Nonsteroidal Anti-Inflammatory Drugs

  • Leslie J. Crofford


Pain (dolor), swelling (tumor), erythema (rubor), and warmth (calor), the cardinal features of inflammation, are present in most patients with rheumatic diseases. Therapeutic strategies to reduce inflammation have been used for centuries, beginning with botanical treatments in both Western and Eastern medical traditions (1). The first isolated plant constituent to be tested as an anti-inflammatory drug was salicylic acid from willow bark, which was chemically altered to acetyl salicylic acid to improve its pharmacologic properties. Acetyl salicylic acid became “aspirin” in 1899, one of the first drugs to be widely marketed, and aspirin remains one of the most widely used drugs today. Other drugs that share the anti-inflammatory, analgesic, and antipyretic properties of aspirin are termed nonsteroidal anti-inflammatory drugs (NSAIDs), and are a chemically diverse group of compounds (Table 41-1). It was established in 1971 that salicylates and other NSAIDs act by blocking the synthesis of prostaglandins (PGs), products of the metabolism of the membrane-associated fatty acid arachidonic acid. This finding demonstrated conclusively that PGs play an important role in mediating symptoms and signs of inflammation. However, PGs play a role in normal physiology as well as in disease. As a consequence, all NSAIDs possess predictable therapeutic and adverse effects that must be understood in order to use these drugs safely.


