Efficacy Study of Glyceryl-Trinitrate Patch and Parecoxib (Valdecoxib) for the Prevention of Pancreatitis After Endoscopic Retrograde Cholangiopancreatography (ERCP)
Efficacy Study of Glyceryl-Trinitrate Patch and Parecoxib (Valdecoxib) for the Prevention of Pancreatitis After Endoscopic Retrograde Cholangiopancreatography (ERCP)
ERCP is a diagnostic and therapeutic procedure that is required in patients with suspected
 common bile duct stone, malignant biliary obstruction, biliary fistula, etc. Pancreatitis may
 occur as a complication of this procedure after about 5-10% of the ERCP procedures. This
 complication manifests as persisting pain 24 hours or more after ERCP, along with raised
 levels of pancreatic enzymes in the blood. Most of the cases of post-ERCP pancreatitis are
 mild, but may be severe and lead to prolonged hospitalization a few patients. The occurrence
 of this complication is unpredictable. There have been a number of attempts to prevent this
 complication. These include giving certain drugs before ERCP e.g. octreotide, somatostatin,
 steroids, etc. However, these have not been successful. Recently, a study showed that
 application of glyceryl trinitrate patch on the skin before ERCP might reduce the incidence
 of post ERCP-pancreatitis. Another study showed that per rectal administration of diclofenac
 tablet after the ERCP procedure also reduced occurrence of post ERCP pancreatitis. Other
 experimental studies have shown that certain anti-inflammatory drugs like cox-2 inhibitors
 may also be effective.

 The investigators want to study whether transdermal patch of glyceryl trinitrate or
 administration of injectable cox-2 inhibitor Valdecoxib (pro-drug Parecoxib) can prevent
 post-ERCP pancreatitis in our patients who undergo an 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.
Inclusion Criteria:

 -  All patients aged 18 years and above undergoing first ERCP procedure

 Exclusion Criteria:

 -  Active acute pancreatitis,

 -  Lower end malignant bile duct block,

 -  Patients undergoing repeat procedures,including those with previous sphincterotomy

 -  Ongoing therapy with nitrates, calcium channel blockers, somatostatin or octreotide

 -  Patients with bleeding diathesis.

 -  Patients with chronic pancreatitis

 -  Patients with cardiac comorbidity