Nonsteroidal Anti-inflammatory Drugs for the Prevention of Post-endoscopic Retrograde Cholangiopancreatography Pancreatitis

Abstract

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains the most frequent and severe complication following ERCP, elevating both patient suffering and healthcare costs, and posing challenges to the advancement of ERCP techniques. Empirical evidence supports the prophylactic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of PEP, especially in high-risk populations, as endorsed by both the American Society for Gastrointestinal Endoscopy (ASGE) and the European Society for Gastrointestinal Endoscopy (ESGE). However, the prophylactic efficacy of NSAIDs in average-risk individuals, alongside the ideal drug selection, dosing, and timing of NSAID administration, remains to be elucidated. Furthermore, the synergistic preventive potential of NSAIDs when integrated with other interventions, such as hydration, pancreatic stenting, somatostatin administration, sublingual nitrate application, and epinephrine, warrants further clarification. In this paper, we conduct an exhaustive review of the prophylactic effect and clinical administration of NSAIDs for PEP. We comprehensively synthesize findings from clinical trials investigating NSAIDs, both in monotherapy and combination regimens, for PEP prevention. Additionally, we scrutinize the current landscape of NSAID usage in clinical practice and evaluate their cost-effectiveness. Future research should concentrate on refining NSAID prophylaxis strategies for PEP in patients at different risk levels, while also enhancing adherence to clinical guidelines and alleviating the issue of NSAID cost inflation.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are potent inhibitors of phospholipase A2, cyclooxygenase, and neutrophil-endothelial interactions, which are believed to mediate a pro-inflammatory cascade, leading to subsequent intense local and systemic clinical manifestations of pancreatitis [1, 2]. Recent studies have shown that NSAIDs can down-regulate HMGB1 and TNF-α and prevent post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) by reducing pancreatic apoptosis through inhibition of cyclooxygenase 2 [3, 4]. NSAIDs are inexpensive, easy to administer, and have a low risk when administered as a single dose, and so are commonly used for the prevention of PEP. However, there is heterogeneity in reports of the use of NSAIDs, mainly in terms of the preventive effect of NSAIDs in patients with different risk stratifications, the type and dosage of medication, and the optimal prevention of PEP using NSAIDs in combination with different techniques. In recent years, research on the use and cost-effectiveness of NSAIDs has significantly increased, providing valuable insights into PEP prevention strategies. In this study, we review the literature on NSAIDs for PEP prevention, to systematize the issue and provide guidance for future research.

Prophylactic Effect of NSAIDs on PEP

Prophylactic Effect of NSAIDs on High-Risk Patients

NSAIDs were initially studied only in patients at high risk for PEP, and multiple previous randomized controlled trials (RCTs) have clarified the benefits of using NSAIDs for prevention in high-risk patients [5–7]. The 2023 guidelines from the American Society for Gastrointestinal Endoscopy (ASGE) included a systematic review and meta-analysis of 10 RCTs involving 2006 patients, which found a significant reduction of PEP in high-risk patients treated with rectal NSAIDs compared with placebo (odds ratio [OR] = 0.50; 95% confidence interval [CI] 0.30–0.83; I² = 56.6%). There were no significant differences between the two groups in terms of common complications of NSAIDs, such as renal failure and bleeding. The ASGE and the European Society for Gastrointestinal Endoscopy (ESGE) both highly recommend preoperative rectal NSAIDs for high-risk patients.

However, it's important to acknowledge that many high-risk patients included in NSAIDs studies were simultaneously treated with pancreatic stents (PS) for the prevention of PEP. For example, in Elmunzer’s RCT on NSAIDs to prevent PEP, PSs were placed in > 80% of the patients in both groups [8]. In most studies, the number of PSs in the experimental and control groups was not controlled. It is unclear whether NSAIDs were the only factor influencing the outcome of PEP (i.e., in isolation of PS) in the original studies that explored NSAIDs for PEP prevention.

Although the current research conclusions are relatively uniform, whether differences in the groups included in research studies are important requires attention. ESGE 2021 summarizes the risk factors for PEP in detail, including suspected sphincter of Oddi dysfunction (SOD) as a definite patient-related risk factor [9]. However, evidence suggests that sphincterotomy does not reduce disability due to pain when treated with endoscopic retrograde cholangiopancreatography (ERCP) with manometry compared to sham treatment. ERCP and sphincterotomy were not supported in patients with SOD [10], and there was a sudden and sustained decline in endoscopic sphincterotomy rates for newly diagnosed SOD after 2013 [11]. PEP is increasingly associated with pancreatic precut sphincterotomy, difficult cannulation and trauma associated with pancreatic injections [3, 12]. Thus, the high-risk population with SOD, for whom early NSAIDs showed the greatest benefit, may not fully reflect contemporary clinical practice.

