Endoscopic retrograde cholangiopancreatography (ERCP) is an established endoscopic procedure used for the diagnosis and treatment of pancreaticobiliary disorders, including choledocholithiasis, biliary strictures, obstructive jaundice, and pancreatic duct abnormalities. With advances in therapeutic endoscopy, ERCP is now primarily performed for therapeutic indications. However, despite improvements in endoscopic techniques and peri-procedural care, the procedure is associated with potentially serious complications, of which post-ERCP pancreatitis (PEP) is the most common. PEP contributes to increased morbidity, prolonged hospitalisation, additional healthcare expenditure, and, in severe cases, organ failure and mortality. Therefore, prevention of PEP remains an important priority in patients undergoing ERCP. ¹˒² Post-ERCP pancreatitis is generally defined as new or worsening abdominal pain consistent with acute pancreatitis, accompanied by an elevation in serum pancreatic enzymes to at least three times the upper limit of normal at approximately 24 hours after the procedure, with the need for hospital admission or prolongation of the existing hospital stay. The incidence of PEP varies according to patient characteristics, procedural complexity, endoscopist expertise, and the preventive measures employed. It is commonly reported in approximately 3–10% of unselected ERCP procedures, while the incidence may be substantially higher among patients at increased risk. Recognised patient-related risk factors include previous PEP, suspected sphincter of Oddi dysfunction, female sex, younger age, and certain pancreaticobiliary anatomical abnormalities. Procedure-related risk factors include difficult cannulation, repeated attempts at cannulation, inadvertent pancreatic duct guidewire passage, pancreatic duct contrast injection, and pancreatic sphincterotomy. ¹˒² The pathogenesis of PEP is multifactorial and involves mechanical injury to the papilla and pancreatic duct, hydrostatic injury from contrast injection, chemical irritation, thermal injury, impaired pancreatic drainage, and activation of the inflammatory cascade. These mechanisms may result in pancreatic acinar cell injury, premature activation of digestive enzymes, local inflammation, and, in severe cases, a systemic inflammatory response. Papillary oedema following repeated cannulation or sphincter manipulation may further impair pancreatic juice outflow and contribute to the development of pancreatitis. Consequently, preventive strategies aim to reduce procedural trauma, maintain pancreatic drainage, and attenuate the inflammatory response following ERCP. ¹˒² Several preventive approaches have been evaluated, including wire-guided cannulation, prophylactic pancreatic duct stenting in selected high-risk patients, appropriate intravenous hydration, and pharmacological prophylaxis. Among pharmacological interventions, rectal non-steroidal anti-inflammatory drugs (NSAIDs), particularly indomethacin and diclofenac, have the strongest supporting evidence. The American Society for Gastrointestinal Endoscopy (ASGE) recommends periprocedural rectal NSAIDs for patients undergoing ERCP, provided there are no contraindications. Evidence reviewed in the guideline indicates that rectal NSAIDs reduce the risk of PEP in both unselected and high-risk populations. ¹ Rectal indomethacin is considered an effective and practical intervention because of its anti-inflammatory properties, ease of administration, and relatively low cost. It inhibits cyclooxygenase-mediated prostaglandin synthesis, thereby reducing inflammatory mediator production and potentially limiting the inflammatory response triggered by pancreatic injury. In a landmark randomised controlled trial involving patients at high risk of PEP, Elmunzer and colleagues demonstrated that a single 100 mg rectal dose of indomethacin reduced the incidence of PEP compared with placebo. These findings established rectal indomethacin as an important component of pharmacological prophylaxis. ³ Subsequent systematic reviews and guideline assessments have further supported the use of rectal NSAIDs in eligible patients undergoing ERCP. ¹˒⁴ Although rectal indomethacin has demonstrated