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Endoscopic pancreatic-stent placement and sphincterotomy for relief of pain in tropical pancreatitis: results of a 1-year follow-up
ORIGINAL ARTICLE: Clinical Endoscopy
Endoscopic pancreatic-stent placement and sphincterotomy for relief of pain in tropical pancreatitis: results of a 1-year follow-up C. Ganesh Pai, MD, DM, Jose Filipe Alvares, MD, DM, DNB Manipal, India
Background: Tropical chronic pancreatitis frequently presents with intractable abdominal pain. Surgical treatment has its own morbidity and mortality, and long-term results may not be satisfactory. Objective: To analyze the results of endoscopic pancreatic-stent placement and sphincterotomy for the pain of tropical pancreatitis. Design: Retrospective review. Setting: Tertiary-referral hospital. Patients: Twenty-four patients with tropical pancreatitis with severe, persistent pain not responding to standard medical therapy over a period of 30 months beginning January 1998. Interventions: Stent placement of the pancreatic duct, along with sphincterotomy. Main Outcome Measurements: At least 80% global improvement in pain as reported by the patient during follow-up after the procedure. Results: In the 19 evaluable patients, the intended procedure, pancreatic stent placement along with sphincterotomy, was successful in 14 (73.7%); 3 others had sphincterotomy alone. Over a follow-up period of 6 to 38 months, 12 of the 14 patients (85.7%) who underwent stent placement plus sphincterotomy and 2 of the 3 patients who had sphincterotomy alone responded. Twelve of these were completely free of pain, and the remaining 2 patients had mild infrequent pain that occurred once in 2 to 4 months, lasting a few hours at a time and never needing hospitalization. The only major complication was the development of pancreatic sepsis, which required stent removal in 1 patient. Eight patients were stent free at the end of 6 months, and, over a further follow-up of 6 to 20 months, the pattern of pain relief persisted in them. Limitations: The retrospective nature of the study, the limited numbers studied, and the lack of assessment of pain on a standard visual analog scale. Conclusions: Stent placement of the pancreatic duct with pancreatic sphincterotomy constitutes an important nonsurgical therapeutic option for the intractable pain of tropical pancreatitis. (Gastrointest Endosc 2007;66:70-5.)
Tropical chronic pancreatitis (TP) represents an idiopathic form of the disease seen predominantly in the tropical developing countries.1,2 It appears to differ from the idiopathic chronic pancreatitis (CP) of the temperate zones in its younger age of onset, more aggressive course, higher prevalence of calculi and diabetes, and a greater propensity to develop malignancy.2,3 Abdominal pain is the most common presenting symptom in these patients, Copyright ª 2007 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2007.02.043
70 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 1 : 2007
and this may be severe and is frequently intractable. Surgery, the mainstay of treatment for the severe pain of CP, has a morbidity of 20% to 35% and a mortality of 1% to 4%, the long-term results being far from satisfactory.4-6 The role of supplementation of pancreatic enzymes or antioxidants and celiac plexus block for the CP pain remains controversial.7,8 Less is known about the usefulness of these modalities of treatment in TP.1-3,9-11 The American Gastroenterology Association recommends endoscopic therapy as an option in the management of pain of CP.12 Most published reports on endoscopic therapy of CP are from the West, and very little data exist on the usefulness www.giejournal.org
Pai & Alvares
of this treatment in patients with TP. We hypothesized that placement of stents along the length of the abnormal pancreatic duct in patients with TP, together with pancreatic sphincterotomy, would facilitate proper drainage to provide adequate relief of pain.
Endotherapy of tropical pancreatitis
Capsule Summary What is already known on this topic d
PATIENTS AND METHODS For the purpose of this study, TP was defined as idiopathic CP of the tropics.1-3 CP was diagnosed based on typical changes of calcification on plain radiographs, US, or CT, or on ductal changes seen at ERCP.3 Patients with any history of alcohol intake before the onset of symptoms and those with other causes of CP were excluded. Hypercalcemia and hypertriglyceridemia were ruled out by appropriate investigations. Written informed consent for the procedure was obtained from all patients. The patients with TP who underwent an attempt at therapeutic ERCP for pain over a 30-month period from January 1998 were included. They had persistent or recurrent severe pain of pancreatic origin that needed frequent hospitalization and that did not respond to at least 8 weeks of treatment with non-narcotic oral analgesics, acid suppressants, pancreatic enzyme therapy, and antioxidant supplementation. Those with a frequency of pain less than 1 episode per month were not considered. Patients who underwent procedures specifically for complications such as pseudocysts, fistulas, or ascites, and those with associated disorders that might explain the pain (eg, peptic ulcer disease) were excluded. At ERCP, the pancreatic duct was accessed by using a standard cannula; a tapered-tip cannula; or a Tapertome (Boston Scientific Corp, Natick, Mass), with or without the use of a 0.025-inch Jagwire (Boston Scientific Corp, Natick, Mass). The severity of pancreatitis was assessed according to the Cambridge classification as mild (more than 3 abnormal side branches with a normal main duct), moderate (abnormal main duct and side branches), and severe (same as for moderate disease but with 1 or more additional abnormalities, such as large cavity, ductal stone/filling defect, duct obstruction/ stricture, gross irregularity).13,14 Failure to cannulate the pancreatic duct led to pre-cut papillotomy to deroof the papilla to expose the pancreatic ductal orifice as previously described.15,16 After achieving selective cannulation, a 12- or 15-cm–long 7F stent was placed as deeply into the duct as possible (Fig. 1). A 5-mm–long pancreatic sphincterotomy was done with an over-the-wire papillotome before stent placement or with a needle knife over the stent. Pancreatic calculi were not extracted. The patients were asked to report for follow-up in the event of recurrence of pain or every 2 months for the first 6 months and then every 4 to 6 months until the end of follow-up. Response was defined as complete relief or a www.giejournal.org
Tropical chronic pancreatitis (TP), an idiopathic form of disease seen in tropical developing countries, is characterized by severe, often intractable, abdominal pain.
