Cancer Pain ManagementPaul A. Sloan, M.D.Professor and Vice Chair for ResearchProgram Director, Pain Medicine FellowshipDepartment of AnesthesiologyUniversity of KentuckyPaul.Sloan@UKY.edu

Editor-in-Chief, Journal of Opioid Management

Objectives

1. Review recent pain physiology2. Understand basic analgesic techniques for

cancer pain management3. Understand the role of interventional

techniques for cancer pain management

I. Pain Physiology Update

Pain Definitions • Nociception: a potentially tissue-damaging

energy acting on nociceptors• Pain: an unpleasant sensory and/or emotional

experience associated with actual or potential tissue damage

• Suffering: a negative existential response• Pain Behavior: behaviors understood to suggest the existence of tissue-damaging stimulus

Anatomy of Pain Pathways

Sloan PA. J Support Oncol 2004; 2:491-506.

Dorsal Horn Afferent Pharmacology

Graeber MB. Changing face of microglia. Science 2010; 330:783-788.

• Rat model of facial cancer pain• IP administration of glial cell

antagonist (PPF) inhibits glial cell activation, resulting in reduced pain behaviors (facial grooming, fig A)

• Suggest that CNS glial cell activation, but not peripheral, mediates the enhancement of spontaneous pain as well as development of allodynia and hyperalgesia (fig C)

Hidaka K. Neuroscience 2011; 180:334.

Spinal Opioid Receptors• Opioids are 3D compounds with

stereochemical structure/opioid analgesic activity relationship

• 1967 opioid receptor subtypes proposed: Bill Martin-UK Anesthesiology

• 1973 opioid receptor identified in man• 3 receptor types with multiple subtypes• u-receptor: all opioid actions (analgesia,

sedation, resp dep, etc); located brain (PAG) and spinal cord (SG)

• d-receptor: supraspinal analgesia, ? resp dep• k-receptor: spinal analgesia, weak resp dep

Martin WR. Opioid Antagonists. Pharmacology Reviews 1967; 19:463-521.

Otis V. Neuroscience 2011; 183:221.

• Rat model of bony cancer pain• IT administration of delta opioid agonist

shows dose-related analgesia from cancer pain; both neuropathic and nociceptive

• Specific d-opioid agonists represent a new potential target for cancer pain analgesics

Genetic Differences in Pain Sensitivity

• 484 pts with cancer of pancreas• 26% reporting severe pain• Interleukin-8 correlated strongly as

a predictor of severe pain• Cytokine gene polymorphisms are a

significant predictor of cancer pain

Reyes-Gibby CC. JPSM Dec 2009; 38:894

Genetic Differences in Morphine Receptors

Argoff CE. Clinical implications of opioid pharmacogentics. Clin J Pain 2010; Jan 26, Supp 10:S16

• Effects of opioids mediated by interaction with mu, delta, kappa and nociceptin/orphanin receptors

• Mu1 opioid receptor located on chromasome 6

• Most common polymorphism is allele 118 (2-48%) with AA exchange of arginine to aspartate: results in reduced effect of opioid agonists

5-HT1A receptor agonist repinotan prevents remifentanil-induced ventilatory depression and

prolongs antinociception

Guenther U. Anesthesiology 2012; 116:56-64.

II. Basic Analgesics for Cancer Pain Management

Pain Assessment • Pain history, pain rating• Psychosocial history• Medical history• Physical exam• Lab exam• Imaging• Records from referring physicians• ? multidisciplinary consultants

Sloan PA. Pain 1996; 67:475-481.

Validation of WHO Guidelines• Prospective review, 2118 patients, 10-yrs• Opioids used in 80% of Rx days• PO (82%), parenteral (9%), spinal (2%),

other (6%)• Co-analgesics (37%), palliative chemo

(42%)• Nerve blocks (8%), PT (5%)

DF Zech, Pain 1995; 63:65-76

Atlanta, April, 2008

Validation of WHO Guidelines• Pain relief: good 67%, satisfactory 12%,

inadequate 12%• Terminal symptoms: neuropsych 38%,

anorexia 25%, dyspnea 23%, nausea 15%, constipation 17%

DF Zech, Pain 1995; 63:65-76June, 2006

Pharmacotherapy• Nonsteroidal Anti-inflammatory drugs

• Eg. ASA• Opioid Analgesics

• Eg. Morphine• Adjuvant Analgesics

• Drugs with primary indications other than analgesia.

