Time Course and Pattern of Blood Loss With Ibuprofen Treatment in Healthy Subjects
2005; Elsevier BV; Volume: 3; Issue: 11 Linguagem: Inglês
10.1016/s1542-3565(05)00605-1
ISSN1542-7714
AutoresBarry M. Bowen, Yuhong Yuan, Cindy James, Ferid Rashid, Richard H. Hunt,
Tópico(s)Drug-Induced Adverse Reactions
ResumoBackground & Aims: Nonselective nonsteroidal anti-inflammatory drug (NSAID) users are at increased risk of gastrointestinal bleeding. We aimed to assess the pattern and extent of fecal blood loss (FBL) with ibuprofen, which is considered to have a favorable gastrointestinal safety profile. Methods: We conducted a post hoc analysis of 2 separate randomized, parallel-group, double-blind studies, in which ibuprofen was used as a positive control. FBL was measured by radioactive analysis of chromium-51 labeled red cells in stools during baseline and then followed by 4 weeks of treatment with ibuprofen (800 mg 3 times daily) or placebo in 68 healthy volunteers. FBL was considered significant when blood loss was >2 mL daily. Results: The baseline period was identical for all subjects, with an average FBL of 0.36 mL (standard deviation, ±0.075) per day. During the study period, all subjects receiving ibuprofen had a daily mean FBL >2 mL, with a group daily mean loss 3.64-fold greater than in the placebo group (2.55 mL [±3.2] vs 0.7 mL [±0.37], P < .001). In the ibuprofen group (n = 31), 26 subjects had between 1 and 7 random episodes of microbleeding with FBL >3 mL. Nine had a maximum FBL >10 mL (29.35 ± 23.32 mL), and in 2 subjects blood loss reached 73 mL and 66 mL, respectively. Conclusions: Treatment with a therapeutic dose of ibuprofen, a commonly used nonselective NSAID, in healthy subjects is associated with significant FBL, which occurs randomly with spikes of bleeding, sometimes exceeding 66 mL in a single day. Chronic anemia or gastrointestinal bleeding in patients taking nonselective NSAIDs should be thoroughly investigated. Background & Aims: Nonselective nonsteroidal anti-inflammatory drug (NSAID) users are at increased risk of gastrointestinal bleeding. We aimed to assess the pattern and extent of fecal blood loss (FBL) with ibuprofen, which is considered to have a favorable gastrointestinal safety profile. Methods: We conducted a post hoc analysis of 2 separate randomized, parallel-group, double-blind studies, in which ibuprofen was used as a positive control. FBL was measured by radioactive analysis of chromium-51 labeled red cells in stools during baseline and then followed by 4 weeks of treatment with ibuprofen (800 mg 3 times daily) or placebo in 68 healthy volunteers. FBL was considered significant when blood loss was >2 mL daily. Results: The baseline period was identical for all subjects, with an average FBL of 0.36 mL (standard deviation, ±0.075) per day. During the study period, all subjects receiving ibuprofen had a daily mean FBL >2 mL, with a group daily mean loss 3.64-fold greater than in the placebo group (2.55 mL [±3.2] vs 0.7 mL [±0.37], P < .001). In the ibuprofen group (n = 31), 26 subjects had between 1 and 7 random episodes of microbleeding with FBL >3 mL. Nine had a maximum FBL >10 mL (29.35 ± 23.32 mL), and in 2 subjects blood loss reached 73 mL and 66 mL, respectively. Conclusions: Treatment with a therapeutic dose of ibuprofen, a commonly used nonselective NSAID, in healthy subjects is associated with significant FBL, which occurs randomly with spikes of bleeding, sometimes exceeding 66 mL in a single day. Chronic anemia or gastrointestinal bleeding in patients taking nonselective NSAIDs should be thoroughly investigated. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used because of their established anti-inflammatory, antipyretic, and analgesic properties. However, use of NSAIDs increases the risk for gastrointestinal (GI) tract mucosal injury and other complications, especially bleeding, and the effects of platelet dysfunction.1Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient.Gastroenterology. 2001; 120: 594-606Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar Serious events can occur throughout the GI tract,2Laine L. Connors L.G. Reicin A. et al.Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use.Gastroenterology. 