Prophylactic Effect of NSAIDs on Unselected Patients

In recent years, NSAID utilization has expanded to include unselected PEP patients due to their cost-effectiveness. Luo et al. first suggested in a large RCT that generalized pre-ERCP indomethacin administration was superior to not taking indomethacin perioperatively in average-risk patients (OR, 0.46; 95% CI 0.30–0.71) [13]. Subsequently, several RCTs and meta-analyses have supported the effectiveness of NSAIDs in unselected patients [14]. In 2016, the ESGE recommended NSAIDs for all patients without contraindications.

However, Levenick explicitly suggested that NSAIDs are ineffective in preventing PEP in unselected patients [15]. In their RCT, 449 consecutive patients undergoing ERCP randomly received either 100 mg of rectal indomethacin or a placebo, and the results showed no difference between the two groups in terms of PEP occurrence and severity. Owing to a lack of evidence of efficacy, the Data Safety Monitoring Board terminated the trail. However, this study was criticized for the early termination of the trial, which may have led to a type II statistical error.

Similarly, meta-analyses like that by Inamdar et al. have concluded that NSAIDs do not offer protective effects in unselected patients [16]. These findings have been subject to methodological critique, and the results were affected after excluding Levenick’s study [17, 18].

Despite ongoing debates, the latest recommendations from ASGE 2023 and ESGE 2019 strongly advocate for NSAID use in patients without contraindications.

Clinical Administration of NSAIDs to Prevent PEP

Type of NSAIDs: Indomethacin or Diclofenac? Any Other Opinions?

The comparative effectiveness of indomethacin and diclofenac, both recommended by guidelines, warrants further investigation.

Indomethacin may be effective in high-risk patients but shows mixed results in unselected patient populations, while diclofenac appears promising in preventing PEP across various patient groups. Studies by Víctor et al. in 2015 demonstrated a significant reduction in PEP incidence with indomethacin in high-risk patients, with a notable decrease from 20.23 to 4.87% [19]. However, in 2020, Mayra et al. conducted a retrospective study involving 524 unselected patients, showing no significant difference in the incidence of PEP between the indomethacin and control groups [20]. Two other studies that included unselected patients also failed to find a significant effect regarding the effectiveness of indomethacin in preventing PEP [21, 22]. Diclofenac has shown efficacy in unselected patients, as evidenced by studies such as Geraci et al.’s 2019 prospective study, which also highlighted its analgesic benefits [23]. In an RCT conducted in 2020 by Kumar et al., diclofenac was also found to have analgesic effects similar to those of tramadol in patients with acute pancreatitis, with the added benefit of fewer complications [24].

The applicability of these two drugs in different patient groups is a subject of considerable research interest. Meta-analyses by Kang et al. in 2022 [25] and Yang et al. in 2020 [26] favored diclofenac, indicating lower PEP incidence compared to indomethacin. These findings collectively highlight the growing evidence supporting the use of diclofenac for the prevention of PEP. However, subgroup analysis based on patient risk levels was lacking.

The route of administration could significantly affects the effectiveness, as mentioned by Serrano JPR et al. [27, 28] and Lyu et al. [29] in their meta-analysis, oral, intravenous and intramuscular administration of diclofenac did not reduce the incidence of PEP. To our best knowledge, there has been no study applied indomethacin other than rectal administration in prevention of PEP.

Several studies have explored alternative NSAIDs for PEP prevention, with mixed results. A promising result comes from a RCT conducted by Fariborz et al., they applied 500 mg rectal naproxen pre-ERCP and found PEP was significantly reduced compared to placebo group (7.4 vs 17%, n = 162 in each group). Intravenous injection of 10 mg/kg ibuprofen reduced the incidence of PEP in a pediatric population (7 vs. 17%); however, the difference was not statistically significant (P = 0.42) [30]. Intramuscular injection of dexketoprofen tromethamine during ERCP could potentially reduce the incidence of PEP in animal experiment, this result requires further verification through clinical experiments [31]. Other types of NSAIDs, including intravenous injection of 20 mg valdecoxib [32], 100 mg ketoprofen [33], and oral administration of 400 mg celecoxib, did not effectively reduce the incidence of PEP.

Current guidelines do not specify preferred NSAIDs. Though diclofenac may be more effective for both average- and high-risk patients, future large-scale RCTs are needed to determine the optimal NSAID choice for different patient populations.

Dose of NSAIDs

Balancing efficacy with safety, the recommended dosage of NSAIDs for PEP prevention is crucial due to potential side effects like renal dysfunction and peptic ulcers associated with higher doses. Since 2010, the ESGE has advocated for the rectal application of 100 mg of indomethacin or diclofenac as the standard dosage for PEP prevention, reducing PEP incidence in high-risk patients by approximately 50%.

