1. S
PAIN MANAGEMENT
IN CHRONIC
PANCREATITIS

2. AGENDA
S MECHANISM OF PAIN
S MANAGEMENT
S MEDICAL
S ENDOTHERAPY
S SURGICAL
S CELIAC PLEXUS BLOCK
S REVIEW OF LITERATURE

3. CHRONIC PANCREATITIS
Defined as a progressive inflammatory response of the
pancreas that has lead to irreversible and permanent
changes
Parenchyma
Fibrosis
Loss of acini and islets of Langerhans
Formation of pancreatic stones
Pancreatic duct
Stenosis
Pancreatic stones
Histologic evidence of chronic inflammation, fibrosis, and destruction of
exocrine (acinar cell) and endocrine (islets of Langerhans) tissue
Two forms
Large-duct calcifying type
Small-duct variant

5. Pain
S Predominant symptom - 90% patients
S Intermittent
S Constant
S Continuous with superimposed acute flare

6. CAUSES OF PAIN
S Caused by disease – active inflammation
S Altered nociception
S Hypertension – ductal or tissue via increased cholecystokinin
S Tissue ischemia
S Complications – inflammatory mass in the head; obstruction of
bile duct or duodenum, pseudocyst or cancer of pancreas

7. MECHANISM OF PAIN IN CP
PLUMBING PROBLEMS
S Pancreatic duct hypertension
S Pancreatic parenchymal hypertension
S Pancreas morphology
S Poulsen JL et al . Pain mechanisms in chronic
pancreatitis. World J Gastroenterol 2013 November 14;
19(42): 7282-7291

8. Pancreatic neuropathy and
neuroplasticity
S Neuropathy - Increased neural density, hypertrophy,
sprouting and neuritis of the intrapancreatic nerves
S Neuroplasticity - Remodeling of the intrapancreatic
innervation

9. WIRING PROBLEMS
S Peripheral nociception
S Nociception refers to the perception of pain sensation as
a result of activation of pain receptors (nociceptors)
S The proteinase-activated receptor 2 (PAR-2) and the
transient receptor potential vanilloid 1 have been shown
to be present in the pancreas specific sensory nerves
and dorsal root ganglia

10. S Neurotrophic factors
S Nerve growth factor (NGF),
S Brain derived neurotrophic factor (BDNF),
S Glial-derived neurotrophic factor
S Artemin
Expressed locally in the pancreas in response to inflammation and bind to
specific receptors at different regions within the nerves

14. S
MANAGEMENT OF
CHRONIC
PANCREATIC PAIN

15. GOALS
S Pain management
S Correction of pancreatic insufficiency
S Management of complications

16. MANAGEMENT OF PAIN
S ESTABLISH A SECURE DIAGNOSIS
S A significant change in the pain pattern or a sudden onset of
persistent symptoms
S Other potential etiologies should be ruled out
S Peptic ulcer disease
S Biliary obstruction
S Pseudocysts
S Pancreatic carcinoma

17. BASICS
S Cessation of alcohol intake
S Cessation of smoking
S Small meals and hydration
S Low in fat
S Supplementation with medium chain triglycerides (MCTs)
may be of benefit
S MCTs can be directly absorbed by the intestinal mucosa
and are less of a stimulant to pancreatic secretion

18. An enteral therapy containing medium-chain
triglycerides and hydrolyzed peptides reduces
postprandial pain associated with chronic
pancreatitis Pancreatology. 2003
S Oral administration of the enteral formula Peptamen, which is
enriched in MCTs and hydrolyzed peptides for 10 weeks
S CCK blood levels were compared between normal fat diet, high
fat diet and enteral formulation
S Enteral formulation resulted in a minimal increase in plasma
CCK levels
S The average improvement in pain scores from baseline to the
conclusion of the study was 61.8% (p = 0.01).
S MCTs may also be administered to prevent weight loss in
individuals who develop steatorrhea

19. Pancreatic enzyme
supplements
S Rationale for this therapy is based upon suppression of feedback
loops in the duodenum that regulate the release of
cholecystokinin
S CCK-release from the duodenum is regulated by CCK-releasing
factors, and these factors are destroyed by pancreatic digestive
enzymes
S Increasing intraduodenal enzyme activity may reduce
stimulation-associated pancreatic pain

20. CHOLECYSTOKININ RELEASING FACTOR (CCK-RF) secreted into the
proximal intestine is inactivated by trypsin. Dietary protein competes for trypsin
and prevents it from inactivating CCK-RF. The resulting increase of CCK-RF in
the intestinal lumen releases CCK and stimulates pancreatic enzyme secretion.

