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S
PAIN MANAGEMENT IN CHRONIC
PANCREATITIS
AGENDA
MECHANISM OF PAIN
MANAGEMENT
MEDICAL
ENDOTHERAPY
SURGICAL
CELIAC PLEXUS BLOCK
REVIEW OF LITERATURE
Defined as a progressive inflammatory response of the pancreas that has lead to irreversible and permanent changes
Parenchyma FibrosisLoss of acini and islets of LangerhansFormation of pancreatic stones
CHRONIC PANCREATITIS
Pancreatic duct Stenosis Pancreatic stones
Histologic evidence of chronic inflammation, fibrosis, and destruction of exocrine (acinar cell) and endocrine (islets of Langerhans) tissue
Two formsLarge-duct calcifying typeSmall-duct variant
Pain
Predominant symptom - 90% patients
Intermittent
Constant
Continuous with superimposed acute flare
CAUSES OF PAIN
Caused by disease – active inflammation
Altered nociception
Hypertension – ductal or tissue via increased cholecystokinin
Tissue ischemia
Complications – inflammatory mass in the head; obstruction of bile duct or duodenum, pseudocyst or cancer of pancreas
MECHANISM OF PAIN IN CP
PLUMBING PROBLEMS
Pancreatic duct hypertension
Pancreatic parenchymal hypertension
Pancreas morphology
Poulsen JL et al . Pain mechanisms in chronic pancreatitis. World J Gastroenterol 2013 November 14; 19(42): 7282-7291
Pancreatic neuropathy and neuroplasticity
Neuropathy - Increased neural density, hypertrophy, sprouting and neuritis of the intrapancreatic nerves
Neuroplasticity - Remodeling of the intrapancreatic innervation
WIRING PROBLEMS
Peripheral nociception
Nociception refers to the perception of pain sensation as a result of activation of pain receptors (nociceptors)
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
Neurotrophic factors Nerve growth factor (NGF), Brain derived neurotrophic factor (BDNF), Glial-derived neurotrophic factor Artemin
Expressed locally in the pancreas in response to inflammation and bind to specific receptors at different regions within the nerves
S
MANAGEMENT OF CHRONIC
PANCREATIC PAIN
GOALS
Pain management
Correction of pancreatic insufficiency
Management of complications
MANAGEMENT OF PAIN
ESTABLISH A SECURE DIAGNOSIS
A significant change in the pain pattern or a sudden onset of persistent symptoms
Other potential etiologies should be ruled out Peptic ulcer disease Biliary obstruction Pseudocysts Pancreatic carcinoma
BASICS
Cessation of alcohol intake
Cessation of smoking
Small meals and hydration
Low in fat
Supplementation with medium chain triglycerides (MCTs) may be of benefit
MCTs can be directly absorbed by the intestinal mucosa and are less of a stimulant to pancreatic secretion
An enteral therapy containing medium-chain triglycerides and hydrolyzed peptides reduces postprandial pain associated with chronic pancreatitis
Pancreatology. 2003
Oral administration of the enteral formula Peptamen, which is enriched in MCTs and hydrolyzed peptides for 10 weeks
CCK blood levels were compared between normal fat diet, high fat diet and enteral formulation
Enteral formulation resulted in a minimal increase in plasma CCK levels
The average improvement in pain scores from baseline to the conclusion of the study was 61.8% (p = 0.01).
MCTs may also be administered to prevent weight loss in individuals who develop steatorrhea
Pancreatic enzyme supplements
Rationale for this therapy is based upon suppression of feedback loops in the duodenum that regulate the release of cholecystokinin
CCK-release from the duodenum is regulated by CCK-releasing factors, and these factors are destroyed by pancreatic digestive enzymes
Increasing intraduodenal enzyme activity may reduce stimulation-associated pancreatic pain
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.
Does pancreatic enzyme supplementation reduce pain in
patients with chronic pancreatitis: a meta-analysis Am J Gastroenterol. 1997
Six randomized, double-blind, placebo-controlled trials.
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
Six trials were included
Study Conclusion
No statistically significant benefit of supplemental pancreatic enzyme therapy to treat pain associated with chronic pancreatitis
Enzyme supplementation is safe and thus is a reasonable initial strategy in patients with severe pain who have not responded to other conservative measures
STEATORRHEA
Fat intake of 20 grams per day or less
Provide approximately 5 to 10 percent of the pancreatic enzymatic output
Approximately 30,000 international units (IU) of lipase per meal
Enzymes should be taken with the first bite of a meal
Fat-soluble vitamin analogues
ANALGESICS
Considered if pancreatic enzyme therapy fails to control pain
Amitriptyline and nortriptyline have been shown to reduce daily pain from neuropathic conditions
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
Matter of clinical judgment
Gabapentoids
Pregabalin, have effectively been used to treat various neuropathic pain disorders, including diabetic neuropathy, postherpetic neuralgia, and neuropathic pain of central origin
Pregabalin Reduces Pain in Patients With Chronic Pancreatitis in a Randomized,
Controlled TrialOlesen SS,
Gastroenterology 2011
Double-blind RCT to evaluate the effects of the gabapentoid pregabalin as an adjuvant analgesic
N=64 [Pregabinin – 34, Placebo – 30]
3 weeks
Primary end point - pain relief, based on a visual analogue scale documented by a pain diary
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.
