15 Aug, 05 KKU 1

Overview of Overview of Neuropathic painNeuropathic pain

Kongkiat Kongkiat Kulkantrakorn,M.DKulkantrakorn,M.D..Neurology divisionNeurology division

Thammasat UniversityThammasat University

15 Aug, 05 2KKU

ContentsContents

Overview of Overview of ““painpain””New concepts and mechanismNew concepts and mechanismTreatment optionsTreatment optionsNew data in managementNew data in management

15 Aug, 05 3KKU

15 Aug, 05 4KKU

Breaking the vicious cycleBreaking the vicious cycle

Can we make patients Can we make patients pain free?pain free?

Without side effectsWithout side effectsChronic toxicitiesChronic toxicitiesCost?Cost?

Can we keep them Can we keep them pain free?pain free?

Disease progressionDisease progressionPharmacological tolerancePharmacological tolerance

15 Aug, 05 5KKU

15 Aug, 05 6KKU

NociceptionNociception

Recognition that local phenomena may affect Recognition that local phenomena may affect nociceptionnociception

Facilitating/sensitization of Facilitating/sensitization of nociceptorsnociceptors by a variety by a variety of local mediatorsof local mediatorsPGs, CCK, CGP, Substance P, monoamines, PGs, CCK, CGP, Substance P, monoamines, bradykininsbradykinins

Local phenomena may also act to spontaneously Local phenomena may also act to spontaneously create signals of create signals of nociceptionnociception

15 Aug, 05 7KKU

Clinical relevanceClinical relevanceNeurophysiology Neurophysiology Pain progress over Pain progress over time, both intensity time, both intensity and locationand locationDevelopment of de Development of de novo pain outside novo pain outside ““normalnormal”” boundariesboundariesCentral Central hypealgesiahypealgesia

15 Aug, 05 8KKU

PharmacologyPharmacologyAround the clock dosing Around the clock dosing vsvs PRN dosingPRN dosing

Development of new Development of new drugs, preparationdrugs, preparation

COXCOX--2 inhibitors2 inhibitorsTramadolTramadolLong acting Long acting opioidsopioids

Opioid receptorsOpioid receptorsPharmacogenomicsPharmacogenomicsVariable responsesVariable responses

15 Aug, 05 9KKU

15 Aug, 05 10KKU

15 Aug, 05 11KKU

Balanced analgesiaBalanced analgesia

Targeted Targeted pharmacotherapy to pharmacotherapy to affect multiple points in affect multiple points in the pain signaling the pain signaling pathwaypathwayAnalgesicsAnalgesics

OpioidsOpioidsNSAIDS, COXNSAIDS, COX--2 2 InhInh..

AdjuvantsAdjuvants

15 Aug, 05 12KKU

Addiction?Addiction?AddictionAddiction

CChronic neurobiologyhronic neurobiologyImpaired Impaired CControl over useontrol over useCCompulsive useompulsive useCContinued use despite harmontinued use despite harmCCravingraving

Physical dependencePhysical dependenceSpecific withdrawal syndrome Specific withdrawal syndrome for each drugfor each drug

ToleranceToleranceAdaptation: diminution of Adaptation: diminution of drug effect over timedrug effect over time

15 Aug, 05 13KKU

Features suggestive of neuropathic painFeatures suggestive of neuropathic pain

Pain in the absence of ongoing tissue damagePain in the absence of ongoing tissue damagePain in an area of sensory lossPain in an area of sensory lossParoxysmal or spontaneous painParoxysmal or spontaneous painAllodyniaAllodyniaHyperalgesiaHyperalgesiaDysaesthesiaDysaesthesiaHyperpathiaHyperpathiaDifferent characteristic of pain (vs nociception): burning, pulsDifferent characteristic of pain (vs nociception): burning, pulsing, ing, stabbing painstabbing painTinelTinel’’s signs signSometimes a delay in onset of pain after nerve injurySometimes a delay in onset of pain after nerve injuryPoor response (not unresponsiveness) to opioidsPoor response (not unresponsiveness) to opioidsPresence of a major neurological deficitPresence of a major neurological deficit

Acute Pain Management: Scientific Evidence. NHMRC 1998Acute Pain Management: Scientific Evidence. NHMRC 1998

15 Aug, 05 14KKU

Clinical approachClinical approach

1.1. Diagnosis of neuropathic pain, differentiate Diagnosis of neuropathic pain, differentiate from other types of painfrom other types of pain

Is this pain neuropathic?Is this pain neuropathic?

