Reducing Clinically Significant Gastrointestinal Toxicity Associated with Nonsteroidal Antiinflammatory Drugs

Abstract

Spanish

French

OBJECTIVE:

To evaluate the efficacy of treatment strategies to reduce clinically significant gastrointestinal adverse effects associated with nonsteroidal antiinflammatory drugs (NSAIDs).

DATA SOURCES:

A MEDLINE search (1966–November 2003) was performed to identify relevant articles. Key search terms included proton-pump inhibitors, histamine H₂ antagonists, misoprostol, cyclooxygenase-2 (COX-2) selective inhibitors, nonsteroidal antiinflammatory agents, stomach ulcer, prevention, and economics. Additional references were obtained from cross-referencing the bibliographies of selected articles.

STUDY SELECTION AND DATA EXTRACTION:

All information obtained from the MEDLINE search was reviewed. To provide the most clinically relevant information, only randomized controlled trials are included in this review.

DATA SYNTHESIS:

Clinically significant upper gastrointestinal adverse events, such as ulcers and ulcer complications, associated with NSAIDs are a cause of significant morbidity and mortality in the US. Interest in strategies to reduce the risk of these adverse events is high among clinicians and patients. Misoprostol, high-dose H₂-receptor antagonists, proton-pump inhibitors, and COX-2 inhibitors have been shown to reduce this risk. Misoprostol and proton-pump inhibitors are more effective than H₂-receptor antagonists; dose-related diarrhea limits the clinical utility of misoprostol. These strategies may not provide enough protection in patients taking concomitant low-dose aspirin therapy or patients with a history of ulcer complications.

CONCLUSIONS:

COX-2 inhibitors and proton-pump inhibitors are effective and well-tolerated therapies to reduce clinically significant upper gastrointestinal adverse events associated with NSAIDs.

Keywords

adverse effects COX-2 inhibitors misoprostol nonsteroidal antiinflammatory drugs proton-pump inhibitors ulcer complications ulcers

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References

1 Wolfe

Lichtenstein

Singh

. Gastrointestinal toxicity of non-steroidal antiinflammatory drugs. N Engl J Med 1999;340:1888–99.

2 Griffin

Scheiman

. Prospects for changing the burden of non-steroidal anti-inflammatory drug toxicity. Am J Med 2001;110(suppl 1A):33S–7S.

3 Ray

Griffin

Shorr

. Adverse drug reactions and the elderly. Health Aff (Millwood) 1990;9:114–22.

4 Singh

Ramey

Terry

Khraishi

Triadafilopoulos

. NSAID-related effects on the GI tract: An ever widening spectrum (abstract). Arthritis Rheum 1997;40(suppl):S93.

5 Wallace

. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: The second hundred years. Gastroenterology 1997;112:1000–16.

6 Larkai

Smith

Lidsky

Graham

. Gastroduodenal mucosa and dyspeptic symptoms in arthritic patients during chronic nonsteroidal anti-inflammatory drug use. Am J Gastroenterol 1987;82:1153–8.

7 Singh

Ramey

Morfeld

Shi

Hatoum

Fries

. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis: A prospective observational cohort study. Arch Intern Med 1996;156:1530–6.

8 Larkai

Pounder

. Silent peptic ulceration: Deadly silence or golden silence? Gastroenterology 1989;96(suppl):626–31.

9 Graham

Agrawal

Roth

. Prevention of NSAID-induced gastric ulcer with misoprostol: Multicentre, double-blind, placebo-controlled trial. Lancet 1988;2:1277–80.

10.

10 Langman

MJS

. Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use. Gastroenterology 1989;96(suppl):640–6.

11.

11 Schoen

Vender

. Mechanisms of non-steroidal anti-inflammatory drug—induced gastric damage. Am J Med 1989;86:449–58.

12.

12 Crofford

. COX-1 and COX-2 tissue expression: Implications and predictions. J Rhuematol 1997;24(suppl 49):15–9.

13.

13 Wang

Hajibeigi

Loose-Mitchell

. Characterization of the promoter of human prostaglandin H synthase-1 gene. Biochem Biophys Res Commun 1993;190:406–11.

14.

14 O'Neill

Ford-Hutchinson

. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 1993;330:156–60.

15.

15 Bakhle

Botting

. Cyclooxygenase-2 and its regulation in inflammation. Mediators Inflamm 1996;5:305–23.

16.

Seibert

Zhang

Leahy

Hauser

Masferrer

Perkins

Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci U S A 1994;91:12013–7.

17.