• Eg. TCA’s; gabapentanoids

Sloan PA. Supp Care Anesth Analg 1999; 89:760.

Barkin RL, et al. Dis Mon. 1996;42:389-454.

Acetaminophen• First-line drug• IV formulation• Effective for mild-to-moderate pain• Hepatotoxicity >4 gm/d (? 2gm/d)• Mechanism of action

– peripheral action blocking the generation of pain impulses

– central action on nociceptive impulse transmission

– ?activation of TRPA1 in spinal cord (Yoshida N. Mol Pain 2011; 7:41)

Opioid Therapy Definitions I. ToleranceII. Physical DependenceIII. Addiction

Oral OpioidsTreatment Principles:

• Titrate dose to effect or intolerable side effects.

• Give scheduled doses, with PRN rescues doses (10% of total daily opioid dose).

• Titrate dose on individual basis.• Treat side effects.• Use in context of whole-person care.

Thirlwell MP, Sloan PA. Cancer 1989; 63:2275.

Oxymorphone ER for Chronic Pain:1-Year follow-up results

Mean Pain Intensity Score (VAS)Mean Pain Intensity Score (VAS)

Cancer Pain Nonmalignant Pain

-10

0

10

20

30

40

50

60

70

1 2 3 4 5 6 7 8 9 10 11 12

Month

Sloan PA. Supp Care Cancer 2005; 13:57-65.

Opioids:• Morphine• Hydromorphone• Hydrocodone• Oxycodone• Methadone• Remifentanil• Pentazocine• Tramadol• Tapentadol

• Meperidine• Fentanyl• Sufentanil• Codeine • Levorphanol• Heroin• Oxymorphone• Alfentanil• Levacetylmethadol• Embeda

Sloan PA. Exp Opin Drug Deliv 2006; 3:489-497.

Sloan PA. Ther Clin Risk Manage 2008; 4:1-11.

• Effects of opioids mediated by interaction with mu, delta, kappa and nociceptin/orphanin receptors

• Mu1 opioid receptor located on chromasome 6

• Most common polymorphism is allele 118 (2-48%) with AA exchange of arginine to aspartate: results in reduced effect of opioid agonists

Morphine

Pain Relief with Long-term Fentanyl Patch

Fig 2: Study day on fentanyl patch for cancer pain management

Mea

n Pa

tient

Pai

n Sc

ore

0

100

30

Sloan PA. J Pain Symptom Manage 1998; 16:102-111.

Methadone• Synthetic• Very long-lasting• Very high oral bioavailability (80%)• Terminal half-life around 35 hours!!! (low hepatic

clearance)• Genetic polymorphism of CYP-450 metabolism• L-isomer opioid agonist• D-isomer NMDA antagonist• Serotonin reuptake inhibitor (serotonin syndrome

possible)• Prolongs QT interval

OralTransmucosalFentanyl

•Fentanyl embedded on sweet lozenge•Transmucosal and GI absorption•Dose of 10 mcg/kg•T max 23 min•½ life 8h•Used for breakthrough cancer pain

Onsolis: Buccal Fentanyl Patch

•Fentanyl embedded on mucosal patch•Transmucosal and GI absorption•Starting dose of 200 mcg•T max 1 hr•½ life 5h•Used for breakthrough cancer pain only

Recent Opioid: Tapentadol

•Similar to tramadol•Mu opioid agonist; also NA reuptake inhibitor•50 mg dose comparable to oxycodone 10 mg•?less nausea/vomiting than oxycodone

Sloan PA. Exp Opin Pharmacother 2010; 11:1783.

Opioid Side Effects:• Nausea & vomiting• Sedation• Constipation• Dry mouth• Confusion, mood change• Urinary retention• Sweating, pruritus,

myoclonus• Respiratory depression• Intentional overdose

Sloan PA. Exp Opin Drug Deliv 2006; 3:489.

Codeine Metabolism

• Codeine metabolized via CYP450-2D6 to morphine, the active drug!

