Celiac Plexus Block for Chronic Pancreatitis RCT

1.0 Background and Hypothesis: Chronic pancreatitis is an inflammatory disease of the
pancreas characterized by painful scarring and loss of glandular function.The prevalence of
chronic pancreatitis in the United States is estimated to be 0.2 to 5% and results in 86,000
hospitalizations. The majority of patients with chronic pancreatitis will develop significant
abdominal pain which is debilitating and results in a significant burden on the health care
system.

Multiple approaches, including pancreatic enzymes, narcotic analgesia, celiac plexus block
and surgical ganglionectomy have been used to treat pancreatic pain with variable success.
Injection of local anesthesia agents and steroids into the celiac plexus for pain control has
been used for many years via both surgical and percutaneous approaches. Topical therapy
theoretically prevents the conduction of painful stimuli from the pancreas and addresses
inflammatory changes in the afferent nerves themselves. Splanchnic nerves pass from the
pancreas to the thoracic root ganglia via the celiac ganglia which are the target for
intervention. Nerve changes in chronic pancreatitis including perineural inflammation,
altered diameter, and upregulation of pain neuropeptides (including Substance P) are
associated with increased sensitivity to stimuli from the pancreas (distension and
inflammation) as well as pain independent of stimuli (neuropathic). Endoscopic ultrasound
allows for close proximity, high resolution assessment of the gastrointestinal tract wall and
adjacent anatomic structures. Physicians are able to perform EUS-guided celiac plexus
injections in the outpatient setting under conscious sedation. The EUS guided approach offers
better visualization of the celiac region and direct access to the celiac plexus. EUS guided
celiac plexus block is a core part of the routine care of patients at Los Angeles County
Hospital with chronic pancreatitis. Celiac plexus block is a recommendation for refractory
chronic pancreatitis pain by the European Society of Gastrointestinal Endoscopy (ESGE).

Several studies have shown that EUS-guided CPB has a beneficial role in treating pain caused
by chronic pancreatitis. A randomized trial by Gress et al looked at the efficacy of
EUS-guided versus CT-guided celiac plexus block for controlling abdominal pain of chronic
pancreatitis in 18 patients. They found significant improvement in pain symptoms in patients
randomized to EUS-guided celiac plexus block over a mean time period of 10 weeks. A study by
the same group showed an improvement in overall pain score in 55% at 4 and 8 weeks of
follow-up in 90 patients. Adverse events including diarrhea and infection occurred in 3%. A
comprehensive review by Kaufman et al in 2010 evaluated the efficacy of EUS-guided celiac
plexus block and celiac plexus neurolysis in alleviating chronic abdominal pain due to
chronic pancreatitis and pancreatic cancer respectively. A total of 6 studies were included
in their analysis, comprising 221 patients, and found that EUS-guided celiac plexus block was
effective in 51.46% of patients with chronic pancreatitis. EUS-guided celiac plexus
neurolysis (with alcohol) was effective in 72.54% of those with pancreas cancer.

These modest improvement for celiac block for chronic pancreatitis (especially in comparison
to celiac plexus neurolysis in pancreas cancer) have led some investigators to question
whether EUS guided celiac plexus block is an effective treatment for chronic pancreatitis
pain despite its routine use. Prospective randomized controlled studies examining the
efficacy of endoscopic ultrasound guided celiac plexus block are lacking.

2.0 Objectives and Purpose Our aim is to perform a pilot randomized trial to gauge the degree
to which celiac plexus block performed under endoscopic ultrasound guidance will benefit
patients with chronic pancreatitis. We will assess whether celiac plexus block significantly
decreases pain scores, hospitalization, and pain medication requirements and increases the
ability to return to normal activities.

3.0 Study Design Patients presenting to the Los Angeles County Medical Center and
Gastroenterology Clinic with chronic upper abdominal pain are the focus population of this
study. Patients who are undergoing endoscopic ultrasound for standard clinical care to assess
for chronic pancreatitis will be enrolled. They must have a M-ANNHEIM severity score of 6 or
greater. Additionally, they must have at least intermittent if not chronic pain of intensity
>3 on the visual analogue scale requiring opiate medication.

The procedures will be performed by experienced endosonographers. The EUS-guided celiac
plexus block will be performed under the guidance of linear array endosonography. A visual
exam will first be performed with the EUS scope or a standard endoscope. Patients found to
have a significant peptic ulcer or other mucosal abnormality will be excluded as the symptoms
may be secondary to peptic disease. An EUS exam will then be performed to determine whether
the patient has findings of chronic pancreatitis. The diagnosis of chronic pancreatitis will
be confirmed based on EUS criteria (meeting four or more criteria of hyperechoic foci,
hyperechoic strands, lobularity, cysts, stones, dilation of the main pancreatic duct,
irregular pancreatic-duct margins, presence of side branches and hyperechoic pancreatic
duct-margins).

Those who are confirmed to have chronic pancreatitis will be randomized (1:1) during the
procedure to celiac plexus block versus no injection treatment. Randomization will be
performed using a computer program with concealed allocation. The research coordinator
obtaining data for follow up visits and the patient will be blinded to randomization. The
endosonographer will not be blinded. Ninety patients will be enrolled (see statistical
considerations for sample size calculation).

