Tolerance of Nonsteroidal AntiinflammatoryDrugs in Patients With Inflammatory Bowel DiseaseGregory F. Bonner, M.D., Michelle Walczak, P.A., Laurel Kitchen, P.A., and Manuel Bayona, M.D., Ph.D.Department of Gastroenterology, Cleveland Clinic Florida and the School of Public Health,Nova-Southeastern University, Fort Lauderdale, Florida

OBJECTIVE: We sought to examine whether use of nonste-roidal antiinflammatory drugs (NSAIDs) in an outpatientinflammatory bowel disease (IBD) population is associatedwith an increased likelihood of active disease.

METHODS: We reviewed records of initial outpatient visitsof IBD patients to the principal author from June 1995 toDecember 1997, with regard to use of aspirin and otherNSAIDs and disease activity.

RESULTS: Of 40 Crohn’s patients seen with active disease,three (7.5%) were using NSAIDs; 14 of 72 (19.4%) Crohn’spatients seen with inactive disease were using NSAIDs.Fifty-eight ulcerative colitis patients were seen with activedisease, with eight (13.7%) using NSAIDs. Among 21 UCpatients initially seen while in remission, five (23.8%) wereusing NSAIDs.

CONCLUSIONS: Among this group of outpatients, NSAIDuse was not associated with a higher likelihood of activeIBD. NSAID use in IBD deserves further study beforerecommending that patients refrain from their use under allcircumstances. (Am J Gastroenterol 2000;95:1946–1948.© 2000 by Am. Coll. of Gastroenterology)

INTRODUCTION

Nonsteroidal antiinflammatory drugs (NSAIDs) have beenreported to cause initial onset of inflammatory bowel dis-ease (IBD) and to be associated with reactivation of quies-cent disease. This conclusion has been based largely on casereports and small series of patients (1–9). More recently,authors have noted a higher than expected use of NSAIDsamong patients admitted to the hospital for flares of IBD(10, 11). Subsequently, some physicians recommend thatIBD patients strictly avoid use of NSAIDs.

Our local patient population contains a substantial retire-ment community, including elderly IBD patients. Our gen-eral clinical impression was that NSAID use was relativelycommon and generally well tolerated.

It is not clear how NSAIDs would exacerbate IBD orunder what circumstances patients might be susceptible tothese adverse events. Prior reports, which focused on pa-tients hospitalized for flares of IBD, might be prejudiced bypatients with more severe IBD. It may be that patients with

less severe disease, as is encountered in the outpatient set-ting, may better tolerate NSAIDs. We examined the rela-tionship of NSAID use with disease activity among ouroutpatients with inflammatory bowel disease.

MATERIALS AND METHODS

Records of initial outpatient office visits of IBD patients toa single gastroenterologist, the principal author, from June1995 to December 1997 were retrospectively reviewed.General information obtained from the chart on each patientincluded age, gender, years since disease diagnosis, smok-ing and alcohol use, hormone replacement therapy for fe-males, and NSAID usage for all patients. Because of theretrospective nature of the study, a numerical disease activ-ity index had not been maintained. Disease activity wastherefore categorized only as active or inactive. A decisionto categorize disease activity as active was made by thesame gastroenterologist retrospectively reviewing the chart,with respect to the clinical impression recorded in therecord, symptoms of diarrhea and abdominal pain, and en-doscopic and radiographic studies, when available. Activedisease included mild, moderate, or severe disease, as wellas chronically active disease. Because it was not clearwhether NSAID use carried the same risk for different typesof IBD, Crohn’s disease patients and ulcerative colitis pa-tients were analyzed separately.

Statistical AnalysisEpi Info and SPSS statistical packages were used for dataanalysis (12, 13). Cases of active disease were compared tocontrols or inactive disease by using a case-control design.The odds ratio and the mean difference were used as mea-sures of association (14). The cornfield or the exact 95%confidence interval was calculated for the odds ratio, and thex2 or Fisher’s exact test was used to assess the statisticalsignificance of the odds ratio. Thet test or Wilcoxon testwas used to assess the significance of the mean difference(15).

RESULTS

There were 112 initial visits for patients with Crohn’s dis-ease and 80 initial visits for patients with ulcerative colitis.

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 95, No. 8, 2000© 2000 by Am. Coll. of Gastroenterology ISSN 0002-9270/00/$20.00Published by Elsevier Science Inc. PII S0002-9270(00)01055-8

Reflective of our elderly South Florida retirement commu-nity, the average age was 52.9 yr for Crohn’s patients and 61yr for ulcerative colitis patients. Among Crohn’s diseasepatients, 40 were seen with active disease and 72 withinactive disease. Sixty-one ulcerative colitis patients wereseen with active disease and 19 with inactive disease. Sev-enty-three Crohn’s disease and 36 ulcerative colitis patientswere women.

Use of NSAIDs among patients with active and inactiveCrohn’s disease is shown in Table 1. Table 2 provides thecorresponding data for patients with ulcerative colitis. Con-trary to what might have been expected, NSAID use wasactually more common among patients with inactive diseasefor both categories of IBD. For ulcerative colitis, NSAIDuse was only slightly more common among patients withinactive disease (21.1%), compared to active disease(14.8%). For Crohn’s disease patients, NSAID use wasmore than twice as common among patients with inactivedisease (19.4%), compared to those with active disease(7.5%). This suggestion of a protective effect for NSAIDuse was not statistically significant.