What this study adds to our knowledge d
In a retrospective review of 17 patients with pain because of TP, pancreatic sphincterotomy with or without stent placement resulted in complete relief of pain in 5 patients; 9 patients were left with mild infrequent pain.
decrease in pain, as a composite of severity, duration, and frequency of episodes by at least 80% as assessed by the patient during follow-up. The severity of pain was scored on a scale of 4, as ‘‘none,’’ ‘‘mild,’’ ‘‘moderate,’’ or ‘‘severe’’; the same words were used each time for all patients to decrease subjectivity and the same person (C.G.P.) assessed the pain scores in all patients. No patient received somatostatin or octreotide before or after the procedure.
RESULTS Patients Twenty-four patients presented for the therapeutic procedure during the study period. Four of the patients who failed the procedure and 1 who had a successful stent placement were found to have carcinoma of the pancreas on cytology obtained during the endoscopic procedure (n Z 1) or at subsequent laparotomy for persistent pain (n Z 4). They were excluded from further analysis (Fig. 2). The mean age of the evaluable patients was 28.3 years (range, 10–56 years). Thirteen were men (68.4%). Twelve patients (63.2%) had pancreatic calcification (parenchymatous in 4 and ductal calculi in 8). Diabetes mellitus was present in 8 (42.1%). Nine patients (47.4%) had severe pain daily as per the scale described, whereas the rest had episodes of severe pain that occurred once in 7 to 30 days and lasted for 2 to 7 days each time. The ductal changes were severe in 11 (57.9%) and moderate in 8 (42.1%); no patient had mild disease. The main pancreatic duct was dilated in all, with a maximum diameter of 6 to 13 mm (median, 9 mm); none had ductal strictures. Two patients (10.5%) needed pre-cut papillotomy to deroof the papilla to facilitate selective cannulation of the pancreatic duct; both underwent successful pancreatic sphincterotomy and stent placement. Thirteen patients (68.4%) had a successful procedure in 1 session; 6 (31.6%) needed 2 sessions. Volume 66, No. 1 : 2007 GASTROINTESTINAL ENDOSCOPY 71
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Figure 1. A and C, Radiographs done during the procedure, showing the pancreatic duct in 2 patients. B and D, Radiographs done during the procedure, showing the stent in place in 2 patients.
Immediate outcome
Follow-up
The intended procedure (stent placement þ pancreatic sphincterotomy) was successful in 14 of the 19 evaluable patients (73.7%). Five patients (26.3%) failed because of an inability to place a guidewire deep into the duct because of its coiling up in between the calculi or in the dilated side branches, despite repeated attempts. In 3 of these, only pancreatic sphincterotomy could be done by using an over-the-wire papillotome. Thus, 17 patients (89.5%) had a procedure done; 14 of them had stent placement plus sphincterotomy and 3 had sphincterotomy alone.
With good response to treatment, the stents were left in place for 6 months (initial 6 patients) to 12 months; no stent exchanges were done during this period. Over a total follow-up of 6 to 38 months (median, 12 months), 14 patients (73.7%) responded to treatment as defined above. Five had complete relief of pain and the rest had mild infrequent pain that occurred once in 3 to 4 months, lasting a few hours at a time and never needing hospitalization. Of the 14 who had a response, 12 received a stent and 2 underwent pancreatic sphincterotomy only. Thus, 12 of the 14 patients (85.7%) who had stent placement plus sphincterotomy and 2 of the 3 patients (66.6%) who had sphincterotomy alone responded to treatment. Initially, the stents were planned to be left in situ for 6 months. One of these patients expelled the stent through the anus 3 months after the procedure, but the pain relief continued, and, hence, the patient was not re-stented. In the 5 other initial patients, the stents were removed at the end of 6 months. These 6 patients had a subsequent follow-up of 6 to 32 months after being stent free. The
Adverse events Four patients (21%) developed acute exacerbation of pain after the procedure. In 3, this subsided with conservative management over 24 hours. The other patient continued to have pain and later developed fever. He was found to have partial dislodgement of the stent into the duodenum, with purulent discharge 3 weeks after the procedure. He improved only after stent removal and, hence, he is considered a nonresponder. 72 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 1 : 2007
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Endotherapy of tropical pancreatitis
Figure 2. The outcome of endoscopic therapy in TP.
pattern of pain relief continued in these patients. The other patients, 6 of them with the stent in situ for 6 to 12 months and the 2 with sphincterotomy alone, continued to maintain response at their last follow-up.