17 Warner

Giuliano

Vojnovic

Bukasa

Mitchell

Vane

. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis. Proc Natl Acad Sci U S A 1999;96:7563–8.

18.

18 Kato

Nishida

Kitasato

Sakata

Kawai

. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs: Investigation using human peripheral monocytes. J Pharm Pharmacol 2001;53:1679–85.

19.

19 Cryer

Feldman

. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med 1998;104:413–21.

20.

20National Institute for Clinical Excellence. Guidance on the use of cyclo-oxygenase (Cox) II selective inhibitors, celecoxib, rofecoxib, meloxicam and etodolac for osteoarthritis and rheumatoid arthritis. NICE Technology Appraisal No. 27, London, UK, July, 2001.

21.

21Celebrex capsules. Physicians' Desk Reference. Electronic version. Greenwood Village, CO: MICROMEDEX (Edition expired 3/2004).

22.

Weil

Colin-Jones

Langman

Lawson

Logan

Murphy

Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995;310:827–30.

23.

23 Lee

Cryer

Feldman

. Dose effects of aspirin on gastric prostaglandins and stomach mucosal injury. Ann Intern Med 1994;120:184–9.

24.

24 Yeomans

. Approaches to healing and prophylaxis of nonsteroidal anti-inflammatory drug—associated ulcers. Am J Med 2001;110(suppl 1A):24S–8S.

25.

Agrawal

Roth

Graham

White

Germain

Brown

Misoprostol compared with sucralfate in the prevention of non-steroidal anti-inflammatory drug—induced gastric ulcer. Ann Intern Med 1991;115:195–200.

26.

26 Porro

Lazzaroni

Manzionna

Petrillo

. Omeprazole and sucralfate in the treatment of NSAID-induced gastric and duodenal ulcer. Aliment Pharmacol Ther 1998;12:355–60.

27.

Bardhan

Bjarnason

Scott

Griffin

Fenn

Shield

The prevention and healing of acute non-steroidal anti-inflammatory drug—associated gastroduodenal mucosal damage by misoprostol. Brit J Rheum 1993;32:990–5.

28.

Graham

White

Moreland

Schubert

Katz

Jaszewski

Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs. Ann Intern Med 1993;119:257–62.

29.

29 Elliott

Yeomans

Buchanan

RRC

Smallwood

. Efficacy of 12 months' misoprostol as prophylaxis against NSAID-induced gastric ulcers. Rheumatology 1994;23:171–6.

30.

30 Agrawal

Van Kerckhove

HEJM

Erhardt

Geis

. Misoprostol coadministered with diclofenac for prevention of gastroduodenal ulcers. Dig Dis Sci 1995;40:1125–31.

31.

Raskin

White

Jackson

Weaver

Tindall

Lies

Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug—induced gastric and duodenal ulcers: A comparison of three regimens. Ann Intern Med 1995;123:344–50.

32.

Silverstein

Graham

Senior

Davies

Struthers

Bittman

Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. Ann Intern Med 1995;123:241–9.

33.

Bocanegra

Weaver

Tindall

Sikes

Ball

Wallemark

Diclofenac/misoprostol compared with diclofenac in the treatment of osteoarthritis of the knee or hip: A randomized, placebo controlled trial. J Rheumatol 1998;25:1602–11.

34.

34 Ehsanullah

RSB

Page

Tildesley

Wood

. Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: Controlled trial of ranitidine. BMJ 1988;297:1017–21.

35.

Robinson

Griffin

Bowers

Kogan

Kogut

Lanza

Effect of ranitidine gastroduodenal mucosal damage induced by nonsteroidal antiinflammatory drugs. Dig Dis Sci 1989;34:424–8.

36.

Taha

Hudson

Hawkey

Swannell

Trye

Cottrell

Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 1996;334:1435–9.

37.

Hudson

Taha

Russell

Trye

Cottrell

Mann

Famotidine for healing and maintenance in nonsteroidal anti-inflammatory drug—associated gastroduodenal ulceration. Gastroenterology 1997;112:1817–22.

38.

Ekstrom

Carling

Wetterhus

Wingren

Anker-Hansen

Lundegardh

Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving continuous non-steroidal anti-inflammatory drug therapy. Scand J Gastroenterol 1996;31:753–8.

39.

39 Daneshmend

Stein

Bhaskar

Hawkey

. Abolition by omeprazole of aspirin induced gastric mucosal injury in man. Gut 1990;31:514–7.

40.

40 Scheiman

Behler

Loeffler

Elta

. Omeprazole ameliorates aspirin-induced gastroduodenal injury. Dig Dis Sci 1994;39:97–103.

