CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT

Diclofenac Reduces the Incidence of Acute Pancreatitis AfterEndoscopic Retrograde Cholangiopancreatography

BILL MURRAY, ROSS CARTER, CLEM IMRIE, SUSAN EVANS, andCRIOSTOIR O’SUILLEABHAINLister Department of Surgery, Glasgow Royal Infirmary, Glasgow, Scotland

See editorial on page 1977.

Background & Aims: Acute pancreatitis following endo-scopic retrograde cholangiopancreatography presents aunique opportunity for prophylaxis and early modifica-tion of the disease process because the initial triggeringevent is temporally well defined and takes place in thehospital. We report a prospective, single-center, random-ized, double-blind controlled trial to determine if rectaldiclofenac reduces the incidence of pancreatitis follow-ing cholangiopancreatography. Methods: Entry to thetrial was restricted to patients who underwent endo-scopic retrograde pancreatography or had manometri-cally verified sphincter of Oddi hypertension. Immedi-ately after endoscopy, patients were given a suppositorycontaining either 100 mg diclofenac or placebo. Estima-tion of serum amylase levels and clinical evaluationwere performed in all patients. Results: A total of 220patients entered the trial, and 110 received rectal di-clofenac. Twenty-four patients developed pancreatitis(11%), of whom 7 received rectal diclofenac and 17received placebo (P < 0.05). Conclusions: This trialshows that rectal diclofenac given immediately afterendoscopic retrograde cholangiopancreatography canreduce the incidence of acute pancreatitis.

Acute pancreatitis is the most frequent major com-plication of endoscopic retrograde cholangiopancre-

atography (ERCP); it occurs in 1%–10% of patientsoverall, with a higher incidence when only patients whohave had imaging or instrumentation of the pancreaticduct are considered.1–4 The incidence of post-ERCP pan-creatitis varies according to the indications for the pro-cedure and intervention performed. Patient-related fac-tors are also important, and mortality rates of between0.2% and 0.6% have been reported.5–7 Risk factors re-ported for ERCP-induced pancreatitis include a historyof pancreatitis,8 difficult cannulation,6 repeated injectionof the pancreatic duct,8 pancreatic acinar opacification,9

sphincter of Oddi hypertension (SOH),7,10 and precut orneedle-knife endoscopic sphincterotomy.3,7

Although the pathogenesis of ERCP-induced pancre-atitis is not clearly understood, it seems that the patient’sinflammatory response to pancreatic duct imaging and/orinstrumentation plays a critical role.11 Initial intracellu-lar events resulting in pancreatic acinar cell damage arefollowed by a local inflammatory response that in turnleads to the release of chemokines and proinflammatorycytokines into the general circulation.12 The severity ofthe attack is determined by the magnitude of the result-ant systemic inflammatory response.13

The fact that the initial triggering event is temporallywell defined makes post-ERCP pancreatitis a uniquemodel to study the potential benefit of early immuno-modulation.11 The results of several placebo-controlled,randomized trials using prophylactic agents such as glu-cagon,14 calcitonin,15 nifedipine,16 octreotide,17 and cor-ticosteroids18 have been disappointing. Somatostatin hasbeen studied in several prospective trials. Although ear-lier studies failed to show a reduction in the incidence ofpost-ERCP pancreatitis, recent studies have shown abeneficial effect.19 Pretreatment with glyceryl trinitratehas been shown to reduce the incidence of post-ERCPpancreatitis,20,21 an effect that may be due to relaxationof pancreatic sphincter hypertension. In 2001, Deviere etal. reported a study showing that a single intravenousprophylactic dose of interleukin 10, a major anti-inflam-matory cytokine, given 30 minutes before therapeuticERCP at a dose of either 4 or 20 �g/kg can reduce theincidence of post-ERCP pancreatitis.22 Dumot et al.,however, failed to show any reduction in the incidence ofpancreatitis following ERCP when interleukin 10 was

Abbreviations used in this paper: ERCP, endoscopic retrogradecholangiopancreatography; NSAID, nonsteroidal anti-inflammatorydrug; PLA2, phospholipase A2; SOH, sphincter of Oddi hypertension.