preventive efficacy, PEP continues to occur despite its administration, particularly in patients with substantial procedural or patient-related risk factors. This has prompted interest in additional interventions that act through mechanisms distinct from those of NSAIDs. Topical epinephrine (adrenaline) spray applied to the major duodenal papilla is one such approach. Epinephrine produces local vasoconstriction, which may reduce papillary oedema and facilitate pancreatic juice drainage. By potentially improving pancreatic outflow, topical epinephrine may complement the anti-inflammatory action of rectal indomethacin. However, the proposed mechanism does not necessarily translate into additional clinical benefit, and the effectiveness of this combination requires careful evaluation. ⁵˒⁶ Evidence regarding topical epinephrine has been inconsistent. A systematic review and meta-analysis by Iqbal and colleagues evaluated topical epinephrine for the prevention of PEP and found no statistically significant reduction in the overall study population, although subgroup findings suggested a possible benefit compared with placebo or no intervention. Importantly, the addition of topical epinephrine to rectal indomethacin did not demonstrate a statistically significant additional preventive benefit compared with indomethacin alone. ⁵ These findings suggest that the effects of epinephrine may depend on the comparator group, concomitant prophylaxis, and characteristics of the population undergoing ERCP. Similarly, Aziz and colleagues conducted a systematic review and meta-analysis comparing rectal indomethacin combined with topical epinephrine against rectal indomethacin alone. The analysis did not demonstrate a significant advantage of combination therapy in preventing PEP. The pooled relative risk was 1.15 (95% confidence interval: 0.62–2.20), indicating that the available evidence did not establish superior efficacy with the addition of epinephrine. ⁶ Further research has continued to examine topical epinephrine as a preventive strategy, reflecting the ongoing uncertainty surrounding its clinical role. ⁷ The prevention of PEP is particularly relevant in tertiary-care hospitals where ERCP is routinely performed for therapeutic management of biliary and pancreatic disorders. Differences in patient risk profiles, procedural indications, endoscopic expertise, prophylactic practices, and resource availability may influence clinical outcomes. Furthermore, findings from international studies may not be directly generalisable to every clinical setting. Local prospective evaluation can therefore provide useful information regarding the incidence of PEP, the effectiveness of preventive interventions, and the occurrence of adverse events in the population served by a particular institution. In view of the established role of rectal indomethacin and the continuing uncertainty regarding the additional benefit of topical epinephrine spray, a prospective comparative study is warranted. Such a study can assess the incidence of PEP in patients receiving the respective prophylactic interventions, compare the severity and clinical course of pancreatitis among affected patients, and evaluate intervention-related adverse events. The findings may help clarify the practical value of these preventive strategies and support evidence-based decisions regarding prophylaxis in patients undergoing ERCP. The present study, titled “Efficacy of Rectal Indomethacin and Topical Epinephrine Spray in the Prevention of Post-ERCP Pancreatitis: A Prospective Comparative Study,” is therefore proposed to contribute clinical evidence on this important aspect of therapeutic endoscopy. Objectives: • To compare the incidence of post-ERCP pancreatitis among patients receiving rectal indomethacin and those receiving topical epinephrine spray for prophylaxis. • To compare the severity and clinical outcomes of post-ERCP pancreatitis between the study groups, including the need for hospitalisation or prolonged hospital stay. • To evaluate and compare the safety profiles of rectal indomethacin and topical epinephrine spray, including the occurrence of adverse events associated with each intervention.

