Tag Archives: NSAIDs

IBD Brief Updates: Anti-TNF Loss of Response, Upadacitinib for ASUC, Risk Factors for Developing IBD

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EHJ Savelkoul et al. Inflamm Bowel Dis 2023; 29: 1633-1647. Open Access! Systematic Review and Meta-analysis: Loss of Response and Need for Dose Escalation of Infliximab and Adalimumab in Ulcerative Colitis

Methods: A systematic search was conducted from August 1999 to July 2021 for studies (50 studies identified) reporting loss of response and dose escalation during infliximab and/or adalimumab use in ulcerative colitis patients with primary response

Key findings:

  • Annual loss of response was 10% for infliximab and 13% for adalimumab, with higher rates during the first year.
  • The annual LOR incidences were higher during the first 65 weeks of treatment for both IFX (14%) and ADA (23%).
  • Annual dose escalation rates were 14% (infliximab) and 21% (adalimumab), with clinical benefit in 72% and 52%, respectively

CH Zinger et al. Inflamm Bowel Dis 2023; 29: 1667-1669. Upadacitinib for Acute Severe Ulcerative Colitis

Key finding: 4 patients (age 18-25 yrs) received upadacitinib for acute severe ulcerative colitis (ASUC) after failing to respond to infliximab and IV steroids. 3 of 4 responded to treatment (45 mg/day) between 4 to 8 days. Three months later, two of these patients were in steroid-free clinical-endoscopic remission and one had maintained a clinical response.

In their discussion, the authors note a similar response rate to tofacitinib, another JAK inhibitor, for ASUC; though, the authors speculate that upadacitinib may be efficacious.

N Narula et al. Clin Gastroenterol Hepatol 2023; 21: 2649-2659. Associations of Antibiotics, Hormonal Therapies, Oral Contraceptives, and Long-Term NSAIDS With Inflammatory Bowel Disease: Results From the Prospective Urban Rural Epidemiology (PURE) Study

In a a prospective cohort study of 133,137 individuals between the ages of 20 and 80 from 24 countries, the authors examined the relationship between exposures to antibiotics, NSAIDs and hormonal therapies with the development of IBD over a median 11 year period.

Key findings:

  • Incident IBD was associated significantly with baseline antibiotic (aOR, 2.81; P = .0001) and hormonal medication use (aOR, 4.43; P = .001).
  • Nonsteroidal anti-inflammatory drug users also were observed to have increased odds of IBD (aOR, 1.80 P = .002), which was driven by long-term use (aOR, 5.58; P < .001)
Near Cassis, France

Rethinking the Link between NSAIDs and IBD Flares

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This is the 4000th blog post for GutsandGrowth!

S Cohen-Meckelburg et al. American Journal of Gastroenterology 2022: doi:10.14309/ajg.0000000000001932. The association between non-steroidal anti-inflammatory drug use and inflammatory bowel disease exacerbations: a true association or residual bias?

Background: NSAIDs are well-known to cause gastrointestinal injury. While single center studies have suggested that NSAIDs are associated with increased IBD flares, a systemic review of 18 studies found no consistent association between NSAIDs and IBD exacerbation.

This study included 15,705 (44.8%) and 19,326 (55.2%) IBD patients with and without an NSAID exposure.

Key findings:

  • Findings from a Cox proportional hazards model suggest an association between NSAIDs and IBD exacerbation (HR 1.24; 95%CI 1.16-1.33)
  • However, the likelihood of an IBD exacerbation in the NSAID exposed arm preceding NSAID exposure was similar (HR 1.30; 95%CI 1.21-1.39).
  • Those who received NSAIDs were already at increased risk of experiencing a disease flare. And 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).
  • “A self-controlled case series analysis of 3,968 patients who had both an NSAID exposure and IBD exacerbation demonstrated similar exacerbation rates in the 1-year preceding exposure, 2-6 weeks post-exposure, and 6-weeks to 6-months post-exposure, but higher incidence 0-2 weeks post-exposure, suggesting potential confounding by reverse causality.” The self-controlled part of the study allowed patients to serve as their own controls which allowed adjustment for many factors that are difficult to control with retrospective studies.
  • 75% of patients with IBD who were prescribed an NSAID did not have an IBD exacerbation during a mean of 5.9 years of follow-up
  • NSAIDs were commonly used: 36.5% of patients with IBD had received at least one NSAID prescription
  • NSAIDs use was prescribed more frequently in patients with immune targeted therapy (likely a marker for moderate to severe disease)