Several other factors were examined for possible corre-lation with disease activity. Gender, smoking, and alcoholuse were not found to correlate (data not shown). As shownin Tables 3 and 4, visits for active disease were associatedwith a younger patient age for both Crohn’s disease andulcerative colitis, although this difference reached statisticalsignificance only for Crohn’s disease. For both categories ofIBD, active disease visits were statistically associated withfewer years of disease duration.

It has previously been suggested that use of birth controlpills is associated with an increase in flares of IBD. Use ofbirth control pills was uncommon because of the age of ourpatient population. However, hormone replacement therapywas examined. As shown in Tables 3 and 4, use of hormonereplacement therapy was not associated with an increased

likelihood of active disease. The incidence of hormonereplacement therapy was actually slightly less commonamong active Crohn’s disease patients, but was not statis-tically significant. For ulcerative colitis, the use of hormonereplacement therapy was equivalent among patients withactive or inactive disease.

DISCUSSION

Contrary to prior studies, we did not find use of NSAIDs tobe associated with an increased risk of active inflammatorybowel disease. One possible explanation is that the associ-ation of NSAIDs leading to flares of IBD is simply over-stated. Case reports or series of just a few patients suggestbut do not prove association. However, the report of Evanset al. (10) was a case-control study of an entire geographicarea of more than 300,000 patients and also indicated thatuse of NSAIDs was associated with an increased likelihoodof hospitalization for IBD.

Another possible explanation is that not all patients withIBD are equally susceptible to NSAIDs. Some patients mayuse NSAIDs for IBD-associated arthralgias when their un-derlying bowel disease may already have begun to flare. IfNSAIDs do exert an adverse influence on IBD, it is not clearhow this would occur. NSAIDs suppress prostaglandin syn-thesis as well as exacerbate some experimental models ofcolitis (16). Most currently available NSAIDs are known toinhibit prostaglandin synthesis through both the COX-1 andCOX-2 isoforms of cyclooxygenase. COX-2 is generallyexpressed in low levels, except in sites of inflammation.COX-2 is expressed at increased levels in colonic mucosaboth in experimental colitis (16) and in colitis of IBD (17),and appears to have a beneficial effect in healing experi-mental colitis (16). Perhaps patients with active IBD andelevated COX-2 levels are susceptible to deterioration from

Table 2. NSAID Use Among Patients With Active andQuiescent Ulcerative Colitis

NSAIDUse

ActiveCases

InactiveCases

OddsRatio 95% C.I. p Value

Yes 9 (14.8%) 4 (21.1%) 0.65 0.15–3.31 0.50No 52 (85.2%) 15 (78.9%)

Abbreviations as in Table 1.

Table 1. NSAID Use Among Patients With Active andQuiescent Crohn’s Disease

NSAIDUse

ActiveCases

InactiveCases

OddsRatio 95% C.I. p Value

Yes 3 (7.5%) 14 (19.4%) 0.34 0.07–1.39 0.157No 37 (92.5%) 58 (80.6%)

NSAID 5 nonsteroidal antiinflammatory drugs; C.I.5 confidence interval.

Table 3. Relationship of Age, Hormone Replacement Therapy, and Years of Disease Duration With Regard to Disease ActivityAmong Crohn’s Disease Patients

Factor Active Cases Inactive Cases

Odds Ratioor Mean

Difference 95% C.I. p Value

Age, yr 45.8 56.9 11.1 0.001Hormone replacement

Yes 2 (8.7%) 14 (19.4%) 0.34 0.07–1.39 0.157No 21 (91.3%) 58 (80.6%)

Years of disease 11.3 18.2 6.9 0.004

C.I. 5 confidence interval.

1947AJG – August, 2000 Tolerance of NSAIDs in IBD Patients

use of NSAIDs, whereas those with quiescent disease oronly mildly active disease are not.

There are significant limitations that should be placed oninterpretation of the available data because of the retrospec-tive nature of this study. As no quantitative disease activityindex was kept, there is no way to exclude the possibility offlares associated with NSAID use being more serious thanflares among patients not using NSAIDs. Though the prin-ciple author would generally enquire regarding NSAID use,it is certainly possible with the retrospective nature of thisstudy that use of over-the-counter NSAIDs by some patientsmay not have been captured. It is also possible that some ofour patients with active IBD were selecting against the useof NSAIDs, having previously been informed of potentialadverse effects or having previously experienced problemswith use of NSAIDs. Nonetheless, the data indicate that—atleast for many patients—use of NSAIDs is not associatedwith activation of their IBD. NSAID use in IBD deservesfurther study before recommending that patients refrainfrom their use under all circumstances.

Reprint requests and correspondence:Gregory F. Bonner,M.D., Department of Gastroenterology, Cleveland Clinic Florida,3000 W. Cypress Creek Road, Ft. Lauderdale, FL 33309.

Received Dec. 10, 1998; accepted Mar. 3, 2000.

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Table 4. Relationships of Age, Hormone Replacement Therapy, and Years of Disease Duration With Regard to Disease ActivityAmong Ulcerative Colitis Patients

FactorActiveCases

InactiveCases

Odds Ratioor Mean

Difference 95% C.I. p Value

Age 60.1 64 3.92 0.15–3.31 0.474Hormone replacement

Yes 9 (33.3%) 3 (33.3%) 1.0 0.16–7.63 0.999No 18 (66.6%) 6 (66.7%)

Years of disease 9.93 13.47 3.54 0.036

C.I. 5 confidence interval.

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