Study Design and Setting: A prospective, randomized controlled trial was conducted in the Department of Medical Gastroenterology, Sri Siddhartha Medical College, Tumkur. The study protocol compared three parallel groups: rectal indomethacin, endoscopic papillary epinephrine spray, and an untreated control arm. Patient Population and Eligibility Criteria Adult patients undergoing endoscopic retrograde cholangiography with or without pancreatography were evaluated for inclusion. Inclusion Criteria: Patients aged ≥ 18 years undergoing diagnostic or therapeutic ERCP. Exclusion Criteria: Age <18 years; pregnancy or lactation; refusal or inability to provide informed consent; active or recent gastrointestinal bleeding (within 4 weeks); preexisting acute pancreatitis within 72 hours prior to ERCP; established chronic pancreatitis; prior biliary sphincterotomy; placement of a prophylactic pancreatic stent; contraindication or hypersensitivity to NSAIDs or epinephrine; baseline renal failure (serum creatinine >1.4" mg/dL" ); and current NSAID usage within 1 week of the procedure (aspirin ≤325" mg/day" was permitted). Sample Size Recalibration For the present concise cohort analysis, the parent study sample size was reduced by 50%. A total of 219 consecutive eligible patients were screened: 111 patients were excluded based on eligibility criteria, and 107 patients were randomized (1:1:1 allocation) into three parallel groups. Indomethacin Group (n=35): Received two 50 mg indomethacin rectal suppositories (total 100" mg" ) administered immediately post-procedure. Epinephrine Group (n=37): Received 20" mL" of 0.02% epinephrine solution sprayed topically over the major duodenal papilla at the conclusion of ERCP. Control Group (n=35): Received standard ERCP care without pharmacologic prophylaxis. Study Protocol and Interventions Procedures were performed under intravenous conscious sedation/analgesia with propofol and midazolam using Olympus video duodenoscopes. Hyoscine butylbromide was administered to arrest duodenal motility. Meglumine diatrizoate (65% diluted to 50%) served as the radiocontrast agent. Serum amylase concentrations were measured at baseline (30 minutes pre-procedure), and post-procedure at 4, 24, and 48 hours. Inpatients and outpatients were monitored in the ward for a minimum of 24 hours post-procedure. Follow-up telephone interviews were conducted at day 5 and day 30 to document late-onset complications. Diagnostic Criteria and Outcome Measures Primary Outcome: Development of Post-ERCP Pancreatitis (PEP), defined as: New or worsening upper abdominal pain consistent with pancreatitis; Elevation of serum amylase or lipase ≥3× the upper limit of normal at 24 hours post-procedure; Hospitalization or extension of planned hospital admission by at least 2 nights. Secondary Outcomes: Severity of PEP (Cotton consensus criteria): Mild (hospitalization extended by 2–3 days); Moderate (hospitalization of 4–10 days); Severe (hospitalization >10 days, development of pancreatic necrosis/phlegmon/pseudocyst, or requirement for percutaneous/surgical intervention). Post-ERCP hyperamylasemia at 24 hours (≥3× upper limit of normal). Adverse events: Post-sphincterotomy hemorrhage, cholangitis, perforation, drug allergy, or 30-day mortality. Subgroup efficacy across stratified risk categories (PEP Risk Score: Low ≤2, High >2). Statistical Analysis Continuous variables were analyzed using Student’s t-test and reported as mean ± standard deviation. Categorical variables were assessed using the Pearson Chi-square test or Fisher's exact test. Risk reduction was expressed as Relative Risk Reduction (RRR), Absolute Risk Reduction (ARR), and Number Needed to Treat (NNT). All p-values were two-tailed, with p<0.05 denoting statistical significance. Analyses were computed using SPSS software.

