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Meta-Analysis: Acetaminophen, NSAIDs Don't Consistently Worsen IBD
But authors stop short of recommending change in guidelines
by Diana Swift, Contributing Writer
May 02, 2018
A systematic review and meta-analysis has found no consistent overall association between worsening inflammatory bowel disease (IBD) and acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase 2 (COX-2) inhibitors.
The findings, published in Alimentary Pharmacology and Therapeutics, run contrary to prevailing thought that NSAIDs may exacerbate Crohn's disease (CD) and ulcerative colitis (UC). For example, the American College of Gastroenterology's guidelines for management of IBD recognize NSAIDs as potential triggers for disease exacerbation.
"Contrary to the general belief, we did not find a consistent association between use of NSAIDs and risk of IBD exacerbations," Hamed Khalili, MD, MPH, of Massachusetts General Hospital in Boston, told MedPage Today. "This was surprising to us as generally clinicians advise against use of NSAIDs in patients with established IBD. But we caution against any changes in current practice as significantly more work is required to examine the safety of acetaminophen and NSAIDs in patients with CD and UC."
He and his colleagues identified 18 heterogeneous English-language studies published from 1983 to 2016 and yielding inconsistent results on exacerbation with NSAIDs and acetaminophen. From these the team calculated pooled relative risk (RR) ratios. Study designs ranged widely, from cases and controls to retrospective and prospective cohorts and randomized and non-randomized clinical trials. Sample size also varied, from seven patients to 1,940, and drug exposures spanned periods of 15 days to 18 months. Exacerbation outcomes also varied, from emergency department admission to clinical relapse, and disease activity and endoscopic scores.
Not surprisingly, inter-study heterogeneity (I2) was significant, but showed no evidence of publication bias, the authors stated.
For NSAID use, the RR for exacerbation across studies was 1.42 (95% CI 0.65-3.09, I2=60.3%) for CD, while for UC it was 1.52 (95% CI 0.87-2.63, I2=56.1%).
The corresponding values for acetaminophen were 1.40 (95% CI 0.96-2.04, I2=45.6%) for UC and 1.56 (95% CI 1.22-1.99, I2=0.0%) for IBD.
"This study addresses one of the most common queries from IBD patients," Simon S.M. Chan, MD, PhD, from the University of East Anglia in Norwich, U.K.,who was not associated with the study, commented to MedPage Today. "The lack of associations between NSAIDs or COX-2 inhibitors and risk of CD and UC exacerbations in this meta-analysis, despite the existence of plausible biological mechanisms, brings into question the belief that these drugs increase the risk of inflammatory bowel disease flares. While this is reassuring, many of these were small in size and I would agree with the authors about the need for larger well-designed trials."
Among studies identified with a low risk of bias, Khalili's group did find an apparent associated risk with NSAIDs for CD only, with sensitivity analyses showing a significant risk of CD exacerbation (1.53, 95% CI 1.08-2.16) but not of UC exacerbation (0.94, 95% CI 0.36-2.42).
"Although it's well-established that NSAIDs may cause de novo damage throughout the gastrointestinal tract, the precise mechanism through which NSAIDs promote IBD exacerbation remains largely unknown," Khalili and associates wrote.
They explained that inhibition of intestinal prostaglandin synthesis through dual inactivation of COX-1 and COX-2 may be partly responsible for the worsening. "It is however unclear whether COX-1 inhibition is primarily responsible for mucosal injury and whether patients taking COX-2 inhibitors have a similar, potentially increased risk of exacerbation compared to those consuming nonselective NSAIDs," the team wrote, citing research by Hirofumi Matsui and colleagues.
Chan called the finding of an association of acetaminophen use with CD exacerbation in two studies "interesting, particularly as clinicians tend to favor this drug over NSAIDs or COX-2 inhibitors for pain relief in those with IBD," but added the called-for cautious interpretation since no association was found for UC.
"We recognize that IBD is a heterogeneous disease and therefore, there may be subgroups of patients particularly at risk of disease exacerbations with use of NSAIDs," Khalili and co-authors wrote. "Therefore, future studies focused on examining predictors of disease exacerbations/progression with use of NSAIDs are needed."
The researchers said they plan to design large prospective cohort studies that will systematically examine the link between IBD and the use of acetaminophen and NSAIDs, as well as aspirin.
Among the meta-analysis's limitations, the team said, were heterogeneity, especially different definitions of disease exacerbation, and the possibility of confounding by indication since some studies did not document the reason for specific drug use. Nor was the analysis necessarily powered to detect modest associations. In addition, since the only available studies were in English, the findings may not be generalizable to broader world populations.
