Gastroduodenal Mucosal Damage With Salsalate Versus Aspirin: Results of Experimental Models and Endoscopic Studies in Humans

By James M. Scheiman and Grace H. Elta

Animal models have identified multiple mecha- NSAID-induced GI toxicity may represent the nisms of aspirin toxicity. Aspirin inhibits cycloox- most frequent drug side effect in the US.’ This ygenase in the gastroduodenal mucosa leading situation has generated interest in the develop- to a decrease in endogenous prostaglandins. ment of strategies designed to limit gastroduode- Prostaglandin mediated mucus and bicarbonate nal injury caused by chronic NSAID use. Con- secretion, epithelial hydrophobicity, blood flow, comitant use of conventional antiulcer therapy and cellular proliferation are all decreased. for both prevention of upper GI tract ulceration Salicylates may cause direct cellular toxicity via and treatment of NSAID-induced damage while inhibition of energy metabolism and membrane transport properties. Salicylate preparations the NSAID is continued, has shown mixed and have been designed to decrease gastroduode- largely disappointing results.3 Recently it has nal absorption. Endoscopic studies in humans been suggested that oral prostaglandins may have confirmed that buffering of aspirin does have a role in the prophylaxis of gastroduodenal not ameliorate damage, but enteric coating damage caused by NSAIDS.~ Unfortunately, does. Salicylsalicylic acid (salsalate) is an effec- they are costly and have significant side effects. tive antirheumatic drug that bypasses gastric An alternative to the administration of an absorption and also avoids cyclooxygenase inhi- additional drug, such as a prostaglandin, is to bition. In a randomized, single-blind, endoscopic utilize an NSAID which spares the upper GI comparison of salsalate versus enteric-coated tract. Salicylsalicylic acid (salsalate), a salicy- aspirin, significantly less gastroduodenal dam- late ester of salicylic acid, was originally devel- age was observed in volunteers after salsalate administration compared to enteric-coated as- oped as a safer, nonacetylated alternative to pirin. An endoscopic study in rheumatoid arthrit- aspirin (acetylsalicylic acid).5 In this review we its also confirmed the ability of salsalate to will discuss the mechanisms of salicylate-induced spare gastroduodenal mucosa when compared gastroduodenal damage in animal models and to naproxen administration. Salsalate may cause the results of endoscopic studies in humans that less gastroduodenal damage than enteric- suggest salsalate has potential as a gastroduode- coated aspirin based on the results of animal nal sparing agent. models and endoscopic studies in humans. @ 1990 by W.B. Saunders Company. MUCOSAL INJURY BY SALICYLATES IN ANIMAL MODELS INDEX WORDS: Salicylates; gastroduodenal damage: animal models: endoscopic studies. Aspirin is absorbed passively in the upper GI tract. This absorption is dependent on its concen- ALICYLATES and other nonsteroidal anti- tration and its lipid solubility at acid pH (the S inflammatory drugs (NSAIDs) are some of pKa of aspirin is 3.5). The compound is more the most commonly used drugs in clinical prac- tice. Epidemiological studies have estimated that they are prescribed in quantities sufficient to From the Department of Internal Medicine, Division of treat three million people on a daily basis, suggest- Gastroenterology. University of Michigan Medical School, ing as many as 1.2% of the United States and Veterans Administration Medical Center, Ann Arbor. MI. population may use these agents daily. In 1983, James M. Scheiman, MD: Instructor in Internal Medicine; over half the physician visits for arthritis involved University of Michigan Medical School; Grace H. Elta; MD: prescriptions for NSAIDs.’ Assistant Professor of Internal Medicine, University of While these agents are very effective in the Michigan Medical School. care of patients with painful musculoskeletal Address reprint requests to James M. Scheiman, MD, GI Section (1 IID), V.4 Medical Center, 2215 Fuller Rd. Ann disorders, their gastrointestinal (GI) side effects Arbor, MI 48105. remain a vexing clinical problem. Given the large 0 1990 by W.B. Saunders Company. number of patients exposed to these drugs, 0049-0172/90/2002-0007$5.00/O

