Misoprostol Dosage in the Prevention of Nonsteroidal Anti-inflammatory Drug-Induced Gastric and Duodenal Ulcers: A Comparison of Three Regimens

  1. Jeffrey B. Raskin, MD;
  2. Richard H. White, MD;
  3. Joseph E. Jackson, MD;
  4. Arthur L. Weaver, MD;
  5. Elizabeth A. Tindall, MD;
  6. Richard B. Lies, MD; and
  7. David S. Stanton, MD
  1. From the Veterans Affairs Medical Center and the University of Miami School of Medicine, Miami, Florida; University of California Davis Medical Center, Sacramento, California; Walker Clinical Evaluations, Inc., Indianapolis, Indiana; Arthritis Center of Nebraska, Lincoln, Nebraska; Portland Adventist Medical Center, Portland, Oregon; Wichita Clinic, Wichita, Kansas; and Western Medical Center, Santa Ana, California. Acknowledgments: The authors thank John G. Fort, MD, MBA, for help in preparing the manuscript; William Archambault, PhD, for help in the statistical analyses; and Paula Meier for secretarial support. Grant Support: In part by a grant from G.D. Searle & Co. Requests for Reprints: Jeffrey B. Raskin, MD, 1611 NW 12th Avenue, South Wing #220, Miami, FL 33136. Current Author Addresses: Dr. Raskin: 1611 NW 12th Avenue, South Wing #220, Miami, FL 33136.

    Abstract

    Objective: To compare the effectiveness and tolerability of three misoprostol dosing regimens for the prevention of gastric and duodenal ulcers associated with long-term nonsteroidal anti-inflammatory drug (NSAID) therapy.

    Design: A multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel, four-limb study.

    Patients: Eligibility criteria included upper gastrointestinal symptoms during NSAID therapy and no endoscopic evidence of gastric or duodenal ulcers. A total of 1623 patients was enrolled; 1197 of these met major accession and regimen-compliance criteria and completed the trial. These 1197 patients composed the evaluable group.

    Interventions: Patients were randomly assigned to one of four regimens: placebo four times daily; 200 µg of misoprostol twice daily and placebo twice daily; 200 µg of misoprostol three times daily and placebo once daily; and 200 µg of misoprostol four times daily.

    Measurements: Upper gastrointestinal endoscopic examinations for ulcers were done after 4, 8, and 12 weeks of therapy. Tolerability and safety of the regimens were assessed by adverse-event monitoring.

    Results: In the placebo group, the incidence of gastric ulcers was 15.7% and the incidence of duodenal ulcers was 7.5%. The incidence of gastric ulcers was significantly lower in the groups receiving misoprostol twice daily (8.1%; difference, 7.6% [95% CI, 2.7% to 12.5%]; P = 0.002), three times daily (3.9%; difference, 11.8% [CI, 7.4% to 16.3%]; P < 0.001), and four times daily (4%; difference, 11.7% [CI, 6.7% to 16.8%]; P < 0.001) compared with placebo. The gastric ulcer rate was significantly higher in patients receiving misoprostol twice daily compared with those receiving misoprostol three times daily (difference, 4.2% [95% CI, 0.7% to 7.7%]; P = 0.02). A significant (P = 0.02) misoprostol dose-response effect was noted in the prevention of gastric ulcers. The incidence of duodenal ulcers was significantly lower in the groups receiving misoprostol twice daily (2.6%; difference, 4.9% [CI, 1.5% to 8.2%]; P = 0.004), three times daily (3.3%; difference, 4.2% [CI, 0.6% to 7.7%]; P = 0.019), and four times daily (1.4%; difference, 6.1% [CI, 2.6% to 9.6%]; P = 0.007) compared with placebo. No significant difference was detected between patients receiving misoprostol twice daily and those receiving misoprostol three times daily, and no dose-response effect was noted with duodenal ulcers. The incidence of withdrawals for adverse events was significantly lower in the groups receiving misoprostol twice daily (12%) and three times daily (12%) than in the group receiving it four times daily (20%). The incidence of gastrointestinal adverse events was significantly higher in the group receiving misoprostol four times daily (74%) than in the placebo group (62%).

    Conclusion: Misoprostol, 200 µg twice or three times daily, offers substantial protection against gastric and duodenal ulcers in patients receiving long-term NSAID therapy. These dosages were better tolerated than the currently approved regimen of 200 µg four times daily.

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    1. Ann Intern Med September 1, 1995 vol. 123 no. 5 344-350
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