Over-the-counter (OTC) ibuprofen (200 mg), available

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2004;2: ORIGINAL ARTICLES A Randomized, Controlled Comparison of Ibuprofen at the Maximal Over-the-Counter Dose Compared With Prescription- Dose Celecoxib on Upper Gastrointestinal Mucosal Injury JAMES M. SCHEIMAN,* BYRON CRYER, MICHAEL B. KIMMEY, RICHARD I. ROTHSTEIN, DENNIS S. RIFF, and MICHAEL M. WOLFE # *Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, Division of Gastroenterology, University of Texas Southwestern, Dallas Veteran Affairs Medical Center, Dallas, Texas; Division of Gastroenterology, University of Washington, Seattle, Washington; Dartmouth College, Hanover, New Hampshire; Associated Gastroenterology, Anaheim, California; and # Section of Gastroenterology, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts Background & Aims: Ibuprofen is a well-tolerated nonsteroidal anti-inflammatory drug (NSAID), particularly at over-the-counter (OTC) doses. Cyclooxygenase 2 (COX- 2) selective inhibitors cause less ulceration than prescription-dose nonselective NSAIDs. We compared endoscopic injury related to nonprescription ibuprofen doses with celecoxib, also comparing prescription doses of naproxen with placebo as a positive control. Methods: The study was a randomized, placebo-controlled, double blind, double-dummy endoscopic evaluation with concealed allocation. A 2-way crossover with a 4 5-week washout period was used. Participants were healthy adults with normal baseline findings from endoscopy. Ninety-five subjects were randomly assigned, and 79 subjects completed both study phases. Age distribution was reflective of the target population of the OTC agent. Twenty percent were infected with Helicobacter pylori, and 79% and 67% had a current or past medical problem, respectively. Qualifying subjects, stratified by the presence or absence of H. pylori infection (n 20), were randomly assigned to 1 of the 4 sequences (phase I/II) as follows: ibuprofen/celecoxib; celecoxib/ibuprofen, naproxen/placebo, or placebo/naproxen. Primary end points were the frequency of endoscopic ulcers and erosions in the groups administered: (1) celecoxib vs. ibuprofen and (2) naproxen vs. placebo. Results: In celecoxibtreated subjects, 2.6% developed ulcers compared with 17.9% of those treated with ibuprofen (P 0.056). Naproxen treatment was associated with a significantly greater ulceration rate compared with placebo. Conclusions: Short-term use of the nonselective COX inhibitors ibuprofen and naproxen is associated with a greater risk for endoscopic mucosal injury compared with the COX- 2 selective inhibitor celecoxib or placebo. A prospective analysis appropriately powered to address the incidence of clinically significant gastroduodenal ulceration associated with the short-term use of these agents would be required to further define the clinical relevance of these findings. Over-the-counter (OTC) ibuprofen (200 mg), available as a Liqui-Gel (Wyeth Consumer Healthcare, Madison, NJ) (solubilized potassium ibuprofen) or tablet, is an approved nonprescription analgesic and antipyretic. In a study requested by the U.S. Food and Drug Administration (FDA), the frequency of gastrointestinal (GI) adverse experiences and positive occult blood test results during treatment with the maximum labeled dose (1200 mg/d for 10 consecutive days) was similar among subjects administered ibuprofen liquigel and film-coated ibuprofen tablets. 1 Both ibuprofen preparations were indistinguishable from placebo for these end points. Ibuprofen is among the best-tolerated nonsteroidal anti-inflammatory drugs (NSAIDs), particularly at OTC doses. No significant difference between ibuprofen, 1200 mg, and placebo on the appearance of gastric mucosa was seen in a 7-day endoscopy study. 