Update: What evidence supports rectal indomethacin for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis?
Introduction
Endoscopic retrograde cholangiopancreatography (ERCP) is a highly successful diagnostic and therapeutic procedure used commonly for management of biliary and pancreatic disorders. 1 With the advent of less invasive diagnostic tools and procedures, ERCP has evolved into primarily a therapeutic modality. As effective as ERCP is, there are potentially serious adverse events associated with the procedure, most common being post-ERCP pancreatitis (PEP). Additional complications may include hemorrhage, cholangitis, or perforation. Non-steroidal anti-inflammatory drugs (NSAIDs), specifically rectal indomethacin and rectal diclofenac, are recommended for the prevention of PEP. 2,3
A frequently asked question (FAQ) was published in July 2019 (available here) with information on the use of rectal indomethacin and its alternatives for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis. 4 At the time the FAQ was published, the authors found that existing literature generally supported similar efficacy and safety of rectal indomethacin and rectal diclofenac for the prevention of PEP, but controversy remained over the optimal patient population to target for PEP prevention, as various protocols for NSAID administration have not consistently found value in universal rectal indomethacin or diclofenac administration. Since the publication of the FAQ, additional literature and updated guidelines have been published that may help address these unanswered questions. The purpose of this FAQ update is to summarize updated guidelines and literature on the use of rectal indomethacin or diclofenac for the prevention of PEP.
Guideline recommendations
The American Society for Gastrointestinal Endoscopy (ASGE) published an updated guideline on the management of adverse events associated with ERCP in 2023. 2 Previous iterations of the guidelines recommended rectal NSAIDs for the prevention of PEP in high-risk patients without contraindications, with a suggestion to use rectal NSAIDs in average-risk individuals. 5 This most recent iteration makes a strong recommendation for periprocedural rectal NSAIDs to prevent PEP in all patients, at average- and high-risk. 2 Additionally, pancreatic duct (PD) stenting is strongly recommended in patients with repeated or deep PD access or those undergoing ampullectomy to reduce the risk of PEP. In other high-risk groups, PD stenting is suggested if PD access can be achieved easily. No recommendation is given on combination of rectal NSAIDs with other modalities in PEP prevention. The European Society of Gastrointestinal Endoscopy (ESGE) also updated their official statement addressing the prophylaxis of PEP in 2020. 3 Similarly to ASGE recommendations, the guideline recommends routine rectal diclofenac or indomethacin immediately before ERCP in all patients without contraindication to NSAIDs. The placement of pancreatic duct stents is also endorsed in high-risk patients. The ESGE does not suggest routine combination of rectal NSAIDs with other measures to prevent PEP based on lack of evidence.
Literature review
Updated guideline recommendations were informed by systematic reviews and meta-analyses. 2,3 Overall, studies evaluating NSAIDs, specifically rectal indomethacin and rectal diclofenac, have found them both to be effective in reducing the incidence of PEP in the overall, high-risk, and average-risk populations. Recently, network meta-analyses have been published evaluating indirect comparisons of NSAIDs for the prevention of PEP (Table 1). The analyses vary in their inclusion criteria, but they all evaluate randomized controlled trials comparing one or more NSAID to either an active comparator or control, generally in average-risk patients. Out of 4 meta-analyses comparing various NSAID, 1 found that rectal indomethacin was superior for PEP prophylaxis, 1 found that diclofenac was superior, and 1 found no differences between indomethacin or diclofenac. 6-8 The last meta-analysis did not differentiate between NSAIDs and only compared NSAIDs alone to NSAIDs with combination of other treatments. 9
| Table. Meta-analyses evaluating NSAIDs for the prevention of PEP (published 2019 to 2023). | |||
|---|---|---|---|
| Study | Included studies | Results | Conclusions |
| Network meta-analyses |