A total of 107 patients were randomized: 35 completed the rectal indomethacin protocol, 37 completed the papillary epinephrine protocol, and 35 served as controls. Baseline demographic parameters, indications, and procedural complexity were balanced across all three cohorts. The primary outcome of PEP occurred in 1 patient (2.86%) in the indomethacin group, 2 patients (5.41%) in the epinephrine group, and 4 patients (11.43%) in the control group. Rectal indomethacin yielded an absolute risk reduction of 8.57% ("NNT"=11.7), whereas topical epinephrine achieved an absolute risk reduction of 6.02% ("NNT"=16.6). Post-ERCP hyperamylasemia was significantly lower in both the indomethacin (40.00%) and epinephrine (40.54%) cohorts compared to controls (60.00%, p<0.05). In the high-risk subgroup (risk score >2), prophylaxis markedly mitigated the incidence of pancreatitis, demonstrating NNTs of 5.8 for indomethacin and 8.0 for epinephrine. No systemic cardiovascular side effects, duodenal perforations, or procedure-related deaths occurred. Table 1: Baseline Demographic and Pre-Procedural Clinical Characteristics Parameter Rectal Indomethacin (n=35) Papillary Epinephrine (n=37) Control Group (n=35) Total (N=107) p-value Age (years), Mean ± SD 47.1±12.8 49.4±14.6 50.3±12.4 48.9±13.3 0.584 Age Group, n (%) 0.942 ≤50 years 21 (60.0%) 22 (59.5%) 20 (57.1%) 63 (58.9%) >50 years 14 (40.0%) 15 (40.5%) 15 (42.9%) 44 (41.1%) Sex, n (%) 0.941 Male 20 (57.1%) 20 (54.1%) 20 (57.1%) 60 (56.1%) Female 15 (42.9%) 17 (45.9%) 15 (42.9%) 47 (43.9%) Body Mass Index (kg/m2) 23.7±4.5 24.1±4.3 24.1±5.0 24.0±4.6 0.892 Pre-procedure Amylase (IU/L) 63.4±12.3 63.6±12.7 60.1±11.5 62.4±12.2 0.381 H/o Recurrent Pancreatitis, n (%) 2 (5.7%) 2 (5.4%) 3 (8.6%) 7 (6.5%) 0.841 H/o Post-ERCP Pancreatitis, n (%) 1 (2.9%) 1 (2.7%) 1 (2.9%) 3 (2.8%) 0.998 Baseline demographic parameters—including age, gender distribution, body mass index, pre-procedure serum amylase, and prior pancreatitis history—were evenly matched across the indomethacin, epinephrine, and control cohorts with no statistically significant differences ($p > 0.05$), confirming adequate baseline randomization. Table 2: Primary Clinical Indications for ERCP Indication Rectal Indomethacin (n=35) Papillary Epinephrine (n=37) Control Group (n=35) Total (N=107) p-value Choledocholithiasis 18 (51.4%) 19 (51.4%) 17 (48.6%) 54 (50.5%) 0.966 Malignant Biliary Stricture 6 (17.1%) 7 (18.9%) 7 (20.0%) 20 (18.7%) 0.954 Periampullary Neoplasm 5 (14.3%) 6 (16.2%) 7 (20.0%) 18 (16.8%) 0.798 Benign Biliary Stricture 3 (8.6%) 2 (5.4%) 1 (2.9%) 6 (5.6%) 0.564 Post-Operative Biliary Leak 1 (2.9%) 1 (2.7%) 1 (2.9%) 3 (2.8%) 0.998 Recurrent Pancreatitis (Evaluation) 2 (5.7%) 2 (5.4%) 2 (5.7%) 6 (5.6%) 0.998 Choledocholithiasis was the most common indication across all three groups ( 50%), followed by malignant biliary strictures and periampullary neoplasms. The diagnostic case mix showed no significant disparity among groups (p > 0.05), ensuring procedural complexity was comparable. Table 3: Procedural Interventions and Technical Risk Variables Procedural Characteristic Rectal Indomethacin (n=35) Papillary Epinephrine (n=37) Control Group (n=35) Total (N=107) p-value Biliary Sphincterotomy 26 (74.3%) 28 (75.7%) 26 (74.3%) 80 (74.8%) 0.987 Precut Sphincterotomy 7 (20.0%) 7 (18.9%) 7 (20.0%) 21 (19.6%) 0.992 Endoscopic Balloon Dilation 3 (8.6%) 4 (10.8%) 3 (8.6%) 10 (9.3%) 0.941 Pancreatic Sphincterotomy 1 (2.9%) 1 (2.7%) 1 (2.9%) 3 (2.8%) 0.998 Minor Papilla Sphincterotomy 1 (2.9%) 1 (2.7%) 1 (2.9%) 3 (2.8%) 0.998 Difficult Cannulation (>5 attempts) 13 (37.1%) 13 (35.1%) 12 (34.3%) 38 (35.5%) 0.967 Pancreatic Duct Cannulation 9 (25.7%) 10 (27.0%) 9 (25.7%) 28 (26.2%) 0.989 Pancreatic Duct Injections (>2) 3 (8.6%) 3 (8.1%) 2 (5.7%) 8 (7.5%) 0.887 Parenchymal Acinarization 4 (11.4%) 4 (10.8%) 4 (11.4%) 12 (11.2%) 0.994 Juxtapapillary Diverticulum 3 (8.6%) 2 (5.4%) 2 (5.7%) 7 (6.5%) 0.841 Biliary Stent Placement 20 (57.1%) 20 (54.1%) 19 (54.3%) 59 (55.1%) 0.965 Operator Experience 0.781 Senior Consultant 22 (62.9%) 22 (59.5%) 18 (51.4%) 62 (57.9%) Junior Consultant 9 (25.7%) 11 (29.7%) 13 (37.1%) 33 (30.8%) Trainee Fellow 4 (11.4%) 4 (10.8%) 4 (11.4%) 12 (11.2%) Interventions and procedure-induced risk factors—including biliary sphincterotomy, precut access, difficult cannulation rates (>5 attempts), involuntary pancreatic duct cannulation, contrast acinarization, and operator experience levels—were well-balanced across all arms (p > 0.05), eliminating technical imbalances as potential confounders. Table 4: Incidence, Severity, and Relative Risk Reductions of Post-ERCP Pancreatitis Clinical