ADVANCED PAIN MANAGEMENT
IN CANCER PATIENTS
PADMA GULUR MD
DIRECTOR, PAIN SERVICES, UCI HEALTH
PROFESSOR, UNIVERSITY OF CALIFORNIA
DISCLOSURES
NONE
OBJECTIVES
• Unique considerations in cancer pain
• Advanced Interventional strategies
Neurolytic blocks
Intrathecal drug delivery systems
Neuromodulation
CANCER PAIN
Tom Zetterstrom. Coast Oak.
CANCER PAIN - CONSIDERATIONS
• Related to tumor involvement
•
•
Accounts for 78% of pain problems in inpatient cancer population and 62% of outpatient cancer population
Metastatic bone disease, hollow viscous involvement and nerve compression or infiltration are most common
causes
• Pain associated with cancer therapy
•
19% of pain problems in inpatient population and 25% in outpatient population
• Pain unrelated to cancer or therapy
•
Approx. 3% of inpatients have pain unrelated to their cancer and 10% in outpatient population
• Generalized pain in a dying cancer patient
Foley KM. Acta Anaesthesiol Scand 1982;74:91-6. Twycross RG. Pain 1982;14:303-10.
PAIN IN CANCER
of cancer patients undergoing
treatment for their cancer and nearly
80-90% of patients with advanced disease
suffer from moderate to severe pain.
30-55%
THERAPEUTIC STRATEGY FOR CANCER PAIN
•Pharmacotherapy
•Non-pharmacological Modalities
• Non-opioid analgesics
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NSAIDs
Acetaminophen
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•
•
•
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Codeine
Morphine
Oxycodone
Fentanyl
Hydromorphone
Methadone
•
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•
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• Opioid analgesics
• Adjuvant analgesics
• Anticonvulsants
• Antidepressants
• Local anesthetic agents
• GABA agonists
• NMDA antagonists
• Others
14% of Cancer patients do not achieve good pain relief with
acceptable side-effects even when treated by experts.
Meuser T. et al., Pain, 2001
Cognitive behavioral interventions
Massage, Physical Therapy
Acupuncture
Radiation Therapy
Surgery
Interventional procedures
COMMON CONCERNS WITH INTERVENTIONS
IN CANCER PATIENTS
• Should we put patients through an “intervention”?
• “Too early” or “too sick” phenomena
• Sick patient population: immunosuppressed,
coagulopathic, concerns with positioning
• Access and follow up with interventionalists
NEUROLYTIC BLOCKS FOR CANCER PAIN
OVERVIEW OF NEUROLYTIC
BLOCKADE
~8% cancer pain patients may need
peripheral nerve block
Intentional injury to a nerve/plexus:
• Chemical* (alcohol or phenol)
• Surgical
Two Types:
• Peripheral (intercostal, extremity)
• Autonomic (celiac, superior
hypogastric plexus)
Zech et al. Validation of World Health Organization Guidelines for Cancer Pain Relief: a 10 year prospective study. Pain 1995; 63:65-76.
10
OVERVIEW OF NEUROLYTIC
BLOCKADE
•
•
“Block” vs “Neurolysis”
•
Effects fade:
• Progression of tumor
• Nerve regeneration
Neurolytic effects typically last
3-6 months
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CELIAC PLEXUS BLOCKADE
CELIAC PLEXUS :UPPER ABDOMINAL
STRUCTURES
CP innervates:
•
•
Pancreas
•
•
Liver/Hepatobiliary Tree
Distal Esophagus to Tranverse
Colon
Adrenals, Kidneys
& Proximal Ureters
•
Mesentery
Copyright Mayo Clinic, 2005
13
CELIAC PLEXUS NEUROLYSIS :
TECHNIQUE
Percutaneous: Fluoro/CT
1) Radio contrast dye is used to
confirm placement of needle
2) Diagnostic block with local
anesthetic
3) Injection of neurolytic agent
Endoscopic by GI
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“TRANSCRURAL” VS. “RETROCRURAL”
Brown: Atlas of Regional Anesthesia, 3rd ed., 2006 Saunders
CELIAC PLEXUS BLOCK PROVIDES
EFFECTIVE ANALGESIA
• Effective analgesia
• Decreased opioid consumption and side effects
Eisenberg et al. Neurolytic Celiac Plexus Block for Treatment of Cancer Pain:
A Meta-Analysis. Anesthesia and Analgesia 1995; 80: 290-295.