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| Shi 20226 | Rectal NSAIDs (indomethacin, diclofenac, naproxen), GTN (sublingual or transdermal), or placebo. 24 RCTs (N=9416) | Risk of PEP Overall vs. Placebo Indomethacin + sublingual GTN: OR, 0.21; 95% CI, 0.09 to 0.50 Diclofenac: OR, 0.34; 95% CI, 0.18 to 0.65 Sublingual GTN: OR, 0.34; 95% CI, 0.12 to 0.97 Indomethacin alone: OR, 0.49; 95% CI, 0.33 to 0.73 Risk of Mild PEP vs. Placebo Indomethacin + GTN: OR, 0.27; 95% CI, 0.11 to 0.67 Diclofenac: OR, 0.46; 95% CI, 0.23 to 0.94 Indomethacin alone: OR, 0.59; 95% CI, 0.40 to 0.88 Risk of Moderate-Severe PEP vs. Placebo Indomethacin + GTN: OR, 0.19; 95% CI, 0.08 to 0.48 Diclofenac: OR, 0.27; 95% CI, 0.09 to 0.79 Indomethacin alone: OR, 0.43; 95% CI, 0.28 to 0.66 NMA For all analyses, diclofenac 100 mg performed best in pairwise comparisons between NSAIDs (SUCRA, 75.8%, 71.9%, 77.9%), followed by indomethacin (54.9%, 56.1%, 58.4%) for prevention of overall, mild, and moderate-severe PEP, respectively. | Of NSAIDs included, rectal diclofenac 100 mg was the best for PEP prophylaxis. Additionally, combination of GTN with rectal indomethacin was effective as combination therapy for PEP prophylaxis. |
| Du 20229 | Rectal NSAIDs (≤100 mg), high-dose rectal NSAIDs (≥150 mg), a combination of rectal NSAIDs (≤100 mg) with other drugs or modalities, or placebo. 32 RCTs (N=15019) | Incidence of PEP vs. Placebo NSAIDs alone: OR, 0.44; 95% CI, 0.33 to 0.56 High-dose NSAIDs: OR, 0.44, 95% CI, 0.22 to 1.00 NSAIDs + sublingual nitrates: OR, 0.22; 95% CI, 0.11 to 0.39 NSAIDs + aggressive hydration: OR, 0.32; 95% CI, 0.12 to 0.71 NSAIDs + standard hydration: OR, 0.34; 95% CI, 0.08 to 1.3 NSAIDs + epinephrine: OR, 0.44; 95% CI, 0.21 to 0.75 NSAIDs + somatostatin: OR, 0.36; 95% CI, 0.17 to 0.73 NSAIDs + melatonin: OR, 0.30; 95% CI, 0.10 to 0.88 NMA vs. NSAIDs alone NSAIDs + sublingual nitrates: OR, 0.50; 95% CI, 0.27 to 0.89 Probability ranking plot showed that NSAIDs + sublingual nitrate was the most effective treatment for preventing PEP, followed by NSAIDs + standard hydration, NSAIDs + melatonin, NSAIDs + aggressive hydration, NSAIDs + somatostatin, NSAIDs alone, NSAIDs + epinephrine, high-dose NSAIDs, and placebo. NMA: High-risk patients (n=11 studies) NSAIDs alone, high-dose NSAIDs, and NSAID combinations may be effective compared with placebo, but there were no statistically significant differences observed. | Combination of NSAIDs with nitrates was the most effective intervention for prevention of PEP in average-risk populations compared to other interventions. For high-risk patients, there were no statistically significant differences in prevention strategies compared to placebo. |
| Yu 20217 | Rectal indomethacin, rectal diclofenac, or placebo in average-risk patients 10 RCTs (N=2928) | Overall PEP risk vs. Placebo Rectal indomethacin + diclofenac: RR, 0.62; 95% CI, 0.46 to 0.83 Indomethacin alone: RR, 0.67; 95% CI, 0.49 to 0.94 Diclofenac alone: RR, 0.42; 95% CI, 0.23 to 0.75) NMA No significant difference between indomethacin and diclofenac in the prevention of PEP (RR, 1.607; 95% CI, 0.824 to 3.136) | Both rectal indomethacin and rectal diclofenac are effective against PEP in average-risk patients, with no significant difference between them. |
| Yang 20208 | Rectal NSAIDs (indomethacin, diclofenac, and others) given pre-ERCP, during ERCP, or post-ERCP, and placebo. 23 RCTs (N=9382) | Rate of Overall PEP vs. Placebo Post-ERCP diclofenac: OR, 0.24; 95% CI, 0.11 to 0.51 Pre-ERCP diclofenac: OR, 0.25; 95% CI, 0.14 to 0.46 Pre-ERCP indomethacin: OR, 0.44; 95% CI, 0.32 to 0.62 Post-ERCP indomethacin: NS Indomethacin during: NS Pre-ERCP naproxen: NS NMA: Overall PEP Pre-ERCP diclofenac vs post-ERCP indomethacin: OR, 3.30; 95% CI, 1.38 to 7.87 Pre-ERCP diclofenac vs pre-ERCP naproxen: OR, 2.53; 95% CI, 1.24 to 5.18 Moderate-Severe PEP vs. Placebo Pre-ERCP diclofenac: OR, 0.18; 95% CI, 0.06 to 0.55 Pre-ERCP indomethacin: OR, 0.37; 95% CI, 0.17 to 0.79 Probabilities of rank plot were presented with pre-ERCP diclofenac as first, followed by pre-ERCP indomethacin, post-ERCP diclofenac, indomethacin during ERCP, post-ERCP indomethacin, pre-ERCP naproxen, and placebo. | Pre-ERCP diclofenac appears to be the optimal prevention method for PEP compared to other NSAIDs at differing time points. |
