The relationship between NSAID-induced platelet dysfunction and GI bleeding has been demonstrated by measuring platelet pros- taglandin production at the time of a bleeding epi- sode. Eighty percent of patients with upper or lower GI bleeding have evidence of impaired platelet pros- taglandin 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 prostaglan- din-independent mechanisms. Damage to both the upper and lower GI tract is associated with an in- flammatory response and leukocyte margination in mucosal vessels that can be inhibited by immuno- suppressive agents. ~222-25 The exact nature and rel- ative 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 complications without the lo- cal effects. This is demonstrated by the fact that rec- tal or parenteral NSAID formulations produce the same GI complications 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 with- out H. pylori, suggesting that the presence of the organism is not a predisposing factor. '~s-3~ However, the precise interaction between 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 prompt a change in therapy in 10% of patients. Unfortunately, symptoms produced by NSAIDs have little relationship to erosions or ulcer- ations seen endoscopically. Patients with endoscop- icaUy visible lesions are usually asymptomatic, and patients with symptoms often have no identifiable lesions. 5 Although the mechanism responsible for GI symptoms is not known, results from multiple stud- ies show that symptoms are reduced with standard ulcer therapy. 5,~'35 The treatment 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 symp- toms persist (> 2 weeks) or if patients have evidence of a complication, such as iron deficiency anemia, GI bleeding, dysphagia, or weight loss, endoscopic eval- uation is indicated. 2'9 In addition to upper GI symptoms, diarrhea oc- curs in 10-15% of patients taking NSAIDs. The cause of the diarrhea appears to be multifactorial. NSAIDs increase intestinal permeability, allow pas- sage of toxins and bacteria through the intestinal wall, and cause nonspecific erosions and ulcera- tions. I0-12'21'36'37 NSAIDs also may unmask or exac- erbate idiopathic inflammatory bowel disease. ~0.38.39 As with upper GI symptoms, treatment of choice is discontinuation of the NSAID; however, some pa- tients will tolerate a different NSAID or a lower dose. 1A-26S July 31, 1996 The American Journal of Medicine ® Volume 101 (suppl 1A)
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`SYMPOSIUM ON MANAGEMENT OF CHRONIC PAIN/BJORKMAN Ulcers and Ulcer Complications Gastroduodenal ulcerations and erosions occur with increased frequency in patients taking NSAIDs. The majority of patients with these lesions have no symptoms unless bleeding or perforation 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 four- fold 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 ad- verse GI effects in patients taldng NSAlDs.~5 Because NSAID-induced ulcers often occur with- out warning symptoms, it is important to identify subgroups of patients who are more likely to develop a complication. Although nunerous 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 com- plication, prior ulcer disease, advanced age, and con- comitant corticosteroid 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 ero- sions of the small bowel and colon. ~°'11'3~ These ul- cers 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 in- testinal permeability, mucosal cell damage, and neu- trophil 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 asymp- tomatic, making their diagnosis difficult. Often the initial symptom of an NSAID-induced ulcer is bleed- ing or perforation. When an ulcer is suspected, the most accurate diagnostic test is endoscopy. Al- though barium contrast studies can detect large ul- cers, they are less effective in identifying shallow ul- cers 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 symp- toms 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 fre- quency of positive tests, fecal occult blood testing is not helpful in the diagnosis of NSAID-induced ul- cers. 56 However, a positive occult blood test should be treated like any positive test in screening because July 31, 1996 The American Journal of Medicine ® Volume 101 (suppl 1A) 1A-27S
