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. 2000;2002(3):CD002296.
doi: 10.1002/14651858.CD002296.

Prevention of chronic NSAID induced upper gastrointestinal toxicity

A Rostom  1 , G Wells, P Tugwell, V Welch, C Dube, J McGowan
Affiliations

Prevention of chronic NSAID induced upper gastrointestinal toxicity

A Rostom et al. Cochrane Database Syst Rev. 2000.

Update in

Abstract

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are important agents in the management of arthritic and inflammatory conditions, and are among the most frequently prescribed medications in North America and Europe. However, there is overwhelming evidence linking these agents to a variety of gastrointestinal (GI) toxicities.

Objectives: To review the effectiveness of common interventions for the prevention of NSAID induced upper GI toxicity.

Search strategy: A literature search was conducted, according to the Cochrane methodology for identification of randomized controlled trials in electronic databases, including MEDLINE from 1966 to January 2000, Current Contents for 6 months prior to January 2000, Embase to Febuary 1999, and a search of the Cochrane Controlled Trials Register from 1973 to 1999. Recent conference proceedings were reviewed and content experts and companies were contacted.

Selection criteria: Randomized controlled clinical trials (RCTs) of prostaglandin analogues (PA), H2-receptor antagonists (H2RA) or proton pump inhibitors (PPI) for the prevention of chronic NSAID induced upper GI toxicity were included.

Data collection and analysis: Two independent reviewers extracted data regarding population characteristics, study design, methodological quality and number of patients with endoscopic ulcers, ulcer complications, symptoms, overall drop-outs, drop outs due to symptoms. Dichotomous data was pooled using Revman V3.1. Heterogeneity was evaluated using a chi square test.

Main results: Thirty-three RCTs met the inclusion criteria. All doses of misoprostol significantly reduced the risk of endoscopic ulcers. Misoprostol 800 ug/day was superior to 400 ug/day for the prevention of endoscopic gastric ulcers (RR=0.18, and RR=0. 38 respectively, p=0.0055). A dose response relationship was not seen with duodenal ulcers. Misoprostol caused diarrhea at all doses, although significantly more at 800ug/day than 400ug/day (p=0.0012). Misoprostol was the only prophylactic agent documented to reduce ulcer complications. Standard doses of H2RAs were effective at reducing the risk of endoscopic duodenal (RR=0.24; 95% CI: 0.10-0. 57) but not gastric ulcers(RR=0.73; 95% CI:0.50-1.09). Both double dose H2RAs and PPIs were effective at reducing the risk of endoscopic duodenal and gastric ulcers (RR=0.44; 95% CI:0.26-0.74 and RR=0.37;95% CI;0.27-0.51 respectively for gastric ulcer), and were better tolerated than misoprostol.

Reviewer's conclusions: Misoprostol, PPIs, and double dose H2RAs are effective at preventing chronic NSAID related endoscopic gastric and duodenal ulcers. Lower doses of misoprostol are less effective and are still associated with diarrhea. Only Misoprostol 800ug/day has been directly shown to reduce the risk of ulcer complications.

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Conflict of interest statement

None.

