6/11/2013
Pancreatic Cancer: Pain
and Symptom Management
Kevin E. Vorenkamp, MD
Department of Anesthesiology & Pain Medicine
Virginia Mason Medical Center, Seattle, WA
Understanding Pancreatic Cancer
An Educational Seminar – Seattle
June 7, 2013
Disclosures
I have no financial disclosures to report.
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6/11/2013
Overview
• Discussion of definitions
• Challenges with treatment of malignant pain,
particularly pancreatic cancer
• Classic types of pain related to pancreatic cancer
• Strategies for treatment of side effects from
pancreatic cancer and pain management
• Overview of typical progression of analgesia
• Description of interventional methods of pain relief
and factors associated with their success
IASP definition of pain
An unpleasant sensory and
emotional experience
associated with actual or
potential tissue damage, or
described in terms of such
damage.
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6/11/2013
Treatment Options for Pain
• Education
• Therapy: Physical, occupational and
•
psychological
Medications
Systemic
Spinal/epidural
• Interventional Procedures
Spinal
Chemoradiation
Radiation
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6/11/2013
Our patients’ description of pain
A 65 year-old gentleman presents with a 6 month
history of indigestion, 20 # weight loss, and now
severe upper abdominal pain that spreads
through to his back. He has been diagnosed
with pancreatic cancer by his out-of-town
gastroenterologist and was sent for consultation
with our oncologist.
Our patients’ description of pain
• He states the pain is constant, worse with
eating, wakes him up from sleep, and is
making him irritable with his wife and
grandchildren.
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6/11/2013
Our patients’ description of pain
Just make it go away!
Miserable mood
An unrelenting force
Interferes with enjoying
time with loved ones
What causes the pain?
Tumor in the head and tail of pancreas
can cause visceral (deep inside) pain
that can radiate to the back or ribs
Lymph node involvement and liver
capsular stretch from metastases can
cause somatic pain around the
abdominal wall
Obstruction of intestines, stomach outlet
and biliary drainage can also cause
pain
Pain may radiate to other locations due to
shared nerve supply (e.g. shoulder
pain from diaphragmatic irritation
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6/11/2013
How do we ask patients to
describe their pain?
Pain has more dimensions
What makes it worse?
What makes it better?
Are there things that can distract you?
Is there a time relationship to the pain?
Does the pain wake you up?
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6/11/2013
Goals for Pain Therapy:
A Balancing Act
• Alleviate pain and suffering
• Improve quality of life
• Return to daily activities
• Fewest possible side effects
Although the goal is to provide all of the
above, it is essential to discuss the
prioritization of these goals of therapy
(dynamic)
Challenges of Pancreatic Cancer
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It is terrifying!!
Frequently diagnosed at an advanced stage
There may already be considerable loss of weight and
appetite-malnourishment
Bile duct obstruction with jaundice may be present
Concurrent illnesses such as diabetes are often present
Treatment is not always as effective as we would want
Individual understanding of the illness is just beginning
Physicians, other healthcare givers and family/friends are
often not up
to date on the latest treatments
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6/11/2013
What are the typical strategies?
• Strong opioids
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• Codeine
• Tramdol
• Adjuvants*
III.Severe Pain
• Non-opioids
• Tylenol
• NSAIDs
(ibuprofen,
naprosyn,
diclofenac)
• Adjuvants*
II.Moderate Pain
I.Mild pain
• Weak opioids
Morphine
Hydromorphone
Oxycodone
Oxymorphone
Fentanyl
Methadone
Adjuvants
*Adjuvants include antinausea meds, anxiety
meds, antidepressants, anti-neuropathic pain
meds, stimulants, osteoporosis meds
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Common symptoms
Pain
Loss of appetite (anorexia) and early satiety
Malabsorption
Loss of weight (cachexia)
Nausea and/or vomiting
Swollen legs (edema) and/or abdomen (ascites)
Clots in the legs (DVT) and emboli to the lungs
Depression
Fatigue and somnolence
Jaundice
Constipation and/or diarrhea
Side effects of chemotherapy
Side effects of radiation therapy
Side effects of surgery
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Depression
Antidepressants
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Loss of appetite (Anorexia)
Weight Loss
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Swelling of legs and feet
Ascites
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Blood clots
Why use non-opioids?
