Digestive Diseases and Sciences, Vol. 37, No. 12 (December 1992), pp. 1820-1824

Treatment of Nonsteroidal Antiinflammatory Drug-Induced Gastric Ulcers with Misoprostol A Double-Blind Multicenter Study RICHARD JASZEWSKI, MD, DAVID Y. GRAHAM, MD, and SCOTT C. STROMATT, MD

One hundred sixty-two patients chronically ingesting ibuprofen, piroxicam, or naproxen for osteoarthritis, who had abdominal pain and an endoscopically proven gastric ulcer were evaluated for eight weeks in a randomized, double-blind trial comparing misoprostol (200 Ixg four times daily with meals and at bedtime) (N = 77) with placebo (N = 85). Patients discontinued their usual daily dose o f antiarthritic medication throughout the study period, and an endoscopy was performed at four weeks and eight weeks (if necessary) to assess ulcer healing. Gastric ulcers were defined as circumscribed breaks in the gastric mucosa of 0.3 cm in diameter or greater. Misoprostol therapy significantly accelerated the rate o f gastric ulcer healing compared to placebo (P = 0.033). The cumulative percent healed after four and eight weeks o f therapy for misoprostol versus placebo were: 83% vs 61% at four weeks and 96% vs 90% at eight weeks (P = 0.0028 and P = 0.0977, respectively by lifetable analysis). Relief of abdominal pain did not differ significantly between the treatment groups. Misoprostol significantly accelerates the healing of ibuprofen-, piroxicam-, or naproxen-induced gastric ulcers. KEY WORDS: ulcer; prostaglandin; stomach; arthritis.

Nonsteroidal antiinflammatory drugs (NSAIDs) can cause gastroduodenal mucosal injury in humans (1-4). The susceptibility of the gastric mucosa to injury by these drugs is thought to be related to an inhibition of prostaglandin synthesis (5-7). The spectrum of injury can vary from erosions and submucosal hemorrhage to frank ulceration (8, 9). Furthermore, there is evidence to suggest that chronic NSAID therapy can increase the morbidity Manuscript received September 25, 1991; revised manuscript received March 24, 1992; accepted March 27, 1992. From the Veterans Administration Medical Center, Wayne State University Affiliate Hospital, Allen Park, Michigan; Baylor College of Medicine and VA Medical Center, Houston, Texas; and Searle Corporation, Skokie, Illinois. Address for reprint requests: Dr. Richard Jaszewski, VA Medical Center, Department of Gastroenterology (111C1), Allen Park, Michigan 48101.

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and mortality of peptic ulcer disease, particularly in elderly patients (10-12). In previous studies of NSAID-induced gastric ulcers, standard antiulcer therapy (H 2 antagonists, sucralfate, antacids) was effective in healing 6586% at four to six weeks, if NSAID therapy was discontinued (13, 14). With continued NSA1D use, resistance to H 2 antagonist therapy has been noted with ulcer healing rates of 45-70% (15-17). Misoprostol, a synthetic prostaglandin E l analog, has been demonstrated to be effective in healing gastric (18) and duodenal ulcers (19) as well as in the prevention of NSAID-induced gastric ulcers (20). The present study was undertaken to determine the effectiveness of misoprostol in healing NSAID induced gastric ulcers. Digestive Diseases and Sciences, Vol. 37, No. 12 (December 1992)