Figures

1
1
Funnel plot of comparison: 1 misoprostol vs placebo ‐ Primary Efficacy, outcome: 1.6 Total endoscopic ulcers ‐ 12 weeks or longer studies.
2
2
Funnel plot of comparison: 11 PPI vs placebo ‐ 8 weeks or longer studies, outcome: 11.3 Total endoscopic ulcers.
1.1
1.1. Analysis
Comparison 1: Misoprostol vs placebo ‐ primary efficacy, Outcome 1: Gastric ulcers ‐ 4 ‐ 11 week studies
1.2
1.2. Analysis
Comparison 1: Misoprostol vs placebo ‐ primary efficacy, Outcome 2: Duodenal ulcers ‐ 4 ‐ 11 week studies
1.3
1.3. Analysis
Comparison 1: Misoprostol vs placebo ‐ primary efficacy, Outcome 3: Total ulcers ‐ 4 ‐ 11 week studies
1.4
1.4. Analysis
Comparison 1: Misoprostol vs placebo ‐ primary efficacy, Outcome 4: Gastric ulcers ‐ 12 weeks or longer studies
1.5
1.5. Analysis
Comparison 1: Misoprostol vs placebo ‐ primary efficacy, Outcome 5: Duodenal ulcers ‐ 12 weeks or longer studies
1.6
1.6. Analysis
Comparison 1: Misoprostol vs placebo ‐ primary efficacy, Outcome 6: Total endoscopic ulcers ‐ 12 weeks or longer studies
1.7
1.7. Analysis
Comparison 1: Misoprostol vs placebo ‐ primary efficacy, Outcome 7: Total endoscopic ulcers Chan 2001 removed ‐ 12 weeks or longer studies
1.8
1.8. Analysis
Comparison 1: Misoprostol vs placebo ‐ primary efficacy, Outcome 8: Clinical ulcers ‐ 12 weeks or longer studies
2.1
2.1. Analysis
Comparison 2: Misoprostol vs placebo ‐ toxicity causing withdrawal, Outcome 1: Nausea
2.2
2.2. Analysis
Comparison 2: Misoprostol vs placebo ‐ toxicity causing withdrawal, Outcome 2: Dyspepsia
2.3
2.3. Analysis
Comparison 2: Misoprostol vs placebo ‐ toxicity causing withdrawal, Outcome 3: Constipation
2.4
2.4. Analysis
Comparison 2: Misoprostol vs placebo ‐ toxicity causing withdrawal, Outcome 4: Diarrhea
2.5
2.5. Analysis
Comparison 2: Misoprostol vs placebo ‐ toxicity causing withdrawal, Outcome 5: Abdominal pain
2.6
2.6. Analysis
Comparison 2: Misoprostol vs placebo ‐ toxicity causing withdrawal, Outcome 6: Flatulence
2.7
2.7. Analysis
Comparison 2: Misoprostol vs placebo ‐ toxicity causing withdrawal, Outcome 7: Vomiting
2.8
2.8. Analysis
Comparison 2: Misoprostol vs placebo ‐ toxicity causing withdrawal, Outcome 8: Drop‐outs due to side‐effects
2.9
2.9. Analysis
Comparison 2: Misoprostol vs placebo ‐ toxicity causing withdrawal, Outcome 9: Drop‐outs overall
3.1
3.1. Analysis
Comparison 3: Misoprostol vs placebo ‐ toxicity symptoms only, Outcome 1: Nausea
3.2
3.2. Analysis
Comparison 3: Misoprostol vs placebo ‐ toxicity symptoms only, Outcome 2: Dyspepsia
3.3
3.3. Analysis
Comparison 3: Misoprostol vs placebo ‐ toxicity symptoms only, Outcome 3: Constipation
3.4
3.4. Analysis
Comparison 3: Misoprostol vs placebo ‐ toxicity symptoms only, Outcome 4: Diarrhea
3.5
3.5. Analysis
Comparison 3: Misoprostol vs placebo ‐ toxicity symptoms only, Outcome 5: Abdominal pain
3.6
3.6. Analysis
Comparison 3: Misoprostol vs placebo ‐ toxicity symptoms only, Outcome 6: Flatulence
4.1
4.1. Analysis
Comparison 4: Misoprostol vs placebo ‐ efficacy by dosage, Outcome 1: Gastric ulcers ‐ 1 month
4.2
4.2. Analysis
Comparison 4: Misoprostol vs placebo ‐ efficacy by dosage, Outcome 2: Duodenal ulcers ‐ 1 month