2 In a large database study, Strom et al. 3 found that the frequency of hospitalization for upper-gi bleeding during the first 2 weeks of prescription ibuprofen use was 0.013%, similar to the background frequency of GI bleeding in the study population. In a recent large meta-analysis of dose-response relationships among individual NSAIDs, ibuprofen showed the lowest odds ratio of 1.7 (95% confidence interval [CI ], ) for bleeding risk. 4 In that analysis, doses 1200 mg/d were associated with an odds ratio of 1.1 (95% CI, ), and mg/d, with an odds ratio of 1.8 (95% CI, ). A recent Abbreviations used in this paper: AE, adverse event; CI, confidence interval; COX-2, cyclooxygenase isoenzyme 2; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug; OTC, over the counter by the American Gastroenterological Association /04/$30.00 PII: /S (04)

2 April 2004 OTC IBUPROFEN COMPARED WITH CELECOXIB 291 study of 2000 patients administered the medications for 10 days showed that 1200 mg of ibuprofen was associated with adverse symptom profiles and rates of positive occult blood test results in stool similar to those for celecoxib, 200 mg/d. 5 It has been theorized that the deleterious GI effects of prescription-dose NSAIDs are related to inhibition of cyclooxygenase isoenzyme 1 (COX-1), whereas the antiinflammatory effects of NSAIDs are believed to be a function of inhibition of the COX-2 congener. 6 Based on this proposed mechanism of action, the new COX-2 selective inhibitors are widely perceived to be safer than nonspecific NSAIDs with regard to GI ulcers and their complications. Celecoxib was the first COX-2 selective inhibitor introduced in the United States. Although endoscopic data showed that celecoxib was associated with less GI ulceration than prescription-dose nonselective NSAIDs, the FDA ruled that labeling for celecoxib include the GI toxicity class warning for NSAIDs. 6 This decision was rendered because of insufficient data on clinical outcome measures, such as frequency of GI bleeding. Subsequent outcome studies failed to change class labeling for the GI safety of celecoxib. 7 To date, there are no studies in the literature directly comparing GI tolerability, measured by endoscopy, of celecoxib with nonprescription does of such NSAIDs as ibuprofen. This study is designed to directly compare the effects of ibuprofen, 1200 mg/d, and celecoxib, 200 mg/d, on the mucosa of the stomach and duodenum in a cohort of typical OTC analgesic users when administered during a 10-day period. From a clinical standpoint, this maximal OTC exposure to ibuprofen Liqui-Gels would, in theory, provide evidence of the relative safety of ibuprofen compared with celecoxib for short-term use. Like ibuprofen, naproxen is a nonselective COX-1/COX-2 inhibitor and typically is administered as a prescription medication at a dose of 1000 mg/d. Using a placebo-controlled design, naproxen was included as a positive control, given its well-characterized GI toxicity profile when administered at prescription doses of 1000 mg/d. 4 Methods The objective of this study was to evaluate the endoscopic appearance of the gastric and duodenal mucosae in healthy human volunteers administered ibuprofen, 200-mg Liqui-Gels, at the maximum labeled OTC dose (1200 mg/d for 10 days) compared with celecoxib, 200 mg/d, for 10 days. After a washout period, subjects crossed over to naproxen, 1000 mg/d (500 mg twice daily) or placebo for 10 days. The order of medication allocated was randomly assigned within each study period. Table 1. Study Design Sequence Phase I Phase II No. of subjects 1 Ibuprofen Celecoxib 20 2 Celecoxib Ibuprofen 20 3 Naproxen Placebo 20 4 Placebo Naproxen 20 The specific hypothesis is that the proportion of subjects with endoscopic ulcer(s) 5 mm in diameter administered maximum ibuprofen, 1200 mg/d, would be the same as that for celecoxib, 200 mg/d, for 10 days. The design is a multicenter, outpatient, randomized, double blind, placebo-controlled, double-dummy, 