16
PERCUTANEOUS CPN SERIOUS SIDE EFFECTS
& ADVERSE EVENTS ARE RARE
• Review of 2700 CPB/CPN in UK:
• ~ 0.1% risk of paraplegia
Eisenberg et al. Neurolytic Celiac Plexus Block for Treatment of Cancer Pain: A Meta-Analysis. Anesthesia and Analgesia
1995; 80: 290-295.
Yan, B and Myers, R. Neurolytic Celiac Plexus Block for Pain Control in Unresectable Pancreatic Cancer. American Journal of
Gastroenterology 2007; 102: 430-438)
*Davies et al. Incidence of major complications of neurolytic coeliac plexus block. Journal of Royal Soc Med 1993; 86 (5): 264-6.
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SUPERIOR HYPOGASTRIC PLEXUS BLOCKADE
SUPERIOR HYPOGASTRIC PLEXUS :
LOWER ABDOMEN/PELVIC ORGANS
Anterior to sacral promontory at L5-S1
Innervates:
• Descending Colon to Rectum
• Bladder/Prostate/Gonads
• Uterus/Vaginal Fundus
• Some Input from Perineum/Anus
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SUPERIOR HYPOGASTRIC PLEXUS BLOCK
1)
Needles advanced anterior to L5/S1
–
–
Bilateral
Unilateral Transdiscal
2) Radio contrast dye is used to confirm
placement of needle
3) Diagnostic block with local anesthetic
or
Neurolytic block with alcohol or phenol
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SHP NEUROLYSIS EFFICACY
Plancarte et al, Reg Anesth 1997
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•
Prospective Study: 227 patients w/ Gyn/GU/Colorectal CA
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Diagnostic Block --> Bilateral SHPN
Refractory pain or opioid side effects
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SHP NEUROLYSIS EFFICACY
All 227 pts w/ >7/10 pre-block
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•
159 (70%) pts responded to diagnostic block
115 (51%) pts underwent SHPN w/ pain < 4/10 (16
of these required 2nd block for this effect)
• 43% decrease in opioid consumption
• No additional blocks at 3 months
• No complications related to procedure
*Poorer results in pts w/ extensive RP disease
22
MULTI-PLEXUS BLOCKADE: ? MORE
EFFECTIVE IN PATIENTS W/ DIFFUSE
TUMOR BURDEN
• Prospective Study of 35 pts with extensive abdominal or pelvic CA w/
uncontrolled pain
• Underwent combination of CPB, SHPB and Inferior Mesenteric plexus block, most w/
Transdiscal Approach
• Pain scores fell from 8.8 to 2.3 over first 3 months or until death
• Morphine consumption fell from 96+/-29 to 31 +/- 10 at 1 month
• No Serious complications
Kitoh T, Tanaka S, Ono K, et al. Combined neurolytic block of celiac, inferior mesenteric and superior hypogastric
plexuses for incapacitating abdominaland/or pelvic cancer pain. J Anesth 2005; 19:328–332.
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GANGLION IMPAR BLOCK
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GANGLION IMPAR
• Aka “Ganglion of Walther”
• Sits just anterior to
sacrococcygeal junction
• Provides Innervation to:
• Perineum*
• Distal Rectum/Anus
• Distal Urethra
• Distal 1/3 Vagina
• Vulva
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GANGLION IMPAR NEUROLYSIS
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Trans-Sacrococcygeal Approach
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Neurolysis
Cryoablation (described)
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GANGLION IMPAR NEUROLYSIS OUTCOMES
•
Limited to multiple small prospective studies only
• eg, Plancarte et al, Anesthesiology 1990
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16 pts (9 w/ cervical, 1 endometrial)
Rectal/perineal/vaginal pain
8 pts w/ complete relief
Remainder w/ 60-90% relief
Follow-up up to 120 days or death
No complications reported from this technique in literature
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SPINAL DRUG DELIVERY FOR
REFRACTORY PAIN IN CANCER
PATIENTS
EVIDENCE
IDDS OUTCOMES
Clinical Success and Failure
Pain and
Toxicity
Both
Reduced by
≥ 20%
Neither
Reduced by
≥ 20%
CMM
37.5%
23.6%
IDDS
57.7%
11.3%
Smith TJ et al.