4.3
4.3. Analysis
Comparison 4: Misoprostol vs placebo ‐ efficacy by dosage, Outcome 3: Total ulcers ‐ 1 month
4.4
4.4. Analysis
Comparison 4: Misoprostol vs placebo ‐ efficacy by dosage, Outcome 4: Gastric ulcers ‐ 3‐24 months
4.5
4.5. Analysis
Comparison 4: Misoprostol vs placebo ‐ efficacy by dosage, Outcome 5: Gastric ulcers ‐ 3‐24 months (sensitivity analysis excluding Chan 2001)
4.6
4.6. Analysis
Comparison 4: Misoprostol vs placebo ‐ efficacy by dosage, Outcome 6: Duodenal ulcers ‐ 3‐24 months
4.7
4.7. Analysis
Comparison 4: Misoprostol vs placebo ‐ efficacy by dosage, Outcome 7: Total endoscopic ulcers 3‐24 months
4.8
4.8. Analysis
Comparison 4: Misoprostol vs placebo ‐ efficacy by dosage, Outcome 8: Clinical ulcers ‐ 3‐24 months
5.1
5.1. Analysis
Comparison 5: Misoprostol vs placebo ‐ toxicity causing withdrawal ‐ by dose, Outcome 1: Nausea
5.2
5.2. Analysis
Comparison 5: Misoprostol vs placebo ‐ toxicity causing withdrawal ‐ by dose, Outcome 2: Dyspepsia
5.3
5.3. Analysis
Comparison 5: Misoprostol vs placebo ‐ toxicity causing withdrawal ‐ by dose, Outcome 3: Constipation
5.4
5.4. Analysis
Comparison 5: Misoprostol vs placebo ‐ toxicity causing withdrawal ‐ by dose, Outcome 4: Diarrhea
5.5
5.5. Analysis
Comparison 5: Misoprostol vs placebo ‐ toxicity causing withdrawal ‐ by dose, Outcome 5: Abdominal pain
5.6
5.6. Analysis
Comparison 5: Misoprostol vs placebo ‐ toxicity causing withdrawal ‐ by dose, Outcome 6: Flatulence
5.7
5.7. Analysis
Comparison 5: Misoprostol vs placebo ‐ toxicity causing withdrawal ‐ by dose, Outcome 7: Vomiting
5.8
5.8. Analysis
Comparison 5: Misoprostol vs placebo ‐ toxicity causing withdrawal ‐ by dose, Outcome 8: Dropouts due to side effects
5.9
5.9. Analysis
Comparison 5: Misoprostol vs placebo ‐ toxicity causing withdrawal ‐ by dose, Outcome 9: Dropouts overall
6.1
6.1. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 1: Nausea
6.2
6.2. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 2: Dyspepsia
6.3
6.3. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 3: Constipation
6.4
6.4. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 4: Diarrhea
6.5
6.5. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 5: Abdominal pain
6.6
6.6. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 6: Flatulence
6.7
6.7. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 7: Vomiting
6.8
6.8. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 8: Dropouts due to side effects
6.9
6.9. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 9: Dropouts overall
6.10
6.10. Analysis
Comparison 6: Misoprostol vs placebo ‐ symptoms ‐ by dose, Outcome 10: Headache
7.1
7.1. Analysis
Comparison 7: H2 Receptor vs placebo ‐ 4 ‐ 11 week studies by dose, Outcome 1: Gastric ulcer
7.2
7.2. Analysis
Comparison 7: H2 Receptor vs placebo ‐ 4 ‐ 11 week studies by dose, Outcome 2: Duodenal ulcer
7.3
7.3. Analysis
Comparison 7: H2 Receptor vs placebo ‐ 4 ‐ 11 week studies by dose, Outcome 3: Total endoscopic ulcers
8.1
8.1. Analysis
Comparison 8: H2 Receptor vs placebo 12 weeks or longer ‐ by dose, Outcome 1: Gastric ulcer
8.2
8.2. Analysis
Comparison 8: H2 Receptor vs placebo 12 weeks or longer ‐ by dose, Outcome 2: Duodenal ulcer