2-way crossover study with a 4 5-week washout period. Eighty subjects were required to complete this study. To recruit a population that represented the age distribution of the OTC analgesic consumer population, approximately 20% of subjects were 65 years, 50% were aged years, and 30% were aged years. Subjects underwent screening (within 14 days of performing the phase I baseline endoscopy) that included providing informed consent; medical history, physical examination, and laboratory testing (complete blood count and SMA-21). A carbon 13 urea blood test (EZ-HBT for determination of the presence or absence of Helicobacter pylori; Metabolic Solutions Inc., Nashua, NH) was performed. Subjects meeting all inclusion and exclusion criteria underwent a baseline esophagogastoduodenoscopy on day 0, at which time they must have had a normal mucosal appearance without erosions and/or ulcerations to continue in the study. All female subjects had to have a negative result of a pregnancy test performed day 0 before the baseline endoscopy. Subjects were stratified by the presence or absence of H pylori infection. Qualifying subjects were randomly assigned to 1 of 4 sequences in a 1:1:1:1 ratio, as listed in Table 1. During each phase of the study, subjects were required to take 3 doses/d of study medication at approximately 8:00 A.M., 2:00 P.M., and 8:00 P.M. for 10 days. Dosing began on the morning of the next calendar day after the baseline endoscopy (day 0). On the morning of day 11 of each study phase, subjects returned to the study center and underwent a follow-up physical examination and endoscopy. Subjects who discontinued prematurely from the study underwent an endof-study physical examination and endoscopy as soon as possible after discontinuing the study medication. A 4 5-week washout period was required between treatment phases I and II. Subjects who had erosions and/or ulcerations of any size at the end of phase I were treated as follows: subjects abstained from using NSAIDs and underwent a 4-week course of treatment with a proton pump inhibitor, with follow-up endoscopy performed at 6 7 weeks. If the lesions resolved, the subject proceeded to phase II of the study. If a mucosal lesion persisted after this regimen, they were terminated from the study and received appropriate follow-up. For subjects who had erosions and/or ulcerations at the end of phase II, treatment was at the discretion of the investigator.

3 292 SCHEIMAN ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 4 All subjects were required to abstain from consuming alcoholic beverages during the study, including the washout period. Subjects were required to abstain from taking NSAIDs for 2 weeks (or 6 half-lives, whichever was longer) before and during the study, including the 4 5-week washout period. Acetaminophen, 325 mg, was provided to subjects during the study in the event they experienced pain and/or fever unrelieved by study medications. Individuals were not eligible for participation in this study if any of the following were noted: abnormal (1.5 normal range) clinical laboratory findings at screening; a history of peptic ulcer or GI complications (such as bleeding, perforation, obstruction, or gastroesophageal reflux); women who were pregnant, nursing, or of childbearing potential or postmenopausal for 2 years and not using a medically approved method of contraception; presence of a serious medical condition or hypersensitivity to celecoxib or any other NSAID; a history of any illness that might increase the risks associated with performing an esophagogastoduodenoscopy (e.g., malignancy, coagulopathy, or cardiopulmonary or renal disease); history of poorly controlled hypertension, chronic hepatic disease, collagen vascular disease, or endocrinopathies; use of anticoagulant or antiplatelet drugs within the past 30 days; history of alcohol abuse ( 3 drinks/d) or drug dependency; use of any systemic steroids or antibiotic within the past 14 days; use of any antineoplastic/antimetabolic agent within the past 3 months; use of any analgesic (OTC or prescription) other than acetaminophen within the past 14 days (a 4-week washout period of discontinued aspirin use before study entry was allowed if medically appropriate); or use of any medication (prescription or OTC) that would influence the gastric or duodenal mucosa (e.g., histamine 2 blockers, proton pump inhibitors, antacids, antiulcer drugs, motility-altering agents, or ulcerogenic medications) within 6 half-lives or a minimum of 7 days before study entry. At each of the 4 endoscopies, all abnormalities were noted and recorded on a standardized form. The gastric and duodenal mucosae were graded separately for the presence and numbers of erosions and/or ulcers. Lesion diameter was measured as the widest distance across the lesion using the tip-to-tip distance of opened endoscopy forceps as a reference. Ulcers are defined as a break in the mucosa 5 mm, with erosions defined as smaller mucosal breaks. This rigorous size definition for an ulcer was chosen to provide data of greater potential clinical relevance than a 3-mm ulcer end point. Each subject received a diary at the beginning of each phase of the study in which they recorded the date, time, and number of capsules taken, as well as other concomitant medications, and any adverse reactions. Subjects were asked if they consumed any alcohol. A compliance assessment and diary review was performed at the day-11 visit of each treatment phase. The following definitions were used to grade the severity of adverse experiences. Mild is defined as asymptomatic or aware of symptom that is easily tolerated; moderate, symptom interferes with usual activity; and severe, incapacitation with inability to perform usual activity. Predefined definitions for causality for adverse events (AEs) included definite, probable, possible, remote, and unrelated and were determined by the investigators before breaking the study blind. This study was approved by the institutional review boards of each study site. Statistical Methods and Data Handling Statistical analysis (pairwise comparisons of naproxen vs. placebo and ibuprofen vs. celecoxib) of the incidence and number of ulcers and/or erosions was based on within-subject differences in the respective response. These differences were subjected to the Cochran-Mantel-Haenzel row mean test using table scores, stratifying by the presence or absence of H. pylori infection. 8 Statistical analysis of each variable (dichotomous, including incidence of AEs, and count data) assumed no carry-over effect of treatments. All analyses were based on within-subject differences (i.e., [phase II phase I] difference), and except for the AE analysis, were stratified by the presence or absence of H. pylori infection. All AEs were summarized by COSTART term and body system and subsequently summarized according to their severity (mild, moderate, or severe) and relationship (possibly, probably, definitely, remote, or none) to study medication. For the summary by severity, subjects who had multiple occurrences of the same AE were classified according to the worst reported severity of the AE. The study is designed to compare the frequency of endoscopic ulcers in the groups administered: (1) celecoxib vs. ibuprofen and (2) naproxen vs. placebo. The validity of the study would be considered shown only if the naproxen vs. placebo comparison was significant. All computations were performed using SAS, version 6.12 (SAS Institute, Cary, NC). All between-treatment tests were 2 sided. Power calculation. This design with 80 subjects provided at least 80% power to detect a treatment difference between ibuprofen and celecoxib and between naproxen and placebo, assuming a 2% ulcer rate