Journal of Clinical Oncology, October, 2002
IDDS AND SURVIVAL
RESULTS AND CONCLUSION
• Results
•
• 85% IDDS vs 70% CMM (p=.05) achieved clinical success
• IDDS pts more often achieved >20% reduction in VAS and toxicity
• Mean VAS reduction 52% IDDS vs 39% CMM (p=.055)
• Mean Toxicity reduction 50% IDDS vs 17% CMM (p=.04)
• Survival IDDS 54% alive at 6m vs 37% CMM (p=.06)
Conclusion
• “IDDSs improved clinical success in pain control, reduced pain, significantly relieved
common drug toxicities, and improved survival in patients with refractory cancer pain”
INDICATIONS
• Unacceptable side effects from medical management
• Uncontrolled pain with medical management
CONTRA-INDICATIONS
• Active infection
• Obstruction to CSF flow
• Mechanical barriers
• < 3 month anticipated survival for implanted pump
TRIAL
• No consensus protocol
• Bolus injection vs Continuous infusion
• Epidural vs Intrathecal
• Continuous intrathecal is most commonly used
• Most closely simulates infusion via implanted pump
EXTERNAL CATHETER
External Catheter
-
Tunneled subcutaneously &
remain external to the body
-
3-4 weeks with reduced
infection risk
SUBCUTANEOUS
PORT
IMPLANTABLE INFUSION PUMP
 Catheter:
- Tunneled under the skin
- Attached to the pump
 Pump:
- Implanted in a subcutaneous
pocket in the abdomen
 2 types of pump
- Constant flow rate
- Multiple flow rate, Programmable
IMPLANTABLE PUMPS VS EXTERNAL CATHETERS
Disadvantages
Advantages
 ↓ risk of
infection
 Fully independent of
external devices
Little maintenance
Infrequent refill
High initial cost
•
Opioid conversion by route is
Morphine
•
•
PO
300mg
IV
100mg
Epidural
10mg
Intrathecal
1 mg
Intrathecal Morphine 3mg/day – Opioid equivalence?
On about 12.5mg IV Morphine per hour or about 2.5mg per
hour of IV Dilaudid (if we use 5:1 M:HM)
MORPHINE
• One of 2 FDA approved IT drugs
• First line drug
• Opioids act at the substantia gelatinosa of
• Produce dose-dependent analgesia
the dorsal horn of the spinal cord
• HPLC of morphine (with bupivacaine and clonidine) stored in SynchroMed pump at 37o
for 90 days was 96% intact
MORPHINE
Paice et al (1999)
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429 patients ,Cancer and non-cancer
After one year mean morphine dose of 14.2mg/d for cancer pts (9.2mg/d for non-cancer)
Cancer patients required higher initial doses and less escalation then non-cancer pain
Wallace and Yaksh (2000) reviewed 20 studies of IT morphine
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Cancer and Non-cancer
Pain relief varied widely from minimal to ≥70% reporting excellent relief
Bennett et al (2000) reviewed 61 studies covering >2000 pts from ’78-’99, including 3 prospective
studies
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Cancer and non-cancer
34/61 studies reported >50% pain relief
Wide variations in IT doses of morphine, patient selection, etc. among studies
MORPHINE
• Catheter-tip granuloma
• Dependent on concentration, not dose (in dog studies)
• Max recommended concentration 20mg/ml
ZICONITIDE (PRIALT):
GOOD POTENTIAL, BUT SIDE EFFECTS LIMIT USE
• Synthetic peptide derived from the venom
of the marine snail Conus magus.