NSAIDs may attenuate the inflammatory pain response
They help prevent peripheral/central sensitization
Reduce opioid requirements when used in combination
Reduce opioid-related side effects
Excessive sedation
GI dysfunction
Urinary retention
Pruritis
Nausea
Respiratory depression
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6/11/2013
Why use non-opioids?
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Acetaminophen (Tylenol) acts to inhibit PG synthesis
Greater effect centrally than peripherally
Synergistic with both opioids as well as NSAIDs
Toxicity is rare in patients taking less than 4g/d
Acute overdose may result in
Hepatic toxicity
Nephrotoxicity
Thrombocytopenia
Be careful with non-opioid meds
• Use of both Tylenol and NSAIDs (Advil,
Aleve, ibuprofen, etc) should be discussed
with your physician
Despite the availability of these medications
over the counter, some patients may have
conditions or other medications that make the
use of these medications more risky
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6/11/2013
Opioids
-Opium plant derivatives
have been described as
analgesics for thousands
of years (3500 BC)
-1806-pure opioid
substance “morphine”
isolated
-Now, several other
derivatives and synthetic
analogues
Opioids
• Produce pain relief by
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binding receptors in the
brain and spinal cord that
reduce transmission of pain
signals from peripheral
nerves to the spinal cord
and up
Opioids also act by
modulating the signals once
they’re in the brain and help
facilitate pain inhibition
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Nausea and Vomiting
Constipation
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Mild opioids
• Tramadol – weak opioid agonist, also has
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tricyclic effects (like nortriptyline) to
increase Serotonin and Norepinephrine
Is generally well-tolerated
Metabolized to O-desmethyltramadol which binds
opioid receptors 200x stronger than tramadol
Tramadol lasts around 6 hours, but Odesmethyltramadol lasts around 9 hours
Mild opioids
• Codeine – a natural alkaloid isolated from
the opium poppy
Most widely used opioid in the world
Metabolized to Morphine and codeine-6-glucuronide
Roughly 1/6th as potent as morphine
6-10% of Caucasian population and 2% of Asians are
poor metabolizers and have less pain relief from
codeine
Often prescribed as a compound with acetaminophen
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6/11/2013
Strong opioids
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Strong oral agents include
Morphine
Hydromorphone
Hydrocodone
Oxycodone
Oxymorphone
Methadone
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Transdermal/ transmucosal
Fentanyl
Strong opioids
• Short-acting
Oxycodone
Hydromorphone
Morphine IR
Hydrocodone
Fentanyl
transmucosal/buccal
(Actiq and Fentora)
• Extended release
Morphine ER (MS Contin)
Oxycodone ER (Oxycontin)
Methadone (not truly an
extended release drug, but
has long half-life
Fentanyl transdermal
(Duragesic)
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Strong opioids
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May also be administered IV
with intermittent dosing or IV
Patient Controlled Analgesia (or
less commonly subcuticular if IV
access is challenging)
Faster acting than oral
More predictable effects
Requires persistent IV access, a
pump, infusion bags,
nursing/pharmacy coordination
May require continuous dosing
to prevent peak/valley effects
Opioid side effects
• Constipation
• Itching
• Sedation
• Nausea
• Confusion & Delirium
• Respiratory depression
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6/11/2013
Management of opioid side effects
• Constipation
Hydration
Laxatives (senna,
miralax, lactulose)
Prokinetic medications
(metoclopramide)
Methylnaltrexone
• An opioid antagonist
that acts locally within
the bowels without
reversing systemic pain
relief
• Nausea
Ondansetron/dolasetron
Compazine
Promethazine
Corticosteroids
Antihistamines
Cannabanoids
Emend
Management of opioid side effects
• Delirium-must also
rule out other
conditions such as
infection and/or
disease progression
May need
antipsychotics
Review meds to rule
out interactions
• Sedation
May be helped by use
of stimulants such as
modafinil (Provigil) and
methylphenidate
(Ritalin)
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6/11/2013
The 4th step
(but maybe it should be earlier!)