with celecoxib and placebo and the ulcer rate with ibuprofen and naproxen would be 15% greater than the rate for their respective control, with an intraclass correlation of 0.5. Results Demographic Data A total of 95 subjects were randomly assigned. Seventy-nine subjects who completed both study phases had endoscopic data evaluated, and 77 subjects completed both phases per protocol. Demographic data for 93 subjects with endoscopy data for at least 1 period from the intent-to-treat cohort are listed in Table 2. There were equal numbers of men and women, and 68% of subjects were white. Age distribution was per protocol, reflective of the target population of the OTC agent. Eighteen percent were infected with H. pylori, and 78%

4 April 2004 OTC IBUPROFEN COMPARED WITH CELECOXIB 293 Table 2. Demographic Data Overall total (N 93) NAP/PBO (N 21) NAP and PBO PBO/NAP (N 23) Total (N 44) IBU/CLBX (N 26) IBU and CLBX CLBX/IBU (N 23) Total (N 49) Sex Male 49 (52.7) 9 (42.9) 13 (56.5) 22 (50.0) 18 (69.2) 9 (39.1) 27 (55.1) Female 44 (47.3) Race White 64 (68.8) 15 (71.4) 16 (69.6) 31 (70.5) 18 (69.2) 15 (65.2) 33 (67.3) Black 18 (19.4) 4 (19.0) 5 (21.7) 9 (20.5) 5 (19.2) 4 (17.4) 9 (18.4) Asian 4 (4.3) 0 (0.0) 1 (4.3) 1 (2.3) 0 (0.0) 3 (13.0) 3 (6.1) Hispanic 7 (7.5) 2 (9.5) 1 (4.3) 3 (6.8) 3 (11.5) 1 (4.3) 4 (8.2) Age (yr) (32.3) 10 (47.6) 9 (39.1) 19 (43.2) 6 (23.1) 5 (21.7) 11 (22.4) (51.6) 9 (42.9) 8 (34.8) 17 (38.6) 18 (69.2) 13 (56.5) 31 (63.3) (16.1) 2 (9.5) 6 (26.1) 8 (18.2) 2 (7.7) 5 (21.7) 7 (14.3) Mean SD Median Range Past medical conditions Yes 63 (67.7) 14 (66.7) 12 (52.2) 26 (59.1) 19 (73.1) 18 (78.3) 37 (75.5) No 30 (32.3) 7 (33.3) 11 (47.8) 18 (40.9) 7 (26.9) 5 (21.7) 12 (24.5) Current medical conditions Yes 72 (77.4) 13 (61.9) 19 (82.6) 32 (72.7) 22 (84.6) 18 (78.3) 40 (81.6) No 21 (22.6) 8 (38.1) 4 (17.4) 12 (27.3) 4 (15.4) 5 (21.7) 9 (18.4) H. pylori status Positive 17 (18.3) 3 (14.3) 3 (13.0) 6 (13.6) 7 (26.9) 4 (17.4) 11 (22.4) Negative 76 (81.7) 18 (85.7) 20 (87.0) 38 (86.4) 19 (73.1) 19 (82.6) 38 (77.6) NOTE. Total doses: ibuprofen Liqui-Gels, 1200 mg/d; celecoxib, 200 mg/d; naproxen, 1000 mg/d; during 10 consecutive days. Values expressed as number (percent) unless noted otherwise. IBU, ibuprofen Liqui-Gels; CLBX; Celecoxib; NAP, naproxen; PBO, placebo. a P from the Cochran-Mantel Haenszel test, controlling for site and H. pylori status. P a and 68% had some current or past medical problem that did not mandate exclusion from the study, respectively. Endoscopic Findings The incidence of endoscopic ulcers ( 5 mm) and erosions for subjects administered each drug is shown in Figures 1 and 2. In celecoxib-treated subjects, 2.6% developed ulcers compared with 17.9% of ibuprofentreated subjects (P 0.056). The incidence of erosions also was greater with ibuprofen (23%) compared with celecoxib (P 0.052). Although the incidence of ulcers was greater in the H. pylori positive (5 of 17 subjects) than H. pylori negative volunteers (17 of 76 subjects), this difference did not reach statistical significance. When the analysis was repeated post hoc without stratification for H. pylori infection, the ulcer incidence between ibuprofen and celecoxib reached statistical significance (P 0.036). Naproxen was associated with a 25% incidence of ulcers, significantly greater than placebo (2.5%; P 0.01). The incidence of erosions followed the same pattern as ulcers, with the frequency significantly greater for naproxen compared with placebo. When ex- Figure 1. Incidence of endoscopic ulcers in patients administered placebo; naproxen, 1000 mg/d; ibuprofen, 1200 mg/d; and celecoxib, 200 mg/d. Values shown as mean SE. *P 0.01 vs. placebo. #P vs. celecoxib. Figure 2. Incidence of erosions in patients administered placebo; naproxen, 1000 mg/d; ibuprofen, 1200 mg/d; and celecoxib, 200 mg/d. Values shown as mean SE. *P 0.01 vs. placebo. #P vs. celecoxib.

