Clinical Context

One of the main goals in the care of patients with inflammatory bowel disease (IBD) is avoiding flares, which can result in substantial morbidity and disability. A number of different factors have been proposed as risk factors for IBD flares, but which of these variables actually makes a difference? A previous case-control study by Feagins and colleagues, published in the April 21, 2014, issue of the World Journal of Gastroenterology, answered this question.^[1]

Patients at a single Veterans Affairs medical center who had an IBD flare were compared with patients who had IBD that was in remission. The only variable associated with a higher risk for IBD flare was nonadherence to medication. Tobacco use, stress, antibiotic use, other infections, and travel were not significantly related to the risk for IBD flare.

Nonsteroidal anti-inflammatory drug (NSAID) use was also not significantly associated with the risk for IBD flare in this research, but the role of NSAIDs in promoting IBD flare has been controversial. The current study provides a nuanced analysis to inform this issue.

Study Synopsis and Perspective

A new study has found no convincing evidence to suggest a causal relationship between NSAID use and IBD exacerbations.

Rather, the study suggests that observed associations between IBD exacerbation and NSAID exposure may be explained by preexisting underlying risks for IBD flares, residual confounding, and reverse causality.

"We hope these study findings will aid providers in better directing IBD patients on their risk for IBD exacerbation with NSAID use," write Shirley Cohen-Mekelburg, MD, from the University of Michigan Medicine, Ann Arbor, and colleagues. "This may guide therapy for both IBD and non-IBD related pain management, and the comfort of patients with IBD and the clinicians who treat them when considering NSAIDs as a non-opioid treatment option," they add.

The study was published online in the American Journal of Gastroenterology.^[2]

Taking a Second Look

Patients with IBD (Crohn's disease and ulcerative colitis) are prone to both inflammatory and noninflammatory pain, and there has been long-standing concern that NSAIDs may play a role in disease flare-ups.

To see whether a true association exists, Dr Cohen-Mekelburg and colleagues conducted a series of studies that involved roughly 35,000 patients with IBD.

First, they created a propensity-matched cohort of 15,705 patients who had received NSAIDs and 19,326 who had not received NSAIDs. Findings from a Cox proportional hazards model suggested a higher likelihood of IBD exacerbation in the group that had received NSAIDs (hazard ratio [HR], 1.24; 95% CI, 1.16-1.33) after adjusting for age, sex, race, Charlson comorbidity index, smoking status, IBD type, and use of immunomodulator or biologic medications.

However, those who received NSAIDs were already at increased risk of experiencing a disease flare. In addition, the prior event rate ratio for IBD exacerbation, as determined by dividing the adjusted HR after NSAID exposure by the adjusted HR for pre-NSAID exposure, was 0.95 (95% CI, 0.89-1.01).

The researchers used a self-controlled case series to verify their findings and to adjust for other immeasurable patient-level confounders. In this analysis, which involved 3968 patients, the risk for IBD flare did not increase in the period from 2 weeks to 6 months after exposure to an NSAID.

The incidence of IBD exacerbations was higher in the 0- to 2-week transition period after an NSAID was prescribed, but it dropped after the 2-week "risk" window. This suggests that these short-term flares may be secondary to residual confounding related to reverse causality, rather than the NSAIDs themselves, the researchers say.

Although NSAIDs represent the most common first-line analgesic, their use for patients with IBD is variable, in part because of the suspected risk for IBD exacerbation, "despite inconclusive evidence of harm to date," Dr Cohen-Mekelburg and colleagues note.

They also note that about 37% of patients with IBD in their cohort received at least 1 NSAID prescription, and three-quarters of these patients did not experience an IBD exacerbation during an average of 5.9 years of follow-up.

Good Study, Reassuring Data

"This is a good study trying to understand the potential sources of bias in associations," Ashwin Ananthakrishnan, MD, MPH, from Massachusetts General Hospital and Harvard Medical School in Boston, Massachusetts, who was not involved in the study, told Medscape Medical News.