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`SYMPOSIUM ON MANAGEMENT OF CHRONIC PAIN/BJORKMAN 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 co- lon 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 stomach and duodenum for lesions. The treatment 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-inflam- matory medications can be utilized. For example, pa- tients with osteoarthritis can take acetaminopheny and patients with inflammatory disorders may re- spond 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 usu- ally is recommended. In patients requiring continued NSAID therapy, initial ulcer treatment is similar to that for peptic ulcer disease. Acid reduction therapy with an He-receptor antagonist (e.g., cimetidine, ran- itidine) 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 heal- ing of aspirin-induced gastric lesions but has not been studied extensively in ulcers caused by other NSAIDs and appears less effective than acid-reduc- tion therapyP ~ Another prostaglandin analogue, en- prostil, 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 sim- ilar risk for GI complications. However, retrospec- tive 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 differ- ent NSAIDs. In their retrospective study, risk of de- veloping peptic ulcer disease was four times greater in patients taking meclofenamate or tolmetin than in patients taking ibuprofen. Other studies have dem- onstrated 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 be- tween nabumetone, naproxen, aspirin, and ibupro- fen indicate fewer endoscopic lesions with chronic nabumetone useY Findings from similar studies comparing etodolac, naproxen, ibuprofen, and in- domethacin 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 var- ies 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 ex- plain differences seen in retrospective studies. Many NSAIDs, including indomethacin, diclofenac, na- proxen, 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 pros- taglandin synthesis. Meade and colleagues v° have demonstrated that NSAIDs produce different rela- tive effects on two mouse prostaglandin synthase en- zymes (also called cyclooxygenase). Flurbiprofen, ibuprofen, and meclofenamate inhibited both en- zymes equally. Piroxicam, indomethacin, and sulin- dac preferentially inhibited the type 1 isoenzyme (PGHS-1 or COX-l) that is produced in most tissues, including platelets, kidneys, joint synovium, and gas- tric 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 is-expressed in inflamed tissue, activated monocytes, and macrophages. ~' Data using human enzymes also indicate that etodolac and nabumetone 1A-28S July 31, 1996 The American Journal of Medicine ® Volume 101 (suppl 1A)
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`SYMPOSIUM ON MANAGEMENT OF CHRONIC PAIN/BJORKMAN have a greater relative effect on the type 2 isoenzyme than other NSAIDs. However, no agent is totally se- lective for inhibiting human COX-2. 72 It is possible that differences in cyclooxygenase inhibitory effects may contribute to the differences in adverse GI ef- fects observed with various NSAIDs. Although assuming that selective inhibitors of the type 2 isoenzyme are safer is still premature, differ- ences in systemic effects may lead to identification or development of NSAIDs that have fewer GI ef- fects. 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 pa- tients without prior GI problems have a low risk of NSAID-induced complications. 4'6'9'43'45-47 Under these circumstances, the cost of drug prophylaxis outweighs potential therapeutic gain. For other pa- tients, the risk of an NSAID-induced complication is much higher; therefore, prophylactic therapy is in- dicated. Identification of patients who should re- ceive prophylactic therapy has been attempted 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 com- plication 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 anticoagu- lants. 9'4~-'~° Other factors that may warrant prophy- lactic 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 in- crease the risk of NSAID-induced ulceration or bleeding. 9 Selecting a Prophylactic Regimen Upon determining that an NSAID user requires prophylactic therapy, a treatment plan must be de- veloped. A variety of approaches have been sug- gested. 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 pro- tective 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 secre- tion. 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 de- crease 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 compli- cations 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 pa- tients. 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-in- duced 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 antag- onist in standard doses is effective in preventing du- odenal ulcers but not gastric ulcers. ~9-a' However, preliminary data suggest that higher doses of He-re- ceptor antagonists also may decrease gastric ul- cers. 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 sucral- fate 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 July 31, 1996 The American Journal of Medicine ® Volume 101 (suppl 1A) 1A-29S
