Scandinavian Journal of Rheumatology

ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20

Making Sense of NSAID Gastropathy and Considering the Therapeutic Options N. M. Agrawal To cite this article: N. M. Agrawal (1992) Making Sense of NSAID Gastropathy and Considering the Therapeutic Options, Scandinavian Journal of Rheumatology, 21:sup92, 13-19, DOI: 10.3109/03009749209101384 To link to this article: http://dx.doi.org/10.3109/03009749209101384

Published online: 12 Jul 2009.

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Date: 15 April 2016, At: 20:32

Scand J Rheumatol 1992; Suppl. 92: 13-19

Making Sense of NSAID Gastropathy and Considering the Therapeutic Options N.M. AGRAWAL

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Tulane University School of Medicine, New Orleans, Louisiana There is increasing recognition that nonsteroidal anti-inflammatory drugs (NSAIDs), while quite effective in treating arthritic symptoms. are associated with gastrointestinal mucosal damage. Although therapy for patients with NSAID-induced ulcers or those at high risk of developing them is still a matter of debate, the current literature supports the use of misoprostol as the only drug effective for the prevention of both NSAID-induced gastric and duodenal ulceration. It has also been shown to treat NSAID-induced gastropathy in patients continuing their NSAID therapy. In a s!udy of misoprostol (100 or 200 p g QID) plus NSAID, after three months of continuous therapy, a significantly lower frequency of gastric ulcers in the misoprostol-treated group was revealed: 100 p g misoprostol. 5.6%; 200 pg misoprostol, 1.4%; placebo, 21.7%. A recent threemonth, placebo-controlled study established the efficacy of misoprostol 200 p g QID in the prevention of NSAID-induced duodenal ulcers in 429 patients with osteoarthritis (OA), rheumatoid arthritis (RA), or other rheumatic disease, who were receiving daily treatment with various NSAIDs. The incidence of duodenal ulcer development over three months was 1 .O% in patients treated with misoprostol versus 6.3% in placebo-treated patients (P = 0.004). The same trial also evaluated the efficacy of rnisoprostol 200 Lrg QID versus placebo in preventing NSAID-izduced gastric ulcers. The incidence of gastric ulcer over the threc-month treatment period was 1.5% in patients treated with misoprostol versus 9.0% in placebo-treated patients (P = 0.001). Preliminary findings of a recent comparison of rnisoprostol (200 p g QID) and ranitidine (150 mg BID) given concurrently with NSAID therapy, clearly denionstr;itcs thc supcriority of rnisoprostol in preventing NSAID-induced gastric ulcers (2 0.3 em in diameter). At the end of cighl weeks. I. 1 % of the misoprostol-treated patients developed gastric ulcer versus 5.2% o f the ranitidine-treated paticnls (1’ = 0.003). In another comparative trial, rniso~rostol(200 p g Qlll) and sucralfatc (1 gm QID) were coadministered with the NSAID therapy. The frequency of gastric ulcers (2 0.3 cm in diamcter) at the end of three months was 1.6% in the rnisoprostoltreated group versus 16% in thc sucrallatc-treated group (I’ 2 0.001). Finally, the long-term efficacy of misoprostol in the prevention of NSAID-induced gastroduodenal lesions and ulcers was also evaluated. A 12-month, multicenter, randomized, double-blind, parallel group comparison trial was conducted. Misoprostol 200 p g (BIDKID) was coadministered with diclofenac 5 0 mg (RIDKID). Endoscopic evaluations were performed at 3, 6 , and 12 months. Patients who developed clinically significant lesions (defined as oozing or intraluminal blood, > 10 erosions, ulceration or visible vessel) at 3 and 6 months were removed from the study. Endoscopic evaluation at 12 months showed that the incidence of gastroduodcnal ulccrs was 15% in the misoprostol group versus 31% in the placebo group (p = 0.018, Kaplan-Meier analysis).

Key words: Hz-receptors, ranitidine, sucralfale, rnisoprosiol, diclofcnac, omeprazole, rheumatoid arthritis, osteoarthritis

Introduction Gastroenterologists gencrally accept that nonsteroidal anti-inflammatory drugs (NSAIDs) may cause gastric, duodenal, and intestinal lesions. From many studies, it appears that all NSAIDs are capable of producing this kind of gastroinlestinal damage. Consequently, therapcutic options that prevent NSAID-induccd gastropathy should bc cxamined and their use seriously considcred. The most effective method for preventing NSAID-induced gastropathy is discontinuation of NSAIDs. Discontinuation is not a realistic approach for many arthritic patients because they rely Correspondence: N.M. Agrawal. Tulane Medical School, 1430 Tulane Avenue, New Orleans, LA 701 12. USA.