2003; 124: 288-292Abstract Full Text PDF PubMed Scopus (336) Google Scholar and the hospitalization rates in the US for upper GI bleeding and for any GI bleeding range between 150–170 and 350–385 per 100,000 population, respectively.3Lewis J.D. Bilker W.B. Brensinger C. et al.Hospitalization and mortality rates from peptic ulcer disease and GI bleeding in the 1990s relationship to sales of nonsteroidal anti-inflammatory drugs and acid suppression medications.Am J Gastroenterol. 2002; 97: 2540-2549Crossref PubMed Google Scholar As many as 15%–20% of patients will have continued or recurrent bleeding, putting them at increased risk for surgery and death.4Marmo R. Rotondano G. Bianco M.A. et al.Outcome of endoscopic treatment for peptic ulcer bleeding is a second look necessary? a meta-analysis.Gastrointest Endosc. 2003; 57: 62-67Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 5van Leerdam M.E. Vreeburg E.M. Rauws E.A. et al.Acute upper GI bleeding: did anything change? time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000.Am J Gastroentero. 2003; 98: 1494-1499PubMed Google Scholar A recent survey of a US ambulatory adult population sample found that during the preceding week, consumption of aspirin, ibuprofen, and naproxen was 17%, 17%, and 3.5%, respectively.6Kaufman D.W. Kelly J.P. Rosenberg L. et al.Recent patterns of medication use in the ambulatory adult population of the United States the Slone survey.JAMA. 2002; 287: 337-344Crossref PubMed Scopus (1608) Google Scholar Increasing NSAID use, together with the increasing number of older patients with several comorbid conditions, has offset advances in diagnosis and improved patient care. The mortality rate of upper GI bleeding ranges from 5%–14% and has been essentially unchanged during the past 40 years.3Lewis J.D. Bilker W.B. Brensinger C. et al.Hospitalization and mortality rates from peptic ulcer disease and GI bleeding in the 1990s relationship to sales of nonsteroidal anti-inflammatory drugs and acid suppression medications.Am J Gastroenterol. 2002; 97: 2540-2549Crossref PubMed Google Scholar, 5van Leerdam M.E. Vreeburg E.M. Rauws E.A. et al.Acute upper GI bleeding: did anything change? time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000.Am J Gastroentero. 2003; 98: 1494-1499PubMed Google Scholar Moreover, small intestine7Graham D.Y. Opekun A.R. Willingham F.F. et al.Visible small-intestinal mucosal injury in chronic NSAID users.Clin Gastroenterol Hepatol. 2005; 3: 55-59Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar, 8Allison M.C. Howatson A.G. Torrance C.J. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs.N Engl J Med. 1992; 327: 749-754Crossref PubMed Scopus (996) Google Scholar and colon2Laine L. Connors L.G. Reicin A. et al.Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use.Gastroenterology. 2003; 124: 288-292Abstract Full Text PDF PubMed Scopus (336) Google Scholar mucosal injury is common in chronic NSAID users, but anemia caused by chronic microbleeding from other than visible upper GI lesions is seldom considered9Upadhyay R. Torley H.I. McKinlay A.W. et al.Iron deficiency anaemia in patients with rheumatic disease receiving non-steroidal anti-inflammatory drugs the role of upper gastrointestinal lesions.Ann Rheum Dis. 1990; 49: 359-362Crossref PubMed Scopus (28) Google Scholar and is thus underestimated. Ibuprofen is considered to have the most favorable GI safety profile of all nonselective NSAIDs.10Henry D. McGettigan P. Epidemiology overview of gastrointestinal and renal toxicity of NSAIDs.Int J Clin Pract Suppl. 2003; 135: 43-49PubMed Google Scholar, 11Lewis S.C. Langman M.J. Laporte J.R. et al.Dose-response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding a meta-analysis based on individual patient data.Br J Clin Pharmacol. 2002; 54: 320-326Crossref PubMed Scopus (219) Google Scholar, 12FDA, NDAC meeting on risks of NSAIDs, on Sep 20, 2002. Available at: http://www.fda.gov/ohrms/dockets/ac/02/briefing/3882B2_04_Wyeth-Ibuprophen.pdf. (Accessed April 01, 2005).Google Scholar In Canada, the US, and many other countries, ibuprofen is available as 400-mg tablets without prescription. In most countries, the approved over-the-counter (OTC) daily dose of ibuprofen is 1200 mg (2400 mg prescription only medicine in the UK), which is 37.5% of the maximum daily prescription dose of 3200 mg. However, the pattern and extent of ibuprofen-induced GI bleeding are unclear. Whole gut microbleeding can be assessed precisely, continuously, and quantitatively by the measurement of 51Cr-labeled red blood cells in stool.13James M.W. Hawkey C.J. Assessment of non-steroidal anti-inflammatory drug (NSAID) damage in the human gastrointestinal tract.Br J Clin Pharmacol. 