• Strong opioids
• Morphine
• Hydromorphone
• Oxycodone
• Oxymorphone
• Fentanyl
• Methadone
• Adjuvants
• Codeine
• Tramdol
• Adjuvants*
•Celiac Plexus Block
•Intrathecal Pumps
•Epidurals
•Other nerve
injections
Severe Pain
• Non-opioids
• Tylenol
• NSAIDs
(ibuprofen,
naprosyn,
diclofenac)
• Adjuvants*
Moderate Pain
Mild pain
• Weak opioids
•Interventional
modalities
Interventional procedures
for cancer pain
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6/11/2013
Celiac Plexus Block
• The Celiac plexus is a
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group of nerves that
surround the aorta
and carry pain signals
from organs of the
upper abdomen
Blockade of these
nerves first described
in 1914
Brown D,e d. Atlas of Regional
Anesthesia, 3rd ed., 2006
Celiac Plexus Neurolysis for Cancer
Pain: Indications
• Celiac plexus neurolysis can provide
excellent pain relief and reduce the need for
additional analgesics
• Primary indication: alleviate pain from the abdomen
• Neurolysis is typically reserved for malignancies of the
upper abdominal viscera (primarily pancreatic cancer),
often for patients whose pain is poorly controlled by
opioid analgesics
– Some advocate early intervention for those with
aggressive disease before their pain becomes
uncontrolled
» Some evidence suggesting that opioids may have detrimental
effect on tumor growth and recurrence
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6/11/2013
Celiac Plexus: Anatomy &
Technique
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There are two traditional posterior
approaches to the celiac plexus and its
nerves
The classic (transcrural) approach involves
placing a needle anterior to the aorta at the
L1 level. Both transaortic and periaortic
approaches have been advocated
The other approach involves a retrocrural
approach to the deep splanchnic nerves at
the T12 level (see image)
Bilateral splanchnic (celiac)
neurolysis (retrocrural
approach)
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Celiac Plexus Block
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Patients are usually
lightly sedated during the
procedure
Under fluoroscopic or CT
guidance, needles are
placed near these nerves
An injection of alcohol or
phenol is made to disrupt
and destroy these nerves
Procedure typically lasts
30 minutes or less
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6/11/2013
Diagnostic Block?
• Historically, a diagnostic block was done first
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to make sure the patient receives benefit
before performing the neurolytic
(destructive) block
That “requirement” may no longer be valid
when symptoms are straightforward and
typical of pain from pancreatic cancer1
Increased safety with use of fluroscopy
(XRAY) and digital subtraction angiography
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6/11/2013
Sympathetic Neurolysis for Cancer
Pain: Neurolytic Agents
• Alcohol (50% to 100%) and phenol (5%-12%)
are both neurolytic agents
Alcohol exerts its analgesic affect by non-selective
neuronal destruction
• Its local irritant effect may produce dose-dependent
burning and dysesthesia and therefore local anesthetic
should first be injected
Phenol exhibits non-selective neuronal destruction
by Wallerian degeneration and also has local
anesthetic properties
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Celiac Plexus Block
• May also be
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performed by
gastroenterologists
during endoscopy
procedures
Initial reported results
were promising,
though no head-tohead trials with
CT/fluoro guided
blocks
Arcidiacono PG and Rossi M. Celiac
Plexus Neurolysis. J Pancreas (Online)
2004; 5(4):315-321.
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Celiac Plexus Block:
side effects and complications
• Discomfort at site of injection
• Low blood pressure
• Diarrhea
• Less commonly perforation of kidney or lung
• Extremely rare incidence of nerve injury or
paraplegia (<1/1000 BEFORE using XRAY)
Celiac Plexus Neurolysis for
Cancer Pain: Evidence
• Meta-analysis in 1995 by Eisenberg
showed long-lasting benefit for 70%-90%
of patients with intra-abdominal
malignancy
Subsequent studies show similar benefit
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6/11/2013
Celiac plexus block
effectiveness
• 24 papers with 1145
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patients reported
(67% with pancreatic
cancer)
89% of patients
reported good to
excellent pain relief in
first 2 weeks
• Partial to complete
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pain relief persisted at
3 months post-block
Serious adverse
events were rare (1%
neurologic problems,
1% other adverse
events)
Celiac plexus block: Success
Assessment of Celiac Plexus Block and Neurolysis Outcomes and
Technique in the Management of Refractory Visceral Cancer Pain.
