• 1
    Elnachef N, Scheiman JM, Fendrick AM, Howden CW, Chey WD. Changing perceptions and practices regarding aspirin, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs among US primary care providers. Aliment Pharmacol Ther 2008; 28: 124958.
  • 2
    Laine L. Gastrointestinal effects of NSAIDs and coxibs. J Pain Symptom Manage 2003; 25(2 Suppl): S3240.
  • 3
    Cryer B. NSAID-associated deaths: the rise and fall of NSAID-associated GI mortality. Am J Gastroenterol 2005; 100: 16945.
    Direct Link:
  • 4
    Lanas A, Perez-Aisa MA, Feu F, et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol 2005; 100: 168593.
    Direct Link:
  • 5
    Straube S, Tramèr MR, Moore RA, Derry S, McQuay HJ. Mortality with upper gastrointestinal bleeding and perforation: effects of time and NSAID use. BMC Gastroenterol 2009; 9: 41.
  • 6
    Jones R, Rubin G, Berenbaum F, Scheiman J. Gastrointestinal and cardiovascular risks of nonsteroidal anti-inflammatory drugs. Am J Med 2008; 121: 46474.
  • 7
    Lanas A. A review of the gastrointestinal safety data – a gastroenterologist’s perspective. Rheumatology (Oxford) 2010; 49(Suppl 2): ii310.
  • 8
    García Rodríguez LA, Tolosa LB. Risk of upper gastrointestinal complications among users of traditional NSAIDs and COXIBs in the general population. Gastroenterology 2007; 132: 498506.
  • 9
    Hernández-Díaz S, Rodríguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000; 160: 20939.
  • 10
    Musumba C, Pritchard DM, Pirmohamed M. Review article: cellular and molecular mechanisms of NSAID-induced peptic ulcers. Aliment Pharmacol Ther 2009; 30: 51731.
  • 11
    Bjarnason I, Scarpignato C, Takeuchi K, Rainsford KD. Determinants of the short-term gastric damage caused by NSAIDs in man. Aliment Pharmacol Ther 2007; 26: 95106.
  • 12
    Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 2008; 135: 4160.
  • 13
    Rich M, Scheiman JM. Nonsteroidal anti-inflammatory drug gastropathy at the new millennium: mechanisms and prevention. Semin Arthritis Rheum 2000; 30: 16779.
  • 14
    Scheiman JM. NSAIDs, gastrointestinal injury, and cytoprotection. Gastroenterol Clin North Am 1996; 25: 27998.
  • 15
    Sostres C, Gargallo CJ, Arroyo MT, Lanas A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol 2010; 24: 12132.
  • 16
    Ham M, Kaunitz JD. Gastroduodenal mucosal defense. Curr Opin Gastroenterol 2007; 23: 607.
  • 17
    Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med 1998; 104: 41321.
  • 18
    Petruzzelli M, Vacca M, Moschetta A, et al. Intestinal mucosal damage caused by non-steroidal anti-inflammatory drugs: role of bile salts. Clin Biochem 2007; 40: 50310.
  • 19
    Rainsford KD. Profile and mechanisms of gastrointestinal and other side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Am J Med 1999; 107(6A): 27S35S.
  • 20
    Giraud MN, Motta C, Romero JJ, Bommelaer G, Lichtenberger LM. Interaction of indomethacin and naproxen with gastric surface-active phospholipids: a possible mechanism for the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs). Biochem Pharmacol 1999; 57: 247.
  • 21
    Lichtenberger LM, Zhou Y, Dial EJ, Raphael RM. NSAID injury to the gastrointestinal tract: evidence that NSAIDs interact with phospholipids to weaken the hydrophobic surface barrier and induce the formation of unstable pores in membranes. J Pharm Pharmacol 2006; 58: 14218.
  • 22
    Goldstein JL. Challenges in managing NSAID-associated gastrointestinal tract injury. Digestion 2004; 69(Suppl 1): 2533.
  • 23
    Goldstein JL, Hochberg MC, Fort JG, Zhang Y, Hwang C, Sostek M. Clinical trial: incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone. Aliment Pharmacol Ther 2010; 32: 40113.
