• 1
    Bajarnason I, Hayllar J, MacPherson AJ, et al. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104: 183247.
  • 2
    Hawkey CJ. Nonsteroidal anti-inflammatory drug gastropathy. Gastroenterology 2000; 119: 52135.
  • 3
    Weihrauch TR, Gauler TC. Placebo--efficacy and adverse effects in controlled clinical trials. Arzneimittelforschung 1999; 49: 38593.
  • 4
    De Craen AJ, Moerman DE, Heisterkamp SH, et al. Placebo effect in the treatment of duodenal ulcer. Br J Clin Pharmacol 1999; 48: 85360.
  • 5
    De Craen AJ, Kaptchuk TJ, Tijssen JG, et al. Placebos and placebo effects in medicine: historical overview. J R Soc Med 1999; 92: 5115.
  • 6
    Rosenzweig P, Brohier S, Zipfel A. The placebo effect in healthy volunteers: influence of experimental conditions on the adverse events profile during phase I studies. Clin Pharmacol Ther 1993; 54: 57883.
  • 7
    Genta RM. Review article: after gastritis – an imaginary journey into a Helicobacter-free world. Aliment Pharmacol Ther 2002; 16(Suppl. 4): 8994.
  • 8
    Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002; 359: 1422.
  • 9
    Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 112.
  • 10
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 153958.
  • 11
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 55760.
  • 12
    Siersma V, Als-Nielsen B, Chen W, et al. Multivariable modelling for meta-epidemiological assessment of the association between trial quality and treatment effects estimated in randomized clinical trials. Stat Med 2007; 26: 274558.
  • 13
    Friedrich JO, Adhikari NK, Beyene J. Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data. BMC Med Res Methodol 2007; 7: 5.
  • 14
    Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 2007; 26: 5377.
  • 15
    Lanza F, Royer G, Nelson R. An endoscopic evaluation of the effects of non-steroidal anti-inflammatory drugs on the gastric mucosa. Gastrointest Endosc 1975; 21: 1035.
  • 16
    Lanza FL, Royer GL Jr, Nelson RS, et al. The effects of ibuprofen, indomethacin, aspirin, naproxen, and placebo on the gastric mucosa of normal volunteers: a gastroscopic and photographic study. Dig Dis Sci 1979; 24: 8238.
  • 17
    Lanza FL, Nelson RS, Royer GL. Effects of ibuprofen, tolmetin and placebo on the gastric mucosa of aspirin-sensitive volunteers. Am J Gastroenterol 1979; 71: 52834.
  • 18
    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; 17: 303.
  • 19
    Lanza FL, Royer GL Jr, Nelson RS, et al. A comparative endoscopic evaluation of the damaging effects of nonsteroidal anti-inflammatory agents on the gastric and duodenal mucosa. Am J Gastroenterol 1981; 75: 1721.
  • 20
    Lanza FL, Umbenhauer ER, Nelson RS, et al. A double-blind randomized placebo controlled gastroscopic study to compare the effects of indomethacin capsules and indomethacin suppositories on the gastric mucosa of human volunteers. J Rheumatol 1982; 9: 4159.
  • 21
    Lanza FL, Nelson RS, Greenberg BP. Effects of fenbufen, indomethacin, naproxen, and placebo on gastric mucosa of normal volunteers. A comparative endoscopic and photographic evaluation. Am J Med 1983; 75(4B):759.
  • 22
    Lanza FL, Nelson RS, Rack MF. A controlled endoscopic study comparing the toxic effects of sulindac, naproxen, aspirin, and placebo on the gastric mucosa of health volunteers. J Clin Pharmacol 1984; 24: 8995.
  • 23
    Lanza F, Rack MF, Lynn M, et al. An endoscopic comparison of the effects of etodolac, indomethacin, ibuprofen, naproxen, and placebo on the gastrointestinal mucosa. J Rheumatol 1987; 14: 33841.
  • 24
    Cryer B, Goldschmiedt M, Redfern JS, et al. Comparison of salsalate and aspirin on mucosal injury and gastroduodenal mucosal prostaglandins. Gastroenterology 1990; 99: 161621.
  • 25
    Marini U, Spotti D. Gastric tolerability of nimesulide. A double-blind comparison of 2 oral dosage regimens and placebo. Drugs 1993; 46(Suppl. 1): 24952.