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.
Pregabalin reduces pain in patients with chronic pancreatitis
in a randomized, controlled trial. Gastroenterology. 2011
Pregabalin, compared with placebo, caused more effective pain relief after 3 weeks of treatment
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)
ANTIOXIDANT
There is a significant reduction in antioxidant defense in patients with CP
Primary aim of antioxidant micronutrient therapy in CP is to supply methyl and thiol moieties for the transsulfuration pathway,
Essential for protection against reactive oxygen species (ROS) mediated electrophilic stress
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])
Antioxidant supplementation
Organic selenium - 600 µg
Ascorbic acid - 0.54 g
Carotene - 9000 IU
Tocopherol - 270 IU
Methionine - 2 g
Results 35 alcoholic, and 92 with idiopathic CP
Antioxidant
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 the level of TBARS
Higher
increase in FRAP
Higher
Conclusions:
Antioxidant supplementation was effective in relieving pain and reducing levels of oxidative stress in patients with CP.
Antioxidant therapy does not reduce pain in patients with
chronic pancreatitis: the ANTICIPATE study Gastroenterology. 2012 Sep
Double-blind, randomized controlled trial
Compared the effects of antioxidant therapy with placebo in 70 patients with chronic pancreatitis.
Followed for 6 months
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
Antioxidants to patients with painful chronic pancreatitis of predominantly alcoholic origin does not reduce pain or improve quality of life
ENDOTHERAPY
Ductal hypertension due to sphincter of Oddi dysfunction,ductal stones or strictures of the main pancreatic duct lead to pain
Decompressing an obstructed pancreatic duct can be associated with pain relief
Difficult to manage - PD strictures in the tail of the pancreas and multiple strictures along the length of the main PD.
Procedure
Pancreatic sphincterotomy
Stricture dilation with a graduated dilating catheter or balloon dilators
Stone extraction with balloon or basket
PD stent – according to duct diameter
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
Endoscopic treatment of chronic pancreatitis: a multicenter study of
1000 patients with long-term follow-upRosch T, Endoscopy, 2002
N=1018
Median age 50 years
follow-up 2 - 12 years (mean 4.9 years)
Profile - Strictures – 47%
Stones - 18%
Strictures plus stones (32%)
complex pathology (3%)
Complications - 13%
Pancreatitis (4 %)
Hemorrhage after endoscopic papillotomy (1%)
Perforation (0.5 %)
Significant infectious complications (1 %)
Minor complications such as early stent dislocation (2 %).
Significant pain relief acc to ITT analysis = 65%
Multiple stenting of refractory pancreatic duct strictures in severe
chronic pancreatitis: long-term results Costamagna G Endoscopy 2006
19 patients with severe chronic pancreatitis
Single pancreatic stent through a refractory dominant stricture in the pancreatic head.
Removal of the single pancreatic stent Balloon dilation of the stricture Iinsertion of the maximum number of stents allowed by
the stricture tightness and the pancreatic duct diameter Removal of stents after 6 to 12 months.
The median number of stents placed through the major or minor papilla was - 3
Diameters ranging from 8.5 to 11.5 Fr and length from 4 to 7 cm.
Only one patient (5.5 %) had persistent stricture after multiple stenting.
During a mean follow-up of 38 months after removal, 84 % of patients were asymptomatic, and 10.5 % had symptomatic stricture recurrence
Extracorporeal shock wave lithotripsy (ESWL)
Pancreatic duct stones are found in approximately 22 to 60 percent of patients with chronic pancreatitis
Causes increased intraductal pressure
Extracorporeal shock wave lithotripsy (ESWL) creates millimetric fragmentation of pancreatic stones, which has improved the results of endoscopic therapy
Short term pain relief following ESWL
Extracorporeal shock wave lithotripsy and endotherapy for pancreatic calculi-
a large single center experience. Indian J Gastroenterol. 2010
Large pancreatic duct (PD) calculi (>5 mm diameter) not amenable to extraction at routine endoscopic retrograde cholangiopancreatography (ERCP) were taken up for ESWL
A total of 1,006 patients underwent ESWL
5,000 shocks were given per session.
Fragmentation was considered successful when the calculi were broken to 3 mm or less in size
ERCP was performed within 48 h of successful fragmentation.