• 10% of population with low CYP2D6 activity, thus codeine not effective in these patients as the prodrug codeine is not metabolized to the active form (morphine)

Dhaliwal H, Sloan PA. J Pain Symptom Manage 1995; 10:612.

Neuropathic PainCharacteristics:• Dysesthesia• Often constant component, with intermittent

lancinating, burning or electric quality.• Allodynia• Hyperalgesia• Hypoalgesia• Hyperesthesia/ hypoesthesia• Neurological dysfunction

Sloan PA. J Pain Pall Care Pharm 2003; 17:89.

Excitatory AA AnatagonistKetamine:• Analgesic & anesthetic agent• LSD cousin• NMDA receptor antagonist• IV, SC, PO, PR ?spinal• ?role of single enantiomer

Ketamine:• Indications• Dosing: 10 mg/hr continuous IV or SC; PCA 5-10

mg q10 min; titrate upward q6h• Opioid reduction• Side effect reduction• Oral dosing• contraindications

Interventional Pain Management Techniques: Surgical

•Cordotomy•Cingulotomy•Thalamotomy•Hypothalamotomy•Dorsal rhizotomy•Intraventricular opioid infusion•Deep brain stimulation

Interventional Pain Management Techniques: Anesthetic

1. Neurolytic blocks• Celiac plexus, superior hypogastric plexus,

thoracic IT neurolysis2. Spinal analgesics

• Epidural (external catheter or implanted pump)• Intrathecal (external catheter or implanted pump)

3. Regional local anesthetic infusions• Brachial plexus, lumbar plexus, peripheral nerve,

interpleural block4. Other techniques

• Spinal cord stimulation, vertebroplasty, human chromaffin cell IT transplants

Anesthetic Interventional Pain Management Techniques

• Indications:– Inadequate pain relief with standard

analgesics/co-analgesics– Intolerable side effects with analgesics– Physician preference– Patient preference– Lack of contraindications

Sloan PA. J Opioid Manage 2010; 7:161.

Spinal Analgesics

Spinal Analgesics•Epidural

•External PCA pump•Less cost when used <3 months•Catheter tip placement near affected nerve roots•Analgesic regimen can be changed quickly and easily

•Intrathecal•Internal implanted pump•Occasional external PCA pump•Less cost when used >6 months•Catheter tip placement near affected nerve roots•Implanted pump difficult to change analgesic regimen quickly•Decreased long-term complications

Log scale

• Chronic IT morphine infusion in pigs

• Morphine distribution in the spinal cord is limited to the 2-3 segments close to the catheter tip

• Thus, catheter tip position may be critical to delivery of IT opioids to the appropriate spinal cord segment

Flack SH. Anesth Analg 2011; 112:460.

Patient Preparation

•Trial of maximal medical analgesic therapy.

•Pain history: including current daily opioid requirements

•Physical examination: including exam of the spine, site

of catheter exit or pump implant, neurological exam

•Imaging of the spine.

•Coagulation profile.

•Spinal analgesia trialing prior to implanted pump.

Tunneled Epidural or Intrathecal Catheter

Spinal Analgesics

Chronic Spinal Analgesics

SebP-1

SebP-2

Common Spinal AnalgesicsMedication Intrathecal Dose

RangeEpidural Dose

RangeComments

Opioids:

morphine 0.5-50 mg/d 5-1000 mg/d gold standard opioid

hydromorphone

0.1-50 mg/d 1-100 mg/d 2nd line opioid

sufentanil 1-200 mcg/d 5-500 mcg/d

fentanyl 10-500 mcg/d 50-5000 mcg/d

Local Anesthetics: bupivacaine 3-60 mg/d 0.1-0.25% @ 1-4

ml/hrmost common LA

Lidocaine 0.5-1% @ 1-4 ml/hr possible IT toxicity

Others:

clonidine 20-800 mcg/d 10-40 mcg/hr watch for side effects

ketamine 50-500 mcg/d 15-75 mg/d possible IT toxicity

Sloan PA. J Supp Oncol 2004; 2:491-506.