2003; 56: 146-155Crossref PubMed Scopus (85) Google Scholar, 14Lussier A. Arsenault A. Varady J. et al.The use of a 51Cr technique to detect gastrointestinal microbleeding associated with nonsteroidal antiinflammatory drugs.Semin Arthritis Rheum. 1987; 17: 40-45Google Scholar Our study aimed to evaluate the pattern and extent of fecal blood loss (FBL) in daily stool caused by a therapeutic dose of ibuprofen 800 mg given 3 times daily for 4 weeks in healthy subjects by undertaking a post hoc analysis of 2 previously reported studies of rofecoxib and etoricoxib, in which our negative control was placebo, and our positive control was ibuprofen.15Hunt R.H. Bowen B. Mortensen E.R. et al.A randomized trial measuring fecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects.Am J Med. 2000; 109: 201-206Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 16Hunt R.H. 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: 201-210Crossref PubMed Scopus (104) Google Scholar Healthy male volunteers, aged 18–60 years, within 20% of ideal body weight were enrolled in the studies if they had a history of regular bowel habits (at least 1 stool per day) and a negative fecal occult blood test at the pre-study visit. Subjects were excluded if they had any one of the following: a history of GI disease or GI surgery; a history or evidence of nasal, oral, or rectal bleeding; hemorrhoids on anorectal examination; or had participated in any other clinical trial within 3 months. Subjects were also excluded if they had used any medication during the 4 weeks before the study. Additional exclusions included daily alcohol consumption of more than 1 drink, cigarette smoking, and daily consumption of more than four 8-ounce cups of caffeinated beverages, or allergy or intolerance to NSAIDs. Use of any medication was prohibited throughout the study. The study was approved by the institutional review board of Chedoke-McMaster Hospitals. All subjects participating in the study gave written informed consent before enrollment. The studies were 2 single center, parallel group, randomized, double-blind, placebo-controlled trials. At the pre-study visit (up to 14 days before radiolabeling), all subjects underwent physical examination, including anoscopy, laboratory evaluation including fecal occult blood testing, and electrocardiography. Twenty milliliters of venous blood was drawn from each eligible subject for erythrocyte separation and labeling. Subjects were re-injected with their own red blood cells labeled with 300 μCi of sodium chromate 51Cr (Merck Frosst Laboratories, Montreal, Quebec, Canada) 1 day before admission to the clinical investigation unit (study day −8). This dose is sufficient to measure the counts/mL of blood throughout the entire 36 days of the study; the initial blood sample is approximately 20,000 counts/mL and drops to 4,000 counts/mL by the end of the study. Administration of 300 μCi results in an estimated radiation dose of 0.8 millisievert, equivalent to approximately 14% of the annual limit recommended for radiation workers by the International Commission on Radiation Protection. The subjects then entered a 1-week, single-blind placebo treatment period to establish their baseline FBL. Subjects were excluded from further study if FBL was >2 mL on any single day, or if their average FBL during the first 6 days of the week was >1.5 mL per day. A computer program was used to generate a randomized patient allocation list before study enrollment. Eligible subjects were treated for 28 days with either 800 mg ibuprofen 3 times daily or identical placebo (Merck & Co, Inc., Blue Bell, PA) 3 times daily at 8-hour intervals. Treatment began on day 0. Study medications for each subject were packaged in numbered containers; the study coordinator monitored daily administration of study medication to ensure protocol compliance. All subjects lived in a dormitory environment, where medication administration, standardized diet, and stool collection were closely monitored. Adverse events were monitored throughout the study; procedures scheduled for the last day of treatment (study day 28) were performed at the time of withdrawal for any subject. Concealment of randomization was achieved in the periods of investigation, data analysis, and report writing. Mean daily fecal red blood cell loss was measured by using 51Cr-labeled red blood cells. The use of labeled red blood cells to measure FBL has been evaluated and described previously.14Lussier A. Arsenault A. Varady J. et al.The use of a 51Cr technique to detect gastrointestinal microbleeding associated with nonsteroidal antiinflammatory drugs.Semin Arthritis Rheum. 