21. Does pancreatic enzyme
supplementation reduce pain in patients
with chronic pancreatitis: a meta-analysis
Am J Gastroenterol. 1997
S Six randomized, double-blind, placebo-controlled
trials.
S Important features of data extraction included the
method of subject inclusion, definition of disease,
enzyme preparation, response to pancreatic
enzyme therapy versus placebo, and modality for
measuring response

22. Six trials were included

24. Study Conclusion
S No statistically significant benefit of
supplemental pancreatic enzyme therapy to
treat pain associated with chronic pancreatitis
S Enzyme supplementation is safe and thus is a
reasonable initial strategy in patients with severe
pain who have not responded to other
conservative measures

25. STEATORRHEA
S Fat intake of 20 grams per day or less
S Provide approximately 5 to 10 percent of the pancreatic
enzymatic output
S Approximately 30,000 international units (IU) of lipase per meal
S Enzymes should be taken with the first bite of a meal
S Fat-soluble vitamin analogues

26. ANALGESICS
S Considered if pancreatic enzyme therapy fails to control
pain
S Amitriptyline and nortriptyline have been shown to reduce daily
pain from neuropathic conditions
S A short course of opiates coupled with low dose amitriptyline (10
mg nightly for three weeks to determine efficacy) and a
nonsteroidal antiinflammatory drug will break the pain cycle
S Matter of clinical judgment

27. Gabapentoids
S Pregabalin, have effectively been used to treat various
neuropathic pain disorders, including diabetic neuropathy,
postherpetic neuralgia, and neuropathic pain of central origin

28. Pregabalin Reduces Pain in Patients With Chronic
Pancreatitis in a Randomized, Controlled Trial
Olesen SS,
Gastroenterology 2011
S Double-blind RCT to evaluate the effects of the
gabapentoid pregabalin as an adjuvant analgesic
S N=64 [Pregabinin – 34, Placebo – 30]
S 3 weeks
S Primary end point - pain relief, based on a visual analogue
scale documented by a pain diary

29. S Initial dose was 75 mg pregabalin twice daily. Gradually
increased to 300 mg twice daily after 1 week and for the
rest of the study period.
S The majority of patients in the current study were treated
with opioids, and one-fourth of patients (n =19) had
undergone interventional therapies for CP pain.

30. Pregabalin reduces pain in patients with
chronic pancreatitis in a randomized,
controlled trial. Gastroenterology. 2011
S Pregabalin, compared with placebo, caused more
effective pain relief after 3 weeks of treatment
S The percentage of patients with much or very
much improved health status at the end of the
study was higher in the pregabalin than the
control group (44% vs 21%; P = .048)

31. ANTIOXIDANT
S There is a significant reduction in antioxidant
defense in patients with CP
S Primary aim of antioxidant micronutrient therapy in
CP is to supply methyl and thiol moieties for the
transsulfuration pathway,
S Essential for protection against reactive oxygen
species (ROS) mediated electrophilic stress

32. A Randomized Controlled Trial of Antioxidant
Supplementation for Pain Relief in Patients With
Chronic Pancreatitis
Bhardwaj P, Garg PK , Maulik SK et al, Gastroenterology 2009
 Double blind RCT
 N = 127 ; Placebo (n=56) or antioxidants (n=71)
 Follow up - 6 months
 Primary outcome
 Pain relief
 Secondary outcome
 analgesic requirements
 Hospitalization
 markers of oxidative stress ( thiobarbituric acid-reactive substances
[TBARS])
 antioxidant status (ferric-reducing ability of plasma [FRAP])

