1. A Case Study in Neuropathic Pain
June 3, 2009
Palliative Care Team
Drs. St. Godard, Loiselle, Hohl and Pilkey

2. 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

3. 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

4. History Ms. G. D. 55 y.o with breast cancer Mets to bone
Pain to left arm

5. 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

6. 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

7. Physical Exam & Investigations
Temp 37.2
Hr 100
Rr 18
Sao2 – 90% on RA
BP 150/88
Lab work normal throughout

8. 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

9. Course in Hospital Dec 30 Jan 14 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

10. 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

11. 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.

12. 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

13. 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.

14. Other Suggestions Discussed:
Consider “rotating” from gabapentin to pregabalin.
Local anesthetic infusion? Logistics? Protocol?
Consider trial of mexilitene as an add on medication.
Consider ketamine infusion

15. Course in Hospital Consult to Dr J. Loiselle Jan 28
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

16. Course in Hospital Jan 28 Jan 29 Jan 30 – Mini Case conference
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 2.5mg/hr
Gabapentin being lowered

17. 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

18. 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

19. 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

20. Pain Receptors A delta C fibres Sleeping receptors (Almeida 2004)
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)

22. Nociceptors Damaged tissue releases: Involved in acute & chronic pain
Serotonin, Substance P, Bradykinin, Prostaglandin
Involved in acute & chronic pain
Influenced by endorphins

23. 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)

24. Sensitization Primary sensitization Secondary 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
Blocked by NMDA antagonists, anti-inflammatories
(McHugh 2000)

25. The Dorsal Root Ganglion

27. Tricyclic Antidepressants (TCAs)
40-60% efficacy for partial relief (NNT~2.5-3)
Start mg/d and  10-25mg each week
Best effects: mg/day
Mechanism:
NE & 5HT reuptake blockade
+/- NMDA antagonism,
+/- Na channel blockade
Anticholinergic effects
Secondary amine better tolerated

28. Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Venlafaxine
Start mg/day
Increase by 37.5 mg weekly
mg/d
Lower doses – results inconsistent
Short vs XR preps
Duloxetine
NNT ~4-5 (~7 for SSRI)
Start & 60mg/day
Antidepressant & anxiolytic
Favorable side effect profile
Limited long term data

29. ά2-δ Ligands (Gabapentinoids)
Bind to ά2-δ subunit of voltage gated Ca channels
 glutamate, NE, substance P release
NNT ~
RCT evidence in:
post herpetic, diabetic, phantom limb, peripheral neuropathy, Guillain-Barre, cancer, cord injury
Negative studies in:
complex regional pain (I), HIV neuropathy, some phantom pain, chemo

30. ά2-δ Ligands (Gabapentinoids)
Bind to ά2-δ subunit of voltage gated Ca channels
 glutamate, NE, substance P release
NNT ~
Gabapentin
Few drug interactions
Dizziness & sleepiness
Exacerbate cognitive impairment
Start mg TID
Titrate to mg/d
Peak effect in >2 weeks
Pregabalin
No drug interactions
Similar side effects to gaba
Start mg divided Q8-12H
Titrate mg/day weekly
Goal mg/d in 1-2 weeks
Peak effect in 2 weeks

31. 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%)

32. Methadone μ-receptor agonist + NMDA antagonist
Very long half-life, variable in individuals
Slow titration:
start 2.5mg TID
Increase % every hours
~5:1 to ~30:1 morphine equivalency (depending on dose)
Little literature support, ++ practical support

33. NMDA Antagonists Ketamine Start IV infusion @ 0.05-0.1mg/kg/hr
Start 2.5-5mg PO TID
Titrate by % dose to 1-2 mg/kg/day
Start IV mg/kg/hr
IV 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

34. Antiepileptics Carbamazepine
Established in trigeminal neuralgia (considered 1st line)
NNT 1.7
VPA
Effective in diabetic or post herpetic neuralgia
Conflicting results
Lamotrigine
mg/day
Slow titration due to hypersensitivity rxn (~7% risk)
Generally considered ineffective
Topiramate
Poor support of efficacy

35. Tramadol Minimal μ-receptor agonism
Action via inhibition reuptake of norepi & serotonin (like SNRI)
NNT ~3.8
Starting dose ~50mg/day div Q12H
Titrate by 50mg/d weekly
Goal ~ mg/day (max 800mg/day)
Good effect in diabetes, herpes, amputation
SE = sleepy, constipation, nausea, ortho BP; gait/cognitive prob,  sz threshold
Serotonin syndrome risk if combined with SSRI or SSNRI

36. 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 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

37. 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)

38. 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)

39. 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
3-5 wks
Antidepressant
Gabapentin
1.5-6 mo
Min drug interactions
Dizzy/sleepy
Pregabalin
1-2 wks
Methadone ?
variable
Opioid, cheap
Opioid, drug interactions
Ketamine
1-4 wks
Opioid sparing
Hallucinations
Tramadol
3.8
4-8 wks
For Diabetes, PHN
Carbamezapine
1.7
For Trigeminal neuralgia
Drug interactions
Lidocaine/Mexilitine 4
IV trial then po
Cardiac, neurologic
Capsaicin
none/days
Topical
Burning, redness
Cannabinoids
For MS, allodynia
GI, drowsiness
Clonidine
Effective IT, topical
Hypotension

40. 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

41. Recommended References
Cruccum, G. Treatment of painful neuropathy. Current Opions in Neurology ; 20;
Dworkin, R. et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007; 132;
Gilron, I. et al. Neuropathic pain: a practical guide for the clinician. CMAJ. 2006; 175(3);