© 2003 by the American Gastroenterological Association0016-5085/03/$30.00

doi:10.1016/S0016-5085(03)00384-6

GASTROENTEROLOGY 2003;124:1786–1791

given 15 minutes before the procedure at an intravenousdose of 8 �g/kg.23 A German study has shown thatpatients receiving heparin for various reasons beforeERCP had a significantly lower incidence of post-ERCPpancreatitis without an increased risk of hemorrhageafter endoscopic sphincterotomy.24 This effect could notbe attributed to other known or suspected confoundersand may have been due to the anti-inflammatory effectsof heparin.

Phospholipase A2 (PLA2) is believed to play a key rolein the initial inflammatory cascade of acute pancreatitisby regulating a number of proinflammatory mediators,including prostaglandins, leukotrienes, and platelet-ac-tivating factor.25 Inhibition of PLA2 has been the targetof several agents used to treat non-ERCP–induced hu-man acute pancreatitis with largely disappointing re-sults. The role of these agents in the prevention ofpost-ERCP acute pancreatitis is more promising. Gabex-ate mesilate, a protease inhibitor, with activity thatincludes inhibition of PLA2, has been shown to preventpancreatic damage related to ERCP and reduces theincidence of post-ERCP pancreatitis.26 It has been shownthat nonsteroidal anti-inflammatory drugs (NSAIDs) arepotent inhibitors of PLA2 activity in the serum frompatients with severe acute pancreatitis, with diclofenacsecond only in potency to indomethacin.27 NSAIDs havealso been shown to have beneficial effects in experimentalacute pancreatitis.28

We conducted a prospective, single-center, random-ized, double-blind controlled trial to determine if asingle diclofenac suppository given immediately afterERCP can reduce the incidence of post-ERCP pancreati-tis.

Patients and MethodsThe study described in this report was approved by the

ethics committee of Glasgow Royal Infirmary University Na-tional Health Service Hospitals Trust. Adult patients withoutclinical or biochemical evidence of acute or severe chronicpancreatitis due to undergo ERCP under the care of 3 expe-rienced endoscopists (B.M., R.C., and C.I.) were asked to giveinformed consent to participate in the study. Patients wereexcluded if they had any contraindications to receiving diclofe-nac or had taken an NSAID during the preceding week. Entryto the study was restricted to patients who underwent endo-scopic retrograde pancreatography � cholangiography or whohad either endoscopic retrograde pancreatography or cholan-giography in the presence of manometrically verified SOH(basal pressure �40 mm Hg in the common sphincter, biliarysphincter, or pancreatic sphincter). These criteria were de-signed to create a study group of patients with an increasedrisk of developing post-ERCP pancreatitis with a estimatedincidence of 12%–18%.

At the end of each procedure, the endoscopist recorded thedetails of the maneuvers performed, particularly the ease ordifficulty of cannulation; number of cannulations; number ofpancreatic duct injections; presence, if any, of pancreatic acinarfilling on radiography; whether a needle-knife sphincterotomywas performed; the diameter of the pancreatic duct and bileduct; the presence of choledocholithiasis; and the anatomy ofthe duct of Wirsung.

Between May 1999 and December 2002, 558 patients wereassessed for eligibility to enter the study (Figure 1). A total of220 of these patients fulfilled the entry criteria. Immediatelyon entering the recovery area after endoscopy, study patientswere given a trial suppository containing either diclofenac(100 mg) or an inert placebo. The trial suppositories wereprepared, sealed, and randomly numbered in batches of 20 inthe pharmacy department. The content of each suppositoryremained unknown until the code was broken after 200 andthen 220 patients entered the study. The study patients wereallowed ice or water orally until estimation of serum amylaselevel 2 hours after the procedure. If the 2-hour serum amylaselevel was �600 IU/L and there was no clinical evidence ofacute pancreatitis at that time, study patients were allowed freeoral fluids and diet. If the 2-hour serum amylase level was�600 IU/L or if a study patient exhibited epigastric pain withguarding, back pain, or nausea/vomiting, then the patient was

Figure 1. Patient flow diagram.

