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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Comparative efficacyComparative efficacy
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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