8.3
8.3. Analysis
Comparison 8: H2 Receptor vs placebo 12 weeks or longer ‐ by dose, Outcome 3: Total endoscopic ulcers
9.1
9.1. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 1: Total drop‐outs
9.2
9.2. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 2: Drop‐outs due to side effects
9.3
9.3. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 3: Dropouts due to GI symptoms
9.4
9.4. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 4: Dropouts due to abdominal pain
9.5
9.5. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 5: Dropouts due to diarrhea
9.6
9.6. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 6: Diarrhea
9.7
9.7. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 7: Abdominal pain
9.8
9.8. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 8: GI symptoms
9.9
9.9. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 9: Flatulence
9.10
9.10. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 10: Dyspepsia
9.11
9.11. Analysis
Comparison 9: H2 Receptor vs placebo ‐ toxicity ‐ by dose, Outcome 11: Rash
10.1
10.1. Analysis
Comparison 10: PPI vs placebo ‐ 4 ‐ 11 week studies, Outcome 1: Endoscopic gastric ulcer
10.2
10.2. Analysis
Comparison 10: PPI vs placebo ‐ 4 ‐ 11 week studies, Outcome 2: Endoscopic duodenal ulcer
10.3
10.3. Analysis
Comparison 10: PPI vs placebo ‐ 4 ‐ 11 week studies, Outcome 3: Total endoscopic ulcers
10.4
10.4. Analysis
Comparison 10: PPI vs placebo ‐ 4 ‐ 11 week studies, Outcome 4: Clinical Ulcer (POB)
10.5
10.5. Analysis
Comparison 10: PPI vs placebo ‐ 4 ‐ 11 week studies, Outcome 5: Clinical Ulcer ‐ PUB (POB + symptomatic ulcer)
11.1
11.1. Analysis
Comparison 11: PPI vs placebo ‐ 8 weeks or longer studies, Outcome 1: Endoscopic gastric ulcer
11.2
11.2. Analysis
Comparison 11: PPI vs placebo ‐ 8 weeks or longer studies, Outcome 2: Endoscopic duodenal ulcer
11.3
11.3. Analysis
Comparison 11: PPI vs placebo ‐ 8 weeks or longer studies, Outcome 3: Total endoscopic ulcers
12.1
12.1. Analysis
Comparison 12: PPI vs placebo ‐ 12 weeks or longer studies, Outcome 1: Endoscopic gastric ulcer
12.2
12.2. Analysis
Comparison 12: PPI vs placebo ‐ 12 weeks or longer studies, Outcome 2: Endoscopic duodenal ulcer
12.3
12.3. Analysis
Comparison 12: PPI vs placebo ‐ 12 weeks or longer studies, Outcome 3: Total endoscopic ulcers
13.1
13.1. Analysis
Comparison 13: PPI vs placebo ‐ toxicity, Outcome 1: Dropouts overall
13.2
13.2. Analysis
Comparison 13: PPI vs placebo ‐ toxicity, Outcome 2: Dropouts due to side effects
13.3
13.3. Analysis
Comparison 13: PPI vs placebo ‐ toxicity, Outcome 3: Diarrhea
13.4
13.4. Analysis
Comparison 13: PPI vs placebo ‐ toxicity, Outcome 4: Abdominal pain
13.5
13.5. Analysis
Comparison 13: PPI vs placebo ‐ toxicity, Outcome 5: Flatulence
13.6
13.6. Analysis
Comparison 13: PPI vs placebo ‐ toxicity, Outcome 6: Dyspepsia
14.1
14.1. Analysis
Comparison 14: PPI vs H2‐antagonist ‐ 12 weeks or longer studies, Outcome 1: Endoscopic gastric ulcers
14.2
14.2. Analysis
Comparison 14: PPI vs H2‐antagonist ‐ 12 weeks or longer studies, Outcome 2: Endoscopic duodenal ulcers
14.3
14.3. Analysis