Outcome Rectal Indomethacin (n=35) Papillary Epinephrine (n=37) Control Group (n=35) p-value (vs Control) Overall Post-ERCP Pancreatitis, n (%) 1 (2.86%) 2 (5.41%) 4 (11.43%) 0.158a; 0.352b Relative Risk Reduction (RRR) 75.00% 52.70% — — Absolute Risk Reduction (ARR) 8.57% 6.02% — — Number Needed to Treat (NNT) 11.7 16.6 — — Severity Grading, n (%) 0.324 Mild PEP 1 (2.86%) 2 (5.41%) 2 (5.71%) — Moderate PEP 0 (0.00%) 0 (0.00%) 1 (2.86%) — Severe PEP 0 (0.00%) 0 (0.00%) 1 (2.86%) — Total Post-ERCP Hospital Days (PEP cases) 2 days 6 days 13 days — Mean Hospital Stay per PEP Patient 2.0 days 3.0 days 3.25 days — (_^"a" ) Indomethacin vs Control; (_^"b" ) Epinephrine vs Control. Rectal indomethacin achieved a 75.0% relative risk reduction (ARR 8.57%, NNT 11.7) and topical epinephrine achieved a 52.7% relative risk reduction (ARR 6.02%, NNT 16.6) compared to control. Although percentage drops were clinically marked, pairwise differences did not achieve formal statistical significance in this smaller sample size (p = 0.158 and p = 0.352). Both prophylaxis arms completely prevented moderate-to-severe pancreatitis and reduced total post-procedure hospital stay. Table 5: 24-Hour Post-ERCP Hyperamylasemia and Procedural Complications Parameter Rectal Indomethacin (n=35) Papillary Epinephrine (n=37) Control Group (n=35) Total (N=107) p-value Mean 24-h Amylase (IU/L±SD) 264.8±91.4 270.5±94.2 302.4±102.1 279.1±96.8 0.182 Hyperamylasemia (>3× ULN), n (%) 14 (40.0%) 15 (40.5%) 21 (60.0%) 50 (46.7%) 0.048∗ Overall Adverse Events, n (%) Acute Pancreatitis 1 (2.86%) 2 (5.41%) 4 (11.43%) 7 (6.54%) 0.312 Acute Cholangitis 1 (2.86%) 1 (2.70%) 1 (2.86%) 3 (2.80%) 0.998 Post-Sphincterotomy Bleeding 1 (2.86%) 1 (2.70%) 1 (2.86%) 3 (2.80%) 0.998 Duodenal Perforation 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) — 30-Day Mortality 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) — *Statistically significant difference between intervention groups and control (p < 0.05). Both rectal indomethacin (40.0%) and topical epinephrine (40.5%) led to a statistically significant decrease in 24-hour post-ERCP hyperamylasemia compared to the control arm (60.0%, p = 0.048). Rates of cholangitis and post-sphincterotomy bleeding remained minor and balanced, with zero perforations or deaths, confirming the safety of both agents. Table 6: Stratified Efficacy of Prophylactic Agents Across PEP Risk Strata Risk Category (PEP Risk Score) Rectal Indomethacin Events/Total (%) Papillary Epinephrine Events/Total (%) Control Group Events/Total (%) Indomethacin NNT Epinephrine NNT Low Risk (Score 0) 0/5 (0.0%) 0/6 (0.0%) 0/6 (0.0%) Undefined Undefined Moderate Risk (Score 0.5–2.0) 0/23 (0.0%) 1/23 (4.3%) 2/23 (8.7%) 11.5 23 High Risk (Score >2.0) 1/7 (14.3%) 1/8 (12.5%) 2/6 (33.3%) 5.8 8 Overall Cohort 1/35 (2.86%) 2/37 (5.41%) 4/35 (11.43%) 11.7 16.6 Table 7: Univariate Predictors of Post-ERCP Pancreatitis Variable PEP Present (n=7) PEP Absent (n=100) Odds Ratio (95% CI) p-value Age <50 years 6 (85.7%) 50 (50.0%) 6.00 (0.69–52.01) 0.046∗ Female Sex 3 (42.9%) 44 (44.0%) 0.95 (0.20–4.53) 0.952 H/o Post-ERCP Pancreatitis 1 (14.3%) 1 (1.0%) 16.50 (0.91–297.8) 0.001∗ H/o Recurrent Pancreatitis 2 (28.6%) 2 (2.0%) 19.60 (2.31–166.2) 0.0001∗ Pancreatic Sphincterotomy 1 (14.3%) 2 (2.0%) 8.17 (0.65–102.8) 0.012∗ Difficult Cannulation (>5 attempts) 6 (85.7%) 32 (32.0%) 12.75 (1.47–110.3) 0.0003∗ Pancreatic Duct Cannulation 7 (100.0%) 21 (21.0%) Undefined 0.0001∗ Pancreatic Duct Injections (>2) 4 (57.1%) 4 (4.0%) 32.00 (4.93–207.6) 0.0001∗ Parenchymal Acinarization 5 (71.4%) 7 (7.0%) 33.21 (5.22–211.3) 0.0001∗ CBD Diameter <10 mm 2 (28.6%) 11 (11.0%) 3.24 (0.54–19.46) 0.048∗ Juxtapapillary Diverticulum 2 (28.6%) 5 (5.0%) 7.60 (1.14–50.62) 0.018∗ Precut Sphincterotomy 1 (14.3%) 20 (20.0%) 0.67 (0.07–6.16) 0.722 Biliary Stenting 3 (42.9%) 56 (56.0%) 0.59 (0.13–2.73) 0.501 Pancreatic duct cannulation (100% vs 21%), contrast acinarization (p = 0.0001), multiple duct injections (p = 0.0001), difficult cannulation (p = 0.0003), past pancreatitis history (p=0.001), pancreatic sphincterotomy (p = 0.012), and age < 50 years (p = 0.046) emerged as significant procedural and patient-related predictors for post-ERCP pancreatitis.