June 2003 DICLOFENAC CAN PREVENT POST–ERCP PANCREATITIS 1787

fasted and intravenous crystalloid fluids with appropriate an-algesia were prescribed.2,29 The following morning, studypatients had their blood tests repeated and were interviewedand examined for clinical evidence of acute pancreatitis by theclinicians responsible for their care. A diagnosis of acute pan-creatitis was made on the basis of a serum amylase level �4times the upper level of normal for the reference laboratory(�800 IU/L) in conjunction with epigastric pain, back pain,and epigastric rebound tenderness. Patients whose symptomsand signs did not settle within 48 hours underwent contrast-enhanced computed tomography scanning. After 200 patientshad entered the trial, the suppository content code was brokenand the incidence of acute pancreatitis in the 2 study groupswas compared. This initial data suggested a protective effect ofdiclofenac (P � 0.07), and 20 additional subjects were thenenrolled. This report discusses the findings for the full series of220 patients.

Statistical Analysis

The difference in incidence of post-ERCP pancreatitisbetween the 2 study groups was subjected to statistical analysisusing Fisher exact test (2-tailed), with P � 0.05 indicating asignificant difference. Serum amylase values were comparedusing Student t test, and patient demographic and clinicalfactors were compared using Fisher exact test or �2 test asappropriate.

ResultsA total of 220 patients entered the study; 110

received 100 mg diclofenac per rectum (diclofenacgroup), and 110 received an inert suppository (controlgroup). There were 69 women in the diclofenac groupand 74 women in the control group. The patients werewell matched in regard to age (mean � SDM; diclofenacgroup, 55 � 15 years; control group, 58 � 14 years).Tables 1 and 2 show that the 2 groups were well matchedfor diagnoses, procedures performed, and factors thatmight increase the risk of post-ERCP acute pancreatitis,particularly a history of acute pancreatitis, SOH, pancre-atic acinar opacification, pancreatic duct instrumenta-

tion, and needle-knife sphincterotomy. The controlgroup contained a larger number of patients with gall-bladder stones, and this was reflected in a larger numberof extrahepatic bile duct stones and a larger number ofendoscopic sphincterotomies in this group. However, thedifferences observed between the 2 groups for thesefactors do not reach statistical significance. The timebetween pancreatic duct imaging/instrumentation andsuppository administration was variable but did not ex-ceed 50 minutes in either group.

Two hours after the endoscopic procedure, the meanserum amylase level was 400 � 67 (SEM) IU/L in thecontrol group and 313 � 38 IU/L in the diclofenacgroup. The morning after the endoscopic procedure, themean serum amylase level was 507 � 90 IU/L in thecontrol group but only 321 � 57 IU/L in the diclofenacgroup. The difference in mean serum amylase valuebetween the 2 groups at 24 hours is statistically signif-icant (P � 0.01). Between 2 and 24 hours after ERCP,24 study patients developed acute pancreatitis (11%)with a serum amylase level �1000 IU/L in each patientplus appropriate clinical findings. The 24 patients whodeveloped post-ERCP pancreatitis had a mean 2-hourserum amylase level of 1190 IU/L and a mean 24-hourserum amylase level of 2107 IU/L (both values signifi-cantly greater than those for the 196 patients withoutpancreatitis; P � 0.001). Seven of the patients whodeveloped pancreatitis were in the diclofenac group and17 in the control group (Table 3). This difference isstatistically significant (P � 0.05; Table 3). Fourteen of116 patients who underwent endoscopic sphincterotomy

Table 3. Incidence of Post-ERCP Pancreatitis

DiclofenacGroup

ControlGroup P

All patients 7/110 17/110 0.049a

Sphincterotomized patients 2/53 12/63 0.021a

Non-SOH patients 4/84 13/83 0.036a

SOH patients 3/26 4/27 NS

aFisher exact test.

Table 1. Patient Details

Diclofenac(n � 110)

Control(n � 110)

Gallbladder stones 31 39Postcholecystectomy 47 45Bile duct stones 25 31Normal pancreatic duct 91 92ERCP 68 68Endoscopic retrograde pancreatography

only 34 30Endoscopic retrograde cholangiography

only � SOH 8 12

NOTE. There were no statistically significant differences.

Table 2. Risk Factors for Post-ERCP Pancreatitis

Diclofenac(n � 110)

Control(n � 110)

Previous acute pancreatitis 38 39SOH 26 27Needle sphincterotomy 29 29Pancreatic duct instrumentation 36 38Pancreatic acinar opacification 8 8Prolonged cannulation 25 18Pancreatic duct stent 13 12

NOTE. There were no statistically significant differences.