Despite interest in determining the minimum effective dose (25–50 mg) of NSAIDs, recent studies have cast doubt on the effectiveness of low-dose NSAID in preventing PEP. In 2023, Hiroaki et al. [34] conducted a retrospective study and patients received either 50 or 25 mg of diclofenac 30 min before the procedure based on their weight (with 50 kg as the cutoff), whereas the control group received no drug treatment. Their results, consistent with three other studies [12, 35, 36] revealed that low-dose diclofenac has no significant protective effect against PEP (medication group vs. control group: 6.7 vs. 9.5%, P > 0.05).

Increasing the dosage of NSAIDs in high-risk patients did not improve outcomes significantly. In a study by Fogel et al., 1037 high-risk patients were treated with either 100 mg (n = 515) or 200 mg (n = 522) indomethacin suppositories after ERCP, showing no significant difference in the incidence between the two groups (100 vs. 200 mg: 15 vs. 12%, P > 0.05) [37]. Similarly, a recent Taiwanese study yielded similar findings. (4.8 vs. 9.5%, P = 0.24) [38].

Thus, the current standard dose of 100 mg indomethacin or diclofenac remains safe and effective for PEP prevention, with no notable benefits from dosage adjustments observed. Further investigation is warranted to compare the effectiveness of 100 mg diclofenac versus indomethacin in preventing PEP.

Timing of NSAIDs Administration

The 2023 ASGE guidelines recommend the perioperative use of NSAIDs as a preventive measure for PEP during ERCP. Ongoing research is exploring the optimal timing of NSAID administration, encompassing preoperative, intraoperative, and postoperative approaches, to elucidate potential differences in efficacy.

Studies comparing preoperative versus postoperative NSAID administration for PEP prevention have yielded mixed results. Serrano JPR et.al underlined the administration must be before ERCP in their meta-analysis across 26 RCTs [28]. While Patai et al.’s study [39] and Liu et al.’s meta-analysis [40] found no significant differences between the two approaches, Rustagi et al. [41] observed a lower incidence of postoperative PEP in patients receiving preoperative NSAIDs. In Rustagi’s meta-analysis subgroup analysis, it was observed that four studies focusing on preoperative medication demonstrated a significantly lower incidence of postoperative PEP compared to the control group, while no significant difference was noted in studies on postoperative NSAIDs. The authors hypothesized that the preoperative administration might be more effective due to the time required for the drug to take effect. Given the rapid and irreversible damage to pancreatic acinar cells during the procedure, postoperative drug treatment may be less effective. Lyu et al. concluded the timing of administration could be affected by the type of NSAIDs, indomethacin for preoperation and diclofenac for postoperation, respectively [29]. Recognizing the short half-life of NSAIDs (up to 2 h), the ASGE guidelines recommend administering them approximately 30 min before or during surgery.

Further investigation is needed to determine if preoperative NSAID administration offers additional benefits. The optimal timing of NSAID administration in ERCP patients may hinge on factors such as the pharmacokinetics of the specific NSAID used and the individual patient's PEP risk profile.

Efficacy of NSAIDs Combined with Other Methods

In recent years, there has been considerable interest in combining NSAIDs with other strategies to prevent PEP. However, recommendations regarding the optimal combination of NSAIDs with different methods vary across guidelines and studies.

Combination of NSAIDs with Hydration

Normal saline (NS) and Ringer's lactate solution (RL) are commonly used for perioperative hydration in ERCP (Table 1). In 2016, Hosseini et al. first conducted an RCT involving 406 patients, showing that combining rectal indomethacin with intravenous NS (1 L NS within 2 h before and 2 L NS for 16 h after ERCP) significantly reduced PEP risk compared to indomethacin alone (5.2 vs. 16.2%) [42]. In 2017, Mok et al. conducted a prospective double-blind study involving a total of 192 patients who received rectal indomethacin and intravenous infusion administered based on patient groups: either 1 l of normal saline or RL solution. They demonstrated that RL combined with indomethacin was more effective in preventing PEP than saline combined with indomethacin (6 vs. 13%). This may be attributed to the ability of RL to elevate intra-acinar cell pH and reduce trypsinogen activation. Consequently, it collaborates with NSAIDs to inhibit early stage inflammation [43].

Table 1.