Discussion points:

  • The estimated prior event ratio of 0.95 suggests that the risk of IBD flares in NSAID-exposed patients preceded the use of NSAIDs. The risk of IBD exacerbation did not increase in the 2 weeks to 6 months after NSAID exposure.
  • The overall association of increased IBD flare is likely related to reverse causation. Patients may take NSAIDs due to arthropathy or other symptoms that may be an early manifestation of a flare.

My take: This study challenges the prevailing view that NSAID use worsen inflammatory bowel disease; it is more likely that IBD exacerbations are due to underlying risk from more severe disease and residual confounding/reverse causality. The study provides reassurance that short-duration use is likely to be well-tolerated in most patients with IBD.

Medscape Gastroenterology (summary of this study): Reassuring Data on NSAIDs in IBD Flares

Mt Hood (picture from a friend)

Nonsteroidal Analgesics and Risk of Empyema

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A recent study (M Le Bourgeois et al. J Pediatr 2016; 175: 47-53) from 15 medical centers in France showed an association between nonsteroidal anti-inflammatory drugs (NSAIDs) and the development of empyema.

Methods: a case-control design with 83 cases of children with empyema and recent acute viral infection (w/in 15 days) and 83 controls who had recent acute viral infection but no emyema. Age range: 3 months-15 years.  To ascertain the underlying initial viral etiology, the investigators utilized molecular techniques and identified respiratory viruses in about half of both groups of children.

Key finding: Exposure to NSAIDs was associated with a modest increase in the rate of empyema (aOR 2.79).  The risk of empyema associated with NSAIDs was diminished if the  child had been prescribed an antibiotic.

My take: This study, by minimizing confounding factors, suggests that the casual use of NSAIDs during acute viral illnesses increases the chance of developing empyema.

 

Grinnell Glacier, Glacier Nat'l Park

Grinnell Glacier, Glacier Nat’l Park

 

Using NSAIDs After Tonsillectomy & More on Coffee

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Many times all of the treatment choices are flawed and choosing the least worst option is required.  A recent study (Kelly LE et al. Pediatrics 2015; 135: 307-13) helps provide some useful data regarding pain management in the setting of tonsillectomy.  I chose to highlight this study because the findings seem at odds with what I would have predicted; that is, I was surprised that, in this small study, use of ibuprofen was not associated with increased bleeding risk.

Background: More than 500,000 tonsillectomies are performed on pediatric patients each year in the U.S.  Pain control afterwards has been problematic.  Codeine-containing products now have a black-box warning for post-tonsillectomy analgesia due to risk of life-threatening respiratory failure.  So choosing between a different narcotic agent like morphine or using a nonsteroidal anti-inflammatory drug (NSAID) which could contribute to bleeding is not clear cut.  While morphine’s metabolism is more predictable than codeine, all narcotics have the potential to suppress breathing.  In addition, patients undergoing tonsillectomy have a higher risk of breathing abnormalities than the general population.

Design: Randomized control trial with 91 children aged 1 to 10 years.

Key findings:

  • No significant difference in reported pain control
  • Similar frequency of tonsillar bleeing –3 in children with ibuprofen and 2 who received morphine.
  • Children in the ibuprofen group were much more likely to see an improvement in oxygen desaturations on the first postoperative night: 68% compared to 14%.
  • One child in the morphine group had a severe drug reaction requiring admittance to the intensive care unit.