  • 24
    Laine L, Schiff M, Genovese M. Does high-dose famotidine reduce gastric and duodenal ulcers in NSAID users? Two double-blind six-month trials of single-tablet combination ibuprofen-famotidine vs. ibuprofen alone (REDUCE-1 and 2) [abstract]. Gastroenterology 2009; 136(5 Suppl 1): A69.
  • 25
    Goldstein JL, Kramer WG, Searle S, et al. LT-NS001, a naproxen pro-drug with minimal COX inhibition while intact, results in equal plasma exposure to naproxen in volunteers aged 45–70 compared with Naprosyn®. Gut 2009; 58(Suppl II): A270.
  • 26
    Lanza FL, Royer GL Jr, Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa. N Engl J Med 1980; 303: 1368.
  • 27
    Goldstein JL, Kivitz AJ, Verburg KM, Recker DP, Palmer RC, Kent JD. A comparison of the upper gastrointestinal mucosal effects of valdecoxib, naproxen and placebo in healthy elderly subjects. Aliment Pharmacol Ther 2003; 18: 12532.
  • 28
    Goldstein JL, Aisenberg J, Lanza F, et al. A multicenter, randomized, double-blind, active-comparator, placebo-controlled, parallel-group comparison of the incidence of endoscopic gastric and duodenal ulcer rates with valdecoxib or naproxen in healthy subjects aged 65 to 75 years. Clin Ther 2006; 28: 34051.
  • 29
    Yeomans ND, Næsdal J. Systematic review: ulcer definition in NSAID ulcer prevention trials. Aliment Pharmacol Ther 2008; 27: 46572.
  • 30
    Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by NSAIDs. N Engl J Med 1996; 34: 14359.
  • 31
    Rabeneck L, Cook KF, Wristers K, Souchek J, Menke T, Wray NP. SODA (severity of dyspepsia assessment): a new effective outcome measure for dyspepsia-related health. J Clin Epidemiol 2001; 54: 75565.
  • 32
    Rabeneck L, Wristers K, Goldstein JL, Eisen G, Dedhiya SD, Burke TA. Reliability, validity, and responsiveness of severity of dyspepsia assessment (SODA) in a randomized clinical trial of a COX-2-specific inhibitor and traditional NSAID therapy. Am J Gastroenterol 2002; 97: 329.
    Direct Link:
  • 33
    Lichtenberger LM. Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal injury? Topical injury revisited. Biochem Pharmacol 2001; 61: 6317.
  • 34
    Tomisato W, Tsutsumi S, Hoshino T, et al. Role of direct cytotoxic effects of NSAIDs in the induction of gastric lesions. Biochem Pharmacol 2004; 67: 57585.
  • 35
    Darling RL, Romero JJ, Dial EJ, Akunda JK, Langenbach R, Lichtenberger LM. The effects of aspirin on gastric mucosal integrity, surface hydrophobicity, and prostaglandin metabolism in cyclooxygenase knockout mice. Gastroenterology 2004; 127: 94104.
  • 36
    Lipscomb GR, Rees WD. Gastric mucosal injury and adaptation to oral and rectal administration of naproxen. Aliment Pharmacol Ther 1996; 10: 1338.
  • 37
    Desager JP, Vanderbist M, Harvengt C. Naproxen plasma levels in volunteers after single-dose administration by oral and rectal routes. J Clin Pharmacol 1976; 16: 18993.
  • 38
    Lanza FL, Rack MF, Simon TJ, et al. Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen. Aliment Pharmacol Ther 1999; 13: 7617.
  • 39
    Rordorf C, Kellett N, Mair S, et al. Gastroduodenal tolerability of lumiracoxib vs placebo and naproxen: a pilot endoscopic study in healthy male subjects. Aliment Pharmacol Ther 2003; 18: 53341.
  • 40
    Simon LS, Lanza FL, Lipsky PE, et al. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum 1998; 41: 1591602.
  • 41
    Cryer B. Reducing the gastrointestinal risks of low-dose aspirin. Gastroenterology 2010; 38: 303.
  • 42
    Moore A, Bjarnason I, Cryer B, et al. Evidence for endoscopic ulcers as meaningful surrogate endpoint for clinically significant upper gastrointestinal harm. Clin Gastroenterol Hepatol 2009; 7: 115663.
  • 43
    Graham DY. Endoscopic ulcers are neither meaningful nor validated as a surrogate for clinically significant upper gastrointestinal harm. Clin Gastroenterol Hepatol 2009; 7: 114750.