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A Case Study in Neuropathic Pain

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  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 • 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. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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)

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

  21. 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)

  22. 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)

  23. The Dorsal Root Ganglion

  24. 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

  25. Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine • Start 37.5 mg/day • Increase by 37.5 mg weekly • Effective @ 150-225 mg/d • Lower doses – results inconsistent • Short vs XR preps Duloxetine • NNT ~4-5 (~7 for SSRI) • Start & efficacious @ 60mg/day • Antidepressant & anxiolytic • Favorable side effect profile • Limited long term data

  26. 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 • Few drug interactions • Dizziness & sleepiness • Exacerbate cognitive impairment • Start 100-300mg TID • Titrate to 1800-3600 mg/d • Peak effect in >2 weeks Pregabalin • No drug interactions • Similar side effects to gaba • Start 50-150mg divided Q8-12H • Titrate 50-150mg/day weekly • Goal 300-600 mg/d in 1-2 weeks • Peak effect in 2 weeks

  27. 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%)

  28. 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

  29. 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

  30. 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

  31. 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)

  32. 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)

  33. A Comparison of Adjuvants

  34. 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

  35. Recommended References • 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.