41.

Cullen

Bardhan

Eisner

Kogut

Peacock

Thomson

Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drug users. Aliment Pharmacol Ther 1998;12:135–40.

42.

Lai

Lam

Chu

Wong

BCY

Hui

WHC

Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002;346:2033–8.

43.

Emery

Zeidler

Kvien

Guslandi

Naudin

Stead

Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: Randomised double-blind comparison. Lancet 1999;354:2106–11.

44.

44 Simon

Weaver

Graham

D Y

Kivitz

Lipsky

Hubbard

. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: A randomized controlled trial. JAMA 1999;282:1921–8.

45.

Goldstein

Correa

Zhao

Burr

Hubbard

Verburg

Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis. Am J Gastroenterol 2001;96:1019–27.

46.

46 Silverstein

Faich

Goldstein

Simon

Pincus

Whelton

. Gastrointestinal toxicity with celecoxib vs. nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS Study: A randomized controlled trial. JAMA 2000;284:1247–55.

47.

Hawkey

Laine

Simon

Beaulieu

Maldonado-Cocco

Acevedo

Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis. Arthritis Rheum 2000;43:370–7.

48.

Laine

Harper

Simon

Bath

Johanson

Schwartz

A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology 1999;117:776–83.

49.

49 Bombardier

Laine

Reicin

Shapiro

Burgos-Vargas

Davis

. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. The VIGOR Study. N Engl J Med 2000;343:1520–8.

50.

50 Kivitz

Eisen

Zhao

Bevirt

Recker

. Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis. J Fam Pract 2002;51:530–7.

51.

51 Sikes

Agrawal

Zhao

Kent

Recker

Verburg

. Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis. Eur J Gastroenterol Hepatol 2002;14:1101–11.

52.

52 Lu

. Statistical reviewer briefing document for the Advisory Committee. www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_04_stats.doc (accessed 2003 Dec 1).

53.

53 Raskin

White

Jaszewski

Korsten

Schubert

Fort

. Misoprostol and ranitidine in the prevention of NSAID-induced ulcers: A prospective, double-blind, multicenter study. Am J Gastroenterol 1996;91:223–7.

54.

54 Porro

G Bianchi

Lazzaroni

Petrillo

. Double-blind, double-dummy endoscopic comparison of the mucosal protective effects of misoprostol versus ranitidine on naproxen-induced mucosal injury to the stomach and duodenum in rheumatic patients. Am J Gastroenterol 1997;92:663–7.

55.

Yeomans

Tulassay

Juhasz

Racz

Howard

Van Rensburg

A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998;338:719–26.

56.

Hawkey

Karrasch

Szczepanski

Walker

Barkun

Swannell

Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998;338:727–34.

57.

Graham

Agrawal

Campbell

Haber

Collis

Lukasik

Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs. Arch Intern Med 2002;162:169–75.

58.

Chan

FKL

Hung

LCT

Suen

B Y

JCY

Lee

Hui

Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:2104–10.

59.

59 Graham

. NSAIDs, Helicobacter pylori, and Pandora's box (editorial). N Engl J Med 2002;347:2162–4.

60.

60 Hrachovec

Mora

. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib (letter). JAMA 2001;286:2398.

61.

61 Wright

Perry

Bassett

Chambers

. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib (letter). JAMA 2001;286:2398–400.

62.

62 Juni

Rutges

AWS

Dieppe

. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs (editorial)? BMJ 2002;324:1287–8.

63.

63 Boers

. Seminal pharmaceutical trials: Maintaining masking in analysis (editorial). Lancet 2002;360:100–1.

64.

64Prescribing information. Prevacid (lansoprazole). Lake Forest, IL: TAP Pharmaceutical Products Inc., 03-5316–R2 Rev. November, 2003.

65.

Lai

Chu

Hui

Wong

Yuen

COX-2 inhibitor compared with proton pump inhibitor in the prevention of recurrent ulcer complications in high-risk patients taking NSAIDs (abstract). Gastroenterology 2001;120(suppl 1):A–104.

66.

66 El-Serag

Graham

Richardson

Inadomi

. Prevention of complicated ulcer disease among chronic users of nonsteroidal anti-inflammatory drugs: The use of a nomogram in cost-effective analysis. Arch Intern Med 2002;162:2105–10.

67.

67 Spiegel

BMR

Targownik

Dulai

Gralnek

. The cost-effectiveness of cyclooxygenase-2 selective inhibitors in the management of chronic arthritis. Ann Intern Med 2003;138:795–806.