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`SYMPOSIUM ON MANAGEMENT OF CHRONIC PAIN/BJORKMAN 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-reduc- tion 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 hospitaliza- tion, 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 dif- ferent circumstances. They determined cost of ther- apy to be $667,400 per year of life saved if all patients taking NSAIDs received misoprostol. Careful evalu- ation of risk factors significantly reduced this cost. When prophylactic treatment was limited to selected populations, reductions in the cost of therapy per year of life saved were observed (Table III). 3 Simi- lar results were calculated by Levine 8a for ulcer pre- vention. These numbers suggest that alternative ap- proaches 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 manage- ment of chronic painful conditions. Unfortunately, they frequently cause adverse GI effects; GI symp- toms 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 ul- cer with acid-reduction therapy. If an alternative medication cannot be substituted for the NSAID, treatment 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 in- cidence of ulcer formation and complications. The use of He-receptor antagonists and proton pump in- hibitors to prevent ulcers and complications requires further study. The high frequency of GI symptoms and compli- cations and the need for prophylactic therapy signif- icantiy increase the overall cost of NSAID therapy. Development of NSAIDs with fewer adverse GI ef- fects and nonaddictive analgesics may provide im- proved therapy for patients with chronic pain or in- flammatory diseases. REFERENCES 1. Roth SH. Nonsteroidal anti-inflammatory drugs: gastropathy, deaths, and medical practice. (Editorial.) Ann Intern Med. 1988;109:353-354. 2. Barrier CH, Hirschowitz BI. Controversies in the detection and management of nonsteroidal anti-inflammatory drug-induced side effects of the upper gastro- intestinal tract. Arthritis Rheum. 1989;32:926-932. 3. Edelson JT, Tosteson ANA, Sax P. Cost-effectiveness of misoprostol for prophylaxis against nonsteroidal anti-inflammatory drug-induced gastrointestinal tract bleeding. JAMA 1990;264:41-47. 4. Langman MJ. Epidemiologic evidence on the association between peptic ulceration and anti-inflammatory drug use. Gastroenterology. 1989;96(2 pt 2 Suppl):640-646. 5. Pincus T, Griffin M. Gastrointestinal disease associated with nonsteroidal anti-inflammatory drugs: new insights from observational studies and functional status questionnaires. Am J Med. 1991 ;91:209-212. 6. Larkai EN, Smith JL, Lidsky MD, Graham DY. Gastroduodenal mucosa and dyspeptic symptoms in arthritic patients during chronic nonsteroidal anti-inflam- matory drug use. Am J Gastroenterol. 1987;82:1153-1158. 7. Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut. 1987;28:527-532. 8. Lockard O0 Jr, Ivey K J, Butt JH, Silvoso GR, Sisk C, Holt S. The prevalence of duodenal lesions in patients with rheumatic diseases on chronic aspirin ther- apy. Gastrointest Endosc. 1980;26:5-7. 9. Fries JF, Williams CA, Bloch DA, Michel BA. Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models. Am J Med. 1991;91:213-222. 10. Bjarnason I, Hayllar J, Macherson A J, Russell AS. Side effects of nonstero oidal anti-inflammatory drugs on the small and large intestine in humans. Gas- troenterology. 1993;104:1832-1847. 11. Allison MC, Howatson AG, Torrance C J, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs. N Engl J Med. 1992;327:749-754. 12. Bjarnason I, Price AB, Zanelli G, et al. Clinicopathological features of non- steroidal anti-inflammatory drug-induced small intestinal stricture. Gastroenter- ology. 1988;94:1070-1074. 13. Isenberg JI. Overview of clinical cytoprotection. Dig Dis Sci. 1985;30(Suppl 11):81S-82S. 14. Wilson DE. Role of prostaglandins in gastroduodenal mucosal protection. .I Clin GastroenteroL 1991;13(Suppl 1):$65-$71. 15. Soil AH, Weinstein WM, Kurata J, McCarthy D. Nonsteroidal anti-inflamma- tory drugs and peptic ulcer disease. Ann Intern Med. 1991;114:307-319. 16. Miller TA. Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol. 1983;245:G601-G623. 17. Davenport HW. Damage to the gastric mucosa: effects of salicylates and stimulation. Gastroenterology. 1965;49:189-196. 18. McCarthy DM. Nonsteroidal anti-inflammatory drug-induced ulcers: man- agement by traditional therapies. Gastroenterology. 1989;96(2 pt 2 Suppl):662-674. IA-30S July 31, 1996 The American Journal of Medicine ® Volume 101 (suppl 1A)
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`SYMPOSIUM ON MANAGEMENT OF CHRONIC PAIN/BJORKMAN 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 non- steroidal 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-gastro- pathy: 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, Gr