RCTs of NSAIDs combined with hydration for PEP prophylaxis

Year	Study design, participants (n)	Risk level	Intervention	Outcome (intervention vs. control arm)
2023 [49]	RCT, 144	High risk	Diclofenac (100 mg) + aggressive RL vs diclofenac sodium vs aggressive RL	8.3 vs 8.3 vs 10.4% (P > 0.05)
2023 [50]	RCT, 352	Unselected	Indomethacin(50 mg) + aggressive RL vs Indomethacin	0.5 vs 2.9% (P > 0.05)
2022 [51]	RCT, 102	High risk	Diclofenac + RL vs RL vs diclofenac	20.5 vs 20.5 vs 26.5% (P > 0.05)
2022 [52]	RCT, 120	Unselected	Indomethacin (100 mg) + aggressive NS vs Indomethacin	0 vs 8.3% (P = 0.022)
2021 [46]	RCT, 826	Moderate to high risk	Diclofenac or indomethacin (100 mg) + aggressive RL vs NSAIDs + normal saline	8 vs 9% (P > 0.05)
2021 [53]	RCT, 171	High risk	Diclofenac (100 mg) + aggressive RL vs Indomethacin vs aggressive RL	10.5 vs 14.0 vs 15.8% (P > 0.05)
2021 [54]	RCT, 241	High risk	Indomethacin(100 mg) + RL vs Indomethacin + NS vs RL + placebo vs NS + placebo	6 vs 13% vs 19 vs 21% (P = 0.03)
2020 [45]	RCT, 281	High risk Average risk	Indomethacin(100 mg) + aggressive RL vs Indomethacin + standard RL 20 ml/kg bolus immediately afterward Indomethacin(100 mg) + standard RL vs Indomethacin	21.4 vs 21.7% (P > 0.05) 30.6 vs 26.3% (P > 0.05)
2016 [42]	RCT, 406	Unselected	Indomethacin (100 mg) + standard NS vs indomethacin vs standard NS vs rectal glycerin (placebo)	0 vs 10 vs 11 vs 17 (P = 0.001)

RL Ringer's lactate; NS normal saline

In the same year, Buxbaum et al.'s critique led to the concept of aggressive RL hydration combined with NSAIDs, advocating for higher fluid volumes to optimize preventive measures against PEP during ERCP. The currently accepted standard for aggressive hydration is a rapid replenishment of 20 mL/kg of fluid before surgery, followed by a rate of 3 mL/kg, compared with standard hydration with no preoperative bolus and a rate of 1.5 mL/kg after the procedure [44]. In 2020, Pasha et al. provided evidence supporting aggressive RL hydration combined with indomethacin, particularly in high-risk patients, as a superior approach compared to standard hydration [45]

However, the practical implementation of aggressive hydration combined with NSAIDs remains contentious. Sperna Weiland et al. found that among 826 patients, those who had received NSAIDs treatment did not have a significantly reduced risk of PEP after further aggressive hydration (8 vs. 9%); however, due to the need for fluid monitoring, active hydration increased the patient's length of stay and hospital admission expenses [46]. Fei et al. also suggested NSAIDs + standard hydration, not aggressive hydration, might be the best choice for high-risk patients [47].

In 2020, the ESGE did not recommend the routine use of hydration combined with NSAID treatment [9]. In 2023, the ASGE issued a conditional recommendation for aggressive hydration during ERCP [48]. It seems that aggressive hydration with RL is potentially more effective. Further multi-center prospective randomized controlled trials are needed to investigate this issue based on patient risk levels.

Combination of NSAIDs with Pancreatic Stent

The 2023 ASGE recommends prophylactic PS placement after ERCP in high-risk individuals [48]. PS placement is beneficial in preventing PEP by facilitating the outflow of pancreatic fluid which can be interrupted by pancreatic duct edema [55]. However, for patients already treated with NSAIDs, the effectiveness of pancreatic stenting to prevent PEP requires further consideration.

Most studies found no significant advantage of combining PS with NSAIDs over the use of NSAIDs alone (Table 2). In 2013, a post hoc RCT showed that the incidence of PEP was similar in high-risk patients treated with NSAIDs alone, combined with pancreatic duct stents, and with stents alone [56]. Economically, NSAID monotherapy was found to be cost-saving, saving approximately $1472 per patient. In 2019, Abdelfatah enrolled 777 patients and found that the effect of combination treatment was similar to that of NSAID monotherapy [57].

Table 2.