5 294 SCHEIMAN ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 2, No. 4 amining the number of ulcers and erosions (Tables 3 and 4), a pattern similar to that of the incidence data was observed. Adverse Experiences There were 3 study discontinuations caused by AEs; 1 discontinuation was caused by GI symptoms, believed to be possibly related to the medication (placebo) by the investigator. An adverse symptom was reported by 50% of those administered placebo, 62.5% of those administered naproxen, 56.4% of those administered ibuprofen, and 48.7% of those administered celecoxib. These differences were not statistically significantly different for naproxen vs. placebo or ibuprofen vs. celecoxib. Across treatment periods, the only adverse experience difference to reach statistical significance was the incidence of nausea in ibuprofen-treated compared with celecoxib-treated subjects (10.3% vs. 0%; P 0.05). Discussion Results of this endoscopic comparison show that the nonselective COX inhibitors are associated with a clinically significant greater likelihood of endoscopic injury compared with celecoxib and placebo. The borderline statistical significance between the incidence of ulcers and erosions in the celecoxib and ibuprofen groups likely is caused by study size, given our design that anticipated a similar degree of endoscopic damage. The number of ulcers or erosions did not show statistically significant differences among treatments in this study, although these data showed trends similar to the incidence data. Our observations confirm that the OTC dose of ibuprofen is associated with less endoscopic ulceration compared with greater prescription doses (2400 mg) when our data are compared with published trials examining celecoxib and rofecoxib. 9,10 The incidence of ulcers in those studies at the 2400-mg dose of ibuprofen at 6 weeks (20% 25%) is consistent with the expected doserelated impact of nonselective COX inhibition on the proximal GI mucosa. Although our study was of shorter duration, the impact of its brevity on the incidence of Table 3. Number of Ulcers Placebo Naproxen Ibuprofen Celecoxib No. of subjects Mean no. of ulcers/subject Range NOTE. Total doses: ibuprofen, 1200 mg/d; celecoxib, 200 mg/d; naproxen, 1000 mg/d; during 10 consecutive days. Table 4. Number of Erosions Placebo Naproxen Ibuprofen Celecoxib No. of subjects Mean no. of erosions/subject Range NOTE. Total doses: ibuprofen, 1200 mg/d; celecoxib, 200 mg/d; naproxen, 1000 mg/d; during 10 consecutive days. ulcers is unknown. Previous animal and human endoscopic studies have shown an adaptive process, in which the rate of mucosal injury decreases with time. 11 Thus, our short-term study may account, in part, for the increased incidence of injury detected in patients treated with low-dose ibuprofen. Consistent with previously published longer term studies is our observation that the rate of injury was low with both placebo and celecoxib and higher with prescription doses of naproxen. 12 Our definition of an endoscopic ulcer is a mucosal break 5 mm. Although other investigators have chosen to include depth in the definition, this distinction is artificial, with size a more reproducible definition, and typically is used by such regulatory agencies as the FDA. Although the incidence of endoscopic ulcers we observed at 10 days may seem high, particularly for naproxen, other investigators have observed an endoscopic ulcer incidence as high as 44% at 1 week at this dose. 13 How can these endoscopic findings be reconciled with the strong body of data supporting the long-term safety of ibuprofen, particularly at a low dose? 4,13 Although it is clear that ibuprofen possesses a strong safety profile compared with other NSAIDs, our data remain consistent with the literature in that the injury we observed in this study, despite the low dose, likely was a consequence of prostaglandin inhibition caused by nonselective COX inhibition. Our observations further suggest that results of endoscopic studies cannot be directly extrapolated to clinically relevant outcomes. Although previous studies have documented a significantly reduced rate of endoscopic ulcers with the use of COX-2 selective agents compared with nonselective COX inhibitors, results of prospective outcome analyses have yielded mixed results. 14 In the VIGOR (Vioxx GI Outcomes Research) trial, a 54% reduction in clinically relevant ulcers was shown with the use of rofecoxib in comparison to naproxen in patients with rheumatoid arthritis. 15 Conversely, the CLASS (Celecoxib Long-Term Arthritis Safety Study) study failed to show a significant reduction in ulcer complications with the use of celecoxib compared with prescription doses (2.4 g/d) of ibuprofen in patients with osteoarthritis or rheumatoid arthritis. 7,16 Therefore, any extrapolation from the differences ob-