1788 MURRAY ET AL. GASTROENTEROLOGY Vol. 124, No. 7

developed acute pancreatitis (12%). Two of these pa-tients were in the diclofenac group (n � 53) and 12 inthe control group (n � 63). This difference is statisticallysignificant (P � 0.021; Table 3). Fifty-three patients hadmanometrically verified SOH (24%), and 7 of thesepatients developed acute pancreatitis (13%). Three ofthese patients were in the diclofenac group and 4 in thecontrol group, suggesting no benefit with respect to post-ERCP pancreatitis from administration of diclofenac inpatients with SOH (Table 3).

Twenty-two of the 24 patients who developed post-ERCP pancreatitis had mild attacks with no furthercomplications. The 2 remaining patients developed ster-ile pancreatic necrosis that resolved without surgicalintervention. Both of these patients were in the controlgroup, and neither had SOH. All of the study patientssurvived their acute pancreatitis and were dischargedfrom hospital alive. The mean inpatient stay for the 24patients who developed acute pancreatitis was 3 days forthe diclofenac group and 5 days for the control group.No adverse effects were noted from the single NSAIDdose given to the patients in the diclofenac group.

Discussion

We have shown that a single inexpensive 100-mgdiclofenac suppository given immediately after ERCPcan reduce the incidence of post-ERCP pancreatitis. Theincidence of acute pancreatitis after ERCP varies accord-ing to the indications for the procedure, patient charac-teristics, and type of intervention performed. It is per-haps optimistically reported as 1%–2% for diagnosticERCP, 1%–4% for endoscopic sphincterotomy, 4%–8%for pancreatic sphincterotomy, and 8%–11% for sphinc-terotomies in patients with SOH.3,4,6 The 10-year auditof the principal investigator of this report (B.M.) showsan all-comers post-ERCP pancreatitis rate of 3.8% (76 of2004).

The overall incidence of post-ERCP pancreatitis inthis study was 10.9%, with a control group incidence of15.5%. These figures are high when compared withall-comers data but reflect the study design, which in-tentionally created a study population with a high inci-dence of post-ERCP pancreatitis by restricting studyentry to patients who had ERCP, pancreatic duct instru-mentation, or manometrically verified SOH. This trendcan be seen in several recent studies of post-ERCP pan-creatitis, with reported incidences of pancreatitis in thecontrol group of 11.3%,2 15%,21 18%,22 and 24%.23 Inthis study, prophylaxis was not given until after a high-risk patient had been identified.

Accepted risk factors for ERCP-induced acute pancre-atitis were prospectively audited in this study, and nosignificant difference was found between the diclofenacand control groups. The incidence of acute pancreatitis inpatients with SOH undergoing ERCP was 13%, which iscomparable with reported results from other centers.10,28

This study has shown that diclofenac protects againstpost-sphincterotomy pancreatitis but did not protectagainst post-ERCP pancreatitis in patients with SOH.30

This may be related to the fact that postmanipulationsphincter spasm or postsphincterotomy edema resultingin an increase in pressure in the pancreatic duct outlaststhe protective effects of diclofenac in patients with SOH.However, this finding requires verification with a largergroup of patients because the observation may be due toa lack of statistical power in the SOH subpopulation(n � 53).

The peak concentration of diclofenac administered bysuppository occurs between 30 and 90 minutes afterinsertion, and bioavailability is complete. The elimina-tion half-life from plasma is 2 hours, and 90% of thedrug clearance has taken place 3–4 hours after adminis-tration.31 All 220 study patients remained in the hospitalat least until the day after their ERCP procedure, andacute pancreatitis was diagnosed or reconfirmed by clin-ical examination and measurement of serum amylaselevel the morning following ERCP. This was between 15and 22 hours after the procedure and hence well beyondany possible analgesic masking effect from the 100-mgdiclofenac suppository given to one half of the studypatients.