33. Antioxidant supplementation
S Organic selenium - 600 μg
S Ascorbic acid - 0.54 g
S Carotene - 9000 IU
S Tocopherol - 270 IU
S Methionine - 2 g

34. Results
S 35 alcoholic, and 92 with idiopathic CP
Antioxidan
t
Placebo P
Reduction
in the
number of
painful days
per month
7.4 ± 6.8 3.2 ± 4 < .001
reduction in
the number
of analgesic
tablets per
month
10.5 ± 11.8 4.4 ± 5.8 < .001
pain free 32% 13% 0.009
reduction in
Higher
the level of
TBARS
increase in
FRAP
Higher
Conclusions:
Antioxidant
supplementation
was effective in
relieving pain
and reducing
levels of
oxidative stress
in patients with
CP.

35. Antioxidant therapy does not reduce pain
in patients with chronic pancreatitis: the
ANTICIPATE study Gastroenterology. 2012 Sep
S Double-blind, randomized controlled trial
S Compared the effects of antioxidant therapy with placebo in 70
patients with chronic pancreatitis.
S Followed for 6 months
S Pain scores reported to the clinic were reduced by 1.97 from
baseline in the placebo group and by 2.33 in the antioxidant
group
S Antioxidants to patients with painful chronic pancreatitis of
predominantly alcoholic origin does not reduce pain or improve
quality of life

36. ENDOTHERAPY
S Ductal hypertension due to sphincter of Oddi
dysfunction,ductal stones or strictures of the main
pancreatic duct lead to pain
S Decompressing an obstructed pancreatic duct can
be associated with pain relief
S Difficult to manage - PD strictures in the tail of the
pancreas and multiple strictures along the length
of the main PD.

37. Procedure
S Pancreatic sphincterotomy
S Stricture dilation with a graduated dilating catheter or
balloon dilators
S Stone extraction with balloon or basket
S PD stent – according to duct diameter
S Timing of pancreatic stent exchange is variable in
practice: routine every 8 -12 weeks prior to stent
occlusion versus on-demand exchange based on
recurrence of symptoms

38. Endoscopic treatment of chronic pancreatitis: a
multicenter study of 1000 patients with long-term
follow-up
Rosch T, Endoscopy, 2002
S N=1018
S Median age 50 years
S follow-up 2 - 12 years (mean 4.9 years)
S Profile - Strictures – 47%
S Stones - 18%
S Strictures plus stones (32%)
S complex pathology (3%)

40. S Complications - 13%
S Pancreatitis (4 %)
S Hemorrhage after endoscopic papillotomy (1%)
S Perforation (0.5 %)
S Significant infectious complications (1 %)
S Minor complications such as early stent dislocation (2 %).

41. Significant pain relief acc to ITT analysis = 65%

42. Multiple stenting of refractory pancreatic duct
strictures in severe chronic pancreatitis: long-term
results Costamagna GEndoscopy 2006
S 19 patients with severe chronic pancreatitis
S Single pancreatic stent through a refractory dominant stricture
in the pancreatic head.
S Removal of the single pancreatic stent
S Balloon dilation of the stricture
S Iinsertion of the maximum number of stents allowed by the
stricture tightness and the pancreatic duct diameter
S Removal of stents after 6 to 12 months.

44. S The median number of stents placed through the major or minor
papilla was - 3
S Diameters ranging from 8.5 to 11.5 Fr and length from 4 to 7 cm.
S Only one patient (5.5 %) had persistent stricture after multiple
stenting.
S During a mean follow-up of 38 months after removal, 84 % of patients
were asymptomatic, and 10.5 % had symptomatic stricture
recurrence

45. Extracorporeal shock wave
lithotripsy (ESWL)
S Pancreatic duct stones are found in approximately 22 to
60 percent of patients with chronic pancreatitis
S Causes increased intraductal pressure
S Extracorporeal shock wave lithotripsy (ESWL) creates
millimetric fragmentation of pancreatic stones, which has
improved the results of endoscopic therapy
S Short term pain relief following ESWL

48. Extracorporeal shock wave lithotripsy and
endotherapy for pancreatic calculi-a large
single center experience. Indian J Gastroenterol.
2010
S Large pancreatic duct (PD) calculi (>5 mm diameter) not
amenable to extraction at routine endoscopic retrograde
cholangiopancreatography (ERCP) were taken up for ESWL
S A total of 1,006 patients underwent ESWL
S 5,000 shocks were given per session.
S Fragmentation was considered successful when the calculi were
broken to 3 mm or less in size
S ERCP was performed within 48 h of successful fragmentation.