DISCUSSION Endoscopic therapy is now an accepted modality of treatment for the relief of pain in CP.17 Previous reports in this area have mainly been in patients with alcoholic and idiopathic pancreatitis of the West.18-24 These patients have 1 specific therapy available to them: abstinence from alcohol.25 We showed that pancreatic endotherapy can also be beneficial in TP, where no specific treatment is available. The stents were left in place for 6 to 12 months, and the pain relief was found to persist in the medium term, even after stent removal; the adverse events were few. Compared with surgery, endoscopic therapy has advantages in the treatment of pain of CP. It is simple and reversible, and carries a low morbidity and virtually no mortality.18-24 Unlike lateral pancreaticojejunostomy, endoscopic therapy can be used even in patients with small-duct disease.26 However, endoscopic therapy needs expertise and experience. The selection of patients, the procedures done, and the pattern of follow-up varied widely in previous series on endoscopic therapy for the pain of CP. We followed a standardized protocol, irrespective of whether calculi were present or not. Stent placement of the pancreatic duct was the primary aim, and sphincterotomy followed as an additional drainage procedure. Dilation of strictures was not necessary in any, because none had strictures. No attempt was made to use a basket for the ductal calculi or to fragment them by using extracorporeal shockwave lithotripsy (ESWL) because of multiple reasons. All patients with intractable pain do not have intraductal calculi, as was the case in 11 of our 19 patients (57.9%). Calculi tend to be large in TP and, hence, not easy to remove.3,27 ESWL was unavailable to us at the time of treating these patients. There are no comparative trials to prove that this form of therapy is better than stent placement alone www.giejournal.org
for relieving pain. In fact, the long-term pain relief in 54% to 86% of patients undergoing treatment of stones and the mean size effect for pain of 0.62 in patients undergoing ESWL as shown in a recent meta-analysis appear to be no better than the results of stent placement alone.28,29 It is possible that a subset of patients with large or impacted stones who do not respond to stent placement or fail the procedure might be the ideal candidates for the latter procedure. The failure rate in this study was higher than those reported in some earlier series.20 There could be many reasons for this. The patients in this series were the first undergoing such therapy by the investigators. Accessories such as thin guidewires with hydrophilic tips and over-thewire papillotomes that were routinely used in the latter half of the series were not available earlier. Ductal changes are more severe in TP compared with alcoholic pancreatitis.3,30 Because of these reasons, stent placement sometimes failed in our patients, even in the absence of complete stricture of the pancreatic duct. The diameter of the stent and the duration of its placement for effective therapy of CP have not been fully worked out. Because of the anticipated difficulty in placing large-diameter stents and also because of the good response in the initial few patients with 7F stents, the former were not used in our patients. Pancreatic stents are known to induce ductal changes similar to those of CP.31 It is possible that preexisting ductal changes might worsen further with the use of larger- as opposed to smaller-diameter stents. This was another reason why stents of larger diameter were not used. In light of recent data showing that pancreatic stents block early, it is reasonable to conclude that a shorter period of stent placement might have been equally beneficial.32 Nonetheless, blocked stents might still facilitate drainage in the presence of a pancreatic sphincterotomy.24,33 This might explain why our patients showed sustained benefit, even when the stents were left in situ for 6 to 12 months without exchanges. In the presence of a ductal stricture, the length of the stent that needs to be used is easily determined. There are no guidelines on the length of stent to be used in Volume 66, No. 1 : 2007 GASTROINTESTINAL ENDOSCOPY 73
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the absence of strictures. Short stents have been used to prevent complications after pancreatic sphincterotomy. Stent placement and not pancreatic sphincterotomy was the primary procedure intended in the present series. There is no reason to believe that lateral pancreaticojejunostomy helps only those with pancreatic-duct strictures, and drainage of the entire length of the duct was the aim of this procedure. Our aim was to similarly provide adequate drainage from the entire length of the abnormal pancreatic duct, alongside the calculi if these are present. Hence, 12- to 15-cm-long stents were used. Whether shorter stents would have served the same purpose is unknown, but this appears unlikely. The mechanisms of pain in CP are not fully understood.34-37 Lateral pancreaticojejunostomy, endoscopicstent placement across ductal strictures, and ESWL of calculi are all supposed to help by improving drainage and consequently decreasing intraductal pressure. Insufficient drainage of the ducts after lateral pancreaticojejunostomy has been suggested as the reason for the poor response to this treatment in some patients. Our results suggest that even small-diameter pancreatic stents, when sufficiently long, can result in relief of pain in patients with TP, even when ductal strictures are absent. The persistence of pain relief over 6 to 12 months in the absence of stent exchanges and also after the removal of the stent could be because of the sphincterotomy and the absence of strictures. Whether either procedure alone would have sufficed cannot be answered by this study. However, the good response we found in 2 of 3 patients who underwent sphincterotomy alone and some data available from previous studies indicate this is possible.38,39 Further studies are necessary before firm conclusions can be drawn about this issue. Unlike stent placement, however, sphincterotomy alone will not provide adequate drainage from the upstream portions of the duct. Pancreatic cancer has been reported to occur in 3.2% to 8.3% of patients with TP, and the detection of this complication is difficult and often delayed.40 The 20% prevalence of cancer in our patients might appear too high. However, this can be explained by the fact that patients who develop malignancy are likely to manifest worsening pain and thus would automatically qualify for inclusion, should the malignancy go undetected during initial evaluation. The present series is not without its limitations. TP is difficult to define, and there are no markers for this disease. Like in many other series, the number of patients reported here is small.18-24 Also, use of a visual analog scale to assess the severity of pain would have given more objective results. CP, especially the tropical variety, may be associated with long pain-free periods for no apparent reason.1 That was the reason why patients with frequent pain over a period of at least 3 months not responding to the usual line of treatment were chosen for the procedure. Nevertheless, there was total or neartotal relief of pain in most patients from the time of stent 74 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 1 : 2007
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placement, suggesting that the treatment was responsible for the benefit. A number of options are now available for the treatment of CP pain. The limitations of surgery for the relief of CP pain are well known. Nonsurgical interventions, such as pancreatic sphincterotomy, stent placement of the pancreatic duct, extraction of calculi, and ESWL, all offer attractive alternative options. The long-term results of these procedures and their exact role singly or in combination have not yet been clearly defined.29 More controlled trials are needed to define the role of each of these modalities of treatment.12,17,33 Future studies should also look into the effect of the length and diameter of stents, and the duration of stent placement on the outcome. Also the relative role of sphincterotomy, stent placement, and using a basket or ESWL for calculi singly or in combination needs to be defined in randomized controlled trials. Meanwhile, it appears reasonable to consider placement of long pancreatic stents to relieve intractable pain in patients with TP, even in the absence of ductal strictures.