2.2. Etiologic diagnosis and work upEtiologic diagnosis and work up3.3. Assessment of pain and patientAssessment of pain and patient4.4. Selection of treatment modalitiesSelection of treatment modalities

15 Aug, 05 15KKU

Lamina I

Lamina VC-fibre

NK1 receptor

Spinal Cord

Painful stimulus

Spinal neurones project to sensory & affective areas

Substance Pglutamate

Amygdalahypothalamus

PB

AFFECTIVESENSORY

Somatosensorycortex

ThalamusPAG

RVM

Descending influences

Superficial

Deep

15 Aug, 05 16KKU

PERIPHERAL ACTIVITY

CENTRAL SENSITIZATION

Decreased threshold to peripheral

stimuli

Increased spontaneous

activityExpansion of

receptive field

Hyperalgesia AllodyniaTissue damage

Nerve damage

Spontaneous pain

15 Aug, 05 17KKU

ReceptiveField

PrimaryafferentC-fiber

Deep dorsal hornconvergent neuron

To B

rain

Superficialdorsal horn

ectopicdischarges

injurednerve

Non-injurednerve

Ca2+

Ca2+

N-type VDCC

P-type VDCC

T-type VDCC

Glutamate(& EAAneurotransmitters)

NMDA-R ( & EAA-Rs)

Ca2+

Increased activity viaexisting N-type VDCCs

IncreasedNMDA etc.

Increasedpain

15 Aug, 05 18KKU

Mechanisms: Neuropathic PainMechanisms: Neuropathic Pain

Peripheral changes in channels Na, K, CaPeripheral changes in channels Na, K, CaEctopic activity, ephaptic, sympathetic nervesEctopic activity, ephaptic, sympathetic nervesIncreased NT release from intact Increased NT release from intact fibersfibersIncreased NMDA activity centrallyIncreased NMDA activity centrallyChanges in opioid, monoamine systems?Changes in opioid, monoamine systems?

15 Aug, 05 19KKU

Treatment optionsTreatment options

Analgesic medicationAnalgesic medicationAdjuvant medicationsAdjuvant medicationsAnesthetic and neurosurgical techniquesAnesthetic and neurosurgical techniquesPhysical therapyPhysical therapyPsychological / behavioral therapyPsychological / behavioral therapyTopicalTopical therapytherapy

15 Aug, 05 20KKU

Pharmacological therapyPharmacological therapy

Patient needs to know what to expect !Patient needs to know what to expect !Neuropathic pain does not generally respond to Neuropathic pain does not generally respond to primary analgesics (Opioid or NSAIDS)primary analgesics (Opioid or NSAIDS)Usually require medication in adjuvant groupUsually require medication in adjuvant group

AnticonvulsantsAnticonvulsants

AntidepressantsAntidepressants

AntispasmAntispasm drugsdrugs

NeurolepticsNeuroleptics

Steroids, etc.Steroids, etc.

15 Aug, 05 21KKU

CarbamazepineCarbamazepine

Na Channel blockerNa Channel blockerIndicationIndication

Approved for Trigeminal neuralgiaApproved for Trigeminal neuralgiaLancinating pain, paresthesia, Lancinating pain, paresthesia, dyesthesiadyesthesia

NNT: 1.5NNT: 1.5--3.6, NNH: 3.43.6, NNH: 3.4Side effect: dizziness, Side effect: dizziness, diplopiadiplopia, nausea, nauseaEnzyme inducing effectEnzyme inducing effect

15 Aug, 05 22KKU

Newly Available DrugsNewly Available DrugsFelbamate Felbamate FelbatolFelbatolGabapentinGabapentin NeurontinNeurontinLamotrigineLamotrigine LamictalLamictalLevetiracetamLevetiracetam KeppraKeppraOxcarbazepineOxcarbazepine TrileptalTrileptalTopiramateTopiramate TopamaxTopamaxTiagabaineTiagabaine GabatrilGabatrilVigabatrinVigabatrin SabrilSabrilZonisamideZonisamide ZonegranZonegran

15 Aug, 05 23KKU

Adapted from Upton N. Trends Pharmacol Sci. 1994;15:456-463.