Gastroduodenal Ulcer Ulcer Complication Duodenogastric Reflux Willow Bark Specific NSAID 
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  1. 1.
    Vane JR, Botting RM. The history of anti-inflammatory drugs and their mechanism of action. In: Bazan N, Botting J, Vane J, eds. New targets in inflammation: inhibitors of COX-2 or adhesion molecules. London: Kluwer Academic Publishers and William Harvey Press; 1996:1–12.Google Scholar
  2. 2.
    Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Ann Rev Biochem 2000;69:145–182.CrossRefPubMedGoogle Scholar
  3. 3.
    Crofford LJ, Lipsky PE, Brooks P, Abramson SB, Simon LS, van de Putte LBA. Basic biology and clinical application of specific COX-2 inhibitors. Arthritis Rheum 2000;43:4–13.CrossRefPubMedGoogle Scholar
  4. 4.
    Stichtenoth DO, Thoren S, Bian H, Peters-Golden M, Jakobsson P-J, Crofford LJ. Microsomal prostaglandin E synthase is regulated by pro-inflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells. J Immunol 2001;167:469–474.PubMedGoogle Scholar
  5. 5.
    Toh H, Ichikawa A, Narumiya S. Molecular evolution of receptors for eicosanoids. FEBS Lett 1995;361:17–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Narumiya S, FitzGerald GA. Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 2001;108:25–30.PubMedGoogle Scholar
  7. 7.
    Tilley SL, Coffman TM, Koller BH. Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest 2001;108:15–23.PubMedGoogle Scholar
  8. 8.
    Boutaud O, Aronoff DM, Richardson JH, Marnett LJ, Oates JA. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H2 synthases. Proc Natl Acad Sci U S A 2002;99:7130–7135.CrossRefPubMedGoogle Scholar
  9. 9.
    Lipsky PE, Abramson SB, Crofford L, DuBois RN, Simon L, van de Putte LBA. The classification of cyclooxygenase inhibitors [editorial]. J Rheumatol 1998;25:2298–2303.PubMedGoogle Scholar
  10. 10.
    Tegeder I, Pfeilschifter J, Geisslinger G. Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J 2001;15:2057–2072.CrossRefPubMedGoogle Scholar
  11. 11.
    Verbeek RK. Pathophysiologic factors affecting the pharmacokinetics of non-steroidal anti-inflammatory drugs. J Rheumatol 1988;15:44–57.Google Scholar
  12. 12.
    Yaksh TL, Dirig DM, Conway CM, Svensson C, Luo ZD, Isakson PC. The acute antihyperalgesic action of non-steroidal, anti-inflammatory drugs and release of spinal prostglandin E2 is mediated by inhibition of constitutive spinal cyclooxygenase-2 (COX-2) but not COX-1. J Neurosci 2001;21:5847–5853.PubMedGoogle Scholar
  13. 13.
    Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;136:161–172.Google Scholar
  14. 14.
    Catella-Lawson F, Reilly M, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809–1817.CrossRefPubMedGoogle Scholar
  15. 15.
    MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 2003;361:573–574.CrossRefPubMedGoogle Scholar
  16. 16.
    Singh G, Ramey DR, Morfeld D, Shi H, Hatoum HT, Fries JF. Gatrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis: a prospective observational cohort study. Arch Intern Med 1996;156:1530–1536.CrossRefPubMedGoogle Scholar
  17. 17.
    Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340:1888–1899.CrossRefPubMedGoogle Scholar
  18. 18.
    Garcia Rodriguez LA, Hernandez-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570–576.CrossRefPubMedGoogle Scholar
  19. 19.
    Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal aniinflammatory drugs. N Engl J Med 1992;327:749–754.CrossRefPubMedGoogle Scholar
  20. 20.
    Wallace JL. Prostaglandin biology in inflammatory bowel disease. Gastroenterol Clin North Am 2001;30:971–980.CrossRefPubMedGoogle Scholar
  21. 21.
    Chan FKL, Hung LCT, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:2104–2110.CrossRefPubMedGoogle Scholar
  22. 22.
    Laine L, Bombardier C, Hawkey CJ, et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterology 2002;123:1006–1012.CrossRefPubMedGoogle Scholar
  23. 23.
    Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520–1528.CrossRefPubMedGoogle Scholar
  24. 24.
    Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA 2000;284:1247–1255.CrossRefPubMedGoogle Scholar
  25. 25.
    Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complica-tions: randomised controlled trial. Lancet 2004;364:665–674.CrossRefPubMedGoogle Scholar
  26. 26.
    Chan FKL, Chung SCS, Suen BY, et al. Preventing recurrent upper gastrointestinal bleeding in patients with helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001;344:967–973.CrossRefPubMedGoogle Scholar
  27. 27.
    Graham DY, Agrawal NM, Campbell DR, et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs. Arch Intern Med 2002;162:169–175.CrossRefPubMedGoogle Scholar
  28. 28.
    Brater DC, Harris C, Redfern JS, Gertz BJ. Renal effects of COX-2 selective inhibitors. Am J Nephrol 2001;21:1–15.CrossRefPubMedGoogle Scholar
  29. 29.
    Qi Z, Hao C-M, Langenbach RI, et al. Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II. J Clin Invest 2002;110:61–69.PubMedGoogle Scholar
  30. 30.
    Belay ED, Bresee JS, Holman RC, Kahn AD, Sharhriai A, Schonberger LB. Reye’s syndrome in the United States from 1981 through 1997. N Engl J Med 1999;340:1377–1382.CrossRefPubMedGoogle Scholar
  31. 31.
    Crofford LJ. COX-2: where are we in 2003? Specific cyclooxygenase-2 inhibitors and aspirin-exacerbated respiratory disease. Arthritis Res Ther 2003;5:25–27.CrossRefPubMedGoogle Scholar
  32. 32.
    FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433–442.CrossRefPubMedGoogle Scholar
  33. 33.
    McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006;296:1633–1644.CrossRefPubMedGoogle Scholar
  34. 34.
    Hudson M, Richard H, Pilote L. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study. BMJ 2005;330:1370.CrossRefPubMedGoogle Scholar
  35. 35.
    Furst DE, Hillson J. Aspirin and other nonsteroidal antiinflammatory drugs. In: Koopman WJ, ed. Arthritis and allied conditions. Philadelphia: Lippincott Williams & Wilkins; 2001:665–716.Google Scholar
  36. 36.
    Karim A, Tolbert DS, Hunt TL, Hubbard RC, Harper KM, Geis GS. Celecoxib, a specific COX-2 inhibitor, has no significant effect on methotrexate pharmacokinetics in patients with rheumatoid arthritis. J Rheumatol 1999;26:2539–2543.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Leslie J. Crofford
    • 1
  1. 1.Division of Rheumatology & Women’s HealthUniversity of KentuckyLexingtonUSA

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