Take-home point: The researchers concluded that ibuprofen is as effective as and safer than morphine for post tonsillectomy analgesia in children, without a higher risk of bleeding.

Related blog posts:

More on coffee:

I often have discussed with families how coffee can improve bowel frequency.  Here is a link on that topic from Huffington Post:  “Why Does Coffee Make You Poop?”

Previous blogs on coffee:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

NSAIDs and IBD

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While data has shown that nonsteroidal antiinflammatory drugs (NSAIDs) may worsen established IBD, whether these medications may serve as a trigger for IBD is less clear. One recent study indicates that NSAIDs may raise the risk of developing IBD (Ann Intern Med 2012; 156: 350-9).

This study examined the risk by using data from the Nurses Health Study which included 76,795 women.  Aspirin and NSAID use were self-reported.

Results:

  • “123 incident cases of CD and 117 cases of UC occurred over 18 years and 1,295,317 person-years of follow-up”
  • Frequent NSAIDs users (at least 15 days per month) had “increased risk for both CD (absolute difference in age-adjusted incidence, 6 cases per 100,000 person-years [95% CI, 0 to 13]; multivariate hazard ratio, 1.59 [CI, 0.99 to 2.56])”
  • And “UC (absolute difference, 7 cases per 100,000 person-years [CI, 1 to 12]; multivariate hazard ratio, 1.87 [CI, 1.16 to 2.99])”
  • There was no association with acetaminophen or aspirin within the same cohort.  This lessens the possibility of a false association; if subjects were treating GI symptoms, it is likely that an association would have been seen with all analgesics

The authors conclude that any absolute risk is low and therefore more important in understanding mechanism rather than in altering clinical use of these medications.

Link to abstract: Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn …

Additional NSAID references:

  • Gastroenterol 1966; 51: 430.  Sentinel article describing NSAID GI risk.
  • Gastroenterol 2008; 134: 1224.  Use of NSAIDs and risk prevention.
  • Clin Gastro & Hep 2007; 5: 1040. Long term effects of NSAIDs similar to COX-2 selective agents on small bowel mucosal damage (62% had abnormalities vs 50% of COX-2)
  • Clin Gastro & Hep 2006; 4: 1082 & 1090. Consensus on gastroprotection with NSAIDs.
  • Clin Gastro & Hep 2006; 4: 196.  NSAIDs worsen IBD.
  • Clin Gastro & Hep 2003; 1: 160.  Ileitis due to NSAIDs.

Indomethacin to prevent post-ERCP pancreatitis

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“Take two and call me in the morning” may now apply to the use of indomethacin in preventing post-ERCP pancreatitis.  A multicenter, randomized, placebo-controlled, double-blind clinical trial has shown that rectal indomethacin (two 50 mg suppositories) can reduce the rate of post-ERCP pancreatitis (NEJM 2012; 366: 1414-22).

A total of 602 adult patients were enrolled.  Patient selection favored those at increased risk for post-ERCP pancreatitis (eg. suspicion of sphincter of Oddi dysfunction) and excluded those at low risk for this complication (eg. routine biliary stent exchange, chronic calcific pancreatitis, or a pancreatic head mass).  Other exclusion criteria included active pancreatitis, elevated creatinine (>1.4 mg/dL), active peptic ulcer disease, and those already receiving a NSAID.

The suppositories (or placebo) were administered immediately after ERCP while the patient remained in the procedure room.

Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in indomethacin group and in 52 of 307 patients (16.9%) in placebo group.  In addition, moderate-to-severe pancreatitis was reduced as well 4.4% compared with 8.8% respectively.  In addition, there were no increased adverse events in the treatment arm; there was no increased risk of bleeding in particular.

While the mechanism of improvement is unclear, NSAIDs are potent inhibitors of phospholipase A2, cyclooxygenase, and neutrophil-endothelial interactions, all of which are known to play a role in the pathogenesis of acute pancreatitis.

