June 3, 2009 Palliative Care Team Drs. St. Godard, Loiselle, Hohl and Pilkey

June 3, 2009Palliative Care Team

Drs. St. Godard, Loiselle, Hohl and Pilkey

ObjectivesBy the end of the hour the learner will be

able to:Define neuropathic painList at least 2 types of Pain receptorsList at least 4 different types of adjuvant pain

medicationsList the mechanisms of action, benefits, and

side-effects of these 4 medicationsList 2 new/different adjuvant pain medications

Talk OutlineCase 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

HistoryMs. G. D. 55 y.o with breast cancerMets to bonePain to left arm

History2 week hx of worsening painMid back – dull ache, PressureBurning to L hand and arm

Since 1997brachial plexus neuropathy

“Pins and needles”“Like dipped in acid”Morphine for 4 weeks not helping

Cancer HistoryBreast cancer dx 1997Lumpectomy, tamoxifen x 2 yrsMastectomy 1999 and LN dissectionOophorectomy 1999Multiple courses of chemo2008- mets to c-spine, ribs, sternum.Sept 2008 – Rx to spinePhx: PUD

Physical Exam & InvestigationsTemp 37.2Hr 100Rr 18Sao2 – 90% on RABP 150/88Lab work normal throughout

Course in HospitalAdmission orders:

Methadone 5mg bidDex 10mg bidPariet 20mg po odDilaudid 8 mg subcut q4h and q1prnFentanyl 50 per IPP

Course in HospitalDec 30

Myoclonus noticed – hydratedRotated to fentanyl patchMethadone increased

Jan 14CT head – mets to R cerebellum and R frontal

lobePain better- on methadone 40 bid, dex 8 bidStarts 12 rdtx to whole brain

Course in HospitalJan 27 Pain Crisis

Severe excruciating burning painFrom neck to top of R shoulderCrying, screamingBT HM ineffectiveSlept with 5mg versedMethadone increasedKetamine added 2.5 mg subcut tidPregabalin added 50mg bidLidocaine 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) blocksEpidural:comparable to bilateral

peripheral nerve block catheter outside dura would be placed at C7/T1

Intrathecal = Spinal catheter enters CSF in

lumbar cisterncan 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 HospitalConsult to Dr J. Loiselle

Nerve-block or epidural too risky given fragility of spine and cerebellar mets

Jan 28Pain continuesOn Methadone 60mg bidStarts fentanyl 50mcg/hr IVHM stopped – twitchingKetamine 5 mg subcut tid

Course in HospitalJan 28

Family concerned about sedation on fentanylJan 29

RR 7 - fentanyl stopped, Pain again severeFentanyl IV not restarted at family requestAtivan started

Jan 30 – Mini Case conferenceKetamine IV @ 2.5mg/hrGabapentin being lowered

Course in HospitalJan 31-Feb 5 – good pain controlFeb 6 – weepy and tired, pain with movementFeb 9 – increase in ketamine IV 3.52mg/hrFeb 13 – increase in ketamine IV 6mg/hrFeb 17 – decrease po intake – deteriorating –

ketamine 7.5mg/hr

Course in HospitalFeb 19 – pt wishes she could sleep until

death – tired of trying to “hold the pain in”

Feb 23 – unresponsiveFeb 26 – prognosis hrs to days/ discussed

sedationFeb 28 – difficulty maintaining sedationMar 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 ReceptorsA delta

Mechanical sensation eg. Cut, prick

C fibresDiffuse, respond to many stimuliBurning sensation

Sleeping receptorsActive in injured tissue onlyAcquire mechanical sensitivity

(Almeida 2004)

NociceptorsDamaged tissue releases:

Serotonin, Substance P, Bradykinin, Prostaglandin

Involved in acute & chronic pain

Influenced by endorphins

SensitizationCan be a tissue level (primary) orAt CNS level (secondary)

Results in: threshold of activation after injury intensity of a response to a noxious stimulus emergence of spontaneous activity