But authors stop short of recommending change in guidelines
by Diana Swift, Contributing Writer
May 02, 2018
A systematic review and meta-analysis has found no consistent overall association between worsening inflammatory bowel disease (IBD) and acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase 2 (COX-2) inhibitors.
The findings, published in Alimentary Pharmacology and Therapeutics, run contrary to prevailing thought that NSAIDs may exacerbate Crohn's disease (CD) and ulcerative colitis (UC). For example, the American College of Gastroenterology's guidelines for management of IBD recognize NSAIDs as potential triggers for disease exacerbation.
"Contrary to the general belief, we did not find a consistent association between use of NSAIDs and risk of IBD exacerbations," Hamed Khalili, MD, MPH, of Massachusetts General Hospital in Boston, told MedPage Today. "This was surprising to us as generally clinicians advise against use of NSAIDs in patients with established IBD. But we caution against any changes in current practice as significantly more work is required to examine the safety of acetaminophen and NSAIDs in patients with CD and UC."
He and his colleagues identified 18 heterogeneous English-language studies published from 1983 to 2016 and yielding inconsistent results on exacerbation with NSAIDs and acetaminophen. From these the team calculated pooled relative risk (RR) ratios. Study designs ranged widely, from cases and controls to retrospective and prospective cohorts and randomized and non-randomized clinical trials. Sample size also varied, from seven patients to 1,940, and drug exposures spanned periods of 15 days to 18 months. Exacerbation outcomes also varied, from emergency department admission to clinical relapse, and disease activity and endoscopic scores.
Not surprisingly, inter-study heterogeneity (I2) was significant, but showed no evidence of publication bias, the authors stated.
For NSAID use, the RR for exacerbation across studies was 1.42 (95% CI 0.65-3.09, I2=60.3%) for CD, while for UC it was 1.52 (95% CI 0.87-2.63, I2=56.1%).
The corresponding values for acetaminophen were 1.40 (95% CI 0.96-2.04, I2=45.6%) for UC and 1.56 (95% CI 1.22-1.99, I2=0.0%) for IBD.
"This study addresses one of the most common queries from IBD patients," Simon S.M. Chan, MD, PhD, from the University of East Anglia in Norwich, U.K.,who was not associated with the study, commented to MedPage Today. "The lack of associations between NSAIDs or COX-2 inhibitors and risk of CD and UC exacerbations in this meta-analysis, despite the existence of plausible biological mechanisms, brings into question the belief that these drugs increase the risk of inflammatory bowel disease flares. While this is reassuring, many of these were small in size and I would agree with the authors about the need for larger well-designed trials."
Among studies identified with a low risk of bias, Khalili's group did find an apparent associated risk with NSAIDs for CD only, with sensitivity analyses showing a significant risk of CD exacerbation (1.53, 95% CI 1.08-2.16) but not of UC exacerbation (0.94, 95% CI 0.36-2.42).
"Although it's well-established that NSAIDs may cause de novo damage throughout the gastrointestinal tract, the precise mechanism through which NSAIDs promote IBD exacerbation remains largely unknown," Khalili and associates wrote.
They explained that inhibition of intestinal prostaglandin synthesis through dual inactivation of COX-1 and COX-2 may be partly responsible for the worsening. "It is however unclear whether COX-1 inhibition is primarily responsible for mucosal injury and whether patients taking COX-2 inhibitors have a similar, potentially increased risk of exacerbation compared to those consuming nonselective NSAIDs," the team wrote, citing research by Hirofumi Matsui and colleagues.
Chan called the finding of an association of acetaminophen use with CD exacerbation in two studies "interesting, particularly as clinicians tend to favor this drug over NSAIDs or COX-2 inhibitors for pain relief in those with IBD," but added the called-for cautious interpretation since no association was found for UC.
"We recognize that IBD is a heterogeneous disease and therefore, there may be subgroups of patients particularly at risk of disease exacerbations with use of NSAIDs," Khalili and co-authors wrote. "Therefore, future studies focused on examining predictors of disease exacerbations/progression with use of NSAIDs are needed."
The researchers said they plan to design large prospective cohort studies that will systematically examine the link between IBD and the use of acetaminophen and NSAIDs, as well as aspirin.
Among the meta-analysis's limitations, the team said, were heterogeneity, especially different definitions of disease exacerbation, and the possibility of confounding by indication since some studies did not document the reason for specific drug use. Nor was the analysis necessarily powered to detect modest associations. In addition, since the only available studies were in English, the findings may not be generalizable to broader world populations.