Additional references:

  • -Am J Gastroenterol 2007; 102: 978-83.  Use of indomethacin to reduce pancreatitis after ERCP
  • -Gut 2008; 57: 1262-7.  Meta-analysis of rectal NSAIDs to prevent post-ERCP pancreatitis

Preventing Cancer in patients with Barrett’s Esophagus

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Though Barrett’s esophagus is rare in pediatric gastroenterology, concerns about esophageal cancer are fairly frequent.  In addition, some conditions that increase the risk of esophageal adenocarcinoma start in childhood.

One way to lessen the risk of Barrett’s esophagus in adults is through the use of medications (Gastroenterology 2012; 142: 442-52).  This study was a pooled analysis of six population-based trials with a total of 1226 esophageal adenocarcinoma (EAC) patients and 1140 esophagogastric junctional adenocarcinoma (EGJA) patients.  NSAIDs (aspirin and nonaspirin) lowered the risk of both EAC and EGJA, with OR of 0.68 and 0.83 respectively.

Although this study suggests a possible role for NSAIDs in preventing cancer in patients with Barrett’s esophagus, the risks and benefits for this intervention need to be individualized.

Related previous blog post: More bad news for smokers

Additional references:

  • -Gastroenterology 2011; 141: 2000. Lower risk of Barrett’s in pts taking NSAIDs & statins. n=570.
  • -Gastroenterology 2011; 141: 1179. Overall, patients with BE and LGD have a low annual incidence of EAC, similar to nondysplastic BE. There are no risk factors for progression and there is significant interobserver variation in diagnosis, even among expert pathologists.
  • -NEJM 2011; 365: 1375. Large Danish study, n=11028. Lower incidence of Barrett’s than previous estimates. Relative risk of 11.3 compared to general population for adenoca of Esophagus with absolute annual risk of 0.12%. Barrett’s patients have the same life expectancy as general population (ed. pg 1437). Detecting cancer only ~1 in 1460 scopes with screening whereas Barrett’s detected in 10% of pts.
  • -Gastroenterology 2011; 141: 417, 460. Durable effects of ablation, n=127..
  • -Gastroenterology 2011; 140: 1084. AGA statement on Barrett’s . Recs screening only in those with multiple risk factors (age 50, male, chronic GERD, white, incr BMI)
  • -Clin Gastro & Hep 2010; 8: 565. Guidelines suggest that screening for Barrett’s is not justified w/o alarm symptoms (dysphagia, odynophagia, wt loss, anemia, hematemesis)
  • -Gastroenterology 2010; 138: 2260. n=11,823. Decrease risk of esophageal adenoCa in patients taking NSAIDs & statins.
  • -Gastroenterology 2010; 138: 854. Nice review.
  • -Gastroenterology 2010; 138: 5. Survival equivalent to general population according to Mayo study, n=366. In Barrett’s patients, leading cause of death was cardiovascular (28%). Esophageal cancer resulted in 7% of deaths. Study presented at ACG Oct 26, 2009.
  • -Clin Gastro & Hepatology 2009; 7: 1266. no benefit from surgery for Barrett’s & unclear if chemoprevention works.
  • -Gastroenterology 2009; 137: 763. Suggests surveillance with Barrett’s is not beneficial.
  • -NEJM 2009; 360: 2277, 2353.. Radiofrequency ablation can be effective.
  • -Gut 2008; 57: 1200-06. Utility of endoscopic Rx.
  • -Clin Gastro & Hep 2008; 6: 1206; editorials: 1180, 1181, 1183.. n=2107 with Barrett’s. 79 w surgery and 80 w endoscopic Rx.
  • -Gastro & Hep 2006; 2: 468. 2-8% of pts in general population have Barrett’s. >90% of ptsc Barretts will never develop cancer. Screening has not been proven to be effective in lowering rate of death from cancer. ~40% of US population has heartburn; only 8000-9000/yr develop esoph adenoCa. Also, the presence of Barrett esophagus does not decrease life expectancy.
  • -Gastroenterology 2005; 129: 1825-31. 1.6% incidence of BE in adult Swedish population. Alcohol, smoking increase risk.