Comparison 14: PPI vs H2‐antagonist ‐ 12 weeks or longer studies, Outcome 3: Total endoscopic ulcers
14.4
14.4. Analysis
Comparison 14: PPI vs H2‐antagonist ‐ 12 weeks or longer studies, Outcome 4: Total clinical ulcers
14.5
14.5. Analysis
Comparison 14: PPI vs H2‐antagonist ‐ 12 weeks or longer studies, Outcome 5: Toxicity‐ dropouts due to side effects
14.6
14.6. Analysis
Comparison 14: PPI vs H2‐antagonist ‐ 12 weeks or longer studies, Outcome 6: Vomiting
14.7
14.7. Analysis
Comparison 14: PPI vs H2‐antagonist ‐ 12 weeks or longer studies, Outcome 7: Abdominal pain
14.8
14.8. Analysis
Comparison 14: PPI vs H2‐antagonist ‐ 12 weeks or longer studies, Outcome 8: Diarrhea
15.1
15.1. Analysis
Comparison 15: Misoprostol Vs PPI (as control) ‐ 12 weeks or longer studies, Outcome 1: Endoscopic gastric ulcer
15.2
15.2. Analysis
Comparison 15: Misoprostol Vs PPI (as control) ‐ 12 weeks or longer studies, Outcome 2: Endoscopic duodenal ulcer
15.3
15.3. Analysis
Comparison 15: Misoprostol Vs PPI (as control) ‐ 12 weeks or longer studies, Outcome 3: Total endoscopic ulcers
16.1
16.1. Analysis
Comparison 16: PPI Vs Misoprostol (as control) ‐ 12 weeks or longer studies, Outcome 1: Endoscopic gastric ulcer
16.2
16.2. Analysis
Comparison 16: PPI Vs Misoprostol (as control) ‐ 12 weeks or longer studies, Outcome 2: Endoscopic duodenal ulcer
16.3
16.3. Analysis
Comparison 16: PPI Vs Misoprostol (as control) ‐ 12 weeks or longer studies, Outcome 3: Total endoscopic ulcers
17.1
17.1. Analysis
Comparison 17: Misoprostol vs PPI ‐ toxicity ‐ 12 weeks or longer studies, Outcome 1: Dropouts overall
17.2
17.2. Analysis
Comparison 17: Misoprostol vs PPI ‐ toxicity ‐ 12 weeks or longer studies, Outcome 2: Dropouts due to side effects
18.1
18.1. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 1: Endoscopic gastric ulcers
18.2
18.2. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 2: Endoscopic duodenal ulcers
18.3
18.3. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 3: Dropouts due to side effects
18.4
18.4. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 4: Total endoscopic ulcers
18.5
18.5. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 5: Dropouts overall
18.6
18.6. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 6: Dropouts due to abdominal pain
18.7
18.7. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 7: Dropouts due to nausea
18.8
18.8. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 8: Dyspepsia
18.9
18.9. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 9: Abdominal pain symptoms
18.10
18.10. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 10: Flatulence symptoms
18.11
18.11. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 11: Nausea symptoms
18.12
18.12. Analysis
Comparison 18: Misoprostol vs ranitidine 150 mg bid ‐ 1‐2 month, Outcome 12: Diarrhea symptoms
19.1
19.1. Analysis
Comparison 19: Nizatidine 150 mg vs 300 mg efficacy, Outcome 1: Total endoscopic ulcers
19.2
19.2. Analysis
Comparison 19: Nizatidine 150 mg vs 300 mg efficacy, Outcome 2: Dropouts overall
20.1
20.1. Analysis
Comparison 20: NSAID + PPI vs COX 2, Outcome 1: Clinical Ulcer (POB)
See this image and copyright information in PMC

