Systematic Review With Meta-analysis

Association Between Acetaminophen and Nonsteroidal Anti–inflammatory Drugs (NSAIDs) and Risk of Crohn's Disease and Ulcerative Colitis Exacerbation

O. O. Moninuola; W. Milligan; P. Lochhead; H. Khalili


Aliment Pharmacol Ther. 2018;47(11):1428-1439. 

In This Article


In this systematic review and meta–analysis of prior studies, we found no consistent association between acetaminophen, NSAIDs or COX–2 inhibitor use and risk of CD and UC exacerbation. However, among studies with low risk of bias, NSAIDs use appeared to be associated with increased risk of exacerbation in CD, but not UC. Although we observed significant heterogeneity between the studies, likely due to variation in outcome ascertainment, we found no evidence for publication bias.

American College of Gastroenterology guidelines for management of IBD recognise NSAIDs as potential triggers for disease exacerbation, highlighting the ongoing concern regarding the use of these medications in patients with established disease.[41] Although, it's well–established that NSAIDs may cause de novo damage throughout the gastrointestinal tract,[42–45] the precise mechanism through which NSAIDs promote IBD exacerbation remains largely unknown. Prior studies have suggested that inhibition of intestinal prostaglandin synthesis due to dual inactivation of COX–1 and COX–2 enzyme isoforms may in part be responsible.[33,46] It is however unclear whether COX–1 inhibition is primarily responsible for mucosal injury and whether patients taking COX–2 inhibitors have similar potentially increased risk of exacerbation compared to those consuming nonselective NSAIDs.[47] In our systematic review, we did not see a consistent association between COX–2 inhibitors and risk of IBD exacerbation.

The observed heterogeneity in our analyses was likely due to variation in study design and outcome definition. For example, the less stringent case–control studies by Bonner et al.,[28] which included irritable bowel syndrome (IBS) patients as controls and utilised a subjective global assessment of disease activity, showed an inverse association between NSAIDs use and risk of CD exacerbation while studies by Evans et al,[6] Hensley et al[8] and Long et al,[9] which appeared to have the most rigorous study designs suggested a positive association. However, even in well–designed, studies, there were significant limitations in definition of outcomes. For example, in the study by Evans et al,[6] exacerbation was defined as emergency admission to hospital. This definition is unlikely to capture the majority of CD exacerbations that are managed in the out–patient settings.[48] In contrast, Hensley et al[8] and Long et al[9] utilised objective disease activity index to measure outcome, which may be a more sensitive method to capturing short term influence of NSAIDs on disease activity.

Our meta–analysis findings of no statistically significant association between NSAIDs use and risk of UC and IBD exacerbation, even among studies with low risk of bias, are in keeping with results of randomised controlled trials (RCT) by Sandborn et al and El Miedany et al, and systematic review works by Forrest et al and Kefalakes et al.[39,40,49,50] Similarly, our review of literature findings of inconsistent results with selective COX–2 use and IBD exacerbation are in keeping with conclusion from earlier systematic review by Miao et al,[51] with our work encompassing more articles. Interestingly, we did observe an association between acetaminophen use and risk of IBD exacerbation, although only two studies have previously examined such an association.

Our study has several strengths that are worth noting. First, this study followed the recommendations for rigorous systematic review and had a pre–defined and published protocol.[10,11,15] Second, to our knowledge, our study represents the most comprehensive evaluation to date of the association between acetaminophen, NSAIDs or COX–2 inhibitor use and risk of IBD exacerbation. Last, two independent reviewers undertook all stages of the data review process and we used an objective assessment to define low risk of bias studies.

We acknowledge several limitations. First, definitions of disease exacerbation varied widely across the studies, introducing significant heterogeneity. Second, confounding by indication may have biased the results of some of the included studies that did not routinely document information on the reason for acetaminophen, NSAIDs or COX–2 inhibitor use. Third, we acknowledge that our meta–analysis may have not been powered to detect modest associations. However, assuming that the prevalence of NSAIDs use is 40% among IBD patients,[9] and there is a 40% rate of IBD exacerbation among non–NSAIDs users,[52,53] we estimated that our meta–analysis had over 80% power to detect a minimum RR of 1.1 at a significance level of 0.05. We recognise that IBD is a heterogeneous disease and therefore, there may be subgroups of patients particularly at risk of disease exacerbations with use of NSAIDs. Therefore, future studies focused on examining predictors of disease exacerbations/progression with use of NSAIDs are needed. Lastly, our work was based on studies reported in English language and though we did not find any non–English reported studies, we acknowledge this may limit generalisability of our findings to populations in geographic regions not well represented by English language literature.