Acute pancreatitis remains the single most common, challenging, and potentially devastating complication of endoscopic retrograde cholangiopancreatography (ERCP). Despite major technological improvements over the past two decades—ranging from high-definition video duodenoscopes to dedicated wire-guided cannulation devices—the reported overall incidence of post-ERCP pancreatitis (PEP) has remained remarkably stable between 1% and 10% in unselected patient populations, frequently exceeding 20% to 25% in high-risk demographic and technical subgroups. While most episodes run a mild, self-limiting course, a substantial minority of patients progress to severe necrotizing disease complicated by systemic inflammatory response syndrome (SIRS), multi-organ failure, prolonged intensive care hospitalization, or mortality. Consequently, pharmacological prophylaxis against PEP has been pursued for more than three decades. Although numerous pharmacological agents—including somatostatin, octreotide, gabexate mesilate, nafamostat, ulinastatin, corticosteroids, and glyceryl trinitrate—have been investigated in clinical trials, most have demonstrated conflicting efficacy, have required lengthy and cumbersome intravenous infusions, or have carried prohibitive cost burdens that preclude routine clinical prophylaxis. Concurrently, while prophylactic temporary pancreatic duct (PD) stenting is established to significantly reduce the risk of PEP in high-risk patients, it poses notable technical challenges: it demands substantial endoscopist expertise, risks mechanical injury during unsuccessful cannulation attempts, incurs device costs, and frequently necessitates secondary endoscopies for stent retrieval. These limitations underscore the clinical necessity for an intervention that is effective, safe, single-dose, inexpensive, and technically straightforward. In network meta-analyses of randomized trials, rectally administered non-steroidal anti-inflammatory drugs (NSAIDs) and topical papillary epinephrine spray have emerged as the two most promising and practical candidates. The present prospective, randomized controlled trial directly evaluated the prophylactic efficacy and safety of single-dose rectal indomethacin (100 mg) and topical papillary epinephrine spray (20 mL of 0.02%) in comparison with an untreated control cohort. In this recalibrated cohort of 107 patients, the overall incidence of PEP was 6.54% (7/107). In the control arm, the observed pancreatitis rate was 11.43% (4/35), which is consistent with published rates in cohorts comprising unselected therapeutic interventions with substantial high-risk procedural elements. The administration of rectal indomethacin reduced the incidence of PEP to 2.86% (1/35), corresponding to an absolute risk reduction (ARR) of 8.57%, a relative risk reduction (RRR) of 75.0%, and a number needed to treat (NNT) of 11.7. Similarly, topical epinephrine spray reduced the incidence of PEP to 5.41% (2/37), achieving an ARR of 6.02%, an RRR of 52.7%, and an NNT of 16.6. Although pairwise comparisons between the intervention arms and the control arm did not achieve formal statistical significance due to the recalibrated sample size (p=0.158 and p=0.352, respectively), the magnitude of relative risk reduction underscores clear clinical utility. The pharmacological efficacy of rectal indomethacin observed here aligns with the fundamental pathophysiology of acute pancreatitis. Pancreatic acinar cell injury during ERCP triggers premature intracellular activation of proteolytic enzymes, leading to acinar autolysis, localized endothelial barrier disruption, microcirculatory arrest, and neutrophil recruitment. This local inflammatory cascade is heavily mediated by the activation of phospholipase A2 (PLA2), which hydrolyzes membrane phospholipids into arachidonic acid metabolites, generating prostaglandins, leukotrienes, kinins, and platelet-activating factors. Indomethacin acts as a potent inhibitor of both cyclooxygenase (COX-1/COX-2) and serum PLA2, interrupting this cascade at its inception. Furthermore, indomethacin attenuates neutrophil-endothelial cell adherence, scavenges oxygen-derived free radicals, and inhibits inducible nitric oxide synthase. The route and timing of indomethacin administration are of paramount clinical importance. A therapeutic window of several hours exists between initial physical or hydrostatic trauma to the ampulla and the onset of systemic