  • 26
    Laine L, Sloane R, Ferretti M, et al. A randomized double-blind comparison of placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production. Gastrointest Endosc 1995; 42: 42833.
  • 27
    Patoia L, Santucci L, Furno P, et al. A 4-week, double-blind, parallel-group study to compare the gastrointestinal effects of meloxicam 7.5 mg, meloxicam 15 mg, piroxicam 20 mg and placebo by means of faecal blood loss, endoscopy and symptom evaluation in healthy volunteers. Br J Rheumatol 1996; 35(Suppl. 1): 617.
  • 28
    Bocanegra TS, Weaver AL, Tindall EA, et al. Diclofenac/misoprostol compared with diclofenac in the treatment of osteoarthritis of the knee or hip: a randomized, placebo controlled trial. Arthrotec Osteoarthritis Study Group. J Rheumatol 1998; 25: 160211.
  • 29
    Lanza FL, Codispoti JR, Nelson EB. An endoscopic comparison of gastroduodenal injury with over-the-counter doses of ketoprofen and acetaminophen. Am J Gastroenterol 1998; 93: 10514.
    Direct Link:
  • 30
    Lipscomb GR, Wallis N, Armstrong G, et al. Gastrointestinal tolerability of meloxicam and piroxicam: a double-blind placebo-controlled study. Br J Clin Pharmacol 1998; 46: 1337.
  • 31
    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.
  • 32
    Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999; 282: 19218.
  • 33
    Agrawal NM, Caldwell J, Kivitz AJ, et al. Comparison of the upper gastrointestinal safety of Arthrotec 75 and nabumetone in osteoarthritis patients at high risk for developing nonsteroidal anti-inflammatory drug-induced gastrointestinal ulcers. Clin Ther 1999; 21: 65974.
  • 34
    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.
  • 35
    Laine L, Harper S, Simon T, et al. 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. Rofecoxib Osteoarthritis Endoscopy Study Group. Gastroenterology 1999; 117: 77683.
  • 36
    Hawkey C, Laine L, Simon T, et al. Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group. Arthritis Rheum 2000; 43: 3707.
  • 37
    Sikes DH, Agrawal NM, Zhao WW, et al. Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis. Eur J Gastroenterol Hepatol 2002; 14: 110111.
  • 38
    Kivitz A, Eisen G, Zhao WW, et al. Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis. J Fam Pract 2002; 51: 5307.
  • 39
    Hunt RH, Harper S, Callegari P, et al. Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib. Aliment Pharmacol Ther 2003; 17: 20110.
  • 40
    Hawkey CJ, Laine L, Simon T, et al. Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study. Gut 2003; 52: 8206.
  • 41
    Goldstein JL, Kivitz AJ, Verburg KM, et al. A comparison of the upper gastrointestinal mucosal effects of valdecoxib, naproxen and placebo in healthy elderly subjects. Aliment Pharmacol Ther 2003; 18: 12532.
  • 42
    Hunt RH, Harper S, Watson DJ, et al. The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events. Am J Gastroenterol 2003; 98: 172533.
    Direct Link:
  • 43
    Fiorucci S, Santucci L, Gresele P, et al. Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study. Gastroenterology 2003; 124: 6007.
  • 44
    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.
  • 45
    Hawkey CJ, Jones JI, Atherton CT, et al. Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans. Gut 2003; 52: 153742.
  • 46
    Scheiman JM, Cryer B, Kimmey MB, et al. A randomized, controlled comparison of ibuprofen at the maximal over-the-counter dose compared with prescription-dose celecoxib on upper gastrointestinal mucosal injury. Clin Gastroenterol Hepatol 2004; 2: 2905.
  • 47
    Laine L, Maller ES, Yu C, et al. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology 2004; 127: 395402.
  • 48
    Bias P, Buchner A, Klesser B, et al. The gastrointestinal tolerability of the LOX/COX inhibitor, licofelone, is similar to placebo and superior to naproxen therapy in healthy volunteers: results from a randomized, controlled trial. Am J Gastroenterol 2004; 99: 6118.
    Direct Link:
  • 49
    Lohmander LS, McKeith D, Svensson O, et al. A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis. Ann Rheum Dis 2005; 64: 44956.
  • 50
    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.
  • 51
    Kimmey MB. Role of endoscopy in nonsteroidal anti-inflammatory drug clinical trials. Am J Med 1998; 105: 28S31S.