Studies of NSAIDs combined with pancreatic stent for PEP prophylaxis

Year	Study design, participants (n)	Risk level	Intervention	Outcome (intervention vs. study arm)
2022 [59]	RCT, 321	Unselected	Diclofenac (50 mg) + PS vs PS vs Diclofenac	2.0 vs 2.0 vs 0.9% (P > 0.05)
2019 [60]	RCT, 414	High risk	pharmacological prophylaxis (indomethacin, dinitrate, or RL) + PS vs pharmacological prophylaxis	12.6 vs 15.9% (P > 0.05)
2019 [57]	Retrospective, 707	Unselected	Indomethacin + PS vs PS	6.1 vs 5.1% (P > 0.05)
2015 [61]	Retrospective, 285	High risk (Type 3 SOD)	Indomethacin (100 mg) + PS vs PS	18 vs 23% (P > 0.05)
2013 [62]	post hoc analysis, 602	High risk	Indomethacin (100 mg) + PS vs indomethacin vs PS vs no prophylaxis (placebo)	9.7 vs 6.3 vs 16.1 vs 20.7% (P < 0.001)

PS pancreatic stent; SOD sphincter of Oddi dysfunction

Although the 2020 version of ESAG ultimately does not recommend the use of stents combined with NSAIDs to prevent PEP, some studies in the past 2 years should be noted. In 2021, Wang et al. analyzed 4456 patients undergoing ERCP and observed that while overall PEP rates were not significantly different between patients receiving NSAIDs with or without stents (12.7 vs 10.2%, P = 0.329), there was a pronounced reduction in PEP cases when combining PS with NSAIDs in patients subjected to the double guidewire technique(DGT). This may be related to repeated stimulation of the pancreatic duct and tail during DGT, indicating the effectiveness of the combined treatment for people at a higher risk of PEP [58]. In 2022, Koshitani et al. explored this further. They compared the effect of 50 mg diclofenac and a PS with that of the drug alone or a PS alone in 321 patients. The results showed that the incidence of PEP was similar between the groups (approximately 10%), and the postoperative serum pancreatic enzyme level was lowest in the NSAID-alone group. The PS injection and wire placement inevitably lead to elevated pancreatic enzyme levels. This result suggests that for average-risk patients, NSAIDs alone may be better than pancreatic duct stenting in preventing PEP [59].

Collectively, NSAID monotherapy remains a potent, cost-effective prophylactic option against PEP, especially in patients without heightened risk factors. Future high-quality RCTs should aim to elucidate the optimal combination of prophylactic strategies tailored to individual patient risk profiles.

Combination of NSAIDs with Somatostatin

Somatostatin is widely used in high-risk patients after ERCP. Somatostatin’s inhibition of pancreatic secretions decreases inflammatory markers and enzymes, lessening abdominal pain and shortening recovery time. Recent studies have focused on the preventive role of rectal NSAIDs in combination with somatostatin in PEP (Table 3).

Table 3.

Studies of NSAIDs combined with somatostatin for PEP prophylaxis

Year	Study design, participants (n)	Risk level	Intervention	Outcome (intervention vs. study arm)
2023 [66]	RCT, 1458	Unselected	Indomethacin + somatostatin vs indomethacin vs somatostatin vs placebo	5.2 vs 17.9 vs 6.0 vs 19.3% (P < 0.001)
2018 [64]	Prospective, 139	Unselected	Octreotide + indomethacin vs no preventive drug	5.97 vs 20.83% (P = 0.021)
2012 [63]	RCT, 540	Unselected	Diclofenac (100 mg) + somatostatin (0.25 mg/h for 6 h) vs placebo + saline	4.7 vs. 10.4% (P = 0.015)

In 2010, Katsinelos et al. reported a significant decrease in PEP incidents with the combination of somatostatin (0.25 mg/h for 6 h) and diclofenac, compared to the control group receiving diclofenac alone (4.7 vs. 10.4%, P = 0.015). Subgroup analysis revealed a significant benefit in high-risk patients (5.8% vs. 12.3%, P = 0.027) but not in low-risk patients. This suggests a multifactorial correlation and synergistic effect, through broad anti-inflammatory actions, reducing pancreatic secretion and local pancreatic IL-6 secretion [63]. In 2018, Wang et al. reinforced these findings, observing a reduced incidence of PEP and lower levels of inflammatory markers (IL-6, IL-8, and TNF-α) in patients treated with the combination therapy of indomethacin and octreotide (5.97 vs 20.83%, P = 0.021) [64]. A recent RCT by Wu et al. support these observations, recommending NSAIDs and somatostatin combination for complex, lengthy ERCPs expected to cause severe postoperative pain [65].

Despite these findings, current guidelines from ESGE and ASGE withhold a general recommendation for somatostatin, pointing to the necessity for more targeted research on its efficacy in conjunction with NSAIDs among patients at substantial risk. Currently, in clinical practice, owing to the need for intravenous cannulation for the continuous infusion of somatostatin, this combination therapy should be reserved only for severe, high-risk patients.