DISCLOSURE The authors have no disclosures to make. REFERENCES 1. Ramesh H. Tropical pancreatitis. Indian J Gastroenterol 1997;16:20-5. 2. Balakrishnan V, Nair P, Radhakrishnan L, et al. Tropical pancreatitis: a distinct entity, or merely a type of chronic pancreatitis? Indian J Gastroenterol 2006;25:74-81. 3. Tandon RK, Sato N, Garg PK. Chronic pancreatitis: Asia-Pacific consensus report. J Gastroenterol Hepatol 2002;17:508-18. 4. Sohn TA, Campbell KA, Pitt HA, et al. Quality of life and long term survival after surgery for chronic pancreatitis. J Gastrointest Surg 2000;4:355-65. 5. Massucco P, Calgaro M, Bertolino F, et al. Outcome of surgical treatment for chronic calcifying pancreatitis. Pancreas 2001;22:378-82. 6. Russel RC, Theis BA. Pancreaticoduodenectomy in the treatment of chronic pancreatitis. World J Surg 2003;27:1203-10. 7. Mossner J. Is there a place for pancreatic enzymes in the treatment of pain in chronic pancreatitis? Digestion 1993;54(Suppl 2):35-9. 8. Uden S, Bilton D, Nathan L, et al. Antioxidant therapy of recurrent pancreatitis: placebo controlled trial. Aliment Pharmacol Ther 1990;4: 357-71. 9. Thomas PG, Augustine P. Surgery in tropical pancreatitis. Br J Surg 1988;75:161-4. 10. Thomas PG, Augustine P, Ramesh H. Observations and surgical management of tropical pancreatitis in Kerala and Southern India. World J Surg 1990;14:32-42. 11. Durgaprasad S, Pai CG, Vasanthkumar, et al. A pilot study of the antioxidant effect of curcumin in tropical pancreatitis. Indian J Med Res 2005;122:315-8. 12. Warshaw AL, Banks PA, Fernandez-Del Castillo C. American Gastroenterology Association technical review statement: treatment of pain in chronic pancreatitis. Gastroenterology 1998;115:763-4. 13. Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25:756-9. 14. Catalano MF, Lahoti S, Geenen JE, et al. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998;489:11-7.
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Pai & Alvares 15. Huibregtse K, Katon RM, Tytgat GJN. Precut papillotomy via needle knife papillotome: a safe and effective technique. Gastrointest Endosc 1986;32:403-5. 16. Pai CG. Precut papillotomy using needle knife fashioned from discarded standard sphincterotomes. Indian J Gastroenterol 2000;19:116-8. 17. Wilcox CM. Endoscopic therapy for pain in chronic pancreatitis: is it time for the naysayers to throw in the towel? Gastrointest Endosc 2005;61:582-6. 18. Dite P, Ruzicka M, Zboril V, et al. A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy 2003;35:553-8. 19. Cremer M, Deviare J, Delhaye M, et al. Stenting in severe chronic pancreatitis: results of medium-term follow-up in seventy-six patients. Endoscopy 1991;23:171-6. 20. Binmoeller KF, Jue P, Seifert H, et al. Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: long-term results. Endoscopy 1995;27:638-44. 21. Smits ME, Badiga SM, Rauws EA, et al. Long-term results of pancreatic stents in chronic pancreatitis. Gastrointest Endosc 1995;42:461-7. 22. Ponchon T, Bory RM, Hedelius F, et al. Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol. Gastrointest Endosc 1995;42:452-6. 23. Hammarstrom L-E, Stridbeck H, Ihse I. Endoscopic drainage in benign pancreatic disease: immediate and medium term outcome. Eur J Surg 1997;163:577-89. 24. Morgan DE, Smith JK, Hawkins K, et al. Endoscopic stent therapy in advanced chronic pancreatitis: relationships between ductal changes, clinical response, and stent patency. Am J Gastroenterol 2003;98: 821-6. 25. Trapnell JE. Chronic relapsing pancreatitis: a review of 64 cases. Br J Surg 1979;66:471-5. 26. Laugier R, Renou C. Endoscopic ductal drainage may avoid resective surgery in painful chronic pancreatitis without large ductal dilatation. Int J Pancreatol 1998;23:145-52. 27. Chari S, Jayanthi V, Mohan V, et al. Radiological appearance of pancreatic calculi in tropical versus alcoholic chronic pancreatitis. J Gastroenterol Hepatol 1992;7:42-4. 28. Lehman GA. Role of ERCP and other endoscopic modalities in chronic pancreatitis. Gastrointest Endosc 2002;56:s237-40.
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Endotherapy of tropical pancreatitis 29. Guda NM, Partington S, Freeman ML. Extracorporeal shockwave lithotripsy in the management of chronic calcific pancreatitis: a metaanalysis. JOP 2005;6:6-12. 30. Saraya A, Acharya SK, Vashist S, et al. A pancreatographic study of chronic calcific pancreatitis of the tropics. Trop Gastroenterol 2002;23:167-9. 31. Smith MT, Sherman S, Ikenberry SO, et al. Alterations in pancreatic ductal morphology following polyethylene pancreatic stent therapy. Gastrointest Endosc 1996;44:268-75. 32. Deviere J. Why do pancreatic stents become occluded? Gastrointest Endosc 2004;61:867-8. 33. Neuhaus H. Pancreatic stents in chronic pancreatitis: do they function as a tube, a wick, or a placebo? Gastrointest Endosc 2006;63: 67-70. 34. Bradley EL. Pancreatic duct pressure in chronic pancreatitis. Am J Surg 1982;144:313-6. 35. Madsen P, Winkler K. The intraductal pancreatic pressure in chronic obstructive pancreatitis. Scand J Gastroenterol 1982;17:553-4. 36. Malfertheiner P, Dominguez-Munoz JE, Buchler MW. Chronic pancreatitis: management of pain. Digestion 1994;55(Suppl 1):29-34. 37. Bockman DE, Buchler M, Malfertheiner P, et al. Analysis of nerves in chronic pancreatitis. Gastroenterology 1988;94:1459-69. 38. Okolo PI 3rd, Pasricha PJ, Kalloo AN. What are the long-term results of endoscopic pancreatic sphincterotomy? Gastrointest Endosc 2000;52: 15-9. 39. Kozarek RA, Ball TJ, Patterson DJ, et al. Endoscopic pancreatic duct sphincterotomy: indications, technique, and analysis of results. Gastrointest Endosc 1994;40:592-8. 40. Chari ST, Mohan V, Pitchumoni CS, et al. Risk of pancreatic carcinoma in tropical calcifying pancreatitis: an epidemiologic study. Pancreas 1994;9:62-6.
Received March 1, 2005. Accepted February 14, 2007. Current affiliations: Department of Gastroenterology, Kasturba Medical College, Manipal, India. Reprint requests: C. Ganesh Pai, MD, Department of Gastroenterology, Kasturba Medical College, Manipal, 576 104 India.