Michael A. Erdek, MD, Daniel E. Halpert, DO,Marlís González
Fernández, MD, PhD and Steven P. Cohen, MD
Pain Medicine 2010; 11: 92–100
• Two factors (most) associated with
successful outcome following neurolytic
celiac plexus block:
1. Shorter duration of symptoms (<6 months)
2. Lower opioid dosages (153 mg morphine
equivalents versus 357)
Early referral and discussion with pain specialist
is essential!
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6/11/2013
Patient #1 Continued
• Seen by oncologist and referred into the
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Anesthesia Pain Clinic that day for
possible CPB
After consultation, plan made for CPB the
following morning after blood work and a 6
hour fast
Following procedure, patient’s pain went
from 6-7/10 to 0/10 in recovery room
Patient #1 Continued
• By telephone the next day, the patient
reported pain 0.5/10 and that he was
barely taking any pain medication
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Table Neurolytic Procedures for
Visceral Cancer Pain
Spinal level
Indication
Adverse
effects/
Efficacy/
complication comments
s
Celiac plexus
(splanchnic
nerve)
L1 (T12)
Pancreatic CA
Other organs
from distal
esophagustransverse
colon
Transient
hypotension,
diarrhea,
pneumothorax.
Paraplegia
(RARE)
~90%
Superior
hypogastric
plexus
L5-S1
Pelvic organs
(bladder,
cervix,
prostate,
rectum)
Transient
hypotension
Good/excellent
pain relief 70%,
decreased
opioid usage
Ganglion of
impar
Sacrococcygeal
Perineum,
rectum
Infection, rectal
perforation
? Limited
reports
Procedur
e
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Other interventional modalities
• Intrathecal pumps
• Epidural catheters
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6/11/2013
Intrathecal Drug Delivery Systems
(IDDS) and Epidural Infusions
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The amount of opioid administered intrathecally to
provide analgesia is typically much smaller than that
which is given intravenously or intramuscularly
1 mg Morphine IT=10 mg Epidural=100 mg IV=300 mg po
Typically a trial is first performed to confirm
effectiveness and tolerable side effects
Delayed onset of respiratory depression is due to opioid
transport from the CSF to brain stem respiratory centers
Pruritus (itchiness) can be as high as 90%
Urinary retention can also occur
The initial cost of an IDDS is high, but cost-effective
compared with traditional care or external infusion
systems (epidural or intrathecal) after 2-3 months
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Intrathecal pumps
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Deliver small amounts of opioids
(e.g. morphine) and other pain
medications directly into the spinal
fluid (generally 1/300th of the
equivalent oral dose)
Entire system is implanted under
the skin in a brief (1-2 hour) surgery
Pump can be reprogrammed with a
special external programmer to
increase medication dose
Pump usually holds 2-6 months
worth of medication
Easily refilled, similar to portacath
access through the skin
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Question: A 58 y.o. man has intractable abdominal
and back pain related to pancreatic cancer. He is
currently taking fentanyl 150 mcg/hr, gabapentin 900
mg po TID and clonazepam, but his pain persists
and the medications cause him to be drowsy and
constipated. The appropriate next step is most likely:
A. Increase his fentanyl
B. Stop his fentanyl
C. Referral to a pain specialist
D. Add another medication such as morphine
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Question: A 58 y.o. man has intractable abdominal
and back pain related to pancreatic cancer. He is
currently taking fentanyl 150 mcg/hr, gabapentin 900
mg po TID and clonazepam, but his pain persists
and the medications cause him to be drowsy and
constipated. The appropriate next step is most likely:
A. Increase his fentanyl-may likely worsen side effects
B. Stop his fentanyl-may likely increase pain and trigger
withdrawal symptoms
C.Referral to a pain specialist-in addition
D.
to medication adjustment recommendations, pain
specialist can evaluate for interventional procedures
(celiac plexus block, intrathecal pump)
Add another medication such as morphine-may likely
worsen side effects
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6/11/2013
Intrathecal pumps
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Patients usually stay overnight for initial dosing of pump
Follow-up visits are involved for adjusting pump to
minimize need for oral pain medications
Less sedation, nausea, and constipation compared to
oral opioids
1/300th of systemic (oral) dose
If on moderate-high dose systemic opioids, then typically
decrease by ~50% to avoid withdrawal symptoms (even if good
pain control)
Effectiveness of IT pumps
• 143 patients
randomized to
implanted therapy
(52) vs conventional
med management
(91)
• At 4 wks, 67% in
implant group had
decreased pain >20%
compared to only
36% in conventional
med group
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Effectiveness of IT pumps, continued
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At 12 wks, drug toxicity
scores decreased 66% in
implant group, but only
37% in CMM group
At 6 months, only 32%
who remained in CMM
group were alive
compared to 52-59% of
patients in implant group
Better pain control/fewer
side effects
More functional?