Complete clearance—clearance of >90% of stone volume
Partial clearance—clearance of 50–90% of stone volume.
Unsuccessful clearance—failure to fragment the calculi to <3 mm diameter or clearance of <50% of stone volume.
Complete clearance - 762 (76%)
Partial clearance in 173 (17%)
Unsuccessful in the rest.
Pancreatic sphincterotomy was done in 938 (93.8%) patients and a stent was placed in 542 (54.2%) patients
ESWL sessions
292 patients needed one session
370 patients needed two sessions
300 patients needed three sessions
Folow up
At 6 months
711 (84%) of 846 patients who returned for follow up had significant relief of pain with a decrease in analgesic use.
Stents were removed after 6 months on follow up.
In patients with MPD strictures, a stent exchange was carried out.
SURGERY
When the initial medical and endoscopic treatments fail to relieve intractable abdominal pain
First line therapy if there is suspicion of pancreatic cancer
Indications for Surgery in Chronic Pancreatitis
Biliary or pancreatic stricture
Duodenal stenosis
Fistulas (peritoneal or pleural effusion)
Hemorrhage
Intractable chronic abdominal pain
Pseudocysts
Suspected pancreatic neoplasm
Vascular complications
PROCEDURES
Decompression/drainage operations
Pancreatic resections
Denervation procedures
Decompression procedures
Large duct disease.
A dilated duct (from a surgical standpoint) is one that would permit anastomosis to a loop of jejunum
Lateral pancreaticojejunostomy is commonly performed and yields pain relief in 60 to 91 percent of patients
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?
Long-term patency, pancreatic function, and pain relief after lateral pancreaticojejunostomy for chronic pancreatitis Gastroenterology. 1980
Ten patients, all with intractable pain due to chronic pancreatitis
Treated by lateral pancreaticojejunostomy (modified Puestow procedure)
Progression of exocrine or endorine pancreatic insufficiency
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.
Endoscopic versus Surgical Drainage of thePancreatic Duct in Chronic Pancreatitis
Djuna L, NEJM 2007
RCT
Chronic pancreatitis and a distal obstruction of the pancreatic duct but without an inflammatory mass were eligible for the study
N=39 Endotherapy-19 (16 underwent lithotripsy)
Operative pancreaticojejunostomy – 20
Follow up 2 years
Primary end point – average pain score (frequency, intensity of pain, use of analgesics and disease-related inability to work)
Study Conclusion
Surgical drainage as the preferred treatment
In cases of less extensive disease and surgical risk patient, endoscopic treatment may still be a valuable alternative
Long-term outcomes of endoscopic vs surgical drainage of the pancreatic duct
in patients with chronic pancreatitis Gastroenterology. 2011 Nov
79-month follow-up period
Patients treated by endoscopy, 68% required additional drainage compared with 5% in the surgery group (P = .001)
Patients assigned to endoscopy underwent more procedures (median, 12 vs 4; P = .001)
47% of the patients in the endoscopy group eventually underwent surgery.
Surgery was still superior in terms of pain relief (80% vs 38%; P = .0.42)
Endoscopic or surgical intervention for painful obstructive chronic pancreatitis
Cochrane Database Syst Rev. 2012
Two trials compared endoscopic intervention to surgical intervention.
These included a total of 111 patients, 55 in the endoscopic group and 56 in the surgical group.
A higher proportion of patients with pain relief was found in the surgical group compared to the endoscopic group
Surgical intervention resulted in improved quality of life and improved preservation of exocrine pancreatic function in one trial.
For patients with obstructive chronic pancreatitis and dilated pancreatic duct, this review showed that surgery is superior to endoscopy in terms of pain control.
RESECTION
Considered in patients with pancreatic mass or small duct disease.
Resective procedures include Whipple procedure Pylorus-preserving pancreaticoduodenectomy Distal pancreatectomy Duodenum-preserving resection of pancreatic head Total pancreatectomy
Whipple procedure - Most widely performed surgery in patients with chronic pancreatitis. Pain relief in 85 percent of patients.
Distal pancreatectomy - Increased risk of early-onset diabetes. Indicated if the disease is confined to the tail of the pancreas
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.
Resection vs drainage in treatment of chronic pancreatitis: long-term results
of a randomized trial. Gastroenterology. 2008 May
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.
Follow up of 7 years
Both procedures provide adequate pain relief and quality of life after long-term follow-up with no differences regarding exocrine and endocrine function.
DENERVATION PROCEDURES
Most afferent nerves emanating from the pancreas pass through the celiac ganglion and splanchnic nerves.
Interruption of these nerve fibers has the potential to alleviate pain originating from the pancreas
Accomplished using an open surgical approach and using thoracoscopic surgery
Quality of life after bilateral thoracoscopic splanchnicectomy: long-
term evaluation in patients with chronic pancreatitis J Gastrointest Surg.