GlutamateGlutamate--Mediated TransmissionMediated Transmission

15 Aug, 05 24KKU

Adapted from Upton N. Trends Pharmacol Sci. 1994;15:456-463McNamara JO. In: Goodman & Gilman’s. 9th ed. 1996:466

Ostergaard LH, et al. In: Antiepileptic Drugs. 4th ed. 1995:1057-1061

GABAGABA--Mediated TransmissionMediated Transmission

15 Aug, 05 25KKU

GabapentinGabapentin

Increase endogenous GABA, Ca channel Increase endogenous GABA, Ca channel modulationmodulationUsage: allodynia, burning pain, paresthesia, sleepUsage: allodynia, burning pain, paresthesia, sleep

PostherpeticPostherpetic neuralgianeuralgiaDiabetic polyneuropathyDiabetic polyneuropathyOthers: mixed neuropathic pain syndrome, migraineOthers: mixed neuropathic pain syndrome, migraine

Almost no drug interaction, no metabolismAlmost no drug interaction, no metabolismSide effect: sedation, ataxia, dizziness, edemaSide effect: sedation, ataxia, dizziness, edema

15 Aug, 05 26KKU

OxcarbazepineOxcarbazepine

Na channel blocker, reduce glutamate and Na channel blocker, reduce glutamate and modulate Ca channel functionmodulate Ca channel functionNo need for hepatic or No need for hepatic or hematologichematologic monitoringmonitoringLess side effect due to lack of Less side effect due to lack of epoxideepoxide formationformationSimilar efficacy, may substitute Similar efficacy, may substitute carbamazepinecarbamazepineMinimal enzyme inducing effectMinimal enzyme inducing effectUsage: trigeminal neuralgia, radiculopathy, failed Usage: trigeminal neuralgia, radiculopathy, failed other other AEDsAEDs, diabetic neuropathy, diabetic neuropathy

15 Aug, 05 27KKU

TopiramateTopiramate

Monosaccharide derivative with Monosaccharide derivative with sulfamatesulfamatefunctionality, multiple mechanisms of actionfunctionality, multiple mechanisms of actionFDA Approved for migraine prophylaxis at 50FDA Approved for migraine prophylaxis at 50--100 mg/d100 mg/dOffOff--label use for pain, bipolar, etc. label use for pain, bipolar, etc. Limited data in neuropathic painLimited data in neuropathic painSide effect: sedation, wt. loss, renal calculi, Side effect: sedation, wt. loss, renal calculi, anhidrosisanhidrosis, myopia, myopia

15 Aug, 05 28KKU

OthersOthers

ClonazepamClonazepamPainful muscle spasm, sleep disorderPainful muscle spasm, sleep disorder

New New AEDsAEDsLevatiracetamLevatiracetamPregabalinPregabalin

15 Aug, 05 29KKU

Mechanisms of AED actionMechanisms of AED action

Functional blockade of Na channelFunctional blockade of Na channelProlong refractory phase of neuronal firingProlong refractory phase of neuronal firing

Phenytoin, Phenytoin, carbamazepinecarbamazepine

Enhancement of Enhancement of GABAergicGABAergic transmissiontransmissionInterfere with GABA receptor functionInterfere with GABA receptor function

Phenobarbital, benzodiazepinePhenobarbital, benzodiazepine

Reduce GABA metabolism, promote releaseReduce GABA metabolism, promote releaseValproate, gabapentin, Valproate, gabapentin, vigabatrinvigabatrin

Inhibition of Inhibition of glutamatergicglutamatergic transmissiontransmissionLamotrigineLamotrigine, , topiramatetopiramate, , pregabalinpregabalin