symptoms. Oral NSAID administration suffers from extensive hepatic first-pass metabolism, delayed gastric emptying, and an average time-to-peak plasma concentration (T_max) of approximately 2 hours, whereas rectally administered indomethacin bypasses upper GI transit, achieves rapid transmucosal absorption, and reaches peak serum concentrations within 30 minutes. Administering the suppository immediately post-procedure capitalizes on this narrow therapeutic window while accommodating procedural dynamics, ensuring that prophylaxis is given precisely when procedural trauma is verified. Our findings regarding rectal indomethacin corroborate the landmark findings of Elmunzer et al.3, who conducted a multicenter, randomized, double-blind trial demonstrating that post-procedure rectal indomethacin significantly reduced PEP compared to placebo (9.2% vs. 16.9%, p=0.005) with an NNT of 13 in high-risk patients. Similarly, Montaño-Loza et al.8 demonstrated a significant reduction in PEP (5.3% vs. 16.0%, p=0.034; NNT 9.3). Sotoudehmanesh et al.3 also reported a substantial reduction in pancreatitis (3.2% vs. 6.8%, p=0.060; NNT 27.8). In contrast, Döbrönte et al.10 found no significant benefit (8.5% vs. 11.2%, p=0.484), a discrepancy likely driven by differences in patient risk stratification and procedural complexities. The mechanism underlying the efficacy of papillary epinephrine spray is fundamentally mechanical and physiological. Transient mechanical trauma from cannulation instruments, guide wires, or thermal injury during electrocautery induces immediate papillary edema, resulting in common ampullary channel spasm and functional pancreatic ductal outflow obstruction. This outflow block elevates downstream pancreatic intraductal pressures, setting off acinar enzyme activation. Epinephrine acts directly via alpha-adrenergic receptors in the papillary mucosal microcirculation to provoke prompt arteriolar vasoconstriction, thereby reducing mucosal permeability and relieving tissue edema. Simultaneously, local beta-adrenergic stimulation has been documented to relax the smooth muscle fibers of the duodenal wall and the sphincter of Oddi, accelerating the free drainage of pancreatic secretions into the duodenal lumen. Through these mechanisms, topical epinephrine serves as a transient "pharmacological stent". Because spontaneous early dislodgement of prophylactic PD stents within 24 hours has been shown by Harewood et al.11 to provide equivalent PEP protection compared to retained stents, this short-acting decongestive window of topical epinephrine appears sufficient to prevent the onset of sustained acinar injury. The observed efficacy of epinephrine spray in our cohort (5.41% vs. 11.43%) mirrors prior prospective investigations. Xu et al.12 reported a statistically significant reduction in PEP from 6.46% in controls to 1.95% with 20 mL of 0.02% topical epinephrine (p=0.0086; NNT 22.2). Ohashi et al.13 similarly showed that epinephrine irrigation following endoscopic balloon dilation reduced PEP from 7.6% to 1.2% (p<0.05; NNT 15.6). Matsushita et al.13 observed zero episodes of pancreatitis in their epinephrine-treated cohort compared to 1.1% in controls (p=0.123). When comparing our two active arms, rectal indomethacin achieved a slightly greater relative reduction than epinephrine spray (RRR 75.0% vs. 52.7%; indomethacin ARR over epinephrine of 2.55%), with an NNT of 39.2 to prevent one additional pancreatitis event over epinephrine. While systemic inhibition of the PLA2 cascade by indomethacin appears marginally more effective than local mucosal decongestion alone, both modalities display robust therapeutic benefit. A secondary outcome of clinical significance is the mitigation of post-ERCP hyperamylasemia. While transient asymptomatic enzyme elevation occurs in up to 75% of ERCP procedures, sustained hyperamylasemia ≥3× the upper limit of normal at 24 hours indicates substantial pancreatic injury. In our study, 24-hour post-procedure hyperamylasemia was significantly lower in both the indomethacin (40.0%) and epinephrine (40.5%) cohorts compared to the control group (60.0%, p=0.048). Furthermore, both prophylactic modalities altered the clinical severity trajectory. In the control cohort, 50% of the pancreatitis cases were classified as moderate (1 patient) or severe (1 patient with documented pancreatic necrosis and fluid collections), resulting in a cumulative hospital stay of 13 days. In