• IT Nonopioid blocks Ca channels in spinal
cord to inhibit afferent pain signal
• FDA approved for refractory chronic pain
• Staats et al RCT vs Placebo for Refractory
Cancer/AIDS Pain in JAMA 2004*
• High rate of cognitive impairment and
psychiatric changes with dose escalation
limit use
Zuurmond et al. New aspects in performing interventional techniques for chronic pain. Current Opinion in Supportive and Palliative Care 2007; 1:132–
136.Christo, P and Mazloomdoost, D. Interventional Treatments for Cancer Pain. Ann. NY Acad. Sci. 2008; 1138:299-328.
HYDROMORPHONE
• Semi-synthetic hydrogenated ketone of
• Activates mu, delta, and kappa
• More lipid soluble then morphine
• Less active metabolites
• Smaller supraspinal distribution
morphine
FENTANYL
• 100x more lipid soluble than morphine
• Activates fewer receptors than morphine to achieve equivalent analgesic effect
• No studies on long term safety of IT fentanyl
SUFENTANIL
• 1000x greater octanol:water partition coeffecient than morphine
• Rapid clearance from CSF with resorption into circulatory system
• Less drug tolerance than morphine
METHADONE
• Racemic mixture
• D – isomer has NMDA antagonist activity
• Mironer et al (2001)
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Prospective study
24 pts
Failed previous IT trials
13/24 reported some level of pain reduction
MEPERIDINE
• Vranken et al (2005)
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Prosective study
10 pts
IT meperidine +/- clonidine
Significantly decreased intractable neuropathic cancer pain
Rapid increase in normeperidine conc 3 weeks after start
BUPIVACAINE
• Multiple studies report improved pain relief
to IT mixture
Most are uncontrolled and not randomized
•
• Mironer et al (2002)
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•
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Multicenter
double-blind
Randomized
• No benefit
with the addition of bupivacaine
ROPIVACAINE
• S-enantiomer
• More selective sensory over motor fibers
• Less toxicity and less potent than bupivacaine
• No published reports on long term IT administration
CLONIDINE
• Selective alpha-2 adrenergic agonist
• Lipophilic
• Induces dose dependent anti-hypersensitivity effect
• In animal models reversed hyperalgesia
• Reduces mean BP and HR, induces urinary voiding and sedation
KETAMINE
• N-Methyl-D-aspartate (NMDA) antagonist
• Increases spinal action of morphine
• S(+)-ketamine traditionally considered less neurotoxic
KETAMINE
• No published studies on stability in pump
• Case report of continuous IT +Ketamine/morphine reduced intractable
cancer related neuropathic pain
• Long-term antinociceptive effect
• Low plasma ketamine levels
• No adverse side-effects over 3 months
BACLOFEN
• GABA-B agonist
• Primary indication for spasticity
• Antinociceptive effects
• May reduce hyperalgesia and allodynia
• Stable (90% recovered) at 37o in pump for 14 weeks
BACLOFEN
• Significant and life threatening overdose and withdrawal symptoms
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Overdose
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Respiratory arrest, obtundation, hypotention, fixed pupils
Widthdrawal
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Hypertention, hyperthermia, hallucinations, DIC, rhabdomyolysis, ARF, and multisystem
organ failure
• Other side effects
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Drowsiness, nausea, HA, muscle weakness and light-headedness
GABAPENTIN
• Many mechanisms of
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•
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action
Voltage-gated ion channels at postsynaptic dorsal horns that inturrupt neuropathic pain
GABA-B agonist ?