Volume 66, No. 1 : 2007 GASTROINTESTINAL ENDOSCOPY 75
Endoscopic pancreatic-stent placement and sphincterotomy for relief of pain in tropical pancreatitis: results of a 1-year follow-up C. Ganesh Pai, MD, DM, Jose Filipe Alvares, MD, DM, DNB Manipal, India
Background: Tropical chronic pancreatitis frequently presents with intractable abdominal pain. Surgical treatment has its own morbidity and mortality, and long-term results may not be satisfactory. Objective: To analyze the results of endoscopic pancreatic-stent placement and sphincterotomy for the pain of tropical pancreatitis. Design: Retrospective review. Setting: Tertiary-referral hospital. Patients: Twenty-four patients with tropical pancreatitis with severe, persistent pain not responding to standard medical therapy over a period of 30 months beginning January 1998. Interventions: Stent placement of the pancreatic duct, along with sphincterotomy. Main Outcome Measurements: At least 80% global improvement in pain as reported by the patient during follow-up after the procedure. Results: In the 19 evaluable patients, the intended procedure, pancreatic stent placement along with sphincterotomy, was successful in 14 (73.7%); 3 others had sphincterotomy alone. Over a follow-up period of 6 to 38 months, 12 of the 14 patients (85.7%) who underwent stent placement plus sphincterotomy and 2 of the 3 patients who had sphincterotomy alone responded. Twelve of these were completely free of pain, and the remaining 2 patients had mild infrequent pain that occurred once in 2 to 4 months, lasting a few hours at a time and never needing hospitalization. The only major complication was the development of pancreatic sepsis, which required stent removal in 1 patient. Eight patients were stent free at the end of 6 months, and, over a further follow-up of 6 to 20 months, the pattern of pain relief persisted in them. Limitations: The retrospective nature of the study, the limited numbers studied, and the lack of assessment of pain on a standard visual analog scale. Conclusions: Stent placement of the pancreatic duct with pancreatic sphincterotomy constitutes an important nonsurgical therapeutic option for the intractable pain of tropical pancreatitis. (Gastrointest Endosc 2007;66:70-5.)
Tropical chronic pancreatitis (TP) represents an idiopathic form of the disease seen predominantly in the tropical developing countries.1,2 It appears to differ from the idiopathic chronic pancreatitis (CP) of the temperate zones in its younger age of onset, more aggressive course, higher prevalence of calculi and diabetes, and a greater propensity to develop malignancy.2,3 Abdominal pain is the most common presenting symptom in these patients, Copyright ª 2007 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2007.02.043
70 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 1 : 2007
and this may be severe and is frequently intractable. Surgery, the mainstay of treatment for the severe pain of CP, has a morbidity of 20% to 35% and a mortality of 1% to 4%, the long-term results being far from satisfactory.4-6 The role of supplementation of pancreatic enzymes or antioxidants and celiac plexus block for the CP pain remains controversial.7,8 Less is known about the usefulness of these modalities of treatment in TP.1-3,9-11 The American Gastroenterology Association recommends endoscopic therapy as an option in the management of pain of CP.12 Most published reports on endoscopic therapy of CP are from the West, and very little data exist on the usefulness www.giejournal.org
Pai & Alvares
of this treatment in patients with TP. We hypothesized that placement of stents along the length of the abnormal pancreatic duct in patients with TP, together with pancreatic sphincterotomy, would facilitate proper drainage to provide adequate relief of pain.
Endotherapy of tropical pancreatitis
Capsule Summary What is already known on this topic d
PATIENTS AND METHODS For the purpose of this study, TP was defined as idiopathic CP of the tropics.1-3 CP was diagnosed based on typical changes of calcification on plain radiographs, US, or CT, or on ductal changes seen at ERCP.3 Patients with any history of alcohol intake before the onset of symptoms and those with other causes of CP were excluded. Hypercalcemia and hypertriglyceridemia were ruled out by appropriate investigations. Written informed consent for the procedure was obtained from all patients. The patients with TP who underwent an attempt at therapeutic ERCP for pain over a 30-month period from January 1998 were included. They had persistent or recurrent severe pain of pancreatic origin that needed frequent hospitalization and that did not respond to at least 8 weeks of treatment with non-narcotic oral analgesics, acid suppressants, pancreatic enzyme therapy, and antioxidant supplementation. Those with a frequency of pain less than 1 episode per month were not considered. Patients who underwent procedures specifically for complications such as pseudocysts, fistulas, or ascites, and those with associated disorders that might explain the pain (eg, peptic ulcer disease) were excluded. At ERCP, the pancreatic duct was accessed by using a standard cannula; a tapered-tip cannula; or a Tapertome (Boston Scientific Corp, Natick, Mass), with or without the use of a 0.025-inch Jagwire (Boston Scientific Corp, Natick, Mass). The severity of pancreatitis was assessed according to the Cambridge classification as mild (more than 3 abnormal side branches with a normal main duct), moderate (abnormal main duct and side branches), and severe (same as for moderate disease but with 1 or more additional abnormalities, such as large cavity, ductal stone/filling defect, duct obstruction/ stricture, gross irregularity).13,14 Failure to cannulate the pancreatic duct led to pre-cut papillotomy to deroof the papilla to expose the pancreatic ductal orifice as previously described.15,16 After achieving selective cannulation, a 12- or 15-cm–long 7F stent was placed as deeply into the duct as possible (Fig. 1). A 5-mm–long pancreatic sphincterotomy was done with an over-the-wire papillotome before stent placement or with a needle knife over the stent. Pancreatic calculi were not extracted. The patients were asked to report for follow-up in the event of recurrence of pain or every 2 months for the first 6 months and then every 4 to 6 months until the end of follow-up. Response was defined as complete relief or a www.giejournal.org
Tropical chronic pancreatitis (TP), an idiopathic form of disease seen in tropical developing countries, is characterized by severe, often intractable, abdominal pain.