LR

RW

Intrathecal morphine/bupivacainein Cancer Pain

• Prospective, 52 pts• Failed systemic opioids• VAS 8/10 pre-Rx• 46/52 with neuropathic

component to pain

Sjoberg. Acta Anesth Scand 1991; 35:30

Intrathecal morphine/bupivacainein Cancer Pain

• 46/52 good pain relief, VAS 0-2/10• Sleep and gait scores improved• IT morphine dose 25-50 mg/d• IT bupivacaine dose 0.5 – 2.5 mg/hr

(75% of pts)

Sjoberg. Acta Anesth Scand 1991; 35:30

Spinal Analgesics for Cancer Pain• Used in 87 of 4107 pts• NPS decreased from 7.9 to 1.6• Follow-up for 8 wks• No difference between epidural and intrathecal• Decreased oral opioids• Decreased opioid side effects

Burton AW. Pain Med 2004; 5:239-247

Efficacy of epidural, subarachnoid, and intracerebroventricular opioids for cancer pain

Ballantyne JC. Cochrane Review. Coch Database Sys Rev 2005

• No controlled trials• Uncontrolled studies report excellent pain

relief among ICV (73%), Epidural (72%) and SA (62%) patients

Novel Spinal Analgesics:• Alpha-2-agonists• NSAID’s• Ketamine• Midazolam• Neostigmine• adenosine• Oxytocin• Ziconotide• Naloxone• Droperidol

Colclough G, McLarney JT, Sloan PA. J Opioid Manage 2008; 4:163-166.

Eisenach JC. Anesthesiology 2010;112:1216

T12/L1 Epidural: bupivacaine/hydromorphone/ketamineDD

Sloan PA. J Pain 2011; 12:S2-P51.

Case Report:• 56 yr M, 90 kg• Refractory low back pain; acute hospitalization q2 wks• Prev Rx: oral opioids, PT, BM, laminectomy, SCS,

IT morphine (50 mg/d), IT ketamine and clonidine• Trial: - IT morphine 2 mg/naloxone 20 ng

- 50% decrease in VAS @ 1 h

• Long-term: - 3 yr f/u with IT morphine 5-8 mg/d plus naloxone 80 ng/d - 60-80% decrease in pain reporting - no acute hospital visits - return to daily function

Enhancement of Intrathecal Morphine with Low-dose Intrathecal Naloxone

Hamann SR, Sloan PA, Witt WO. J Opioid Manage 2008; 4:251-254.

Yang CP. Anesth Analg 2011, Epub ahead of print.

Intrathecal Ultra-Low Dose Naloxone Enhances the Antinociceptive Effect of Morphine by Enhancing the Reuptake of Excitatory Amino

Acids from the Synaptic Cleft in the Spinal Cord of Partial Sciatic Nerve-Transected Rats

Complications• Delivery system failure (5%)• Infection (5%)• Headache (10%)• Catheter leakage (2%)• Failed block (1%)• Epidural abscess/hematoma

(<1%)• Spinal cord injury (rare)• Opioid-induced hyperalgesia

Sloan PA. J Supp Oncol 2004; 2:491-506.

• Bladder CA• Lumbar spine mets and

local invasion• Lower abdominal pain

unresponsive to IV opioids• T9/10 epidural analgesics• Excellent pain relief, but

with toxicity• After XRT, epidural

weaned to IV fentanyl, then change to fentanyl patch

Complications with Externalized Intrathecal Catheters for Cancer Pain

• Meta-analysis; total 821 patients• Deep infection rate: 1:4700 cath days• Sup infection rate: 1:3200 cath days• Bleeding and neurologic injury rare• External IT catheter effective and safe

for home use in cancer pts

Aprilli D. Anesthesiology Dec 2009; 111:1346-1355.

•44 yr woman, Ca of breast widely metastatic to the spine, not yet terminal•Treated with IT morphine: initially good pain relief, then increasing low back pain despite rapidly increasing doses of IT morphine.•What is DDx?•What is treatment plan?

Sloan PA. J Pain Symptom Manage 2010; 39:446.

