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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

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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).

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THANKS