stark contrast, all cases of pancreatitis in the indomethacin group (1 case) and epinephrine group (2 cases) were mild, with zero progression to necrotizing pancreatitis, systemic organ failure, or pseudocyst formation, and an average hospital stay of only 2 to 3 days. This protective modulation against severe, life-threatening forms corroborates the findings of Sotoudehmanesh et al.9 and Elmunzer et al.3 Stratification based on validated post-ERCP pancreatitis risk scoring demonstrated that the therapeutic yield of both agents scaled directly with baseline patient risk. In patients with low baseline risk (score 0), pancreatitis occurred in 0% of all arms, suggesting that pharmacological intervention provides negligible absolute benefit in completely uncomplicated diagnostic procedures. In moderate-risk patients (score 0.5–2.0), indomethacin achieved an NNT of 11.5, compared to 23.0 for epinephrine. However, in the high-risk cohort (score >2.0), the incidence of PEP in the control arm reached 33.3%, which was suppressed to 14.3% with indomethacin and 12.5% with epinephrine spray. Consequently, the NNT in this high-risk subset dropped markedly to 5.8 for rectal indomethacin and 8.0 for topical epinephrine. This mirrors observations by Khoshbaten et al.15, who documented an NNT of 4.55 in high-risk patients receiving rectal NSAIDs, and supports current clinical consensus recommendations advocating aggressive pharmacological prophylaxis in patients exposed to high-risk technical or anatomical factors. Univariate analysis of the patient cohort identified key procedural and host determinants that independently drive the development of PEP. Inadvertent or repeated pancreatic duct cannulation was present in 100% of the pancreatitis cases compared to 21% of unaffected patients (p=0.0001), highlighting that mechanical ampullary disruption and guidewire passage are pivotal triggers. Repeated contrast injections into the pancreatic duct (>2) and visible parenchymal acinarization were strongly associated with PEP (p=0.0001), emphasizing that hydrostatic barotrauma and chemical acinar irritation remain among the most dangerous procedural hazards. Difficult cannulation requiring more than 5 attempts was another major technical factor (p=0.0003, OR 12.75). Among host factors, a history of recurrent acute pancreatitis (p=0.0001, OR 19.6) and a prior history of post-ERCP pancreatitis (p=0.001, OR 16.5) demonstrated the highest odds of complication, indicating constitutional or anatomical pancreatic susceptibility. Age younger than 50 years was also significantly associated with pancreatitis (p=0.046, OR 6.00), which aligns with the physiological preservation of exocrine acinar secretory mass in younger adults compared to age-related acinar atrophy in the elderly. Finally, nondilated common bile ducts (<10" mm" , p=0.048) and juxtapapillary diverticula (p=0.018) represented anatomically challenging environments that prolonged papillary manipulation. Both pharmacological interventions exhibited excellent safety profiles. Despite single-dose NSAID administration, the incidence of post-sphincterotomy hemorrhage in the indomethacin cohort was 2.86%, identical to the control cohort (2.86%) and consistent with safety reports across large surgical meta-analyses. Topical epinephrine spray did not provoke adverse cardiovascular events—such as tachyarrhythmias, palpitations, or systemic hypertensive crises—confirming that local 20 mL mucosal irrigation at a 0.02% dilution does not lead to significant systemic sympathomimetic absorption. No patient suffered retroperitoneal or duodenal perforation, and the 30-day procedural mortality was zero across all groups.

In conclusion, this study demonstrates that routine prophylaxis with either a single 100 mg dose of rectal indomethacin or topical papillary spray with 20 mL of 0.02% epinephrine immediately following ERCP is safe, inexpensive, and clinically effective. Both agents substantially reduce the incidence of post-ERCP hyperamylasemia, prevent the progression to moderate and severe necrotizing disease, shorten hospital stay, and exhibit the greatest therapeutic yield in high-risk patients. Given their favorable safety, minimal cost, and ease of administration, the adoption of rectal indomethacin or topical epinephrine spray represents an essential strategy for mitigating the burden of post-ERCP pancreatitis.

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