Combination of NSAIDs with Sublingual Nitroglycerin

Nitroglycerin, as smooth muscle relaxants, reduce PEP incidence by lowering Oddi sphincter pressure and enhancing pancreatic blood flow. Several RCTs support that combining NSAIDs with nitroglycerin effectively decreases PEP rates and control the severity of PEP (Table 4), as well as a network meta-analysis conducted by Fei et al. suggesting sublingual nitroglycerin combined with NSAIDs showed best efficacy in overall population [47].

Table 4.

Studies of NSAIDs combined with nitroglycerin for PEP prophylaxis

Year	Study design, participants (n)	Risk level	Intervention	Outcome (intervention vs. study arm)	Complications (Hypotension and headache)
2020 [68]	RCT, 526	High risk	indomethacin + nitroglycerin vs PS vs placebo	5.1 vs 12.1 vs 19.3% (P = 0.011)	0 vs 2.3% vs 0 (P = 0.036)
2019 [67]	RCT, 886	Unselected	diclofenac (50 mg) + nitroglycerin vs diclofenac	5.6% vs 9.5% (P = 0.03)	Hypotension: 7.9% vs 2.9% (P = 0.002) Headache: 0.2 vs 0% (P > 0.05)
2013 [69]	RCT, 300	Unselected	Indomethacin(100 mg) + nitroglycerin vs indomethacin + placebo	6.7 vs 15.3% (P = 0.016)	–

However, the biggest obstacle to the use of combined medications is the emergence of complications. In a 2019 study by Tomoda et al., compared with diclofenac treatment alone, when combined with 5 mg sublingual isosorbide dinitrate, the incidence of hypotension increased by approximately 5% [67]. In 2020, Wang et al. found that four patients in the combination group experienced severe hypotension and headache (2.3 vs. 0%) [68].

The latest version of the ESAG does not recommend the combined use of the two drugs because of possible complications. Future research should aim to delineate clear guidelines on patient eligibility, dosing strategies, and monitoring protocols to optimize the benefits of this combination while minimizing risks.

Combination of NSAIDs with Epinephrine

Topical epinephrine application at the duodenal papilla aims to alleviate PEP by reducing sphincter of Oddi edema. Nonetheless, recent investigations demonstrate an unfavorable outcome from the NSAID and epinephrine combination (Table 5). This outcome may be due to vasoconstriction around the papilla caused by topical epinephrine spraying, inhibiting effective NSAID accumulation. Additionally, epinephrine may activate phospholipase A2 through sodium–potassium pumps, making NSAIDs ineffective. A recent systematic review also concluded that the combination of NSAIDs and adrenaline spraying did not reduce the incidence of complications (OR = 0.94, P = 0.86) [70].

Table 5.

RCTs of NSAIDs combined with epinephrine for PEP prophylaxis

Year	Study design, participants (n)	Risk level	Intervention	Outcome (intervention vs. control arm)
2023 [71]	RCT, 164	Unselected	Indomethacin(50 mg) + epinephrine spray vs Indomethacin + saline spray	2.4 vs 4.9% (P > 0.05)
2021 [72]	RCT, 548	Unselected	Indomethacin(100 mg) + epinephrine spray vs Indomethacin + saline spray	5.1 vs 3.6% (P > 0.05)
2021 [73]	RCT, 882	Unselected	Indomethacin (100 mg) + epinephrine spray vs Indomethacin + saline spray	6.4 vs 7.9% (P > 0.05)
2019 [74]	RCT, 1158	Unselected	Indomethacin (100 mg) + epinephrine spray vs Indomethacin + saline spray	8.5% vs 5.3 (P = 0.033)
2019 [75]	RCT, 960	Unselected	Indomethacin + epinephrine spray vs Indomethacin + saline spray	6.7 vs 6.4% (P > 0.05)

The current ESAG guidelines do not recommend this combination approach and explicitly mention its potential to increase the incidence of PEP.

Current Status of the Use of NSAIDs in the Prevention of PEP

Utilization of NSAIDs in the Prevention of PEP: Contemporary Evidence

Over the past decade, the use of NSAIDs for the prevention of PEP has significantly increased. Initially, in 2009, a survey conducted by Dumonceau et al. with 141 endoscopists indicated a minimal adoption of NSAIDs, with only 16.3% using them for PEP prevention [76]. This perspective underwent a dramatic transformation by 2023, as research by Ashat among 319 American Society for Gastrointestinal Endoscopy (ASGE) members showed a leap in NSAIDs usage for PEP prevention to 93.7% [77]. Table 6 underscores the broad acceptance of NSAIDs over the years.

Table 6.

