Efficacy Study of Glyceryl-Trinitrate Patch and Parecoxib (Valdecoxib) for the Prevention of Pancreatitis After Endoscopic Retrograde Cholangiopancreatography (ERCP)

Acute pancreatitis represents the most common complication after ERCP. The reported incidence of this complication varies from less than 1% to 40%, but rates of about 10% are reported in most prospective studies involving non-selected patients. Although most episodes (about 90%) of post-ERCP pancreatitis are mild, a small percentage of patients (about 10%) may develop severe pancreatitis resulting in significant morbidity and occasional mortality. Despite technical improvements in recent years, the incidence of this complication has not decreased.

The risk factors for development of post ERCP acute pancreatitis are now well known. Balloon dilatation of sphincter of Oddi, difficult papillary cannulation, pancreatic sphincterotomy and multiple pancreatic duct injections have been found to be independent risk factors for post-procedure pancreatitis (Odds ratio of 4.5, 3.4, 3.1, 2.7 respectively) in a recent prospective, multicenter study by Freeman et al. Opacification of the main pancreatic duct alone (MPD) is associated with a 31% incidence of hyperamylasemia. This figure is similar to the 24% incidence of hyperamylasemia which occurs after cholangiography alone. However both injection pressure and volume of contrast medium injected into the pancreatic duct contribute to ductal epithelial or acinar injury by disruption of the intercellular tight junctions with a backflow into the interstitial space.

The role of the osmolarity and ionic nature of the contrast medium is controversial. However non-ionic, low osmolarity contrast media is preferred by most endoscopists. Electrocautery in the vicinity of the MPD orifice may produce edema of the tissues with subsequent obstruction. Etta et al recently showed that use of pure cutting current significantly reduced pancreatitis rates when compared with blended current (3% vs 11%).Precut or access papillotomy is associated with higher risk of pancreatitis when used by endoscopists with less experience, but not in the hands of experienced endoscopists.Operator experience also seems to be a potential risk factor for post ERCP complications. Large volume centers performing > 200 procedures per year had significantly less overall complications (2.0% vs 7.1%, p<0.001) and less complication related deaths (0.18% vs 0.75%, p<0.05), compared to low volume centers in a large Italian multicenter prospective study.

Various agents have been tried with an aim to prevent post ERCP pancreatitis in the last 10 years. These include Gabexate, Somatostatin, Nifedipine, Octreotide, Hydrocortisone, Prednisone, Allopurinol, Interleukin-10, and Methylprednisolone which have been evaluated in randomized controlled studies.Of these agents only Interleukin-10, Somatostatin and Gabexate have been found efficacious. However 13 patients need to be treated prophylactically with Somatostatin and 27 with Gabexate to prevent a single case of post ERCP pancreatitis. Hence these agents are unlikely to be cost-effective or universally applicable. The ideal agent to prevent this complication should be cheap, widely applicable and have a rational basis.

It has been found that cannulation trauma to the papilla or electrocautery leads to sphincter of Oddi spasm and/or papillary edema, thus obstructing free flow of pancreatic juice and contrast with resultant acute pancreatic inflammation.

Akashi et al recently showed that although the frequency of pancreatitis was higher in patients who underwent sphincterotomy, the frequency of severe pancreatitis within 48 hours and the worsening of pancreatitis after 48 hours is significantly lower in this group. Thus the lowering of intraductal pressure after endoscopic sphincterotomy (ES) mitigates the severity of post procedural pancreatitis.

In fact pancreatic stent placement has been shown to be effective for the prevention of post ERCP pancreatitis in high risk patients. In a recent randomized trial, patients had either a 5 Fr nasopancreatic catheter/a stent placed at the end of ERCP or no endoprosthesis was placed. Patients undergoing MPD stenting had a lower frequency of pancreatitis as compared with those in the control group (28% vs 5%, p<0.05)10 However pancreatic stenting on a regular basis is difficult and impractical solution. Repeated attempts to place the pancreatic stent may cause more harm, and a second procedure may be required to remove the stent. Hence instituting adequate drainage of MPD at the end of ERCP seems to be rational and useful but pharmacological rather than mechanical means may be desirable.

Sphincter of Oddi relaxation is modified by cholecystokinin (CCK), vasoactive intestinal peptide (VIP) and nitric oxide (NO) in the physiological state besides a complex neural control involving sympathetic, parasympathetic and enteric nervous system. Jurkowska et al studied the role of nitric oxide (NO) in cerulein induced rat pancreatitis model. It was found that glyceryl trinitrate (NTG, a NO donor) and L-arginine (a substrate for NO synthesis) resulted in significant attenuation of pancreatic damage as well as earlier recovery and augmented cell proliferation in comparison to the saline treated or L-NNA (NO synthase inhibitor) group.

In a randomized double-blind study, prophylactive treatment with NTG (2mg given sublingually 5 min before endoscopy) was compared with placebo in 186 patients. The incidence of pancreatitis was lower in the NTG group compared with placebo (7 of 90 vs 17 of 96; p<0.05). Mean serum amylase values were similar in the two groups.

A more recent study tested the hypothesis that transdermal NTG could be effective in the prevention of post ERCP pancreatitis. One hundred forty-four patients were randomized: 71 received a 15mg NTG patch and 73 a placebo patch. In the control group pancreatitis developed in 11 patients versus 3 in the NTG group (p<0.05). Twenty four hour to baseline serum amylase and lipase ratios were also lower in the NTG group. Hence NO donors seem efficacious in preventing hyperamylasemia and post ERCP pancreatitis Regardless of the initial trigger, the acinar cell injury leads to oxidative stress, nuclear translocation of nuclear factor kappa-B and subsequent transcription of chemo and pro-inflammatory cytokines. This is followed by chemo-attraction and activation of macrophages, T lymphocytes and neutrophils, which are responsible for acinar necrosis and amplification of the pro-inflammatory cascade. Finally after amplification by Kupffer cells, systemic inflammatory response syndrome and multiple organ dysfunction occur. All these events occur within a very short period of time, likely within an hour or two. There is thus a very short therapeutic window during which it is theoretically possible to shut the inflammatory cascade.

Cyclooxygenases (COX) are key enzymes of prostaglandin synthesis and have important role in the regulation of inflammation. Both isoforms of COX are synthesized in acinar cells and their expression is differentially regulated. Upon induction of pancreatitis in the rat model, COX-2 mRNA increases while COX-1 expression remains constant. Song et al studied the effect of pharmacological inhibition of COX-2 and genetic deletion of COX-2 in cerulein induced acute pancreatitis in mice. In both groups, the severity of pancreatitis and pancreatitis induced lung injury was reduced compared with the non-inhibited strains of COX-2 sufficient mice. This indicates that COX-2 plays an important proinflammatory role in pancreatitis and that COX-2 inhibitors may be beneficial in preventing acute pancreatitis or reducing its severity.

Parecoxib is the prodrug of Valdecoxib -a selective COX-2 inhibitor. Following IV or IM injection, Parecoxib is rapidly converted to Valdecoxib, the pharmacologically active substance by enzymatic hydrolysis in the liver. Following a single intramuscular injection of 20mg of Valdecoxib, peak blood levels are achieved in approximately 1 hour. Parecoxib demonstrates an incidence of gastroduodenal ulceration similar to placebo and in twice daily doses had no effect on platelet aggregation or bleeding compared to placebo.