The protease inhibitor gabexate is a diffusible, synthetic inhibitor of trypsin, kallikrein, and plasmin. When administered by continuous intravenous infusion, gabexate reaches a steady state within 15 minutes, with a half-life of 55 seconds [10], and is eliminated in its inactive form by the kidneys. In a RCT with 418 patients, an infusion of gabexate 30 to 90 minutes before ERCP and for 12 hours thereafter was associated with a significantly lower rate of pancreatitis (2.4%) compared with the control group (7.6%) [11]. An initial meta-analysis suggested that gabexate significantly reduced the risk of pancreatitis (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.13 to 0.57); however, the number needed to prevent one episode of pancreatitis was relatively high, at 27 [12]. A subsequent large multicenter study of gabexate in a single dose before ERCP and continued for 2 hours thereafter found no significant difference in the frequency of pancreatitis in the treatment group (8.1%) versus the placebo group (6.5%) [13]. The schedule seemed unimportant, because neither a short duration of drug infusion (less than 6 hours) nor a long one (more than 12 hours) was beneficial [9].

Ulinastatin has been studied in four RCTs as an agent to prevent PEP. In two, it was compared with a placebo, and in two it was compared with gabexate. The results of these studies are contradictory [14-17]. In one RCT that included 406 patients [15], the incidence of PEP was significantly lower with ulinastatin (150,000 U administered prior to ERCP) compared with the placebo (2.9% vs. 7.4%, p = 0.041). However, this benefit was not confirmed in another RCT in which 227 patients were randomly allocated to receive either ulinastatin (100,000 U) or a placebo immediately after ERCP (PEP incidence of 6.7% and 5.6%, respectively; p > 0.05) [17].

The inhibition of exocrine pancreatic secretion can be obtained with somatostatin and its synthetic analog, octreotide. This hormone and its analog affect exocrine function directly by reducing the secretion of digestive enzymes, and indirectly by inhibiting secretin and cholecystokinin production. In addition to their antisecretory effects, somatostatin and octreotide have been demonstrated to modulate the cytokine cascade and may also have a cytoprotective effect on pancreatic cells, although the mechanisms of their cytoprotective effect remains unknown [18]. In an initial meta-analysis, somatostatin was found to be effective (OR, 0.38; 95% CI, 0.22 to 0.65) [12]. However, in a subsequent large-scale, multicenter, placebo-controlled trial with 382 patients, Andriulli et al. [13] found that a single dose of somatostatin at 750 µg, started 30 minutes before the procedure and continued for 2 hours afterwards, was ineffective in preventing pancreatitis; pancreatitis occurred in 11.5% of patients who received somatostatin versus 6.5% of those given a placebo. A meta-analysis of somatostatin, in which data from short- and long-term infusion studies were pooled, found somatostatin to be ineffective (OR, 0.68; 95% CI, 0.44 to 1.04; p = 0.075) [13,19]. A recent study from Spain showed that a bolus dose of 250 µg of somatostatin administered immediately before introducing the catheter into the papilla of Vater, did not help prevent post-ERCP acute pancreatitis [20]. Overall, the use of somatostatin did not reduce PEP.

Octreotide, a synthetic analog of somatostatin, has a much longer half-life [21]. It decreases the secretion of pancreatic enzymes and reduces intraductal pressure, and, possibly, proteolysis. However, octreotide increases the basal pressure and frequency of phasic contractions of the sphincter of Oddi and might contribute to pancreatic outflow obstruction and, hence, pancreatitis [22]. Serum levels peak at 4 minutes after intravenous infusion and within 30 minutes after a subcutaneous dose [21]. Of the published studies of octreotide, most have shown no significant reduction in the frequency of PEP compared with a placebo [21,23,24].

NG is a nitric oxide donor with potent relaxant effects on smooth muscle, including the sphincter of Oddi [25]. The use of a low-cost drug such as NG to reduce the incidence of PEP is interesting in view of the potentially fatal cases that could be prevented. The influence of NG on the incidence of PEP was evaluated in two meta-analyses that pooled data from five RCTs involving 1,662 patients [26,27]. The studies were homogeneous, and both meta-analyses showed an overall significant reduction in PEP. In most patients, NG was administered transdermally. When the subanalysis was restricted to these patients, transdermal NG failed to show a significant reduction in PEP [9]. The use of NG was associated with a significant risk of transient hypotension and headache.