15 Aug, 05 30KKU

Common AED in neuropathic pain usage

AED Dose (mg/d) Timing

CarbamazepineOxcarbazepinePhenytoinGabapentinTopiramateValproic acidLamotrigine

200-1200

300-1200

200-400

600-1800

50-200

400-1500

150-500

Bid-qidBidOdBid-qidBidBid-tidBid

15 Aug, 05 31KKU

AntidepressantAntidepressant

TCATCA

Block reuptake of NE/5Block reuptake of NE/5--HT HT NMDA, ion channel NMDA, ion channel blockerblockerEffective for both steady Effective for both steady and and lancinatinglancinating painspainsTCA: 10 studies: 300pt, TCA: 10 studies: 300pt, NNT=2.6NNT=2.6

SSRI/SNRI, new agentsSSRI/SNRI, new agents

SSRISSRI: varied among agents,: varied among agents,Too specific for NTToo specific for NT

NNT: 7NNT: 7

SNRI, atypical agentSNRI, atypical agentDual inhibition Dual inhibition

May be better May be better NNT: 4NNT: 4--55

DuloxetineDuloxetineVenlafaxineVenlafaxine

•Sindrup, S.H., Jensen, T.S., 2001. Antidepressants in the treatment of•neuropathic pain. In: Neuropathic Pain: Pathophysiology andTreatment. IASP PRESS, pp. 169–183.•Bomholt SF, et al. Neuropharmacology. 2005;48:252-63•Sindrup SH, et al. Basic Clin Pharmacol Toxicol 2005;96: 399-409

15 Aug, 05 32KKU

Opioid and Opioid and NePNeP

OxycodoneOxycodone in PHN, DM in PHN, DM polyneuropathypolyneuropathyCombination of Combination of GabapentinGabapentin and and LevorphanolLevorphanol leads to leads to reducing dosage of each drug and minimize side effectreducing dosage of each drug and minimize side effect

Foley KM. NEJM 2003:348:1279Foley KM. NEJM 2003:348:1279--8181GilronGilron I, et al. NEJM 2005; 352:1324I, et al. NEJM 2005; 352:1324--3434

15 Aug, 05 33KKU

FDAFDA--approved treatment for approved treatment for neuropathicneuropathic painpain

CarbamazepineCarbamazepineTrigeminal neuralgiaTrigeminal neuralgia

DuloxetineDuloxetinePainful diabetic neuropathyPainful diabetic neuropathy

LidocaineLidocaine patch 5%patch 5%PostherpeticPostherpetic neuralgianeuralgia

GabapentinGabapentinPostherpeticPostherpetic neuralgianeuralgia

PregabalinPregabalinPostherpeticPostherpetic neuralgianeuralgia

15 Aug, 05 34KKU

What is not working for What is not working for NePNeP??

SSRISSRINSAIDS NSAIDS

COXCOX--2 inhibitors2 inhibitors

Recent withdrawal of Recent withdrawal of VioxxVioxx and and BextraBextraCVS side effectCVS side effectEffective for only inflammatory painEffective for only inflammatory painNot effective for Not effective for neuropathicneuropathic painpain

15 Aug, 05 35KKU

Comparative efficacyComparative efficacy

15 Aug, 05 36KKU

Mechanism of neuropathic pain:Mechanism of neuropathic pain:central sensitizationcentral sensitization

Afferent fibers

C fiber

A-beta fiber

Nerve injury

Phenotypicalchanges

Spinal cord

Neuro-plasticity

Central sensitization

Alterationof modulatory

systems

Ectopicdischarge

Ectopicdischarge

Woolf & Mannion, Lancet 1999Attal & Bouhassira, Acta Neurol Scand 1999

15 Aug, 05 37KKU

Major putative drug targets Major putative drug targets in neuropathic painin neuropathic pain

PNSNa+ channel

(CBZ,OXC,PHT,TPM,LTG,LIDOCAINE,MEXILETINE)

TCAs SPINAL CORD

BRAIN

Norepinephrine / serotonin(TCAs, SSRIs, SNRIs)Opiate receptors

Opiates/Tramadol

Ca2+ channel(GBP,LVT,OXC,LTG)