The mechanism of ERCP-induced pancreatic injury isnot clearly understood, and a number of hypotheses exist.Trauma or thermal injury to the papilla can cause edemaor spasm of the sphincter of Oddi and lead to temporaryobstruction of the pancreatic duct. Contamination of thepancreatic duct by bacterial proteases during cannulationmay activate pancreatic proenzymes intraductally.16 Hy-drostatic pressure from overfilling of the pancreatic ductmay cause acinar damage and initiate pancreatitis.9

Whatever the mechanism of injury, the host inflamma-tory response to endoscopic instrumentation seems toplay an important role in the pathophysiology of acutepancreatitis.11 A time delay of several hours (median of4.5 hours) exists between pancreatic injury during ERCPand the onset of symptoms.11 This “therapeutic window”invites the use of anti-inflammatory strategies to modu-late the premature intracellular activation of proteolyticenzymes and acinar cell damage followed by a localinflammatory response that in turn leads to the release of

June 2003 DICLOFENAC CAN PREVENT POST–ERCP PANCREATITIS 1789

chemokines and proinflammatory cytokines into the gen-eral circulation.12

It has been widely accepted that the mechanism ofaction of NSAIDs is the inhibition of prostaglandinsynthesis. However, the exact role of prostaglandins inacute pancreatitis is unclear and studies of NSAID ad-ministration in animal models of acute pancreatitis haveshown conflicting results. NSAIDs have anti-inflamma-tory mechanisms of action other than inhibition of pros-taglandin synthesis.32 NSAIDs have been shown to bepotent inhibitors of PLA2 activity in the serum of pa-tients with acute pancreatitis when tested in vitro.27

Makela et al.27 showed that diclofenac was second only toindomethacin in its PLA2 inhibitory activity. PLA2 cat-alyzes the hydrolysis of cell membrane phospholipids,leading to the production of numerous inflammatorymediators, and is believed to play a critical role in theinitial inflammatory cascade in acute pancreatitis bygenerating prostaglandins, leukotrienes, kinins, andplatelet-activating factor, which in turn lead to tissuedamage and autodigestion of the pancreas.33

Because inhibition of PLA2 results in suppression ofseveral important classes of proinflammatory lipids (pros-taglandins, leukotrienes, platelet-activating factor, andlysophospholipids), the use of PLA2 inhibitors has beenconsidered an attractive therapeutic strategy in the treat-ment of inflammation-related diseases and tissue injury.However, most studies concerning PLA2 inhibitors inthe prevention of tissue injury in experimental models ofsevere acute pancreatitis have been disappointing. Thismay be due to the fact that the stimulus used to induceacute pancreatitis in these animal models is too potentfor a prophylactic or treatment benefit to be seen.

However, the proteolytic enzyme inhibitor gabexatemesilate has been shown to have a beneficial role in theprevention of post-ERCP acute pancreatitis.26,34 It hasbeen reported that several NSAIDs, including diclofenac,strongly inhibit neutrophil/endothelial cell attachment,thus preventing accumulation of neutrophils at the siteof tissue damage, a key event in the inflammatory re-sponse.31 NSAIDs have been shown in vitro to inhibitcertain phenomena associated with neutrophil activation,such as synthesis of adenosine 3�,5�-cyclic monophos-phate, generation of superoxide anions, and the release oflysosomal enzymes.35 Furthermore, NSAIDs can inhibitthe expression of inducible nitric oxide synthase in vitro,an enzyme clearly associated with inflammation and celldamage.36

This prospective, single-center, randomized, double-blind clinical study has shown that the incidence ofpost-ERCP acute pancreatitis can be reduced in patients

without SOH by the administration of an inexpensive100-mg diclofenac suppository immediately followingthe endoscopic procedure. It is theoretically possible thatthe observed benefit of rectal diclofenac is due to itsability to inhibit PLA2 activity and hence down-regulatethe inflammatory cascade that would otherwise lead toacute pancreatitis. This observation requires validation,more detailed biochemical investigation, and pharmaco-logic manipulation related to the choice of drug, route ofdelivery, and timing of administration.

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Received January 9, 2002. Accepted February 20, 2003.Address requests for reprints to: Bill Murray, M.D., F.R.C.S.(Glas),

Lister Department of Surgery, Glasgow Royal Infirmary, Glasgow G312ER, Scotland. Fax: (44) 141-211-4991.

The data from this study after 200 patients had been entered waspresented to the American Pancreatic Association in November 2001and to the Association of Surgeons of Great Britain and Ireland on May23, 2002.

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