| Abbreviations: CI=confidence interval; ERCP=endoscopic retrograde cholangiopancreatography; GTN=glyceryl trinitrate; NMA=network meta-analysis; NS=not significant; NSAID=non-steroidal anti-inflammatory drug; OR=odds ratio; PEP=post-ERCP pancreatitis; RCT=randomized controlled trial; RR=relative risk; SUCRA=surface under the cumulative ranking curves |
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Increasingly more studies are evaluating rectal NSAIDs in combination with other agents or modalities. 6,9 While some benefit has been demonstrated with combination across studies, more robust studies are needed to demonstrate benefit. Additionally, there remains questions about efficacy of rectal NSAIDs for PEP prevention in patients with certain comorbidities, including ongoing NSAID use, altered renal function, aspirin or NSAID allergy, and a history of peptic ulcer disease, as these populations are generally not included in clinical trials. 2,3 Recent studies and updated guidelines based on meta-analyses have demonstrated benefit of rectal NSAIDs in unselected or average risk patients. 2,3,6-9
Conclusion
The most recent guideline updates addressing PEP recommend universal use of rectal indomethacin or diclofenac unless contraindicated, regardless of risk factors. Meta-analyses evaluating randomized controlled trials and influencing guideline recommendations have generally found both rectal indomethacin and rectal diclofenac to significantly reduce the risk of PEP, both in high-risk patients and patients without specific risk factors. Additional studies are needed to determine the efficacy of NSAIDs combined with other treatment modalities compared to single agents. Potential alternatives to rectal NSAIDs that can be considered still include aggressive intravenous hydration and placement of pancreatic stents, though the latter is only recommended for high-risk patients in current guidelines.
References
- Dolan R, Carr-Locke D, Thompson C. Endoscopic retrograde cholangiopancreatography (ERCP) In: Friedman S, Blumberg R, Saltzman J, eds. Greenberger’s current diagnosis & treatment gastroenterology, hepatology, & endoscopy, 4e: McGraw Hill; 2022. Accessed January 16, 2023. https://accessmedicine.mhmedical.com/content.aspx?bookid=3204§ionid=266864334.
- Buxbaum JL, Freeman M, Amateau SK, et al. American Society for Gastrointestinal Endoscopy guideline on post-ERCP pancreatitis prevention strategies: methodology and review of evidence. Gastrointest Endosc. 2023;97(2):163-183.e140. doi:10.1016/j.gie.2022.09.011
- Dumonceau JM, Kapral C, Aabakken L, et al. ERCP-related adverse events: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2020;52(2):127-149. doi:10.1055/a-1075-4080
- Spencer S, Bridgeman K. What is the evidence for rectal indomethacin for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis? University of Illinois at Chicago Drug Information Group. Published July 2019. Accessed January 16, 2023. https://dig.pharmacy.uic.edu/faqs/2019-2/july-2019-faqs/
- Chandrasekhara V, Khashab MA, Muthusamy VR, et al. Adverse events associated with ERCP. Gastrointest Endosc. 2017;85(1):32-47. doi:10.1016/j.gie.2016.06.051
- Shi QQ, Huang GX, Li W, Yang JR, Ning XY. Rectal nonsteroidal anti-inflammatory drugs, glyceryl trinitrate, or combinations for prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis: A network meta-analysis. World J Clin Cases. 2022;10(22):7859-7871. doi:10.12998/wjcc.v10.i22.7859
- Yu S, Shen X, Li L, Bi X, Chen P, Wu W. Rectal indomethacin and diclofenac are equally efficient in preventing pancreatitis following endoscopic retrograde cholangiopancreatography in average-risk patients. JGH Open. 2021;5(10):1119-1126. doi:10.1002/jgh3.12643
- Yang J, Wang W, Liu C, Zhao Y, Ren M, He S. Rectal nonsteroidal anti-inflammatory drugs for endoscopic retrograde cholangiopancreatography postoperative pancreatitis prevention: A network meta-analysis. J Clin Gastroenterol. 2020;54(4):305-313. doi:10.1097/mcg.0000000000001322
- Du F, Zhang Y, Yang X, et al. Efficacy of combined management with nonsteroidal anti-inflammatory drugs for prevention of pancreatitis after endoscopic retrograde cholangiography: a Bayesian network meta-analysis. J Gastrointest Surg. 2022;26(9):1982-1997. doi:10.1007/s11605-022-05352-7
Prepared by:
Rachel Brunner, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
February 2023
The information presented is current as January 16, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.