Seminars in Arthritis and Rheumatism, Vol 20. No 2 (October). 1990: pp 12 l-127 121 122 SCHEIMAN AND ELTA

than 50% nonionized in gastric or duodenal fluid onstrated that sodium salicylate administration with a pH below 3.5 and rapid absorption occurs. fails to injure gastric mucosa.6’10 Investigators Once absorbed across the cell membrane, the have inferred from these data that cyclooxygen- higher intracellular pH favors dissociation to the ase inhibition is the most important mechanism ionized form, leading to accumulation and high of gastrointestinal injury by salicylates. Recent local cellular concentrations of the drug. When in vitro studies suggest that salicylic acid and the aspirin is completely absorbed, it is hydro- aspirin can damage mucosa equally, but only lyzed to salicylic acid by the action of intestinal, after the gastric luminal pH has been lowered to hepatic, and plasma esterases. The toxicity of 1 .0 . ‘L’~ These damaging effects occur with either acetylsalicylic acid depends upon both a local oral or parenteral administration. Because paren- toxic effect and the systemic effect of the drug. teral salicylic acid inhibits acid secretion to a Animal models have offered insight into the much greater extent than acetylsalicylic acid, the mechanisms of aspirin induced-toxicity. Depend- lack of gastric damage produced by salicylic acid ing upon the model studied, and the criterion to in previous studies may have been caused by measure damage, some animal models show insufficient luminal acidification. When luminal greater toxicity with aspirin than salicylic acid. pH is decreased, salicylate appears to accumu- late in the epithelium and diminish mucosal Cyclooxygenase Independent Mechanisms resistance to proton flux. To further elucidate the role of cyclooxygenase inhibition in the genesis of Acetylsalicylic acid inhibits mucosal cyclooxy- mucosal toxicity, investigators attempt to reverse genase, thereby decreasing levels of endogenous or prevent damage by exogenous administration prostaglandins. In contrast, salicylate is a weak of prostaglandins. Partial amelioration of the inhibitor of the enzyme.6 In addition to this aspirin injury was observed after administration prostaglandin mediated effect, salicylates can of prostaglandin E, (PGE,) but no effect on the have direct cellular toxicity independent of cy- salicylate injury was seen.12 The partial pro- clooxygenase inhibition. tective effect of PGE, points to the complex Pioneering work by Davenport demonstrated mechanisms of aspirin injury and suggests that that the gastric mucosal barrier, the unique additional mechanisms of damage related to ability of the gastric surface epithelium to sur- cyclooxygenase inhibition may be important in vive in the hostile acidic milieu of the stomach, is the intact animal. An understanding of the ef- lost after exposure to either aspirin or salicylic fects of cyclooxygenase inhibition on the compo- acid.’ Both drugs increase proton flux into the nents of gastroduodenal defense is required for mucosa and cause a drop in potential difference, further understanding of the mechanisms of a sensitive measure of epithelial integrity. Other aspirin toxicity. investigators have confirmed this decrease in mucosal potential difference, with increased cat- ion flux after exposure to both aspirin and sali- Cyclooxygenase Dependent Mechanisms cylic acid, yet only aspirin caused a dramatic Robert first described the ability of prostaglan- reduction in mucosal prostaglandin content.8 The dins, independent of their inhibition of acid back diffusion of protons leads to cellular acidifi- secretion, to protect the gastric mucosa against a cation and altered cellular metabolism. variety of noxious agents that produce tissue An additional mechanism of salicylate in- damage and cellular necrosis.13 This was called duced damage independent of cyclooxygenase “cytoprotection.” This observation prompted inhibition is the uncoupling of oxidative phospho- many investigations into the role of endogenous rylation by intracellular salicylates. This results prostaglandins in the maintenance of upper GI in depletion of cellular adenosine triphosphate mucosal integrity. The major prostaglandins syn- (ATP) levels and inhibition of active ion trans- thesized by the action of cyclooxygenase on port essential to maintain cellular integrity. This membrane arachidonic acid within gastrointesti- effect on energy metabolism is a major direct nal mucosa include PGE,, PGI,, PGD,, and toxic effect of salicylate.’ PGF,cu. To investigate the physiological role of Although salicylate has direct toxic effects on endogenous prostaglandins, most studies have gastric epithelia, a number of studies have dem- examined the effect of aspirin or other NSAID GASTRODUODENAL DAMAGE WITH SALSALATE V ASPIRIN 123 cyclooxygenase inhibitors on a parameter impor- dins on mucin synthesis, while others suggest tant in mucosal defense. that aspirin can qualitatively alter mucus, such Recently, Redfern and Feldman demonstrated as inhibition of sulfate incorporation.22 Salicylic that active immunization of rabbits, with the acid exposure appears to have a much weaker principal endogenous prostaglandins of gas- effect.22 Another qualitative deficiency of gastric trointestinal mucosa, induced upper GI tract mucus caused by aspirin exposure is increased ulceration.‘4 These lesions resemble both human sensitivity to pepsin leading to the formation of stress ulcers and the erosive gastric disease seen smaller and less viscous gel which is poorly with NSAID administration. The authors postu- resistant to H+ penetration.23 lated that prostaglandin antibodies led to a An additional important defensive factor that decrease in effective tissue content of prostaglan- appears prostaglandin dependent is the mainte- dins, resulting in either an increase in gastric acid nance of surface hydrophobicity of the gastric secretion or a decrement in mucosal defense. epithelium. The presence of saturated phospholip- Active immunization of dogs with PGE, did not ids, which have surface-active properties, appear increase acid secretion. Therefore, endogenous to cause the gastric surface to be uniquely prostaglandins appear to have a greater role in hydrophobic and thus repel water and acid. This the maintenance of mucosal defensive factors effect can be measured by the formation of a compared to their acid inhibitory effect.” contact angle between a drop of water and the gastric surface. Administration of aspirin leads Prostaglandins and Mucosal Defense to loss of surface hydrophobicity and decreased Critical to the maintenance of gastroduodenal transmucosal potential difference,24 with pros- integrity is the presence of a mucous gel into taglandin administration restoring the surface which bicarbonate is secreted, forming an un- hydrophobicity lost after aspirin exposure.25 The stirred water layer with a protective pH gradient effects of nonaspirin salicylates on surface hydro- adjacent to the mucosa.‘6 A pH gradient from phobicity is unknown. pH 2 in the lumen to approximately pH 7 at the Additional cyclooxygenase dependent effects cell membrane has been confirmed in animals by of aspirin include a decrease in mucosal blood passing a pH probe through the mucous gel.]’ flow due to the loss of tonic vasodilatory pros- Recent work using in vivo microscopy has demon- taglandins. Microcirculatory studies have demon- strated that this gradient is preserved through strated arteriolar constriction and thrombus for- active expulsion of acid from the base of the mation after luminal aspirin exposure.2h These gastric gland with preservation of the mucous gel effects may contribute to ischemia causing mu- and its pH gradient. l8 Prostaglandin administra- cosal injury and intramucosal hemorrhage. Pros- tion has been shown to enhance the release of taglandins also have been shown to have trophic both mucus and bicarbonate, while cyclooxygen- effects on gastric mucosa. Inhibition of prolifera- ase inhibition diminishes them. Aspirin and other tion may be an additional mechanism of aspirin NSAIDs significantly inhibit basal bicarbonate toxicity.’ secretion from an amphibian model in vitro, an In summary, the toxicity of aspirin for the effect reversed by administration of synthetic gastrointestinal epithelium is a combination of PGE,. I9 This observation has been confirmed in the direct effects of salicylate on cellular function humans by Isenberg who found that indometha- and depletion of prostaglandin-dependent mu- tin inhibited duodenal bicarbonate and PGE, cosal defensive factors (Table 1). Most models of production. 2o To our knowledge, the effects of mucosal injury demonstrate a correlation be- salicylates other than aspirin on basal bicarbon- tween mucosal inhibition of cyclooxygenase and ate secretion have not been studied. observed damage. Salicylic acid has little effect Prostaglandins have an important role in the on the enzyme, less interference with prostaglan- maintenance of mucus secretion but seem to have din mediated mucosal defense, and thus less little role in the synthesis of glycoprotein.21 Both injury is generally observed. We turn now to PGE, and PGF, increase secretion of glycopro- endoscopic studies in humans to determine if the tein, while indomethacin has an inhibitory effect. differences noted in animal models can be used These investigators found no effect of prostaglan- for clinical advantage. 124 SCHEIMAN AND ELTA