2002
55 patients with small-duct chronic pancreatitis and abdominal pain
Divided into those who had prior operative or endoscopic interventions (N = 38) and those who did not (N = 17).
Pain score, narcotic use, and symptoms scales improved significantly in both groups at 3 and 6 months postoperatively (P < 0.0001)
The group with no prior surgical or endoscopic intervention did significantly better (P < 0.007)
Bilateral thoracoscopic splanchnicectomy appears to work best in patients who have had no prior operative or endoscopic interventions
CELIAC PLEXUS NEUROLYSIS AND CELIAC
PLEXUS BLOCK
Anterior approach under the guidance of transcutaneous ultrasound, computed tomography, laparoscopy or EUS
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
A prospective randomized comparison of endoscopic ultrasound- and
computed tomography-guided celiac plexus block for managing chronic
pancreatitis pain Am J Gastroenterol. 1999
Prospective randomized study on 22 patients
50% patients who underwent EUS-guided CPB experienced significant improvement in pain scores
25% reduction in pain relief in patients who had CT-guided CPB.
40% and 30% of the EUS-guided CPB patients had continued benefit at 8 wk and 24 wk
12% of the CT-guided CPB patients at 12 wk
EUS-guided celiac plexus block
(basic anatomy)
The celiac plexus is composed of a right and left ganglion, located anterolateral to the aorta at the level of the celiac trunk.
The crura of the diaphragm and the L1 vertebral body are located posterior to the celiac plexus.
Kidneys, adrenals and the inferior vena cava are present laterally
Pancreas covers the celiac plexus anteriorly
Location of the celiac plexus in relation to the celiac trunk is the most reliable landmark
Celiac ganglia are not easily identified by EUS
On average, the left and the right ganglion are located 0.9 cm and 0.6 cm inferior to the celiac artery respectively
CELIAC PLEXUS BLOCK
First described by Kappis in 1914
Corticosteroid injection in patients with benign pancreatic diseases like chronic pancreatitis
Bupivacaine is often used in combination with the steroid injection to provide a more prolonged analgesic effect compared to the local anesthetic alone
Celiac plexus neurolysis
Ablation of the plexus, often achieved with alcohol or phenol administered
Bupivicaine is injected first to prevent pain associated with the alcohol injection.
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
Celiac plexus intervention
Celiac ganglia intervention
Endoscopic ultrasound-guided celiac plexus block for managing abdominal
pain associated with chronic pancreatitis: a prospective single
center experience Am J Gastroenterol. 2001
EUS-guided celiac plexus block under the guidance of linear array endosonography
10 cc bupivacaine (0.25%) and 3 cc (40 mg) triamcinolone on each side of the celiac plexus.
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
90 patients
Improvement in overall pain scores occurred in 55% (50/90) of patients
Mean pain score decreased from 8 to 2 post EUS celiac block at both 4 and 8 wk follow-up (p < 0.05).
In 26% of patients there was persistent benefit beyond 12 wk
10% still had persistent benefit at 24 wk
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
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
Metanalysis
9 studies were included in the final analysis.
For chronic pancreatitis, 6 relevant studies were identified, comprising a total of 221 patients.
EUS-guided CPB was effective in alleviating abdominal pain in 51.46% of patients.
Initial evaluation of the efficacy and safety of endoscopic ultrasound-guided
direct Ganglia neurolysis and block Am J Gastroenterol. 2008
Direct ganglia injection in patients with moderate to severe pain secondary to unresectable pancreatic carcinoma or chronic pancreatitis
36 direct celiac ganglia injections for unresectable pancreatic cancer (CGN N = 17, CGB N = 1) or chronic pancreatitis (CGN N = 5, CGB N = 13)
Bupivacaine (0.25%) and alcohol (99%) for CGN, or DepoMedrol (80 mg/2 cc) for CGB.
For chronic pancreatitis, 4/5 (80%) who received alcohol reported pain relief versus 5/13 (38%) receiving steroids
Thirteen (34%) patients experienced initial pain exacerbation, which correlated with improved therapeutic response (P < 0.05).
EUS-guided direct celiac ganglion block or neurolysis is safe.
Alcohol injection into ganglia appears to be effective in both cancer and chronic pancreatitis
Frequency of visualization of presumed celiac ganglia by endoscopic ultrasound
Endoscopy. 2007
Unknown how often ganglia are visualized during EUS, and what clinical factors are associated with ganglion visualization
200 unselected patients who were undergoing EUS in a tertiary referral center
Presumed celiac ganglia were identified in 81 % of patients overall
More ganglia were seen per patient with linear echo than with radial echo endoscopes ( P = 0.001).
S
THANKS