Post-endoscopic retrograde cholangiopancreatography pancreatitis registries and surveys

Year	Country	Data source, Target population	Participants (n)	Prophylactic rectal NSAIDs use (%)	PS use (%)	IV fluid use (%)	PEP (%)
2023 [77]	the United States	Survey, ASGE member	319	93.7%  For high-risk procedures:34.8%  For average-risk procedures: 53.9%	89%  For high-risk procedures: 89%	94.7%  Ringer’s lactate solution: 78.7%  Normal saline solution: 11% Between 500 and 1000 mL of fluids: 11% Between 1000 and 1500 mL of fluids: 20%	–
2021[78]	India	Survey, Advanced endoscopists	123	97%  For high-risk procedures: 69%	40%  40% put PS after > 2 inadvertent pancreatic duct cannulations	67.5%  For high-risk procedures: 37%	0–5%
2020 [79]	The Netherlands	Survey, Registered gastroenterologists	121	100%  93% used NSAIDs in > 80% of ERCPs performed	78%  Used in < 20% of ERCPs: 80%	33%  Ringer’s lactate solution: 86%  Normal saline solution: 14%	–
2013 [79]			161	98%  Used in > 80% of ERCPs: 62%	62%  Used in < 20% of ERCPs: 85%	–	–
2018 [80]	the United States	Medical records, High-risk patients for PEP	1540	46.3%	3.9%	–	9.1%
2009 [80]			1050	6.4%	37.3%	–	7.9%
2019 [81]	Russia	Medical records, patients for ERCP in a community hospital	422	5.6%	–	–	2.1%
2019 [82]	the United States	Medical records, patients for ERCP in IBM Explorys database	31,050	29.5%  In high-risk procedures: 29.8%  In average-risk procedures: 28%	6.0%  In high-risk procedures: 5.7%  In average-risk procedures: 7.3%	–	6.1%
2018 [83]	the United States	Survey, Advanced endoscopists	62	98.4%  For high-risk procedures: 59.7%  For average-risk procedures: 6.8%  Used in < 25% of ERCPs: 11%  Used in > 50% of ERCPs: 67.8%	100%  For high-risk procedures: 72%  For average-risk procedures: 6.8%  Used in < 25% of ERCPs: 64.4%  Used in > 50% of ERCPs: 6%	83.0%	–
2016 [84]	Portugal	Survey, Credentialed pancreaticobiliary endoscopists	28	92.3%  For high-risk procedures: 21.4%  For average-risk procedures: 53.6%  Used in < 25% of ERCPs: 17.8%  Used in > 50% of ERCPs: 71.4%	–	–	–
2016 [85]	Spain	Survey, practicing biliopancreatic endoscopists	–	92.5%  For high-risk procedures: 17.6%  For average-risk procedures: 75%	In high-risk procedures: 74%	–	< 5%: 75%
2016 [86]	Italy	Medical records, patients for ERCP in 19 hospitals	2400	19%	28%	–	4.3%
2012[87]	the UK	Survey, endoscopists	222	34.6%	52.5%	–	–
2009 [76]	Different countries	Survey, endoscopists	141	16.3%	78.7%	–	–

ASGE American Society for Gastrointestinal Endoscopy; PS pancreatic stent; IV Intravenous injection; PEP Post-endoscopic retrograde cholangiopancreatography pancreatitis; ERCP endoscopic retrograde cholangiopancreatography

The shift toward NSAIDs for PEP prevention signifies a pivotal change in clinical practice. Historically, PS placement, the primary strategy before 2010, faced critical challenges including an elevated risk of PEP in the event of stent failure, the procedural complexity of stent placement, and the ambiguity regarding the optimal timing for stent removal. Research post-2010 has demonstrated NSAIDs' efficacy in preventing PEP matches that of PS in high-risk patients, highlighting their ease of use and cost-effectiveness as key advantages that have shifted physician preference toward pharmacological prevention [62]. Data from studies conducted in 2020 and 2023 corroborate a significant decline in PS utilization, paralleled by an uptick in the adoption of indomethacin, despite a consistent overall incidence of PEP. However, it is noted that hospitalization and mortality rates associated with PEP have increased, suggesting areas for further investigation [77, 80, 83].

Although the current ESGE guidelines do not recommend the combined use of NSAIDs and PS, the level of evidence for this recommendation is weak, and further evidence is needed to confirm whether a multimethod combination should be performed to prevent PEP in high-risk patients.

Barriers and Perspectives to NSAID Utilization

There is still room for improvement in the current use of NSAIDs. The initial hesitance stemmed from a lack of compelling evidence and authoritative guidelines, which limited the broader acceptance of NSAIDs [76]. Even after NSAIDs received endorsement in the 2010 ESGE guidelines, their adoption rate stabilized at around 50%. This plateau can be attributed to slow guideline adaptation. Smith suggested that this may be correlated with insufficient local suppliers of indomethacin in smaller endoscopy centers, as rural community hospitals resulted in lower usage [80]. In addition, a 2016 survey found a negative correlation between the number of ERCPs performed by endoscopists annually and compliance with NSAIDs usage guidelines [84]. Similarly, research by Avila et al. found NSAID utilization below 50% at large endoscopy centers [83], possibly due to a greater focus on complex ERCP procedures over PEP prevention in medium- and low-risk patients.