NMDA antagonistsKetamine, Memantine,

Dextromethorphan

Peripheralsensitization

Centralsensitization

Descending inhibition

PNS, peripheral nervous system; SNRI, serotonin and norepinephrinereuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant

15 Aug, 05 38KKU

PrePre--emptive analgesia in emptive analgesia in NePNeP

GabapentinGabapentin 900 mg 900 mg vsvsPlacebo in acute zoster pain Placebo in acute zoster pain (single dose study)(single dose study)11

Reduce incidence of PHN Reduce incidence of PHN after daily after daily AmitryptylineAmitryptylineduring acute zosterduring acute zoster22

Prevent central sensitization Prevent central sensitization during acute phaseduring acute phase

Berry JD, Petersen KL. Neurology 2005;65:444Berry JD, Petersen KL. Neurology 2005;65:444--77BowsherBowsher D. J Pain Symptom Manage 1997;13:327D. J Pain Symptom Manage 1997;13:327--3131

15 Aug, 05 39KKU

Pharmacological therapyPharmacological therapy

Most are chronic pain and need long term data Most are chronic pain and need long term data from clinical trialfrom clinical trialAdjuvantsAdjuvants: both central and peripheral effects: both central and peripheral effectsConsider Consider ‘‘individuallizedindividuallized’’ therapy for cotherapy for co--morbiditymorbidityAware of individual difference for Aware of individual difference for pharmacodynamics and pharmacokinetics profilepharmacodynamics and pharmacokinetics profileHow to best measure the success of therapeutic How to best measure the success of therapeutic trial, depends on clinical questions and pain trial, depends on clinical questions and pain situation (quality of life)situation (quality of life)

15 Aug, 05 40KKU

Pharmacological therapyPharmacological therapy

Use medication that targets the pharmacologic Use medication that targets the pharmacologic mechanism, balancing with side effectsmechanism, balancing with side effectsStart at low dose and slowly increase to effect, side Start at low dose and slowly increase to effect, side effect or maximum safeeffect or maximum safe--dosagedosageMaintain maximum tolerated dose for at least Maintain maximum tolerated dose for at least several weeks to ensure adequate trialseveral weeks to ensure adequate trialTry other drugs in that category, then another Try other drugs in that category, then another group, or combination (add new group, or combination (add new txtx one at a time)one at a time)

15 Aug, 05 41KKU

Treatment algorithmTreatment algorithm

15 Aug, 05 42KKU

Universal precaution Universal precaution in pain medicinein pain medicine

1.1. Diagnosis with appropriate differential Diagnosis with appropriate differential dxdx2.2. Psychological assessment including riskPsychological assessment including risk3.3. Informed consent (written Informed consent (written vsvs verbal)verbal)4.4. Treatment agreementTreatment agreement5.5. Pre/Post intervention assessment of pain level Pre/Post intervention assessment of pain level

and functionand function

15 Aug, 05 43KKU

Universal precaution Universal precaution in pain medicinein pain medicine

6. Appropriate trial of opioid therapy +/6. Appropriate trial of opioid therapy +/-- adjuvantsadjuvants7. Reassessment of pain score and level of function7. Reassessment of pain score and level of function8. Regularly assess four A8. Regularly assess four A’’s of pain medicines of pain medicine

Analgesia, Activity, Adverse reaction, Aberrant Analgesia, Activity, Adverse reaction, Aberrant behaviourbehaviour

9. Periodic review of pain diagnosis, co9. Periodic review of pain diagnosis, co--morbid conditions morbid conditions and addictive disorderand addictive disorder

10. Documentation10. Documentation

15 Aug, 05 44KKU

To take homeTo take home

Neuropathic pain is common and treatableNeuropathic pain is common and treatableCareful clinical assessment is the keyCareful clinical assessment is the key

History, neurological exam, diagnostic testHistory, neurological exam, diagnostic test

From signs and symptoms to treatmentFrom signs and symptoms to treatmentCurrent treatment and understanding will Current treatment and understanding will facilitate clinician to improve patientfacilitate clinician to improve patient’’s cares care