  • 52
    Lanza F, Sahba B, Schwartz H, et al. The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study. Am J Gastroenterol 2002; 97: 5864.
    Direct Link:
  • 53
    Malaty HM. Epidemiology of Helicobacter pylori infection. Best Pract Res Clin Gastroenterol 2007; 21: 20514.
  • 54
    Musial F, Klosterhalfen S, Enck P. Placebo responses in patients with gastrointestinal disorders. World J Gastroenterol 2007; 13: 34259.
  • 55
    Meyer FP, Tröger U, Röhl FW. Reliability of symptom reports by healthy volunteers treated with placebo over several time periods. Arzneimittelforschung 2000; 50: 76871.
  • 56
    MacDonald AJ, Peden NR, Hayton R, et al. Symptom relief and the placebo effect in the trial of an anti-peptic drug. Gut 1981; 22: 3236.
  • 57
    Krogsboll LT, Hrobjartsson A, Gotzsche PC. Spontaneous improvement in randomised clinical trials: meta-analysis of three-armed trials comparing no treatment, placebo and active intervention. BMC Med Res Methodol 2009; 9: 1.
  • 58
    Dobrilla G, Scarpignato C. Placebo and placebo effect: their impact on the evaluation of drug response in patients. Dig Dis 1994; 12: 36877.
  • 59
    Bernstein CN. Placebos in medicine. Semin Gastrointest Dis 1999; 10: 37.
  • 60
    White L, Tursky B, Schwarz GE. Proposed synthesis of placebo models. In: WhiteL, TurskyB, SchwarzGE, et al. , eds. Placebo, Theory, Research, and Mechanisms. New York-London: Guilford Press, 1985: 43147.
  • 61
    Jones MP. The role of psychosocial factors in peptic ulcer disease: beyond Helicobacter pylori and NSAIDs. J Psychosom Res 2006; 60: 40712.
  • 62
    Lam SK. Differences in peptic ulcer between East and West. Baillieres Best Pract Res Clin Gastroenterol 2000; 14: 4152.
  • 63
    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: 100612.
  • 64
    Laine L. GI risk and risk factors of NSAIDs. J Cardiovasc Pharmacol 2006; 47(Suppl 1): S606.
  • 65
    Lanza FL. Endoscopic studies of gastric and duodenal injury after the use of ibuprofen, aspirin, and other nonsteroidal anti-inflammatory agents. Am J Med 1984; 77(1A):1924.
  • 66
    Lanza FL. A review of gastric ulcer and gastroduodenal injury in normal volunteers receiving aspirin and other non-steroidal anti-inflammatory drugs. Scand J Gastroenterol Suppl 1989; 163: 2431.
  • 67
    Eypasch E, Lefering R, Kum CK, et al. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ 1995; 311: 61920.
  • 68
    Lassen A, Hallas J, Schaffalitzky de Muckadell OB. Complicated and uncomplicated peptic ulcers in a Danish county 1993-2002: a population-based cohort study. Am J Gastroenterol 2006; 101: 94553.
    Direct Link:
  • 69
    Tseng CC, Wolfe MM. Nonsteroidal anti-inflammatory drugs. Med Clin North Am 2000; 84: 132944.
  • 70
    Lanas A, Ferrandez A. Inappropriate prevention of NSAID-induced gastrointestinal events among long-term users in the elderly. Drugs Aging 2007; 24: 12131.
  • 71
    Laine L. Gastrointestinal effects of NSAIDs and coxibs. J Pain Symptom Manage 2003; 25(Suppl. 2): S3240.
  • 72
    Aro P, Storskrubb T, Ronkainen J, et al. Peptic ulcer disease in a general adult population: the Kalixanda study: a random population-based study. Am J Epidemiol 2006; 163: 102534.
  • 73
    Hawkey CJ, Naesdal J, Wilson I, et al. Relative contribution of mucosal injury and Helicobacter pylori in the development of gastroduodenal lesions in patients taking non-steroidal anti-inflammatory drugs. Gut 2002; 51: 33643.
  • 74
    Burdett S, Stewart LA, Tierney JF. Publication bias and meta-analyses: a practical example. Int J Technol Assess Health Care 2003; 19: 12934.
  • 75
    Simmonds MC, Higgins JP. Covariate heterogeneity in meta-analysis: criteria for deciding between meta-regression and individual patient data. Stat Med 2007; 26: 298299.