Overall, he said the study "provides reassurance that cautious, short-duration or low-dose use is likely well tolerated in most patients with IBD. But more work is needed to understand the impact of higher dose or more frequent use."

Also weighing in, Adam Steinlauf, MD, from Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York City, noted that patients with IBD experience pain throughout the course of their disease, both intestinal and extraintestinal.

"Treating the underlying IBD is important, but medications used to treat joint pain and inflammation specifically are few," said Dr Steinlauf, who was not involved in the new study.

"Sulfasalazine has been used with success, but it does not work in everyone, and many are allergic to the sulfa component, limiting its use. Narcotics are often reluctantly used for these issues as well. Medical marijuana has emerged on the scene to control both types of pain, but to date, there is inconclusive evidence that it significantly treats both pain and underlying inflammation," Dr Steinlauf pointed out.

NSAIDs, in contrast, are "excellent" choices for treating joint pain and inflammation, but gastroenterologists often try to avoid these medications, given the fear of triggering flares of underlying IBD, Dr Steinlauf told Medscape Medical News.

In his view, this new study is "important in that it quite elegantly challenges the notion that gastroenterologists should avoid NSAIDs in patients with IBD."

Although more data are needed, Dr Steinlauf said this study "should give practitioners a bit more confidence in prescribing NSAIDs for their patients with IBD if absolutely necessary to control pain and inflammation and improve quality of life when other standard treatments fail.

"The association of NSAIDs with subsequent flares...which we are all so well aware of and afraid of, may in fact be related more to our patients' underlying risks for IBD and reverse causality rather than the NSAIDs themselves. Future studies should further clarify this notion."

The study received no commercial funding. Dr Cohen-Mekelburg, Dr Ananthakrishnan, and Dr Steinlauf have disclosed no relevant financial relationships.

Am J Gastroenterol. Published online August 12, 2022.

Study Highlights

• Study data were drawn from the Veterans Affairs Corporate Data Warehouse. Researchers identified patients with a diagnosis of IBD between 2004 and 2015.
• The primary study variable was NSAID exposure (not including aspirin exposure). The study outcome was IBD exacerbation, which was defined as any outpatient IBD flare that required glucocorticoids, or hospitalization for flare.
• There were 2 study analyses. First, a cohort study was performed matching patients with IBD who were and were not prescribed NSAIDs. This analysis was adjusted to account for demographic and disease variables, as well as the treatment of IBD.
• Second, researchers examined the timing of exacerbation as related to NSAID prescriptions, with patients acting as their own control for periods when they were not receiving NSAIDs. Specifically, researchers were interested in the rate of IBD exacerbation during the 6 months after the NSAID prescription compared with the 6-month period before the prescription.
• 15,705 patients with IBD who received a prescription for NSAIDs were matched with 19,326 patients who did not receive NSAIDs; 93.2% of patients were male and 88.8% were White. The mean age of patients was 60 years.
• Ibuprofen or naproxen was the NSAIDs prescribed in 90% of cases.
• Patients who received NSAIDs were more likely to be younger, female, and White and have more comorbid illnesses.

Figure. Effect of NSAID Use on IBD Exacerbation

• The gross rates of IBD exacerbation in the NSAID and control groups were 53.6% and 46.4%, respectively. The adjusted hazard ratio for exacerbation in comparing the NSAID and control groups was 1.24 (95% CI, 1.16-1.33). However, patients receiving NSAIDs had a higher risk for exacerbation even before their prescription for NSAIDs.
• The incidence rates of exacerbation were similar in the pre-and postexposure periods in the analysis, using patients receiving NSAIDs as their own control. This finding was similar regardless of whether patients received ibuprofen or naproxen.

 

Clinical Implications

• In a previous study, the only variable associated with a higher risk for IBD flare was nonadherence to medication. Tobacco use, stress, antibiotic use, other infections, and travel were not significantly related to the risk for IBD flare.
• The current study suggests that NSAIDs do not cause exacerbation of IBD.

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