References

References to studies included in this review

Agrawal 1991 {published data only}
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Bolten 1992 {published data only}
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Chan 2001a {published data only}
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Chandresekaran 1991 {published data only}
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Cullen 1998 {published data only}
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Delmas 1994 {published data only}
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Ehsanullah 1988 {published data only}
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Ekstrom 1996 {published data only}
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Elliot 1994 {published data only}
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Graham 1988 {published data only}
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Graham 1993 {published data only}
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Graham 2002 {published data only}
    1. Graham DY, Agrawal NM, Campbell DR, Haber MM, Collis C, Lukasik L, et al. Ulcer prevention in long term users of nonsteroidal anti-inflammatory drugs: results of a double-blind randomized, multicenter, active and placebo-controlled study of misoprostol vs lansoprazole. Archives of Internal Medicine 2002;162(2):169-75. - PubMed
Hawkey 1998 {published data only}
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Henriksson 1993 {published data only}
    1. Henriksson K, Uribe A, Sandstedt B, Nord CE. Helicobacter pylori infection, ABO blood group, and effect of misoprostol on gastroduodenal mucosa in NSAID-treated patients with rheumatoid arthritis. Digestive Diseases & Sciences 1993;38(9):1688-96. - PubMed
Hudson 1997 {published data only}
    1. Hudson N, Taha AS, Russell RI, Trye P, Cottrell J, Mann SG, et al. Famotidine for healing and maintenance in nonsteroidal anti-inflammatory drug-associated gastroduodenal ulceration [see comments]. Gastroenterology 1997;112:1817-22. - PubMed
Jensen 2000 {unpublished data only}
    1. Jensen DM, Ho S, Hamamah S, Frankl H, Faigel D, DeMarco D, et al. A randomized study of omeprazole compared to misoprostol for prevention of recurrent ulcers and ulcer hemorrhage in high risk patients ingesting aspirin or NSAIDs. In: Gastroenterology. Vol. 118. 2000:A892.
Lai 2003 {published data only}
    1. Lai KC, Lam SK, Chu KM, Hui WM, Kwok KF, Wong BC et al. Lansoprazole reduces ulcer relapse after eradication of Helicobacter pylori in nonsteroidal anti-inflammatory drug users – a randomized trial. Alimentary Pharmacology and Therapeutics 2003;18(8):829-36. - PubMed
Levine 1993 {published data only}
    1. Levine LR, Cloud ML, Enas NH. Nizatidine prevents peptic ulceration in high-risk patients taking nonsteroidal anti-inflammatory drugs [see comments]. Archives of Internal Medicine 1993;153:2449-54. - PubMed
Melo Gomes 1993 {published data only}
    1. Melo Gomes JA, Roth SH, Zeeh J, Bruyn GA, Woods EM, Geis GS. Double-blind comparison of efficacy and gastroduodenal safety of diclofenac/misoprostol, piroxicam, and naproxen in the treatment of osteoarthritis. Annals of the Rheumatic Diseases 1993;52(12):8 81-5. - PMC - PubMed
Raskin 1995 {published data only}
    1. Raskin J, White R, Jackson J, Weaver A, Tindall E, Lies R et al. Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug-induced gastric and duodenal ulcers: A comparison of three regimens. Annals of Internal Medicine 1995;123:344-50. - PubMed
Raskin 1996 {published data only}
    1. Raskin JB, White RH, Jaszewski R, Korsten MA, Schubert TT, Fort JG. Misoprostol and ranitidine in the prevention of NSAID-induced ulcers: a prospective, double-blind, multicenter study. American Journal of Gastroenterology 1996;91(2):223-7. - PubMed
