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June 3, 2009
Palliative Care Team
Drs. St. Godard, Loiselle, Hohl and Pilkey
Objectives
 By the end of the hour the learner will be able to:
 Define neuropathic pain
 List at least 2 types of Pain receptors
 List at least 4 different types of adjuvant pain
medications
 List the mechanisms of action, benefits, and side-effects
of these 4 medications
 List 2 new/different adjuvant pain medications
Talk Outline
 Case Study – Dr. Ted St. Godard & Dr. Joel Loiselle
 Pathophysiology of Neuropathic Pain – Dr. Jana Pilkey
 Adjuvant Medications – Dr. Chris Hohl
 What’s new/different in Neuropathic Pain – Dr. Jana Pilkey
History
 Ms. G. D.
 55 y.o with breast cancer
 Mets to bone
 Pain to left arm
History
 2 week hx of worsening pain
 Mid back – dull ache, Pressure
 Burning to L hand and arm
 Since 1997
 brachial plexus neuropathy
 “Pins and needles”
 “Like dipped in acid”
 Morphine for 4 weeks not helping
Cancer History
 Breast cancer dx 1997
 Lumpectomy, tamoxifen x 2 yrs
 Mastectomy 1999 and LN dissection
 Oophorectomy 1999
 Multiple courses of chemo
 2008- mets to c-spine, ribs, sternum.
 Sept 2008 – Rx to spine
 Phx: PUD
Physical Exam & Investigations
 Temp 37.2
 Hr 100
 Rr 18
 Sao2 – 90% on RA
 BP 150/88
 Lab work normal throughout
Course in Hospital
 Admission orders:
 Methadone 5mg bid
 Dex 10mg bid
 Pariet 20mg po od
 Dilaudid 8 mg subcut q4h and q1prn
 Fentanyl 50 per IPP
Course in Hospital
 Dec 30
 Myoclonus noticed – hydrated
 Rotated to fentanyl patch
 Methadone increased
 Jan 14
 CT head – mets to R cerebellum and R frontal lobe
 Pain better- on methadone 40 bid, dex 8 bid
 Starts 12 rdtx to whole brain
Course in Hospital
 Jan 27 Pain Crisis
 Severe excruciating burning pain
 From neck to top of R shoulder
 Crying, screaming
 BT HM ineffective
 Slept with 5mg versed
 Methadone increased
 Ketamine added 2.5 mg subcut tid
 Pregabalin added 50mg bid
 Lidocaine 2% gel to shoulder qid prn
Potentially useful Peripheral
Nerve Block in this Case
Interscalene block
-Performed at root level
-“Single shot” -only lasts 12 h.
-Catheter techniques difficult to
maintain (displacement).
-Disease extent limits anesthetic flow.
-Risk of bleeding /epidural hematoma
is prohibitive in this case.
Neuraxial (Intraspinal) blocks
Epidural:
 comparable to bilateral
peripheral nerve block
 catheter outside dura
 would be placed at C7/T1
Intrathecal = Spinal
 catheter enters CSF in
lumbar cistern
 can be guided to high
thoracic level as required
for upper limb pain
Contraindications to Neuraxial
Analgesia in this Case
- Extent of Disease involving C-spine:
- Risk of epidural hematoma if needle at C7-T1.
- Poor CSF flow impedes spread of analgesics
- Brain Metastasis:
- Posterior Fossa- increased risk of “coning”
- Relative contraindication
 Remember coagulopathy (Plt <100; INR >1.3) and need
for ongoing anticoagulation are contraindications.
Course in Hospital
 Consult to Dr J. Loiselle
 Nerve-block or epidural too risky given fragility of spine
and cerebellar mets
 Jan 28
 Pain continues
 On Methadone 60mg bid
 Starts fentanyl 50mcg/hr IV
 HM stopped – twitching
 Ketamine 5 mg subcut tid
Course in Hospital
 Jan 28
 Family concerned about sedation on fentanyl
 Jan 29
 RR 7 - fentanyl stopped, Pain again severe
 Fentanyl IV not restarted at family request
 Ativan started
 Jan 30 – Mini Case conference
 Ketamine IV @ 2.5mg/hr
 Gabapentin being lowered
Course in Hospital
 Jan 31-Feb 5 – good pain control
 Feb 6 – weepy and tired, pain with movement
 Feb 9 – increase in ketamine IV 3.52mg/hr
 Feb 13 – increase in ketamine IV 6mg/hr
 Feb 17 – decrease po intake – deteriorating – ketamine
7.5mg/hr
Course in Hospital
 Feb 19 – pt wishes she could sleep until death
 – tired of trying to “hold the pain in”
 Feb 23 – unresponsive
 Feb 26 – prognosis hrs to days/ discussed sedation
 Feb 28 – difficulty maintaining sedation
 Mar 4 – died sedated and comfortable
What is Neuropathic Pain?
 Pain initiated or caused by a primary lesion or
dysfunction in the nervous system
 Characterized by :
 Burning, Tingling, Electric ,Shooting Pain
Pain Receptors
 A delta
 Mechanical sensation eg. Cut, prick
 C fibres
 Diffuse, respond to many stimuli
 Burning sensation
 Sleeping receptors
 Active in injured tissue only
 Acquire mechanical sensitivity
(Almeida 2004)
Nociceptors
 Damaged tissue releases:
 Serotonin, Substance P,
Bradykinin, Prostaglandin
 Involved in acute & chronic pain
 Influenced by endorphins
Sensitization
 Can be a tissue level (primary) or
 At CNS level (secondary)
 Results in:

threshold of activation after injury

intensity of a response to a noxious stimulus

emergence of spontaneous activity
(Aguggia 2003)
Sensitization
 Primary sensitization
 Sympathetic activity and Inflammatory Mediators

(Chong 2003)
 Secondary sensitization
 CNS changes in spinal cord and brain
 NMDA receptors activated
 “Wind-up” = increased amplitude and frequency summation
in neurons after prolonged stimulation

(Chong 2003)
 Blocked by NMDA antagonists, anti-inflammatories
 (McHugh 2000)
The Dorsal Root Ganglion
Tricyclic Antidepressants (TCAs)
 40-60% efficacy for partial relief (NNT~2.5-3)
 Start 10-25 mg/d and  10-25mg each week
 Best effects: 50-150 mg/day
 Mechanism:
 NE & 5HT reuptake blockade
 +/- NMDA antagonism,
 +/- Na channel blockade
 Anticholinergic effects
 Secondary amine better tolerated
Selective Serotonin-Norepinephrine
Reuptake Inhibitors (SNRIs)
Duloxetine
Venlafaxine
 NNT ~4-5 (~7 for SSRI)
 Start 37.5 mg/day
 Start & efficacious @ 60mg/day  Increase by 37.5 mg weekly
 Effective @ 150-225 mg/d
 Antidepressant & anxiolytic
 Favorable side effect profile
 Limited long term data
 Lower doses – results
inconsistent
 Short vs XR preps
ά2-δ Ligands (Gabapentinoids)
 Bind to ά2-δ subunit of voltage gated Ca channels
  glutamate, NE, substance P release
 NNT ~3.5-4.5
Gabapentin
Pregabalin