What this study adds to our knowledge d
In a retrospective review of 17 patients with pain because of TP, pancreatic sphincterotomy with or without stent placement resulted in complete relief of pain in 5 patients; 9 patients were left with mild infrequent pain.
decrease in pain, as a composite of severity, duration, and frequency of episodes by at least 80% as assessed by the patient during follow-up. The severity of pain was scored on a scale of 4, as ‘‘none,’’ ‘‘mild,’’ ‘‘moderate,’’ or ‘‘severe’’; the same words were used each time for all patients to decrease subjectivity and the same person (C.G.P.) assessed the pain scores in all patients. No patient received somatostatin or octreotide before or after the procedure.
RESULTS Patients Twenty-four patients presented for the therapeutic procedure during the study period. Four of the patients who failed the procedure and 1 who had a successful stent placement were found to have carcinoma of the pancreas on cytology obtained during the endoscopic procedure (n Z 1) or at subsequent laparotomy for persistent pain (n Z 4). They were excluded from further analysis (Fig. 2). The mean age of the evaluable patients was 28.3 years (range, 10–56 years). Thirteen were men (68.4%). Twelve patients (63.2%) had pancreatic calcification (parenchymatous in 4 and ductal calculi in 8). Diabetes mellitus was present in 8 (42.1%). Nine patients (47.4%) had severe pain daily as per the scale described, whereas the rest had episodes of severe pain that occurred once in 7 to 30 days and lasted for 2 to 7 days each time. The ductal changes were severe in 11 (57.9%) and moderate in 8 (42.1%); no patient had mild disease. The main pancreatic duct was dilated in all, with a maximum diameter of 6 to 13 mm (median, 9 mm); none had ductal strictures. Two patients (10.5%) needed pre-cut papillotomy to deroof the papilla to facilitate selective cannulation of the pancreatic duct; both underwent successful pancreatic sphincterotomy and stent placement. Thirteen patients (68.4%) had a successful procedure in 1 session; 6 (31.6%) needed 2 sessions. Volume 66, No. 1 : 2007 GASTROINTESTINAL ENDOSCOPY 71
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Figure 1. A and C, Radiographs done during the procedure, showing the pancreatic duct in 2 patients. B and D, Radiographs done during the procedure, showing the stent in place in 2 patients.
Immediate outcome
Follow-up
The intended procedure (stent placement þ pancreatic sphincterotomy) was successful in 14 of the 19 evaluable patients (73.7%). Five patients (26.3%) failed because of an inability to place a guidewire deep into the duct because of its coiling up in between the calculi or in the dilated side branches, despite repeated attempts. In 3 of these, only pancreatic sphincterotomy could be done by using an over-the-wire papillotome. Thus, 17 patients (89.5%) had a procedure done; 14 of them had stent placement plus sphincterotomy and 3 had sphincterotomy alone.
With good response to treatment, the stents were left in place for 6 months (initial 6 patients) to 12 months; no stent exchanges were done during this period. Over a total follow-up of 6 to 38 months (median, 12 months), 14 patients (73.7%) responded to treatment as defined above. Five had complete relief of pain and the rest had mild infrequent pain that occurred once in 3 to 4 months, lasting a few hours at a time and never needing hospitalization. Of the 14 who had a response, 12 received a stent and 2 underwent pancreatic sphincterotomy only. Thus, 12 of the 14 patients (85.7%) who had stent placement plus sphincterotomy and 2 of the 3 patients (66.6%) who had sphincterotomy alone responded to treatment. Initially, the stents were planned to be left in situ for 6 months. One of these patients expelled the stent through the anus 3 months after the procedure, but the pain relief continued, and, hence, the patient was not re-stented. In the 5 other initial patients, the stents were removed at the end of 6 months. These 6 patients had a subsequent follow-up of 6 to 32 months after being stent free. The
Adverse events Four patients (21%) developed acute exacerbation of pain after the procedure. In 3, this subsided with conservative management over 24 hours. The other patient continued to have pain and later developed fever. He was found to have partial dislodgement of the stent into the duodenum, with purulent discharge 3 weeks after the procedure. He improved only after stent removal and, hence, he is considered a nonresponder. 72 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 1 : 2007
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Figure 2. The outcome of endoscopic therapy in TP.
pattern of pain relief continued in these patients. The other patients, 6 of them with the stent in situ for 6 to 12 months and the 2 with sphincterotomy alone, continued to maintain response at their last follow-up.