Epidural Abscess (T10-12)

Spinal Cord Ischemia

MRI with high signal areaIn conus medullaris A&A 2007, 104:204

IT Injection: Medication Error• Healthy 64 male for TURP; Pakistan• Lumbar IT anesthesia• L3/4 easy. Immediate leg cramping and pain after injection• GA induced and surgery completed!• At 24h: no neurologic Sx or signs, thus send pt home• At 48h: pt returns with lower extremity paraplegia-permanent• Pt dies 2 yr postop

Ajmal M. Anesthesiology 2011; 114:998

Unusual Neurologic Symptoms Following Thoracic Epidural Test DoseRose G, M.D.; Masciarelli R, M.D.; Sloan PA, M.D.; Pinault L, M.D.Department of Anesthesiology, University of Kentucky, Lexington, KY

Introduction:

The purpose of this case report is to present a patient for elective laparotomy surgery who reported unusual and potentially serious neurological signs and symptoms following routine administration of a thoracic epidural test dose.

1) We report the first case of acute pontine ischemia following thoracic epidural test dose.

2) The pathophysiology is postulated that pressure induced by the epidural test dose can be a source of mechanical stimuli to the vascular plexus of the spinal cord, resulting in vasospasm and ischemia.3

3) A literature review revealed a few rare cases of neurological events following epidural procedures.2,4-6

4) This case report highlights the need for vigilance for any unusual symptoms/signs following epidural placement.

5) The acute onset of unusual neurological signs and symptoms following epidural catheter test dosing requires immediate evaluation by the physician and a high index of suspicion to rule out serious neurological injury.

1) Brull R, et al. Neurological complications after regional anesthesia. Anesth Analg 2007; 100:965-74.

2) Visser WA, et al. Persistent cortical blindness after a thoracic epidural test dose of bupivacaine. Anesthesiology 2010; 112:493-5.

3) Scanlon GC, et al. Cervical transforaminal epidural steroid injections: More dangerous than we think? Spine 2007; 15:1249-56.

4) Nishio I, et al. Diplopia, a complication of dural puncture. Anesthesiology 2004; 100:158-64.

5) Chandrasekhar S, et al. Horner’s syndrome following very low concentration bupivacaine infusion for labor epidural analgesia. J Clin Anesth 2003; 15:217-19.

6) Perez M, et al. Facial nerve paralysis after epidural blood patch. Reg Anesth 1993; 18:196-8.

Our patient was a 55 year-old woman with a history of a pancreas tumor presenting for laparotomy and Whipple procedure. Her previous medical/surgical history included hypertension, chronic low back pain, smoking, and surgical treatment of obesity. Preop labs and vital signs were unremarkable. A T9/10 epidural was placed preop in the holding room on the second attempt. Aspiration of the catheter was negative and a test dose of 3 ml of 1.5% lidocaine with epi (15 mcg) was given. Vital signs remained unchanged, the patient reported no unusual symptoms and the test dose was felt to be negative.

Approximately 5 min after the negative epidural test dose, the patient began to complain of new bilateral hand numbness and weakness. An immediate focused history and physical exam was then performed. The patient denied any history of neurologic symptoms other than low back pain. She had no other complaints during this time and remained alert and fully oriented. She specifically denied any symptoms of headache or dizziness. On physical exam she remained calm with a blood pressure of 117/50 and heart rate of 90. She had only 1/5 motor strength in hand grip bilaterally, and 1/5 finger strength bilaterally on adduction. Her triceps and biceps motor strength was normal bilaterally. Peripheral sensory exam revealed decreased sensation to pinprick and light touch in both hands in a glove distribution. Examination of the lower extremities demonstrated a normal motor and sensory exam. There were no other localizing signs.

Surgery was cancelled, the epidural catheter removed and consultation with neurology quickly obtained. The patient’s neurological symptoms and signs started to resolve after 30 minutes, and had completely resolved within 90 minutes of onset. Multiple imaging studies were obtained, including CT of the head and neck, MRI of the C-spine and head, carotid duplex and transcranial Doppler. All studies were normal with the exception of the head MRI that revealed a somewhat triangular area of mildly increased signal (Figure 1) within the pons of the FLAIR and T2-weighted images. This was interpreted as possible ischemic changes and the consultant neurologist agreed with a diagnosis of pontine ischemia.