(Aguggia 2003)

SensitizationPrimary sensitization

Sympathetic activity and Inflammatory Mediators (Chong 2003)

Secondary sensitizationCNS changes in spinal cord and brainNMDA 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/dayMechanism:

NE & 5HT reuptake blockade +/- NMDA antagonism, +/- Na channel blockade

Anticholinergic effectsSecondary amine better tolerated

Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

DuloxetineNNT ~4-5 (~7 for SSRI)Start & efficacious @

60mg/dayAntidepressant &

anxiolyticFavorable side effect

profileLimited long term data

VenlafaxineStart 37.5 mg/day Increase by 37.5 mg

weeklyEffective @ 150-225 mg/dLower doses – results

inconsistentShort vs XR preps

ά2-δ Ligands (Gabapentinoids)

GabapentinFew drug interactionsDizziness & sleepinessExacerbate cognitive

impairment Start 100-300mg TIDTitrate to 1800-3600 mg/dPeak effect in >2 weeks

PregabalinNo drug interactionsSimilar side effects to gabaStart 50-150mg divided Q8-

12HTitrate 50-150mg/day

weeklyGoal 300-600 mg/d in 1-2

weeksPeak effect in 2 weeks

Bind to ά2-δ subunit of voltage gated Ca channels glutamate, NE, substance P releaseNNT ~3.5-4.5

Opioids20-30% pain reduction, NNT

~2.5Provides rapid reliefRapid titration No ceiling effectMultiple forms & delivery

methodsMore side effects than 1st line

treatments Risk of misuse and abuse (5%)

Methadoneμ-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 AntagonistsKetamineStart 2.5-5mg PO TID Titrate by 50-100% dose to 1-2 mg/kg/dayStart IV infusion @ 0.05-0.1mg/kg/hr IV bolus @ 0.1-0.2 mg/kg/dose over 20 minutesNo NNT data

Poor performance in studies, good efficacy in practice

Topical or gargle preparations possible*opioid sparing effects

Other/New Things to TryIV Lidocaine And po Mexilitine

Cochrane Review 2005

Good quality evidence in neuropathic painBoth decrease VAS by 11 on 1-100 scale47% of people in trials had a 30% decrease in pain

(22% in placebo)35% had Side –effects

Numbness, dizziness, fatigue, metallic tasteAuthors conclude similar efficacy to other

adjuvants and good safety profile

Other/New Things to TryCapsaicin – High dose patch in PHN (640mcg/cm2)

1 – 60 min applicationLasts up to 12 weeksMean decrease in pain score of 29.6%Side-effects – Pain and erythema at site

(Backonja – Lancet Neurology, 2008)

Cannabis – Sativex - Neuropathic pain with AllodyniaImprovements of 1.43 on 10 point VASGood safety profile – SE include GI upset & drowsiness

(Nurmikko – Pain 2007)

Other/New Things to TryIntrathecal Ziconotide

N-type Ca Channel blocker (NCCB)Median dose 6.48mcg/dayImproved VASPI scores in 53.1%Decreased opioid usage in 9%Very expensiveSide Effects:

Memory loss, dizziness, nystagmus, somnolence, gait, CK rise

(Pommer - J Pain Symptom – 2009)

A Comparison of AdjuvantsDrug NNT Titratio

nNotes 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/ObjectivesBy the end of the hour the learner will be

able to:Define neuropathic painList at least 2 types of Pain receptorsList at least 4 different types of adjuvant pain

medicationsList the mechanisms of action, benefits, and

side-effects of these 4 medicationsList 2 new/different adjuvant pain medications

Recommended References1. Cruccum, G. Treatment of painful neuropathy.

Current Opions in Neurology. 2007; 20; 531-535.2. Dworkin, R. et al. Pharmacologic management of

neuropathic pain: evidence-based recommendations. Pain. 2007; 132; 237-251.

3. Gilron, I. et al. Neuropathic pain: a practical guide for the clinician. CMAJ. 2006; 175(3); 265-275.