49. S Complete clearance—clearance of >90% of stone
volume
S Partial clearance—clearance of 50–90% of stone volume.
S Unsuccessful clearance—failure to fragment the calculi to
<3 mm diameter or clearance of <50% of stone volume.

50. S Complete clearance - 762 (76%)
S Partial clearance in 173 (17%)
S Unsuccessful in the rest.
S Pancreatic sphincterotomy was done in 938 (93.8%)
patients and a stent was placed in 542 (54.2%) patients

51. ESWL sessions
S 292 patients needed one session
S 370 patients needed two sessions
S 300 patients needed three sessions

52. Folow up
S At 6 months
S 711 (84%) of 846 patients who returned for follow up had
significant relief of pain with a decrease in analgesic use.
S Stents were removed after 6 months on follow up.
S In patients with MPD strictures, a stent exchange was
carried out.

53. SURGERY
S When the initial medical and endoscopic
treatments fail to relieve intractable
abdominal pain
S First line therapy if there is suspicion of
pancreatic cancer

54. Indications for Surgery in
Chronic Pancreatitis
S Biliary or pancreatic stricture
S Duodenal stenosis
S Fistulas (peritoneal or pleural effusion)
S Hemorrhage
S Intractable chronic abdominal pain
S Pseudocysts
S Suspected pancreatic neoplasm
S Vascular complications

55. PROCEDURES
S Decompression/drainage operations
S Pancreatic resections
S Denervation procedures

56. Decompression procedures
S Large duct disease.
S A dilated duct (from a surgical standpoint) is one that
would permit anastomosis to a loop of jejunum
S Lateral pancreaticojejunostomy is commonly
performed and yields pain relief in 60 to 91 percent
of patients

57. Timing of surgery
• Patients with associated complications: Early surgery
• For pain relief:
Early surgery ( < 4years) may delay progress of
Exocrine/ endocrine insufficiency (Alc CP)
Patel AG et al, Ann Surg 1999; Nealon WH et al, Ann Surg 1993
Early surgery in NACP/ Tropical CP improves
nutritional status, weight gain, decreased insulin
requirement
Tripathy BB et al, 1987
• Controversies: How early & what surgery: drainage
or resection?

58. Long-term patency, pancreatic function, and
pain relief after lateral pancreaticojejunostomy
for chronic pancreatitis Gastroenterology. 1980
S Ten patients, all with intractable pain due to chronic pancreatitis
S Treated by lateral pancreaticojejunostomy (modified Puestow
procedure)
S Progression of exocrine or endorine pancreatic insufficiency
S Decompression of the dilated pancreatic duct, although an
effective means for relief of pain in chronic pancreatitis, does not
prevent continuing destruction of pancreatic glandular tissue.

60. Endoscopic versus Surgical Drainage of the
Pancreatic Duct in Chronic Pancreatitis
Djuna L, NEJM 2007
S RCT
S Chronic pancreatitis and a distal obstruction of the pancreatic duct but
without an inflammatory mass were eligible for the study
S N=39 Endotherapy-19 (16 underwent lithotripsy)
S Operative pancreaticojejunostomy – 20
S Follow up 2 years
S Primary end point – average pain score (frequency, intensity of pain,
use of analgesics and disease-related inability to work)

62. Study Conclusion
S Surgical drainage as the preferred treatment
S In cases of less extensive disease and surgical risk
patient, endoscopic treatment may still be a valuable
alternative

63. Long-term outcomes of endoscopic vs surgical
drainage of the pancreatic duct in patients with
chronic pancreatitis Gastroenterology. 2011 Nov
S 79-month follow-up period
S Patients treated by endoscopy, 68% required additional
drainage compared with 5% in the surgery group (P = .001)
S Patients assigned to endoscopy underwent more procedures
(median, 12 vs 4; P = .001)
S 47% of the patients in the endoscopy group eventually
underwent surgery.
S Surgery was still superior in terms of pain relief (80% vs 38%; P
= .0.42)