on this category of drugs to obtain relief from painful symptoms, and, for many, NSAIDs are the only compounds that provide such relief. In addition, NSAIDs are available over-the-counter for self-medication and, if prescriptions are not written, are beyond the control of the physician. Therefore, attention must be focused on the classes of drugs physicians use for the prevention of NSAID-induced gastroduodenal damage. Four classes of drugs have been identified in the literature as potentially having some preventive effect on NSAID-induced gastroduodenal damage: histamine H2-receptor antagonists (eg, ranitidine), antisecretory agents (eg, omeprazole), acid barrier compounds (eg, sucralfate), and prostaglandin El analogs (eg, misoprostol). 13

N . M . Agrawal

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Ehsanullah et al, 1988 (1) P = Placebo + NSAlD R = Ranitidine (1 50 mg BID) + NSAlD

Duration: 8 weeks N: 263 Ulcer size: 50.5cm

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Figure 1: Prevention of NSAID-induced gastropathy - ranitidine.

Therapeutic Trials in Preventing NSAlD-Induced Gast ropathy H2-Receptor Antagonists Two separate, multicenter, double-blind, placebocontrolled, randomized, endoscopic studies, one published by Ehsanullah et al.(l) in 1988 and the other by Robinson et a1.(2) in 1989, evaluated the ability of ranitidine to prevent NSAID-induced gastric and duodenal ulcers. In both studies, ranitidine was coadministered in dosages of 150 mg twice a day (BID) with an NSAID and compared with the coadministration of a placebo and an NSAID for a period of eight weeks. Both trials drew upon a large number of patients; Ehsanullah’s study included 263 patients with rheumatoid arthritis (RA) or osteoarthritis (OA), who were free of gastroduodenal lesions upon entry and taking an NSAID (naproxen, ibuprofen, diclofenac, and indomethacin). The study included a disproportionately large number of patients with a history of duodenal ulcer. This would partially explain the lower incidence of gastric ulceration compared to that of duodenal ulceration in these patients. Robinson’s study was conducted among 144 patients requiring NSAID (ibuprofen, naproxen, sulindac, indomethacin, and piroxicam) therapy, primarily for arthritis. None of the patients had endoscopic evidence of mucosal damage at baseline. In either study, the development of an ulcer 0.5 cm in diameter or larger in either the stomach or duodenum was considered evidence of ulcer disease. 14

Both trials showed that ranitidine was effective in preventing duodenal ulcers in patients who take NSAIDs (Fig. 1). However, gastric ulcers were not prevented by ranitidine. In fact, the proportion of patients who developed gastric ulcers was essentially the same for ranitidine patients and placebo patients in both studies. Thus H2-blockers are seen to prevent NSAID-induced duodenal ulcers but not NSAID-induced gastric ulcers.

Omeprazole A major emphasis in preventing ulcer disease has been placed on the reduction of gastric acid. Omeprazole is the most potent acid-inhibiting agent available today. A one-week trial conducted by Oddsson and colleagues (3), evaluated the protective effect of omeprazole against naproxen injury to the gastroduodenal mucosa (Fig. 2). In this double-blind, crossover study, omeprazole 40 mg QD was coadministered with naproxen 500 mg BID in 15 healthy subjects. Naproxen was administered on day 3 through day 7. Endoscopic evaluations were used to grade gastric and duodenal injury on a scale of 0 (normal) to 4 (numerous erosions or an ulcer). The mean gastric injury score was 1.53 with placebo and 0.93 with omeprazole, and this difference was not significant. The mean duodenal injury scores were 1.93 for placebo and 0.27 for omeprazole, differences that were statistically significant (P = 0.004). These results demonstrate that omeprazae i;, effective in protecting the duodenum

Making Sense of NSAlD Ganropatny and Considering the Therapeutic Options Duodenum

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Oddsson et al, 1990 (3) P = Placebo + naproxen 0 = Omeprazole (40mg QD) + naproxen Cross-over design 7 days with each regimen separated by a 3-week washout 15 Lama scale (0-4) (4)

Figure 2 : Prevention of NSAID-induced gastropathy - orneprazole.