Addressing these barriers to enhance NSAID adoption for PEP prevention requires a comprehensive strategy. Efforts to streamline guidelines, facilitate knowledge exchange through academic forums, and emphasize the importance of research across various settings are crucial steps toward optimizing the use of NSAIDs in PEP prevention.

Cost Analysis of Rectal NSAIDs Therapy

Despite the growing body of evidence for the effectiveness of PEP prevention strategies, only a limited number of studies have examined their cost-effectiveness.

In 2013, Elmunzer et al. performed a post hoc analysis of a large RCT of high-risk patients. The incidences of PEP in patients who received no prophylaxis, stent prophylaxis only, combination prophylaxis with indomethacin and a PS, or indomethacin prophylaxis only were 23.1, 15.7, 9.5, and 7.1%, respectively. The cost-effectiveness analysis showed that indomethacin alone saved $85 million per year compared to combination therapy, with an average savings of $1472.40 per patient [56]. Echoing Elmunzer's findings, a 2015 decision analysis by Nicolás-Pérez et al., examining the same four prevention strategies in a simulated cohort of 300 patients, reinforced the cost-effectiveness of rectal NSAID administration as the most prudent prophylactic approach for averting PEP [88].

However, a notable escalation in the cost of rectal indomethacin suppositories in the United States, soaring from $8 to $340 by 2022, prompted Thiruvengadam et al. to reassess the economic viability of PEP prophylactic measures through two separate decision-tree analyses. The study concluded that in both high- and average-risk patients, rectal indomethacin remained a cost-effective strategy when directly compared with other prevention methods, which underscored the enduring economic viability of rectal indomethacin against a backdrop of escalating costs [89].

This spiraling cost of indomethacin, which has surged by 5600% over the past decade, imposing an additional financial burden of $191 million for PEP prevention in average-risk patients compared to foregoing prophylaxis, casts a shadow over the affordability and accessibility of effective PEP prevention [90]. Such exponential price inflation not only jeopardizes patient care quality but also erodes trust in the healthcare system [91]. To address this issue, McKee et al. suggested potential solutions, including the legislative involvement of the government in drug price regulation under the 2017 FDA Reauthorization Act, the use of compounding pharmacies, and importing drugs from other countries [90].

In light of cost-effectiveness analysis, the exorbitant pricing in markets like the United States may necessitate more studies to reevaluate the most beneficial prophylactic strategies. Efforts must be directed toward identifying and implementing strategies to curb the rising costs of NSAIDs, ensuring their accessibility and affordability for all patients in need of PEP prevention.

Conclusion

1. For high-risk patients, indomethacin or diclofenac are both effective. In unselected patients, diclofenac might be the first choice to prevent PEP.

2. For the dose of NSAIDs in preventing PEP, we recommend 100 mg, lower dose, or double dose were proved ineffective in many studies.

3. Based on our research, the timing of using NSAIDs might not be the determining factor, as there is no difference between preoperative and postoperative.

4. NSAIDs combined with aggressive hydration with LR is potentially more effective, further clinical validation are still needed.

5. NSAIDs combined with PS added no benefit, while PS may be added for patients at high risk due to specific manipulations.

6. NSAIDs combined with nitrates are potentially more effective, however, it is questioned for serious complications primarily include hypotension and headache.

7. NSAIDs combined with topical epinephrine potentially increase the incidence of PEP by constricting blood vessels and antagonizing the effects of NSAIDs.

8. NSAIDs combined with somatostatin are potentially more effective, it should be considered in high-risk patients experiencing complex ERCPs.

9. The usage rate of NSAIDs is increasing year by year, with no significant change in the overall incidence of PEP. There is still room for improvement in the utilization rate of NSAIDs, and improving guideline dissemination and physician compliance is crucial.

10. Preventing PEP with NSAIDs is cost-beneficial for all patients, especially in countries with low-cost NSAIDs. Strategies to mitigate NSAID cost inflation must be rigorously developed and executed.

Author’s contributions

Conception and design: PL, JZ, HL. Article drafting: JZ. Critical revision: PL, SZ. Final approval of the version: JZ, HL, PL, SZ.

Funding Source

Beijing Hospitals Authority "Dengfeng" talent training plan (DFL20220101), National Key R&D Program of China (2023YFC2507400).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing financial interests.

Consent to participate

We obtained written consent from the patient.