Table 1: Gastroduodenal Toxicity of Aspirin: that bypasses gastric absorption (it is insoluble in Cellular Mechanisms acid and is hydrolyzed to two molecules of

f vents related to cyclooxygenase inhibition-Loss salicylic acid at ~7 pH) and a drug that does not of prostaglandin mediated significantly inhibit cyclooxygenase. Enteric- Mucus secretion coated aspirin bypasses gastric absorption, but Viscosity and acid resistance of mucus inhibits cyclooxygenase. Bicarbonate secretion Investigations of endoscopic damage after ad- Hydrophobicity of the epithelial surface ministration of aspirin preparations suggest that Blood flow buffered preparations offer no advantage over Cellular proliferation unbuffered preparations. In a review of many f vents related to the direct cellular toxicity of sali- studies of acute drug administration in normal cylate subjects, Lanza found that neither Bufferin (Bris- Increased permeability-cation flux Decreases in transmucosal membrane potential tol-Meyers; New York, NY) or Ascriptin A-D Inhibition of oxidative phosphorylation (W.H. Rorer, Inc; Fort Washington, PA) caused Inhibition of membrane transport properties less endoscopic damage than unbuffered acetyl- salicylic acid at 2,600 and 3,900 mg/d.30 Enteric- coated aspirin, however, led to significantly less ENDOSCOPIC STUDIES COMPARING damage than aspirin. Hoftiezer et al performed a SALICYLATES IN HUMANS similar endoscopic comparison between plain Because the toxic effects of aspirin relate to and enteric-coated aspirin and observed similar both its local concentration and systemic distribu- protective properties for the enteric-coated tion, attempts to lessen direct gastroduodenal preparation.31 absorption have been used. The antacid ameliora- We studied salsalate, a drug that does not tion of aspirin-induced gastric damage suggests inhibit endogenous prostaglandins and bypasses that decreases in local toxicity could be reduced gastric absorption. This theoretically could repre- if absorption was delayed.27 The use of a sent a therapeutic advantage over enteric-coated “prodrug,” a drug given in an inactive form that aspirin. We performed a randomized, single- requires metabolic activation after absorption, is blind, crossover, endoscopic comparison of the an attempt to lessen the direct gastric absorption two drugs after one week of administration in of active drug. An endoscopic study with sulin- normal volunteers. 32 Subjects were given sal- dac sulfoxide (the prodrug converted to the salate (Disalcid, 3M Pharmaceuticals, St Paul, cyclooxygenase inhibitor sulindac sulfide) demon- MN) 1,500 mg/d (two 750 mg tablets twice a strated markedly less damage compared with day) or enteric-coated aspirin (Ecotrin, Smith- aspirin administration, while no difference was Kline Beckman, Philadelphia, PA) 650 mg (two seen between the prodrug and the active moiety, 325 mg tablets) four times a day. The subjects perhaps because both were insoluble in gastric had endoscopy performed prior to drug adminis- juice. 28 Although little damage was seen after tration and after 6 days of drug ingestion. After a acute administration of sulindac to normal volun- 1 week “washout” period, the subjects began teers, a recent large epidemiological study has treatment with the other study drug. We quanti- indicated that sulindac has no advantage over tated gastroduodenal damage using an endos- other NSAIDs for risk of upper GI bleeding.29 copy rating scale as shown in Table 2. The results These results suggest that prevention of gas- of the endoscopic scores after drug administra- troduodenal absorption is only one aspect in the tion, the order of drug dosing, and the posttreat- prevention of NSAID toxicity, and that cycloox- ment salicylate levels are summarized in Table 3. ygenase inhibition from a systemically distrib- Only a single subject treated with salsalate had uted drug is important. The observation that any evidence of gastroduodenal damage (grade administration of an oral prostaglandin is effec- 1) while 6 of the 10 subjects who received tive in the prevention of NSAID damage also enteric-coated aspirin developed significant dam- underscores the importance of endogenous pros- age (grade 2 in one subject and grade 3 in the taglandins in the maintenance of mucosal integ- remainder, including a duodenal ulcer in one rity. Salicylsalicylic acid (salsalate) is a drug patient). Salsalate caused significantly less gas- GASTRODUODENAL DAMAGE WITH SALSALATE V ASPIRIN 125