0163-2116/92/1200-1820506.50/09 1992PlenumPublishingCorporation

HEALING OF NSAID ULCERS TABLE 1. PATIENT CHARACTERISTICSAT ENTRY

MATERIALS AND METHODS Forty-eight investigators submitted data on at least one patient each in this multiclinic trial. Patients receiving either ibuprofen, piroxicam, or naproxen for osteroarthritis, who had abdominal pain associated with NSAID therapy and an endoscopically proven gastric ulcer >-0.3 cm, were invited to participate. Exclusion criteria included a history of peptic ulcer disease, an active bleeding ulcer, malignancy in the upper gastrointestinal tract, pyloric or duodenal obstruction, acute hepatitis or pancreatitis, inflammatory bowel disease, bleeding diathesis, females of child bearing potential, and severe renal impairment. The protocol was approved by the Human Investigation Review Board at each participating institution, and each patient gave written informed consent. Prior to entry, all study patients received a complete history, physical examination, serum chemistries, urinalysis, and pregnancy test (if applicable). Patients were then randomized in a double-blind fashion to receive either misoprostol 200 I~g or placebo four times daily. NSAID therapy was discontinued for the entire treatment period and acetaminophen was allowed as needed (maximum: 650 mg four times a day) for relief of osteoarthritis pain. Each patient was given 28 tablets of 600 mg aluminum hydroxide (Amphogel) and instructed to take a maximum of four tablets daily for severe abdominal pain during the first week of the study period. All other antiulcer medications were prohibited during the trial. Endoscopic examinations were performed at pretreatment and four weeks and eight weeks (if not healed at four weeks) posttreatment. Gastric ulcers were defined as circumscribed breaks in the gastric mucosa of 0.3 cm in diameter or greater. Treatment success did not require complete ulcer healing and was defined as absence of the ulcer or a reduction in size to 0.5 cm. T h e median n u m b e r of gastric ulcers per patient for the misoprostol and placebo groups was 1.0. A comparison of the pattern of healing d e m o n strated that patients in the misoprostol group healed significantly earlier than those in the placebo group (P = 0.033). Further analysis of the crude rates revealed that complete healing of gastric ulcers occurred in 83% of misoprostol-treated patients c o m p a r e d to 61% of placebo-treated patients (P = 0.0028) after four w e e k s of therapy (Figure 1). Gastric ulcers ---0.5 c m healed in 95% of misoprostol- versus 73% of placebo-treated patients at four weeks (P = 0.0077) (Figure 2). While the respective healing rates for ulcers >0.5 cm was 70% and 49% for the misoprostol- and placebo-group patients at

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O f the 813 patients screened for participation in this study, 20% were found to have a gastric ulcer. The r e m a i n d e r were entered into a prophylaxis study, which has been reported elsewhere (20). Of 162 patients with gastric ulcer, 77 received misoprostol and 85 received placebo. Both study groups

Placebo

No. of patients Mean age Male/female Daily cigarette smoking (>1/2 pack) Daily ethanol intake

40 . RESULTS

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.

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ULCER SIZE *.'x- P = 0 . 0 6 7 4

Fig 1. Ulcer healing rates after four and eight weeks of thei-apy.

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JASZEWSKI ET AL Misoprostol Plocebo

TABLE 2. ADVERSE EFFECTS IN STUDY PATIENTS

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21.5 10.3 11.2 5.6 7.5

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Fig 2. Ulcer healing rates after four weeks of therapy according to initial ulcer size.

four weeks, the difference did not achieve significance (P = 0.0674). After four weeks of treatment, one misoprostol- and 10 placebo-group patients withdrew from the trial because of increasing abdominal pain. At eight weeks, ulcers -0.5 cm were 97% and 86% for the respective groups (P = NS). Only two placebogroup patients required antacid therapy during the study period. There were no clinically meaningful differences between the treatment groups in achieving complete day or night abdominal pain relief as determined by patient diary recordings. Complete relief of day pain was reported in 48% of placebo-treated patients compared to 45% of misoprostol-treated patients at four weeks of therapy, while night pain was relieved in 55% and 44% of placebo and misoprostol patients, respectively. At eight weeks, a total of 52% of placebo- and 52% of misoprostoltreated patients achieved day pain relief, while night pain was relieved in 64% and 52% of the respective groups. The three adverse events occurring with highest frequency in the misoprostol group were diarrhea, nausea, and flatulence; each occurred at rates that were similar to those reported by the placebo group (Table 2). No significant differences in serum chemistries were noted between the treatment groups. DISCUSSION Gastric ulcers occur commonly in patients chronically ingesting NSAIDs with a frequency of 17-

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Diarrhea Flatulence Nausea Abdominal pain Dyspepsia

Misoprostol (%)

31% (9, 21). The ulcerogenic potential of these agents is thought to be related to inhibition of prostaglandin synthesis (5-7). Concomitant administration of synthetic prostaglandins can protect the gastric mucosa from injury with these agents (2225). This protective effect of prostaglandins has been demonstrated at doses that are not antisecretory (22), implicating a role for mucus (26) and bicarbonate (27) secretion as potential mediators of mucosal protection. Misoprostol is a synthetic protaglandin E~ analog that has demonstrated gastric antisecretory (28) and mucosal protective (25) capabilities. Misoprostol has been shown to be effective in healing gastric (18) and duodenal (19) ulcers and in the prevention of NSAID-induced gastric ulcers (20). Furthermore, misoprostol can heal aspirin-induced gastroduodenal injury, including gastric ulcers, despite continued aspirin ingestion (29). In the present study, misoprostol significantly accelerated the healing of NSAID-induced gastric ulcers. Furthermore, gastric ulcers -