64. Endoscopic or surgical intervention for painful
obstructive chronic pancreatitisCochrane
Database Syst Rev. 2012
S Two trials compared endoscopic intervention to surgical
intervention.
S These included a total of 111 patients, 55 in the
endoscopic group and 56 in the surgical group.
S A higher proportion of patients with pain relief was found
in the surgical group compared to the endoscopic group

65. S Surgical intervention resulted in improved quality of life and
improved preservation of exocrine pancreatic function in one trial.
S For patients with obstructive chronic pancreatitis and dilated
pancreatic duct, this review showed that surgery is superior to
endoscopy in terms of pain control.

66. RESECTION
S Considered in patients with pancreatic mass or small duct
disease.
S Resective procedures include
S Whipple procedure
S Pylorus-preserving pancreaticoduodenectomy
S Distal pancreatectomy
S Duodenum-preserving resection of pancreatic head
S Total pancreatectomy

67. S Whipple procedure - Most widely performed surgery in patients
with chronic pancreatitis. Pain relief in 85 percent of patients.
S Distal pancreatectomy - Increased risk of early-onset diabetes.
Indicated if the disease is confined to the tail of the pancreas
S Total pancreatectomy - is a last-resort procedure associated
with a high rate of brittle diabetes and inadequate pain relief
and should be accompanied by autologous islet cell
transplantation.

69. Resection vs drainage in treatment of chronic
pancreatitis: long-term results of a randomized
trial. Gastroenterology. 2008 May
S Aim of this study was to report on long-term results of a
randomized trial comparing a classical resective procedure
(pylorus-preserving Whipple) with an extended drainage procedure
for chronic pancreatitis.
S Follow up of 7 years
S Both procedures provide adequate pain relief and quality of life
after long-term follow-up with no differences regarding exocrine
and endocrine function.

70. DENERVATION
PROCEDURES
S Most afferent nerves emanating from the pancreas pass
through the celiac ganglion and splanchnic nerves.
S Interruption of these nerve fibers has the potential to alleviate
pain originating from the pancreas
S Accomplished using an open surgical approach and using
thoracoscopic surgery

71. Quality of life after bilateral thoracoscopic
splanchnicectomy: long-term evaluation in
patients with chronic pancreatitis J Gastrointest
Surg. 2002
S 55 patients with small-duct chronic pancreatitis and
abdominal pain
S Divided into those who had prior operative or endoscopic
interventions (N = 38) and those who did not (N = 17).
S Pain score, narcotic use, and symptoms scales improved
significantly in both groups at 3 and 6 months postoperatively
(P < 0.0001)

72. S The group with no prior surgical or endoscopic intervention did
significantly better (P < 0.007)
S Bilateral thoracoscopic splanchnicectomy appears to work best in
patients who have had no prior operative or endoscopic
interventions

73. CELIAC PLEXUS
NEUROLYSIS AND CELIAC
PLEXUS BLOCK
S Anterior approach under the guidance of
transcutaneous ultrasound, computed tomography,
laparoscopy or EUS
S EUS allows for real-time imaging of the celiac
space for CPB and CPN as well as fine needle
aspiration (FNA) for diagnostic purposes and tumor
staging

74. A prospective randomized comparison of
endoscopic ultrasound- and computed
tomography-guided celiac plexus block for
managing chronic pancreatitis pain Am J
Gastroenterol. 1999
S Prospective randomized study on 22 patients
S 50% patients who underwent EUS-guided CPB experienced
significant improvement in pain scores
S 25% reduction in pain relief in patients who had CT-guided CPB.
S 40% and 30% of the EUS-guided CPB patients had continued
benefit at 8 wk and 24 wk
S 12% of the CT-guided CPB patients at 12 wk

75. EUS-guided celiac plexus
block
(basic anatomy)
S The celiac plexus is composed of a right and left ganglion,
located anterolateral to the aorta at the level of the celiac
trunk.
S The crura of the diaphragm and the L1 vertebral body are
located posterior to the celiac plexus.
S Kidneys, adrenals and the inferior vena cava are present
laterally
S Pancreas covers the celiac plexus anteriorly