1987; 17: 40-45Google Scholar, 17Lussier A. Lebel E. Radiochromium (Chromium-51) evaluation of gastrointestinal blood loss associated with placebo, aspirin, and nabumetorne.Am J Med. 1987; 83: 15-18Abstract Full Text PDF PubMed Scopus (31) Google Scholar Our study modified these techniques to include measurement of total daily stool collection rather than aliquots. This required adherence to strict sample preparation and analysis. Briefly, all stool samples were collected each day, weighed, and frozen. When there was more than 1 sample in a day, the samples were counted individually, and the results were added together for that day. All subjects practiced a standard technique before the study began to ensure the sampling validity. Stools were compacted to a standardized shape so that the vagaries of stool morphology did not confound results. Blood samples were taken on days −7, −4, −1, +4, +7, +11, +14, +18, +21, +25, and +28 after the intravenous injection of 51Cr-labeled blood cells. All samples of blood and stool were placed in plastic containers (Bayer, Toronto, Canada) with a 3 1/2-inch diameter base, and the volumes were adjusted to assure constant counting geometry. Radioactive standards, representative of the amount of 51Cr injected, were prepared. The same geometry was used for the blood and stool samples throughout the study. Each sample was placed on the center of the top of a 5-inch NaI (Tl) crystal connected to a multichannel analyzer (Aptec Engineering, Concord, Canada). Identical geometry could be achieved between samples placed in this manner. The signal was amplified and then analyzed; the integrated counts for the background and the sample were recorded. The red cell survival, blood specific activity, and the amount of blood in the stool were calculated. Daily 51Cr-labeled blood specific activity was interpolated by calculation of each subject's 51Cr-labeled red blood cell survival curve. The radioactivity/mL of blood was plotted versus time, and a least-squares analysis was performed so that a "best fit" line could be calculated. On each day, the FBL, expressed as milliliters, was calculated by analyzing the radioactivity in each stool sample and then dividing it by the radioactivity/mL of blood present on that day. The primary end point of this post hoc analysis was the daily FBL (mL/day ± standard deviation) for 4 weeks of active treatment and the bleeding patterns observed in any subjects with 1 or more bleeding episodes. Results from all subjects who completed the study were analyzed. The FBL was calculated for each subject and averaged for each day, and standard deviation was calculated for each group for each day. Between-group comparisons were based on a t test analysis. Statistical analysis was conducted in a Lotus 1-2-3 spreadsheet (IBM Corporation, Armonk, NY). A total of 68 healthy men (aged 19–33 years) were enrolled; 31 subjects were given ibuprofen (800 mg 3 times daily), and 37 were given placebo. All subjects completed the study. The yield of the 51Cr labeling of erythrocytes was about 90%. The 7-day placebo evaluation period was similar for all subjects, with an average FBL of 0.39 (±0.07) and 0.34 (±0.08) mL per day in the ibuprofen and placebo groups, respectively. Throughout the remainder of the study, no subject in the placebo group had a single day FBL >2 mL; the daily mean FBL was 0.70 mL (±0.37) for placebo (Figure 1). In contrast, all subjects receiving ibuprofen had daily mean FBL >2 mL from day 3 (Figure 2), with group daily mean FBL being 2.55 mL (±3.2), which was significantly greater than for those on placebo throughout the 4-week treatment period (P < .05). In 27 subjects in the ibuprofen group, the onset of