P = 0.003

n 9.2

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S

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Agrawal et al, 1991 (4) M = Misoprostol (200 pg QID) + NSAlD S = Sucralfate (1 gm QID) + NSAlD Duration: 3 months N: 253 Ulcer size: 20.3 cm or 20.5 cm Figure 3: Prevention of NSAlD-induced gastropathy - sucralfate (GU). Source: Regimens:

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P 10 erosions, oozing, intraluminal blood, the presence of a visible vessel or an ulcer. Seven patients were withdrawn from the placebo group because of the presence of > 10 erosions, compared with only two patients from the misoprostol group. Since the presence of these types of lesions may indicate a predisposition to development of more serious damage, the early withdrawal of these patients may have removed from the study a group of patients who were most likely to develop ulcers. However, despite this effect of the study design, the data still showed misoprosto1 to be effective in preventing diclofenac-induced ulceration. Preliminary findings of the first head to head double-blind comparative trial of misoprostol and ranitidine in the prevention of NSAID-induced gastric ulcers were presented by Raskin et al. (8) recently after this symposium. Patients with upper 17

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N.M.Agrawal gastrointestinal symptoms due to NSAID therapy but no evidence of gastric or duodenal ulcer on endoscopy were enrolled in this study. Those with a history of peptic ulcer, defined as an episode within the last 12 months, were excluded from the study. Patients were taking various NSAIDs daily for osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or Reiter's syndrome. Misoprostol (200 pg QID) or ranitidine (150 mg BID) was coadministered with the NSAID for eight weeks. Patients underwent endoscopic examination at 0, 4, and 8 weeks of therapy. Preliminary results which were reported for 538 treatcd patients demonstrated that misoprostol was significantly more effective than ranitidine in preventing NSAID-induced gastric ulcer (2 0.3 cm) dcvclopment; 1.1% of the patients on misoprostol developed gastric ulcers versus 5.2% of patients on ranitidine (Fig. 7). Safety data are not yet available.

Conclusion NSAIDs are capable of inducing gastric or duodenal ulcers and it is necessary to ~ S S C S SLhc nccd for administering them. Since many of the drugs commonly used to treat ulcers are not cffcctive in preventing NSAID-induced gastric ulcers, this nccd assessment becomes even more important. Whcn

P = 0.003

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538 .0.3cm

Figure 7: Prevention of NSAID-induced gastric ulcers, rnisoprostol versus ranitidine.

NSAlDs must be used, the prostaglandin El analog, misoprostol, coadministered with the NSAID, appears to be the only agent that has been proven to

P = 0.018

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M

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Source: Geis GS. Data on file (6) Regimens: M = Misoprostol (200 bg BIDfllD) + diclofenac (50 mg BID/TID) P = Placebo (BIDDID) + diclofenac (50 mg BID/TID) Duration: 12 months N: 204 (evaluable cohort) Figure 6; Misoprostol in the prevcntion or NSAID-induced gastroduodenal ulceration over 12 months. 18

Making Sense of NSAID Gastropathy and Considering the Therapeutic Options

prevent both gastric and duodenal ulcers induced by NSAIDs.

References

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1. Ehsanullah KSB, Page MC, Tildesley G, Wood JK. Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: Controllcd trial of ranitidine. BMJ 1988; 297: 1017-21. 2. Kobinson MG, Griffin JW, I3owcrs J. et al. Effcct of ranitidine on gastroduodcnal mucosal damage induced by nonsteroidal antiinflammatory drugs. Dig Dis Sci 1989; 34: 424-8. 3. Oddsson E, Gudjonsson H, Thjodlcil‘sson 13. I’rotectivc effect of omeprazole or ranitidine against naproxcn induced damage to the human gastroduodenal mucosa. Scand J Gastroenterol 1990; 25(Suppl. 176): 25.

4. Agrawal N. Koth S . Graham DY, et al. Misoprostol compared with sucralfate in the prevention of non-steroidal antiinflammatory drug-induced gastric ulcer. Ann Intern Med 1991; 115: 195-200. 5 . Graham DY, Agrawal NM, Roth SH. Prevention of NSAIDinduced gastric ulcer with misoprostol: Multicentre, doubleblind, placebo-controlled trial. Lancet 1988; 2: 1277-80. 6. Geis GS. Data o n file, G.D. Searle, Skokie, Illinois. 7. Graham DY, Stromatt SC, Jaszewski R. Prevention of duodenal ulcer in arthritics who are chronic NSAID users: A multicenter trial of the role of misoprostol. (Abstract) Gastroenterol 1991; 100: A75. (Data not included in abstract presented at AGA/AASLD, May 1991, New Orleans, LA.) 8. Kaskin J , White K, Jaszewski R. Double-blind comparative study of the efficacy and safety of rnisoprostol and ranitidine in the prevention of NSAID-induced gastric ulcers and upper GI symptoms: Preliminary findings. (Abstract) Digestion 1991; 49(Suppl. 1): 5&1.

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Making sense of NSAID gastropathy and considering the therapeutic options.

There is increasing recognition that nonsteroidal anti-inflammatory drugs (NSAIDs), while quite effective in treating arthritic symptoms, are associat...
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