Better nutrition?
Patient #2: 51 yo woman with recurrent metastatic
pancreatic cancer. Recurrence 14 months after initial
resection. 8 months of chemoradiation with continued
growth.
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Escalating pain, worsening side effects
Oxycontin 60 mg/day, hydromorphone 64 mg/day
• Celiac block by GI doctor 1 week prior-no relief
At time of consult, was getting bolus dose of 4mg IV
hydromorphone: near unconsciousness x 15 minutes,
then moaning and crying
Epidural catheter placed under fluoroscopy
Bolus of 0.2mg, infusion of 0.08mg/hr
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Goals
• Comfort
• Return to home state in Southeast USA in
3 weeks to spend final days with family
Treatment
• Proceeded next day with intrathecal pump
• Complicated by “spinal headache”
Near-complete relief of abdominal pain,
voracious appetite
Headache improved after “blood patch”
Discharged home on intrathecal (spinal)
hydromorphone at 0.35 mg/day with patient
bolus dose of 0.03mg as needed up to 5x/day
• Currently comfortable with hospice
assistance in her hometown with family
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6/11/2013
What if my cancer goes away?
• Smile and give thanks!
What if my cancer goes away?
• Smile and give thanks!
• The pump medication can be titrated down
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and the device can be removed when
indicated
We will share the joy in your good fortune
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6/11/2013
Patient #3
• 40 year-old man with multiple metastatic
lesions from advanced pancreatic cancer
in the hospital for pain crisis
Currently experiencing significant sedation,
confusion, and poorly controlled pain
Oncologist estimates he may have only a few
weeks to live
Family requesting that we help him get better
pain control, but also allow him to wake up
and spend some time with his children
• Clear goals: improved pain control, less sedation
Epidural Catheters
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Identical to ones placed
for pain during labor, they
can be positioned higher
in the patient’s back to
provide coverage of pain
over the chest and
abdomen.
Can infuse local
anesthetic with opioid to
create a “numb” band of
pain relief around the
abdomen
• Can be placed at
bedside or in clinic
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Epidural Catheters
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Requires an external pump,
pharmacy/nursing care for
infusion bags
Can be accidently pulled out
May cause urinary retention
and the need for a bladder
catheter
Other side effects as noted in
this table
Patient-controlled Epidural Analgesia with Bupivacaine
and Fentanyl on Hospital Wards: Prospective Experience
with 1,030 Surgical Patients.
Liu, Spencer; Allen, Hugh; Olsson, Gayle; BN, MN
Anesthesiology. 88(3):688-695, March 1998.
Patient #3
• After placement of an epidural catheter,
his IV PCA was turned down around 80%,
he became oriented to himself and his
family. He was able to leave the hospital
and return to his home in another state for
hospice.
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Additional Resources
Summary
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Pain from pancreatic cancer is often multifactorial, which
means multiple approaches must be taken to control it
Oral medications remain the mainstay of treatment, but
growing evidence supports earlier use of interventional
therapies for managing the pain
Side effects are a risk of all therapies, but they can be
managed if patients let their physicians know what they
are experiencing and physicians ask about them
Patients and their family members should feel
empowered to speak to their physicians about the pain
they are experiencing and ask for consultation with a
specialist if the pain is not improving
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Pain control for patients with pancreatic cancer
• Get help early! Even if it is before you need it.
• Clearly state goals, OK to change as you go
along
• Challenges later in course of disease:
Malnutrition-poor wound healing, less function,
poor candidate for further therapy, ascites/edema
Centralization of pain-less response to
interventions
Opioid induced tolerance and/or hyperalgesia
• Sedation may interfere with informed decision making
• Other systemic diseases (thromboembolism/blood
clots) may prohibit some treatment options
Thank you!
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