PDE-5 inhibitor is a smooth muscle relaxant. Beyond its original indication for erectile dysfunction [28] and other vascular diseases, including pulmonary artery hypertension [29] and Raynaud's phenomenon [30], clinical investigations have been expanded to include hypercontractile esophageal motility disorders [31] and biliary SOD [32]. PDE-5 inhibitor reduces basal sphincter of Oddi pressure [32]. The administration of PDE-5 inhibitor before ERCP may decrease sphincter of Oddi tone, allow easier cannulation, and ultimately reduce the occurrence of PEP. An RCT that included 278 patients undergoing ERCP showed no significant decrease in the rate of pancreatitis in the treatment group compared with the placebo group (8.0% vs. 7.8%, p = 0.94) [33].

Nifedipine, a calcium channel antagonist, was ineffective in two RCTs [34,35].

NSAIDs have anti-inflammatory mechanisms of action beyond the inhibition of prostaglandin synthesis. NSAIDs have been shown to be potent inhibitors of phospholipase-A2 (PLA2) activity in the serum of patients with acute pancreatitis when tested in vitro [36]. PLA2 catalyzes the hydrolysis of cell membrane phospholipids, leading to the production of numerous inflammatory mediators, and is believed to play a critical role in the initial inflammatory cascade in acute pancreatitis by generating prostaglandins, leukotrienes, kinins, and platelet-activating factor, which, in turn, lead to tissue damage and autodigestion of the pancreas [37]. PLA2 inhibition leads to the suppression of several important classes of proinflammatory lipids; thus, the use of PLA2 inhibitors has been considered an attractive therapeutic strategy in the treatment of inflammation-related diseases and tissue injury. Diclofenac is second only to indomethacin in its PLA2 inhibitory activity [36]. In patients undergoing high-risk ERCP, Murray et al. [38] reported a statistically significant protective effect for 100 mg of diclofenac, administered rectally upon arrival in the recovery area. However, that study showed no benefit in patients with SOD. A study by Cheon et al. [39] demonstrated no difference in PEP incidence between those given oral diclofenac (50 mg before and after ERCP) and a placebo in 207 predominantly high-risk patients (72% of patients had suspected SOD or underwent pancreatic therapy). Recently, a prospective RCT evaluating the protective effect of rectally administered indomethacin on PEP yielded a statistically conclusive result [6]. Of the 602 patients enrolled, the majority (82%) were suspected of having SOD. Overall, PEP occurred in 27/295 (9.2%) patients in the indomethacin group versus 52/307 patients in the placebo group (p = 0.005). This RCT showed that prophylactic rectal indomethacin significantly reduced the incidence and severity of PEP in patients at elevated risk for this complication. Whether the route of delivery of prophylactic NSAIDs affects the clinical efficacy is still an area of uncertainty. Suppository medications have reduced relative bioavailability compared with oral formulations for most drugs [40], attributable to erratic absorption and loss through the anal sphincter. However, by the oral route, drugs may be destroyed by gastric acidity. Delayed-release diclofenac (enteric-coated), as used in this study, resists dissolution at the low pH of gastric fluids but is rapidly released in the higher pH environment of the duodenum. It is completely absorbed from the gastrointestinal tract after oral administration, but the bioavailability is only about 50% to 60% because of extensive first-pass metabolism, possibly as a result of intestinal cytochrome P450 (CYP2C9, 3A4, and 3A5) [41]. After the oral ingestion of diclofenac, peak plasma levels are reached in about 2 hours (range, 1 to 4) in fasting healthy volunteers; on the other hand, peak plasma levels with rectal administration are reached within 30 minutes [39]. These time differences are probably significant clinically.

In summary, the prophylactic rectal administration of NSAIDs (indomethacin and diclofenac) may result in a substantial reduction in the incidence of PEP, translating into major medical and economic benefits.