 No drug interactions
 Similar side effects to gaba
 Start 50-150mg divided Q8-12H
Few drug interactions
Dizziness & sleepiness
Exacerbate cognitive impairment
Start 100-300mg TID
Titrate to 1800-3600 mg/d
Peak effect in >2 weeks
 Titrate 50-150mg/day weekly
 Goal 300-600 mg/d in 1-2 weeks
 Peak effect in 2 weeks
Opioids
 20-30% pain reduction, NNT ~2.5
 Provides rapid relief
 Rapid titration
 No ceiling effect
 Multiple forms & delivery methods
 More side effects than 1st line
treatments
 Risk of misuse and abuse (5%)
Methadone
 μ-receptor agonist + NMDA antagonist
 Very long half-life, variable in individuals
 Slow titration:
 start 2.5mg TID
 Increase 50-100% every 48-72 hours
 ~5:1 to ~30:1 morphine equivalency (depending on dose)
 Little literature support, ++ practical support
NMDA Antagonists
Ketamine
 Start 2.5-5mg PO TID
 Titrate by 50-100% dose to 1-2 mg/kg/day
 Start IV infusion @ 0.05-0.1mg/kg/hr
 IV bolus @ 0.1-0.2 mg/kg/dose over 20 minutes
 No NNT data
 Poor performance in studies, good efficacy in practice
 Topical or gargle preparations possible
 *opioid sparing effects
Other/New Things to Try
IV Lidocaine And po Mexilitine
Cochrane Review 2005
 Good quality evidence in neuropathic pain
 Both decrease VAS by 11 on 1-100 scale
 47% of people in trials had a 30% decrease in pain

(22% in placebo)
 35% had Side –effects

Numbness, dizziness, fatigue, metallic taste
 Authors conclude similar efficacy to other adjuvants and
good safety profile
Other/New Things to Try
 Capsaicin – High dose patch in PHN (640mcg/cm2)
 1 – 60 min application
 Lasts up to 12 weeks
 Mean decrease in pain score of 29.6%
 Side-effects – Pain and erythema at site

(Backonja – Lancet Neurology, 2008)
 Cannabis – Sativex - Neuropathic pain with Allodynia
 Improvements of 1.43 on 10 point VAS
 Good safety profile – SE include GI upset & drowsiness

(Nurmikko – Pain 2007)
Other/New Things to Try
 Intrathecal Ziconotide
 N-type Ca Channel blocker (NCCB)
 Median dose 6.48mcg/day
 Improved VASPI scores in 53.1%
 Decreased opioid usage in 9%
 Very expensive
 Side Effects:

Memory loss, dizziness, nystagmus, somnolence, gait, CK rise
(Pommer - J Pain Symptom – 2009)
A Comparison of Adjuvants
Drug
NNT Titration
Notes
Side Effects
TCA
2.5-3
2-15 wks
Antidepressant, cheap
Anticholinergic
Duloxetine
4-5
none
Anxiolytic, antidepressant
few
Venlafaxine
4-5
3-5 wks
Antidepressant
few
Gabapentin
3.5-4.5
1.5-6 mo
Min drug interactions
Dizzy/sleepy
Pregabalin
3.5-4.5
1-2 wks
Min drug interactions
Dizzy/sleepy
Methadone
?
variable
Opioid, cheap
Opioid, drug interactions
Ketamine
?
1-4 wks
Opioid sparing
Hallucinations
Tramadol
3.8
4-8 wks
For Diabetes, PHN
Anticholinergic
Carbamezapine
1.7
1-4 wks
For Trigeminal neuralgia
Drug interactions
Lidocaine/Mexilitine
4
none
IV trial then po
Cardiac, neurologic
Capsaicin
?
none/days
Topical
Burning, redness
Cannabinoids
?
none/days
For MS, allodynia
GI, drowsiness
Clonidine
?
none/days
Effective IT, topical
Hypotension
Summary/Objectives
 By the end of the hour the learner will be able to:
 Define neuropathic pain
 List at least 2 types of Pain receptors
 List at least 4 different types of adjuvant pain
medications
 List the mechanisms of action, benefits, and side-effects
of these 4 medications
 List 2 new/different adjuvant pain medications
Recommended References
1.
2.
3.
Cruccum, G. Treatment of painful neuropathy. Current Opions
in Neurology. 2007; 20; 531-535.
Dworkin, R. et al. Pharmacologic management of neuropathic
pain: evidence-based recommendations. Pain. 2007; 132; 237-251.
Gilron, I. et al. Neuropathic pain: a practical guide for the
clinician. CMAJ. 2006; 175(3); 265-275.