Table 2: Rating of Gastroduodenal Damage troduodenal injury was graded endoscopically after 1 and 3 months. Patients were eligible if Score Endoscopic Findings they did not have a history of major GI hemor- 0 Normal rhage, ulceration larger than 2 cm, or diffuse 1 Less than 3 areas of mucosal hemorrhage or erosion erosions or ulceration at baseline endoscopy. 2 3- 10 areas of mucosal hemor- Patients were given the study drugs without a rhage or erosion washout period and the initial study doses were 3 Widespread involvement or 1,500 mg of salsalate or 375 mg of naproxen greater than 10 areas of ero- twice a day. Doses were titrated to antirheumatic sions with active bleeding efficacy within the range of 2,000 to 4,000 mg/d of salsalate and 500 to 1,000 mg/d naproxen. The distribution of baseline endoscopy scores in troduodenal damage than enteric-coated aspirin the patients who completed the study were not when analyzed by the Wilcoxon signed rank test significantly different. The final endoscopy scores (P = .Ol), a difference that was maintained were significantly different, with 8 of 2 I (38%) of when the patient with a baseline antral endo- the naproxen-treated patients developing ulcers scopic abnormality was excluded from analysis. (seven patients) or diffuse erosions (one patient) Gastrointestinal symptoms were mild and not significantly different in the two groups. Mean while none of the salsalate patients had either fasting salicylate levels after 6 days of treatment category of lesion (P = ,003 by the Wilcoxon with salsalate and enteric-coated aspirin were signed rank test). This study suggests salsalate 18. I mg/dL and 1 1.2 mg/dL respectively. There causes significantly less gastroduodenal toxicity was no correlation between the serum salicylate than naproxen after chronic administration to level and the development of gastroduodenal rheumatic patients. damage. The usefulness of endoscopic studies after A recent endoscopic study in rheumatoid ar- acute NSAID administration has been ques- thritics has confirmed salsalate’s ability to spare tioned because of poor correlation with chronic the gastroduodenal mucosa from injury while drug epidemiology.34 Also there is poor correla- remaining an effective antirheumatic agent.33 In tion between acute and chronic studies of antiul- this study, eligible patients were randomized to cer drugs used for prophylaxis or therapy of salsalate or naproxen (Naprosyn, Syntex Labora- NSAID-induced toxicity.35 Critics of these endo- tories, Palo Alto, CA) for 3 months and gas- scopic studies are concerned that acute lesions

Table 3: Endoscopy Sores and Serum Salicylate Levels In 10 Volunteers During Treatment With Salsalate and Enteric-Coated Aspirin*

Salsalate Enteric-Coated Aspirin

Endoscopy Salicylate Endoscopy Salicylate Dosing Subject Score Level (mg/dL) Score Level (mg/dL) Order

1 0 38.8 0 10.0 ASA-SAS 2 0 19.0 3 15.6 ASA-SAS 3 0 10.0 2 6.6 ASA-SAS 4 0 24.7 0 5.6 ASA-SAS 5 0 16.5 0 8.9 SAS-ASA 6 0 17.0 3 9.6 SAS-ASA 7 1 16.3 0 12.2 SAS-ASA 8 0 18.0 3 15.4 SAS-ASA 9 0 6.9 3 14.1 ASA-SAS 10” 0 13.4 3 13.8 ASA-SAS L Abbreviations: ASA, aspirin; SAS, salsalate. *Volunteer 10 had a sccre of 1 on each baseline endoscopy All other baseline scores were 0. 126 SCHEIMAN AND ELTA such as hemorrhages and erosions do not always with enteric-coated aspirin.37 An additional chal- correlate with the risk of development of a lenge to the sparing effects of enteric-coated chronic ulcer or significant GI bleeding. Al- aspirin has recently been made.38 Patients who though studies of longer duration in rheumatic had an NSAID-related ulcer but required chronic patients are required to confirm the promising antiarthritic therapy were given enteric-coated results of our endoscopic comparison, salsalate aspirin in addition to a combination of cimetidine may prove to have significant gastroduodenal and antacids. None of the patients taking enteric- sparing properties compared with enteric-coated coated aspirin healed on therapy while 15 out of aspirin. The subjects taking enteric-coated aspi- rin in our endoscopic study developed more 16 who stopped their NSAIDs healed. Thus, gastroduodenal injury than those in prior enteric coating of aspirin may afford some gas- reports. 30*31These differences likely represent troduodenal protection, but it is not risk free. We variability from the small number of subjects conclude that salsalate may cause less gastroduo- studied. Endoscopic studies in rheumatic pa- denal damage than enteric-coated aspirin based tients suggest that the frequency of gastric,36 but on the results of animal models and our endo- not duodenal damage, is reduced with treatment scopic comparison.

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