DISCUSSION Endoscopic therapy is now an accepted modality of treatment for the relief of pain in CP.17 Previous reports in this area have mainly been in patients with alcoholic and idiopathic pancreatitis of the West.18-24 These patients have 1 specific therapy available to them: abstinence from alcohol.25 We showed that pancreatic endotherapy can also be beneficial in TP, where no specific treatment is available. The stents were left in place for 6 to 12 months, and the pain relief was found to persist in the medium term, even after stent removal; the adverse events were few. Compared with surgery, endoscopic therapy has advantages in the treatment of pain of CP. It is simple and reversible, and carries a low morbidity and virtually no mortality.18-24 Unlike lateral pancreaticojejunostomy, endoscopic therapy can be used even in patients with small-duct disease.26 However, endoscopic therapy needs expertise and experience. The selection of patients, the procedures done, and the pattern of follow-up varied widely in previous series on endoscopic therapy for the pain of CP. We followed a standardized protocol, irrespective of whether calculi were present or not. Stent placement of the pancreatic duct was the primary aim, and sphincterotomy followed as an additional drainage procedure. Dilation of strictures was not necessary in any, because none had strictures. No attempt was made to use a basket for the ductal calculi or to fragment them by using extracorporeal shockwave lithotripsy (ESWL) because of multiple reasons. All patients with intractable pain do not have intraductal calculi, as was the case in 11 of our 19 patients (57.9%). Calculi tend to be large in TP and, hence, not easy to remove.3,27 ESWL was unavailable to us at the time of treating these patients. There are no comparative trials to prove that this form of therapy is better than stent placement alone www.giejournal.org
for relieving pain. In fact, the long-term pain relief in 54% to 86% of patients undergoing treatment of stones and the mean size effect for pain of 0.62 in patients undergoing ESWL as shown in a recent meta-analysis appear to be no better than the results of stent placement alone.28,29 It is possible that a subset of patients with large or impacted stones who do not respond to stent placement or fail the procedure might be the ideal candidates for the latter procedure. The failure rate in this study was higher than those reported in some earlier series.20 There could be many reasons for this. The patients in this series were the first undergoing such therapy by the investigators. Accessories such as thin guidewires with hydrophilic tips and over-thewire papillotomes that were routinely used in the latter half of the series were not available earlier. Ductal changes are more severe in TP compared with alcoholic pancreatitis.3,30 Because of these reasons, stent placement sometimes failed in our patients, even in the absence of complete stricture of the pancreatic duct. The diameter of the stent and the duration of its placement for effective therapy of CP have not been fully worked out. Because of the anticipated difficulty in placing large-diameter stents and also because of the good response in the initial few patients with 7F stents, the former were not used in our patients. Pancreatic stents are known to induce ductal changes similar to those of CP.31 It is possible that preexisting ductal changes might worsen further with the use of larger- as opposed to smaller-diameter stents. This was another reason why stents of larger diameter were not used. In light of recent data showing that pancreatic stents block early, it is reasonable to conclude that a shorter period of stent placement might have been equally beneficial.32 Nonetheless, blocked stents might still facilitate drainage in the presence of a pancreatic sphincterotomy.24,33 This might explain why our patients showed sustained benefit, even when the stents were left in situ for 6 to 12 months without exchanges. In the presence of a ductal stricture, the length of the stent that needs to be used is easily determined. There are no guidelines on the length of stent to be used in Volume 66, No. 1 : 2007 GASTROINTESTINAL ENDOSCOPY 73
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the absence of strictures. Short stents have been used to prevent complications after pancreatic sphincterotomy. Stent placement and not pancreatic sphincterotomy was the primary procedure intended in the present series. There is no reason to believe that lateral pancreaticojejunostomy helps only those with pancreatic-duct strictures, and drainage of the entire length of the duct was the aim of this procedure. Our aim was to similarly provide adequate drainage from the entire length of the abnormal pancreatic duct, alongside the calculi if these are present. Hence, 12- to 15-cm-long stents were used. Whether shorter stents would have served the same purpose is unknown, but this appears unlikely. The mechanisms of pain in CP are not fully understood.34-37 Lateral pancreaticojejunostomy, endoscopicstent placement across ductal strictures, and ESWL of calculi are all supposed to help by improving drainage and consequently decreasing intraductal pressure. Insufficient drainage of the ducts after lateral pancreaticojejunostomy has been suggested as the reason for the poor response to this treatment in some patients. Our results suggest that even small-diameter pancreatic stents, when sufficiently long, can result in relief of pain in patients with TP, even when ductal strictures are absent. The persistence of pain relief over 6 to 12 months in the absence of stent exchanges and also after the removal of the stent could be because of the sphincterotomy and the absence of strictures. Whether either procedure alone would have sufficed cannot be answered by this study. However, the good response we found in 2 of 3 patients who underwent sphincterotomy alone and some data available from previous studies indicate this is possible.38,39 Further studies are necessary before firm conclusions can be drawn about this issue. Unlike stent placement, however, sphincterotomy alone will not provide adequate drainage from the upstream portions of the duct. Pancreatic cancer has been reported to occur in 3.2% to 8.3% of patients with TP, and the detection of this complication is difficult and often delayed.40 The 20% prevalence of cancer in our patients might appear too high. However, this can be explained by the fact that patients who develop malignancy are likely to manifest worsening pain and thus would automatically qualify for inclusion, should the malignancy go undetected during initial evaluation. The present series is not without its limitations. TP is difficult to define, and there are no markers for this disease. Like in many other series, the number of patients reported here is small.18-24 Also, use of a visual analog scale to assess the severity of pain would have given more objective results. CP, especially the tropical variety, may be associated with long pain-free periods for no apparent reason.1 That was the reason why patients with frequent pain over a period of at least 3 months not responding to the usual line of treatment were chosen for the procedure. Nevertheless, there was total or neartotal relief of pain in most patients from the time of stent 74 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 1 : 2007
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placement, suggesting that the treatment was responsible for the benefit. A number of options are now available for the treatment of CP pain. The limitations of surgery for the relief of CP pain are well known. Nonsurgical interventions, such as pancreatic sphincterotomy, stent placement of the pancreatic duct, extraction of calculi, and ESWL, all offer attractive alternative options. The long-term results of these procedures and their exact role singly or in combination have not yet been clearly defined.29 More controlled trials are needed to define the role of each of these modalities of treatment.12,17,33 Future studies should also look into the effect of the length and diameter of stents, and the duration of stent placement on the outcome. Also the relative role of sphincterotomy, stent placement, and using a basket or ESWL for calculi singly or in combination needs to be defined in randomized controlled trials. Meanwhile, it appears reasonable to consider placement of long pancreatic stents to relieve intractable pain in patients with TP, even in the absence of ductal strictures.