bleeding occurred within 3 days (±2) after the start of treatment. Compared with baseline, FBL in the ibuprofen treatment group was 3.64-fold greater (P < .001) than in the placebo group. Twenty-one subjects had from 2–7 random episodes of microbleeding with FBL >3 mL (Figure 3A, B); 5 subjects had a single microbleeding episode >3 mL; 5 subjects had 4 episodes of microbleeding with FBL >2 mL but 10 mL (mean, 29.35 ± 23.32 mL), and in 2 subjects the magnitude of blood loss reached 73 mL and 66 mL (Figure 3B and 4), respectively.Figure 2The average and the standard deviation of the mean for the FBL caused by ibuprofen. Both the average FBL and the standard deviation are above 2.5% and as high as 13%. STDS, standard deviations.View Large Image Figure ViewerDownload (PPT)Figure 3Pattern and extent of FBL of several subjects in the ibuprofen group. (A) A subject with several significant bleeding episodes with FBL >3 mL 15 mL/day. (C) A subject with several microbleeding episodes with FBL >2 mL but 3 and 65 mL>15 and 3 and 2 and 3 mL 2-fold increase in FBL.14Lussier A. Arsenault A. Varady J. et al.The use of a 51Cr technique to detect gastrointestinal microbleeding associated with nonsteroidal antiinflammatory drugs.Semin Arthritis Rheum. 1987; 17: 40-45Google Scholar, 18Salom I.L. Jacob G. Jallad N. et al.Gastrointestinal microbleeding associated with the use of etodolac, ibuprofen, indomethacin, and naproxen in normal males.J Clin Pharmacol. 1984; 24: 240-246Crossref PubMed Scopus (50) Google Scholar Although the presence of FBL does not predict the severity of GI bleeding, it can be considered a surrogate, indirect measure of injury over the entire length of the GI tract. Moreover, the magnitude of drug-induced microbleeding might be a marker of the potential to cause clinically significant GI toxicity, and prolonged FBL might result in negative iron balance and anemia in chronic users of NSAIDs.19Black D.A. Fraser C.M. Iron deficiency anaemia and aspirin use in old age.Br J Gen Pract. 1999; 49: 729-730PubMed Google Scholar FBL has not been considered to be of major importance when treating patients with ibuprofen. However, from our results, it is clear that ibuprofen, which is the so-called safest nonselective NSAID, at the therapeutic dose used in this study can also cause significant GI bleeding in healthy subjects. Furthermore, we have shown in this study that the bleeding pattern can result in a significant amount of FBL when measured during a 4-week period. GI bleeding associated with nonselective NSAID use carries a measurable morbidity. A recent systematic review estimated that in the US, nonselective, non-aspirin NSAIDs might account for 34% of all GI bleeding cases and more than 32,000 GI bleeding hospitalizations per year in the 1990s.20Tarone R.E. Blot W.J. McLaughlin J.K. Nonselective nonaspirin nonsteroidal anti-inflammatory drugs and gastrointestinal bleeding relative and absolute risk estimates from recent epidemiologic studies.Am J Ther. 2004; 11: 17-25Crossref PubMed Scopus (40) Google Scholar Low-dose aspirin is also commonly associated with GI bleeding.21Slattery J. Warlow C.P. Shorrock C.J. et al.Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin analysis of gastrointestinal bleeding during the UK-TIA trial.Gut. 1995; 37: 509-511Crossref PubMed Scopus (130) Google Scholar, 22Sørensen H.T. Mellemkjaer L. Blot W.J. et al.Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin.Am J Gastroenterol. 2000; 95: 2218-2224Crossref PubMed Scopus (307) Google Scholar The apparently constant rate of rebleeding and of mortality caused by upper GI bleeding despite medical advances can be explained, at least in part, by changes in the patient population demographics. The prevalence of at least once weekly NSAID use among people aged ≥65 years is 70%, and half of this population take >7 doses/week.23Talley N.J. Evans J.M. Fleming K.C. et al.Nonsteroidal antiinflammatory drugs and dyspepsia in the elderly.Dig Dis Sci. 1995; 40: 1345-1350Crossref PubMed Scopus (143) Google Scholar In the general population, a large proportion of NSAID takers are elderly with comorbidities or an ulcer history and who are using multiple drugs and at a high risk of bleeding complications.1Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient.Gastroenterology. 