Those randomized to control will undergo EUS and confirmation of chronic pancreatitis but not
celiac plexus block. Patients in the treatment group will receive celiac plexus block with
10mL 0.25% bupivacaine and 2ml (40mg/cc) triamcinolone which are the standard doses. The 22
gauge needle will be inserted into the base of the celiac plexus via the transgastric
approach and a single injection will be performed. An intravenous antibiotic will be
administered at the time of the block to those in the celiac plexus block group with the
specific agent depending on the patient's allergy profile. The research coordinator obtaining
data for follow up visits and the patient will be blinded to the details of the block (or
lack thereof) procedure but it will be recorded.

Following the procedure standard recovery room monitoring including assessment of blood
pressure be performed for 2 hours for both groups. Periprocedural fluid and antibiotic use
for celiac plexus block is not standardized and will be at the discretion of the endoscopist
performing the cases.

Patients will be assessed before the procedure, immediately afterward, and at 2 weeks, 6
weeks, 3 months, and 6 months following the procedure. At the initial assessment and follow
up visits Visual analogue pain scores will be recorded as well as an assessment of the
ability to work and conduct activities of daily living. Pain medication requirements and
whether symptoms are alleviated by analgesic or disrupt sleep will be noted. The M-ANNHEIM
scoring system will be used to gauge symptoms as well.

Additionally, patients will complete a focused version of the online CarePrep Program during
each visit. The Online CarePrep (OCA) program is used to clinically evaluate patients with
complex symptoms or conditions generally characterized significant physical symptoms,
psychosocial issues, impaired quality-of-life and functional status, disability, and
substance abuse. It has an online format that has been successfully used by outpatient with
various gastrointestinal illness to report multifactorial symptoms. When performed prior to
appointments it appears to facilitate efficient and productive medical visits.

4.1 Side effects/Toxicities to be monitored:

4.11 Three most common complications from celiac plexus block include hypotension, transient
diarrhea, transient increase in pain. Extraordinarily rare/theoretical complications include
paralysis, pneumothorax, loss of sphincter function, retroperitoneal bleeding, renal puncture
and prolonged gastroparesis.

4.12 Long term toxicities to be monitored after completion of the celiac block during the 6
months the patients are followed.

4.2 Dosage changed based on toxicity There will be no dosage adjustments as the procedure
will be performed once during the study period.

4.3 Adverse Event Reporting: 4.31 Type of event to be reported and timing of reports. If
patients develop adverse events including hypotension, transient diarrhea, transient increase
in pain, or less common complications of unilateral paresis or paraplegia, pneumothorax, loss
of sphincter function, retroperitoneal bleeding, renal puncture, prolonged gastroparesis or
infection, this will be reported to the principal investigators and will be reviewed by the
study team as well as two staff physicians in the gastroenterology division who are not part
of the study team. This will also be reported to the IRB.

If patients experience any further events that are detected during follow up these will be
coded as A) related to study or B) not related to study. Their severity and A) whether they
were expected or B) not expected will also be recorded. These complications will also be
reported to the principal investigators and will be reviewed by the study team as well as two
staff physicians in the gastroenterology division who are not party of the study team. They
will also be reported to the IRB.

4.32 Places for submitting reports: Adverse events will be reported to the IRB and data
safety monitoring committee.

4.4 Data Monitoring Committee: The data safety monitoring committee will include the
principal investigators from medicine/gastroenterology as well as the entire study team. Two
outside senior physician from gastroenterology or surgery will also be asked to participate.
Meetings will be convened if adverse events potentially related to the celiac block occur.

5.0 Statistical Considerations Descriptive statistics will be performed for each group, and
comparisons made to determine if the groups are balanced on the stratification factor of type
of pancreatitis. Patient characteristics will be compared between groups as well to determine
if there is imbalance of other possible covariates. We expect that there will be patients
with chronic pancreatitis secondary to congenital abnormalities of the pancreatic duct,
ethanol abuse, familial, and idiopathic etiologies.

The sample size of 90 patients was chosen based on preliminary sample size calculations.
Based on recent studies 30% of patients with pancreatitis type pain in the placebo arm will
derive benefit.16 The predicted response rate of 51.5% for EUS guided celiac block was based
on the large review by Kaufmann et al. For a 2 sided alpha of 0.05 and a power of 0.80, 83
patients would be necessary to show a difference. Statistical analyses will be performed by
biostatisticians at the Biostatistical and Bioinformatics Resource Group within the SC CTSI.

Inclusion Criteria:

- Presentation with upper abdominal pain suggestive of pancreatitis who are undergoing
EUS for evaluation

- M ANNHEIM severity index of 6 or greater to be included

- Intermittent episodes of pain>3 requiring opiate medication

Exclusion Criteria:

- Patients who have allergic reactions to steroids or bupivacaine

- INR >1.6

- platelets <75

- decompensated cirrhosis

- incarcerated

- <18 years old

- unable to give informed consent

- peptic ulcer disease

- ongoing substance or alcohol use