76. S Location of the celiac plexus in relation to the celiac trunk
is the most reliable landmark
S Celiac ganglia are not easily identified by EUS
S On average, the left and the right ganglion are located
0.9 cm and 0.6 cm inferior to the celiac artery
respectively

78. CELIAC PLEXUS BLOCK
S First described by Kappis in 1914
S Corticosteroid injection in patients with benign pancreatic
diseases like chronic pancreatitis
S Bupivacaine is often used in combination with the steroid
injection to provide a more prolonged analgesic effect
compared to the local anesthetic alone

79. Celiac plexus neurolysis
S Ablation of the plexus, often achieved with alcohol or
phenol administered
S Bupivicaine is injected first to prevent pain associated with
the alcohol injection.
S CPN with alcohol is not routinely used in benign diseases
given the risk of retroperitoneal fibrosis, which would render
any subsequent pancreatic surgery more difficult

80. Celiac plexus intervention

81. Celiac ganglia intervention

83. Endoscopic ultrasound-guided celiac plexus
block for managing abdominal pain associated
with chronic pancreatitis: a prospective single
center experience Am J Gastroenterol. 2001
S EUS-guided celiac plexus block under the guidance of linear array
endosonography
S 10 cc bupivacaine (0.25%) and 3 cc (40 mg) triamcinolone on
each side of the celiac plexus.
S Individual pain scores, based on a visual analog scale (0-10),
were determined preblock and postblock by a nurse at 2, 7, 14
days and monthly thereafter

84. S 90 patients
S Improvement in overall pain scores occurred in 55% (50/90) of
patients
S Mean pain score decreased from 8 to 2 post EUS celiac block at both
4 and 8 wk follow-up (p < 0.05).
S In 26% of patients there was persistent benefit beyond 12 wk
S 10% still had persistent benefit at 24 wk
S Younger patients (<45 yr of age) and those having previous
pancreatic surgery for chronic pancreatitis were unlikely to respond to
the EUS-guided celiac block

85. Efficacy of endoscopic ultrasound-guided celiac
plexus block and celiac plexus neurolysis for
managing abdominal pain associated with chronic
pancreatitis and pancreatic cancer J Clin Gastroenterol.
2010
S Metanalysis
S 9 studies were included in the final analysis.
S For chronic pancreatitis, 6 relevant studies were identified,
comprising a total of 221 patients.
S EUS-guided CPB was effective in alleviating abdominal pain in
51.46% of patients.

86. Initial evaluation of the efficacy and safety of
endoscopic ultrasound-guided direct Ganglia
neurolysis and block Am J Gastroenterol. 2008
S Direct ganglia injection in patients with moderate to severe pain
secondary to unresectable pancreatic carcinoma or chronic
pancreatitis
S 36 direct celiac ganglia injections for unresectable pancreatic
cancer (CGN N = 17, CGB N = 1) or chronic pancreatitis (CGN N
= 5, CGB N = 13)
S Bupivacaine (0.25%) and alcohol (99%) for CGN, or DepoMedrol
(80 mg/2 cc) for CGB.

87. S For chronic pancreatitis, 4/5 (80%) who received alcohol
reported pain relief versus 5/13 (38%) receiving steroids
S Thirteen (34%) patients experienced initial pain exacerbation,
which correlated with improved therapeutic response (P < 0.05).
S EUS-guided direct celiac ganglion block or neurolysis is safe.
S Alcohol injection into ganglia appears to be effective in both
cancer and chronic pancreatitis

88. Frequency of visualization of presumed celiac
ganglia by endoscopic ultrasound Endoscopy.
2007
S Unknown how often ganglia are visualized during EUS, and what
clinical factors are associated with ganglion visualization
S 200 unselected patients who were undergoing EUS in a tertiary
referral center
S Presumed celiac ganglia were identified in 81 % of patients overall
S More ganglia were seen per patient with linear echo than with
radial echo endoscopes ( P = 0.001).

90. S
THANKS