6 April 2004 OTC IBUPROFEN COMPARED WITH CELECOXIB 295 served in the present study to clinically relevant events certainly is problematic. A prospective analysis designed and appropriately powered to address the question of the safety of low-dose short-term use of nonselective COX inhibitors would be required. Another explanation for the differences we observed in endoscopic findings and results of epidemiological studies supportive of ibuprofen safety may reflect the effects of doses used outside clinical trials. Patient compliance with a thrice-daily medication is unlikely to be complete, and in the OTC setting, intermittent dosing likely may lead to recovery of the endoscopic injury we observed before it progresses to endoscopic ulceration. The side effects observed in this endoscopic comparison were mild, and the single observation of significance, more nausea in the ibuprofen vs. celecoxib groups, is consistent with other studies showing modest reductions in bothersome GI symptoms with coxibs compared with traditional NSAIDs. 17 The clinical importance of these modest differences is uncertain, but suggests that even OTC doses of NSAIDs can be associated with these annoying GI symptoms. However, the true frequency of dyspepsia caused by NSAIDs has been difficult to measure. 18 Given the recent randomized placebo-controlled trial that failed to discern clinically meaningful differences in the tolerability of ibuprofen compared with celecoxib or placebo during a 10-day period, the external validity of this result is questionable. In conclusion, OTC doses of ibuprofen are associated with measurable endoscopic injury, significantly greater than that for placebo and celecoxib. Albeit well-tolerated and safe for short-term use, long-term use and use with other anti-inflammatory agents, either prescription or OTC, may be expected to lead to clinically significant ulceration and the risk for ulcer complications. Our data should lead to appropriate caution for both patients and providers when using this OTC product. References 1. Doyle G, Furey S, Berlin R, Cooper S, Jayawardena S, Ashraf E, Baird L. Gastrointestinal safety and tolerance of ibuprofen at maximum over-the-counter doses. Aliment Pharmacol Ther 1999; 13: Lanza F, Royer G, Nelson R. An endoscopic evaluation of the effects of nonsteroidal anti-inflammatory drugs on the gastric mucosa. Gastrointest Endosc 1975;21: Strom BL, Schinnar R, Bilker WB, Feldman H, Farrar JT, Carson JL. Gastrointestinal tract bleeding associated with naproxen sodium vs ibuprofen. Arch Intern Med 1997;157: Lewis SC, Langman MJ, Laporte JR, Matthews JN, Rawlins MD, Wiholm BE. 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: Ashraf E, Cooper S, Marinucci L, Doyle G, Berlin R. GI safety of a non-selective NSAID vs a COX-2 inhibitor: equivalency of ibuprofen and celecoxib in an OTC setting (abstr). Am J Gastroenterol 2002;97(suppl):S Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340: Scheiman JM. Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors. Cleve Clin J Med 2002;69(suppl): SI40 SI Tudor G, Koch GG. Review of nonparametric methods for the analysis of crossover studies. Stat Methods Med Res 1994;3: Hawkey C, Laine L, Simon T, Beaulieu A, Maldonado-Cocco J, Acevedo E, Shahane A, Quan H, Bolognese J, Mortensen E. Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on patients with osteoarthritis. Arthritis Rheum 2000;43: Deeks J, Smith L, Bradley M. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomized controlled trails. BMJ 2002;325: Graham DY, Smith JL, Spjut HJ, Torres E. Gastric adaptation: studies in humans during continuous aspirin administration. Gastroenterology 1988;95: Hernandez S, Rodriguez LAG. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation. Arch Intern Med 2000;160: Laine L, Sloane R, Ferretti M, Cominelli F. A randomized, doubleblind comparison of placbo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production. Gastrointest Endosc 1995;42: Laine L, Harper S, Simon T, Bath R, Johanson J, Schwartz H, Stern S, Quan H, Bolognese J. 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: Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343: 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: Watson DJ, Harper SE, Peng-Liang Z, Quan H, Bolognese JA, Simon TJ. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor refecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis. Arch Intern Med 2000;160: Jones RH. Gastrointestinal side-effects of NSAIDs in the community. Br J Clin Practice 1995;49: Address requests for reprints to: James M. Scheiman, M.D., University of Michigan Medical Center, 3912 Taubman Center, Box 0362, Ann Arbor, Michigan jscheima@umich.edu; fax: (734) Supported in part by a grant from Wyeth Consumer Healthcare Products, Inc.