2001; 120: 594-606Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar However, it has been suggested that age might be a confounding factor, because the older the patient, the more chance of concomitant disease and use of other medications (including aspirin) and of a previous GI history.24Solomon D.H. Gurwitz J.H. Toxicity of nonsteroidal anti-inflammatory drugs in the elderly is advanced age a risk factor?.Am J Med. 1997; 102: 208-215Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Recent studies have shown that this is not the case in ibuprofen users. The elderly have an increased free concentration and low unbound clearance of the active S-enantiomer of ibuprofen than younger patients, which suggests that the elderly have an increased exposure to active ibuprofen, and thus some additional caution might be required when using ibuprofen in the elderly,25Tan S.C. Patel B.K. Jackson S.H. et al.Influence of age on the enantiomeric disposition of ibuprofen in healthy volunteers.Br J Clin Pharmacol. 2003; 55: 579-587Crossref PubMed Scopus (22) Google Scholar who are not represented in our study. Ibuprofen is available OTC and is widely considered to have few side effects and a low incidence of ulcers or GI bleeding. It is stated to have the most favorable GI safety profile of all nonselective NSAIDs in meta-analyses,10Henry D. McGettigan P. Epidemiology overview of gastrointestinal and renal toxicity of NSAIDs.Int J Clin Pract Suppl. 2003; 135: 43-49PubMed Google Scholar systematic reviews,26Moore N. Forty years of ibuprofen use.Int J Clin Pract Suppl. 2003; 135: 28-31PubMed Google Scholar epidemiologic studies,27Fries J.F. Bruce B. Rate of serious gastrointestinal events from low dose use of acetylsalicylic acid, acetaminophen, and ibuprofen in patients with osteoarthritis and rheumatoid arthritis.J Rheumatol. 2003; 30: 2226-2233PubMed Google Scholar and clinical trials.28Moore N. Charlesworth A. Van Ganse E. et al.Risk factors for adverse events in analgesic drug users results from the PAIN study.Pharmacoepidemiol Drug Saf. 2003; 12: 601-610Crossref PubMed Scopus (46) Google Scholar Since it became available to consumers in 1984 up to 2002, more than 100 billion 200-mg tablets of OTC ibuprofen have been sold in the United States alone.12FDA, NDAC meeting on risks of NSAIDs, on Sep 20, 2002. Available at: http://www.fda.gov/ohrms/dockets/ac/02/briefing/3882B2_04_Wyeth-Ibuprophen.pdf. (Accessed April 01, 2005).Google Scholar Ibuprofen at doses ranging from <1200 mg–2400 mg/day contributed to 88 cases of ulcer bleeding in patients older than 60 years (n = 1121) in one UK study (odds ratio [OR], 2.0; 95% confidence interval [CI], 0.4–2.8), and the authors estimated that 669 cases per year of ulcer bleeding were attributable to ibuprofen in the UK in patients aged older than 60 years.29Langman M. Population impact of strategies designed to reduce peptic ulcer risks associated with NSAID use.Int J Clin Pract Suppl. 2003; 135: 38-42PubMed Google Scholar Although ibuprofen has the lowest risk among all nonselective NSAIDs in that study (95% CI encompass unity), this is still not equal to no treatment. The GI tolerability of ibuprofen at OTC doses not exceeding 1200 mg daily for up to 7 days was at least as good as that of paracetamol (acetaminophen) and significantly better than that of aspirin in the large randomized, investigator-blinded PAIN study in France.28Moore N. Charlesworth A. Van Ganse E. et al.Risk factors for adverse events in analgesic drug users results from the PAIN study.Pharmacoepidemiol Drug Saf. 2003; 12: 601-610Crossref PubMed Scopus (46) Google Scholar Only 5.8% of ibuprofen users experienced GI adverse events. However, in that study the ibuprofen users were relatively young, the doses taken were probably lower than in general practice, patients with a history of ulcer were excluded, the length of therapy was short, and the study suffered from considerable methodologic deficiencies that have been criticized.30Peterson G. Down-scheduling of ibuprofen any decision should be based on solid evidence.Pharmacist. 2003; 22 (Available at: http://www.psa.org.au/media/SeptAP03tellingit.pdf) (Accessed April 01, 2005): 688-691Google Scholar Thus, many published studies excluded those at risk, and therefore, the true risk of OTC ibu
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