DISCLOSURE The authors have no disclosures to make. REFERENCES 1. Ramesh H. Tropical pancreatitis. Indian J Gastroenterol 1997;16:20-5. 2. Balakrishnan V, Nair P, Radhakrishnan L, et al. Tropical pancreatitis: a distinct entity, or merely a type of chronic pancreatitis? Indian J Gastroenterol 2006;25:74-81. 3. Tandon RK, Sato N, Garg PK. Chronic pancreatitis: Asia-Pacific consensus report. J Gastroenterol Hepatol 2002;17:508-18. 4. Sohn TA, Campbell KA, Pitt HA, et al. Quality of life and long term survival after surgery for chronic pancreatitis. J Gastrointest Surg 2000;4:355-65. 5. Massucco P, Calgaro M, Bertolino F, et al. Outcome of surgical treatment for chronic calcifying pancreatitis. Pancreas 2001;22:378-82. 6. Russel RC, Theis BA. Pancreaticoduodenectomy in the treatment of chronic pancreatitis. World J Surg 2003;27:1203-10. 7. Mossner J. Is there a place for pancreatic enzymes in the treatment of pain in chronic pancreatitis? Digestion 1993;54(Suppl 2):35-9. 8. Uden S, Bilton D, Nathan L, et al. Antioxidant therapy of recurrent pancreatitis: placebo controlled trial. Aliment Pharmacol Ther 1990;4: 357-71. 9. Thomas PG, Augustine P. Surgery in tropical pancreatitis. Br J Surg 1988;75:161-4. 10. Thomas PG, Augustine P, Ramesh H. Observations and surgical management of tropical pancreatitis in Kerala and Southern India. World J Surg 1990;14:32-42. 11. Durgaprasad S, Pai CG, Vasanthkumar, et al. A pilot study of the antioxidant effect of curcumin in tropical pancreatitis. Indian J Med Res 2005;122:315-8. 12. Warshaw AL, Banks PA, Fernandez-Del Castillo C. American Gastroenterology Association technical review statement: treatment of pain in chronic pancreatitis. Gastroenterology 1998;115:763-4. 13. Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25:756-9. 14. Catalano MF, Lahoti S, Geenen JE, et al. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998;489:11-7.
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Pai & Alvares 15. Huibregtse K, Katon RM, Tytgat GJN. Precut papillotomy via needle knife papillotome: a safe and effective technique. Gastrointest Endosc 1986;32:403-5. 16. Pai CG. Precut papillotomy using needle knife fashioned from discarded standard sphincterotomes. Indian J Gastroenterol 2000;19:116-8. 17. Wilcox CM. Endoscopic therapy for pain in chronic pancreatitis: is it time for the naysayers to throw in the towel? Gastrointest Endosc 2005;61:582-6. 18. Dite P, Ruzicka M, Zboril V, et al. A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy 2003;35:553-8. 19. Cremer M, Deviare J, Delhaye M, et al. Stenting in severe chronic pancreatitis: results of medium-term follow-up in seventy-six patients. Endoscopy 1991;23:171-6. 20. Binmoeller KF, Jue P, Seifert H, et al. Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: long-term results. Endoscopy 1995;27:638-44. 21. Smits ME, Badiga SM, Rauws EA, et al. Long-term results of pancreatic stents in chronic pancreatitis. Gastrointest Endosc 1995;42:461-7. 22. Ponchon T, Bory RM, Hedelius F, et al. Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol. Gastrointest Endosc 1995;42:452-6. 23. Hammarstrom L-E, Stridbeck H, Ihse I. Endoscopic drainage in benign pancreatic disease: immediate and medium term outcome. Eur J Surg 1997;163:577-89. 24. Morgan DE, Smith JK, Hawkins K, et al. Endoscopic stent therapy in advanced chronic pancreatitis: relationships between ductal changes, clinical response, and stent patency. Am J Gastroenterol 2003;98: 821-6. 25. Trapnell JE. Chronic relapsing pancreatitis: a review of 64 cases. Br J Surg 1979;66:471-5. 26. Laugier R, Renou C. Endoscopic ductal drainage may avoid resective surgery in painful chronic pancreatitis without large ductal dilatation. Int J Pancreatol 1998;23:145-52. 27. Chari S, Jayanthi V, Mohan V, et al. Radiological appearance of pancreatic calculi in tropical versus alcoholic chronic pancreatitis. J Gastroenterol Hepatol 1992;7:42-4. 28. Lehman GA. Role of ERCP and other endoscopic modalities in chronic pancreatitis. Gastrointest Endosc 2002;56:s237-40.
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Endotherapy of tropical pancreatitis 29. Guda NM, Partington S, Freeman ML. Extracorporeal shockwave lithotripsy in the management of chronic calcific pancreatitis: a metaanalysis. JOP 2005;6:6-12. 30. Saraya A, Acharya SK, Vashist S, et al. A pancreatographic study of chronic calcific pancreatitis of the tropics. Trop Gastroenterol 2002;23:167-9. 31. Smith MT, Sherman S, Ikenberry SO, et al. Alterations in pancreatic ductal morphology following polyethylene pancreatic stent therapy. Gastrointest Endosc 1996;44:268-75. 32. Deviere J. Why do pancreatic stents become occluded? Gastrointest Endosc 2004;61:867-8. 33. Neuhaus H. Pancreatic stents in chronic pancreatitis: do they function as a tube, a wick, or a placebo? Gastrointest Endosc 2006;63: 67-70. 34. Bradley EL. Pancreatic duct pressure in chronic pancreatitis. Am J Surg 1982;144:313-6. 35. Madsen P, Winkler K. The intraductal pancreatic pressure in chronic obstructive pancreatitis. Scand J Gastroenterol 1982;17:553-4. 36. Malfertheiner P, Dominguez-Munoz JE, Buchler MW. Chronic pancreatitis: management of pain. Digestion 1994;55(Suppl 1):29-34. 37. Bockman DE, Buchler M, Malfertheiner P, et al. Analysis of nerves in chronic pancreatitis. Gastroenterology 1988;94:1459-69. 38. Okolo PI 3rd, Pasricha PJ, Kalloo AN. What are the long-term results of endoscopic pancreatic sphincterotomy? Gastrointest Endosc 2000;52: 15-9. 39. Kozarek RA, Ball TJ, Patterson DJ, et al. Endoscopic pancreatic duct sphincterotomy: indications, technique, and analysis of results. Gastrointest Endosc 1994;40:592-8. 40. Chari ST, Mohan V, Pitchumoni CS, et al. Risk of pancreatic carcinoma in tropical calcifying pancreatitis: an epidemiologic study. Pancreas 1994;9:62-6.
Received March 1, 2005. Accepted February 14, 2007. Current affiliations: Department of Gastroenterology, Kasturba Medical College, Manipal, India. Reprint requests: C. Ganesh Pai, MD, Department of Gastroenterology, Kasturba Medical College, Manipal, 576 104 India.
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