Robinson 1989 {published data only}
    1. Robinson MG, Griffin JW, Bowers J, Kogan FJ, Kogut DG, Lanza FL et al. Effect of ranitidine on gastroduodenal mucosal damage induced by non-steroidal anti-inflammatory drugs. Digestive Diseases and Sciences 1989;34:424-8. - PubMed
Robinson 1991 {published data only}
    1. Robinson M, Mills RJ, Euler AR. Ranitidine prevents duodenal ulcers associated with non-steroidal anti-inflammatory drug therapy. Alimentary Pharmacology and Therapeutics 1991;5:143-50. - PubMed
Roth 1987 {published data only}
    1. Roth SH, Bennett RE, Mitchell CS, Hartman RJ. Cimetidine therapy in nonsteroidal anti-inflammatory drug gastropathy. Double-blind long-term evaluation. Archives of Internal Medicine 1987;147:1798-1801. - PubMed
Roth 1993 {published data only}
    1. Roth S, Tindall E, Jain A, McMahon F, April P, Bockow B et al. A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa. Archives of Internal Medicine 1993;153:2565-71. - PubMed
Saggioro 1991 {published data only}
    1. Saggioro A, Alvisi V, Blasi A, Dobrilla G, Fioravanti A, Marcolongo R. Misoprostol prevents NSAID-induced gastroduodenal lesions in patients with osteoarthritis and rheumatoid arthritis [published erratum appears in Ital J Gastroenterol 1991 Jun;23(5):273]. Italian Journal of Gastroenterology 1991;23:119-123. - PubMed
Silverstein 1995 {published data only}
    1. Silverstein F, Graham D, Senior J, Davies H, Struthers B, Bittmann R et al. Misoprostol reduces gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine 1995;123:241-9. - PubMed
Simon 1994 {published data only}
    1. Simon B, Muller P. Nizatidine in therapy and prevention of non-steroidal anti-inflammatory drug-induced gastroduodenal ulcer in rheumatic patients. Scandinavian Journal of Gastroenterology - Supplement 1994;206:25-28. - PubMed
Stupnicki 2003 {published data only}
    1. Stupnicki T, Dietrich K, Gonzalez-Carro P, Straszak A, Terjung KA, Thomas B et al. Efficacy and tolerability of pantoprazole compared with misoprostol for the prevention of NSAID-related gastrointestinal lesions and symptoms in rheumatic patients. Digestion 2003;68:198–208. - PubMed
Swift 1989 {published data only}
    1. Swift GL, Heneghan M, Williams GT, Williams BD, O'Sullivan MM, Rhodes J. Effect of ranitidine on gastroduodenal mucosal damage in patients on long-term non-steroidal anti-inflammatory drugs. Digestion 1989;44:86-94. - PubMed
Taha 1996 {published data only}
    1. Taha AS, Hudson N, Hawkey CJ, Swannell AJ, Trye PN, Cottrell J, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. New England Journal of Medicine 1996;334:1435-9. - PubMed
Ten Wolde 1996 {published data only}
    1. Wolde S, Dijkmans BA, Janssen M, Hermans J, Lamers CB. High-dose ranitidine for the prevention of recurrent peptic ulcer disease in rheumatoid arthritis patients taking NSAIDs. Alimentary Pharmacology & Therapeutics 1996;10:347-51. - PubMed
Valentini 1995 {published data only}
    1. Valentini M, Cannizzaro R, Poletti M, Bortolussi R, Fracasso A, Testa V, et al. Nonsteroidal antiinflammatory drugs for cancer pain: comparison between misoprostol and ranitidine in prevention of upper gastrointestinal damage. Journal of Clinical Oncology 1995;13(10):2637-42. - PubMed
van Groenendaci 1996 {published data only}
    1. Van Groenendael JH, Markusse HM, Dijkmans BA, Breedveld FC. The effect of ranitidine on NSAID related dyspeptic symptoms with and without peptic ulcer disease of patients with rheumatoid arthritis and osteoarthritis. Clinical Rheumatology 1996;15:450-6. - PubMed
Verdickt 1992 {published data only}
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Yeomans 1998 {published data only}
    1. Yeomans ND, Tulassay Z, Juhasz L, Racz I, Howard J. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. New England Journal of Medicine 1998;338:719-26. - PubMed