The patient was admitted overnight to hospital for observation and started on low-dose aspirin therapy. She was discharged home the following day without any recurrence of her neurological signs or symptoms. Her tumor surgery was completed 4 weeks later without complication. Postoperative analgesia was provided with transversus abdominis plane nerve block and intravenous PCA opioid.

Thoracic epidural placement for the infusion of epidural analgesics is common in the management of postoperative laparotomy pain. Pain relief is excellent with such treatment and the overall complication rate for serious adverse events is low.1 However, rare and unusual neurological events have been described following epidural placement for postoperative pain control,2 thus the physician must always be alert to unusual physical signs and symptoms following epidural placement.

Purpose:

References:

Discussion: Case Report:

University of Kentucky

Figure 1. An axial T2-weighted MRI obtained on the same day the patient's symptoms occurred, but after they had subsided, demonstrates a triangular area of increased signal within the pons centrally. (Arrow)

ASA Annual Mtg; Oct, 2011

JK-1 Sloan PA. J Pain Symptom Manage 2010; 39:391.

CM

R

Sloan PA. Am Acad Pain Management Mtg 2010; Las Vegas, NV

Conclusions• Spinal analgesics effective for

patients with refractory cancer pain

• Opioids/LA’s effective for most patients

• Minimum of complications• Most patients at home• Research needed:

– New spinal analgesics– Spinal opioid rotation

Anesthestic Interventional Pain Management Techniques

1. Neurolytic blocks• Celiac plexus, superior hypogastric plexus,

thoracic IT neurolysis, lumbar symp

2. Regional local anesthetic infusions• Brachial plexus, lumbar plexus, peripheral nerve,

interpleural block

3. Other techniques• Spinal cord stimulation, vertebroplasty, human

chromaffin cell IT transplants, epidural steroid, ICV opioids

Celiac Plexus Block

R

TP

Celiac Plexus Block•Pain from distal esophagus, pancreas, stomach•Side effects: postural hypotension; diarrhea;

neurological

•Wong GY. JAMA 2004; 291:1092•Prospective, double-blind RCT, 100 pts•Better pain relief with celiac plexus block

•Imaging required

Ultrasound-guided Celiac Plexus Block

Wyse JM. J Clinical Oncology 2011; 29:3541-3546.

• Pancreatic cancer pts with pain• Early EUS-guided CPB; vs standard

analgesic treatments• 48 pts each arm• At 3 months: morphine consumption tended

toward lower in block group, and pain scores sig (p<.01) less in block group

• No effect on QOL or survival

Transforaminal Epidural 5% Phenol Neurolysis for Intractable Cancer Pain

Candido K. Anesth Analg 2010; 110:216.

• 76 yr old man with leiomysarcoma• Intractable pain R thorax and lumbar regions in

spite of aggressive opioids• Epidural mets from L1-S2• Transforaminol approach to epidural space L3/4,

L1/2 and T 12/L1 with 5% phenol• Good pain relief

Outpatient continuous interscalene brachial plexus block in cancer-related pain

Buchanan D. JPSM Oct 2009; 38:629-634.

• 66 yr man with pathologic fx left glenoid• 4 wks home brachial plexus catheter with

ropivacaine• Patient-controlled infusion• Excellent pain relief

Cancer Pain Refractory to all other therapies

• Neurosurgical:– Pituitary Ablation– Cordotomy

• Palliative Sedation

Sloan PA. J Palliative Care 1996; 12:51-53.

References• Sloan PA. The evolving role of interventional pain management in

oncology. J Support Oncol 2004;2:491• Brogan SE. Intrathecal therapy for the management of cancer pain.

Curr Pain Headache Rep 2006;10:254• Krames ES. Interventional pain management. Med Clin North Am

1999;83:78• Sloan PA. Neuraxial pain relief for intractable cancer pain. Curr

Pain Headache Rep 2007;11:283• de Leon-Casasola OA. Interventional procedures for cancer pain

management. Cancer Invest 2004; 22:630-642.• de Leon-Casasola OA. IT therapy for cancer and noncancer pain.

Pain Med News 2009;7:75• Deer TR. Consensus guidelines for the selection and implantation of

patients with noncancer pain for intrathecal drug delivery. Pain Physician 2010; 13:E175