Supraspinal NMDA antagonist
Activates descending noradrenergic system to produce analgesia
Supraspinal alpha-2-adrenergic agonist
N-type Ca2+ channels
• Little clinical data available on IT gabapentin
KETOROLAC
• COX 1 & 2 inhibitor
• Continuous infusion and bolus dosing did not cause spinal pathology or CSF
prostaglandin E2 in dogs and rats
• IT ketorolac induces potent analgesic activity in rats
MIDAZOLAM
• Conflicting animal studies on neurotoxicity of
IT midazolam
• 5-15mg/day did not show signs of neurotoxicity in sheep and pigs
• 0.1-0.3mg showed signs of neurotoxicity in rats
• Limited clinical data show increased analgesia and synergistic effects with other
IT medications
NEOSTIGMINE
• IT administration may have anti-nociceptive effects by inhibition of c-fos
• Prospective trial of 60 pts 50ug of IT neostigmine resulted in post-operative
pain relief for ~7hrs with fewer side effects than 300ug IT morphine (Tan et al
2001)
• May be limited by GI side effects
ADENOSINE
• Phase 1 safety studies
• Open label dose escalating
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25 subjects
• Double-blinded, placebo-controlled
•
40 subjects
• No effect on BP, HR, EtCO2, or neurologic function
• Mixed studies showing lack of
post-op pain relief
ADRENAL CHROMAFFIN CELLS – INTRATHECAL
IMPLANTATION
•
Cell therapy using intrathecal chromaffin cell allograft is a promising approach for the management of
cancer pain refractory to traditional drug therapy and pain lesion surgery.
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Preclinical studies on experimental pain models have enabled starting prospective clinical trials. Prior to
transplantation, handling and preparation of the chromaffin tissue is critical for allograft viability.
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The initial results of clinical trials with human chromaffin cell grafts from intractable cancer pain have
reported long-lasting pain relief, in correlation with met-enkephalin release into the CSF.
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The limitations of this innovative cell therapy and especially the lack of human adrenal gland availability
point to the need for new sources of cells.
•
Perspectives include xenogenic or engineered cell lines.
Lazorthes et al Neurochirurgie. 2000 Nov;46(5):454-65
POLYANALGESIC CONSENSUS GROUP
SIDE EFFECTS
• Urinary retention
• Lower extremity edema
• Urinary retention
• Pruritus
• Myoclonic activity
• Sweating
COMPLICATIONS
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Catheter dislodgement 21%
Mechanical failure 20%
CSF leak 19%
Catheter kinking 12%
Cost Effectiveness
Urinary retention
Pruritis
Myoclonic activity
Sweating
3 months
SPINAL CORD STIMULATION
SPINAL CORD STIMULATION
•
Trial
– Patients can trial the therapy
•
•
•
Temporary system
Only component implanted is lead
Patient uses system 3-10 days
– Successful trial can be followed
by implant
•
Implantation of neurostimulator,
lead(s), and extensions(s) if
trial effective
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SPINAL CORD STIMULATION IN CANCER PAIN
• The incidence of neuropathic component in cancer pain is estimated to be around 15% to 40%.
• Spinal cord stimulators have been reported as a safe and effective management of neuropathic
cancer pain.
• Cata et al showed benefit in chemotherapy –induced pain in two patients.
• Hamid and Haider showed improved pain relief in radiatherapy-induced transverse myelitis.
• Yakovlev et al presented two case reports of cancer patients, with uncontrolled neuropathic
pain using conventional medications, who benefitted from the implantation of spinal cord
stimulator.
• In sum multiple case series, no RCT’s.
CATA ET AL
Case report of two patients at MD Anderson:
Pt A: 61M w/ R elbow melanoma, tx’d w/ IL-2
• Developed BLE neuropathic pain refractory to opioids,
gabapentin
• Dual lead SCS placement at L1
Pt B: 46M w/ Ewing’s Sarcoma of R infraclavicular region, tx’d w/
Vincristine
• Developed BLE neuropathic pain refractory to opioids,
gabapentin, amitriptyline
• Dual lead SCS placement at T11
Cata et al. Spinal Cord Stimulation Relieves Chemotherapy-Induced Pain: A Clinical Case Report. Journal of Pain and Symptom
Management. 2004. 27(1): 72-78.
INTERVENTIONS FOR
CHEMOTHERAPY INDUCED
PERIPHERAL NEUROPATHY:
SPINAL CORD STIMULATION
Both patients with improved sensory thresholds
SUMMARY
Interventional Therapies should be Considered for Cancer Pain
General Indications
• Ineffective analgesia
• Intolerable Side effects
Less opioid = less side effects = better QOL
Earlier interventions have shown better outcomes
Possible survival benefit
Even more of an impetus in the dying patient
The Bottom Line: Patient-Tailored Therapy