References to studies excluded from this review

Agrawal 1999 {published data only}
    1. Agrawal NM, Caldwell J, Kivitz AJ, Weaver AL, Bocanegra TS, Ball J, et al. Comparison of the upper gastrointestinal safety of Arthrotec 75 and nabumatone in osteoarthritis patients at high risk for developing nonsteroidal anti-inflammatory drug induced gastrointestinal ulcers. Clinical Therapeutics 1999;21(4):659-74. - PubMed
Agrawal 2000 {published data only}
    1. Agrawal NM, Campbell DR, Safdi MA, Lukasik NL, Huang B, Haber MM, . Superiority of lansoprazole vs ranitidine NSAID drug associated gastric ulcers. Archives of Internal Medicine 2000;160(10):1455-61. - PubMed
Bianchi Porro 1997 {published data only}
    1. Bianchi Porro G, Lazzaroni M, Petrillo M. Double blind, double dummy endoscopic comparison of the mucosal protective effect of misoprostol versus ranitidine on naproxen-induced mucosal injury to the stomach and duodenum in rheumatic patients. American Journal of Gastroenterology 1997;92(4):663-7. - PubMed
Bianchi Porro 1998 {published data only}
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Caldwell 1989 {published data only}
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Daneshmend 1990 {published data only}
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Desai 2008 {published data only}
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Donnelly 2000 {published data only}
    1. Donnely MT, Goddard AF, Filipowicz B, Moran SV, Sheild MJ, Hawkey CJ. Low-dose misoprostol for the prevention of low dose aspirin induced gastroduodenal injury. Alimentary Pharmacology and Therapeutics 2000;14(5):529-34. - PubMed
Geis 1991 {published data only}
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Geis 1992 {published data only}
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Goldstein 2007 {published data only}
    1. Goldstein J, Johanson J, Hawkey C, Suchower L, Brown K. Clinical trial: healing of NSAID-associated gastric ulcers in patients continuing NSAID therapy - a randomized study comparing ranitidine with esomeprazole. Alimentary Pharmacology & Therapeutics 2007;26(8):1101-11. - PubMed
Lanas 2007 {published data only}
    1. Lanas A, Garcia-Rodriguez L, Arroyo M, Bujanda L, Gomollon F, Forne M et al, Investigators of the Asociacion Espanola de Gastroenterologia (AEG). Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. American Journal of Gastroenterology 2007;102(3):507-15. - PubMed
Melo Gomes 1992 {published data only}
    1. Melo Gomes JA. The safety of Arthrotec in patients with rheumatoid arthritis or osteoarthritis: an assessment of the upper gastrointestinal tract by endoscopy. Scandinavian Journal of Rheumatology. Supplement 1992;96:23-31. - PubMed
Miyake 2005 {published data only}
    1. Miyake K, Ueki N, Suzuki K, Shinji Y, Kusunoki M, Hiratsuka T et al. Preventive therapy for non-steroidal anti-inflammatory drug-induced ulcers in Japanese patients with rheumatoid arthritis: the current situation and a prospective controlled-study of the preventive effects of lansoprazole or famotidine. Alimentary Pharmacology and Therapeutics 2005;21(Suppl 2):67–72. - PubMed
Regula 2006 {published data only}
    1. Regula J, Butruk E, Dekkers CP, Boer SY, Raps D, Simon L et al. Prevention of NSAID-associated gastrointestinal lesions: a comparison study pantoprazole versus omeprazole. American Journal of Gastroenterology 2006;101(8):1747-55. - PubMed
Rose 1999 {published and unpublished data}
    1. Rose P, Huang B, Lukasik N, Collis C. Evidence that lansoprazole is effective in preventing NSAID induced ulcers. Gastroenterology 1999;116:A295.
Rugstad 1994 {published data only}
    1. Rugstad HE, Giercksky KE, Husby G, Holme I. Effect of cimetidine on gastrointestinal symptoms in patients taking nonsteroidal anti-inflammatory drugs: a large double-blind placebo controlled study. Scandinavian Journal of Rheumatology 1994;23:177-82. - PubMed
Ryan 1987 {published data only}
    1. Ryan JR, Vargas R, Clay GA, McMahon FG. Role of misoprostol in reducing aspirin-induced gastrointestinal blood loss in arthritic patients. American Journal of Medicine 1987;83(Supplement 1A):41-4. - PubMed
Scheiman 2006 {published data only}
    1. Scheiman J, Yeomans N, Talley N, Vakil N, Chan F, Tulassay Z et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. American Journal of Gastroenterology 2006;12(36):5913-15. - PubMed
Walan 1984 {published data only}
    1. Walan A, Bader J, Classen M, Lamers CBHW, Piper DW, Rutgersson K et al. Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer. New England Journal of Medicine 1989;320(2):69-75. - PubMed
Yilmaz 2007 {published data only}
    1. Yilmaz S, Bayan K, Dursun M, Canoruç F, Kilinç N, Tüzün Y et al. Does adding misoprostol to standard intravenous proton pump inhibitor protocol improve the outcome of aspirin/NSAID induced upper gastrointestinal bleeding? Digestive Diseases and Sciences 2007;110(8):110-8. - PubMed

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References to other published versions of this review

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