Clinical diagnosis and Clinical diagnosis and treatment of NEUROPATHIC treatment of NEUROPATHIC

painpain

MUDr.Rudolf Černý, CScMUDr.Rudolf Černý, CScDept of NeurologyDept of Neurology

2nd School of Medicine2nd School of MedicineCharles University in PragueCharles University in Prague

Definitions Definitions Pain definition IASP Pain definition IASP :: “unpleasant sensorial and “unpleasant sensorial and

affective affective experienceexperience, caused by actual or , caused by actual or potential tissue damage, ore described in terms potential tissue damage, ore described in terms of such a damage”of such a damage”

Pain is always subjective experience, Pain is always subjective experience, psychological psychological elaboration ofelaboration of : : nociceptive afferencenociceptive afference dysfunction of the nervous systemdysfunction of the nervous system stored experience (memory trace, learned pain stored experience (memory trace, learned pain

behavior)behavior) psychosocial dysfunctionpsychosocial dysfunction

Neuropathic pain = Neuropathic pain = generated by the nervous generated by the nervous system system

Components of chronic painComponents of chronic pain

1)1) nociceptivenociceptive - tissue damage, local - tissue damage, local inflammation, activation of nociceptor endingsinflammation, activation of nociceptor endings

2)2) neuropatneuropathhicic - pain is generated by - pain is generated by peripheral or central nervous system peripheral or central nervous system Projected pain into the respective innervation area. Projected pain into the respective innervation area.

Primary NS damage is not a indispensable Primary NS damage is not a indispensable conditioncondition

3)3) psychogenicpsychogenic - transformation of non painful - transformation of non painful perception, affection and cognitive processes into perception, affection and cognitive processes into pain experiencepain experience

4)4) socialsocial subconscious behavior pattern in failing coping with subconscious behavior pattern in failing coping with

work load or family problemswork load or family problems conscious purposeful behavior with the aim to conscious purposeful behavior with the aim to

receive compensation claims, rent or social benefitsreceive compensation claims, rent or social benefits

Criteria of NPCriteria of NP

evidence of NS lesionevidence of NS lesion neuroanatomical correlation of the pain neuroanatomical correlation of the pain

perception (sensory disturbance in perception (sensory disturbance in distribution of radicular dermatome, area distribution of radicular dermatome, area nervina etc…)nervina etc…)

evidence of sensorial disturbance abnormityevidence of sensorial disturbance abnormity chronic conditions – 3- 6 monthschronic conditions – 3- 6 months low efficacy of analgesicslow efficacy of analgesics

Epidemiology of NPEpidemiology of NP

25% patients in 25% patients in centers for Pain treatment centers for Pain treatment Populational prevalence estimated about 1 % !Populational prevalence estimated about 1 % !

like Epilepsylike Epilepsy pprevalence increases with age, above 70 nearly revalence increases with age, above 70 nearly 50% reffer 50% reffer

some symptoms of some symptoms of NP !NP ! Permanent complication in peripheral nerve injuries Permanent complication in peripheral nerve injuries

cca 5%cca 5% MMetabolic polyneuropathyetabolic polyneuropathy - cca - cca 50%  diabetics elder 50%  diabetics elder

then 60 yearsthen 60 years NS INS Infectionsnfections - - cca 30%cca 30% cases of HIV, cases of HIV, neuroboreliosis,neuroboreliosis,

herpes zoster herpes zoster Central NP Central NP ::

syringomyelia syringomyelia - - 75% cases 75% cases 30% in MS30% in MS 88% ischemic strokes% ischemic strokes

Pathophysiology of NPPathophysiology of NP

complex event – NS adaptation to chronic pain complex event – NS adaptation to chronic pain stimulationstimulation

functional adaptation – morphological functional adaptation – morphological restructuralizationrestructuralization

all level of neuraxis involvedall level of neuraxis involved result – result – sensitizationsensitization (periph. and central) (periph. and central)

increased sensitivity to painful stimuliincreased sensitivity to painful stimuli painful perception of innocuous stimulationpainful perception of innocuous stimulation spontaneous pain perception WITHOUT peripheral spontaneous pain perception WITHOUT peripheral

stimulationstimulation

cause-adaptaption-cause-adaptaption-mechanismus-symptomesmechanismus-symptomes

primary causative eventprimary causative event chronic nociceptor stimulachronic nociceptor stimulationtion– neurogenn– neurogennic inflammationic inflammation NS dysfunctionNS dysfunction idiopathic cases (erythromelalgia, SFN)idiopathic cases (erythromelalgia, SFN)

adaptationadaptation changes in PN fibers, sympatical and thermic fibers switched to changes in PN fibers, sympatical and thermic fibers switched to

nociception nociception central sensitization – posterior horn, thalamus, SMA, cingulumcentral sensitization – posterior horn, thalamus, SMA, cingulum

molecular mechanismsmolecular mechanisms Na channels, NMDA receptors, GABA receptors, microglia Na channels, NMDA receptors, GABA receptors, microglia

activationactivation neuronal mechanisms – expansion of receptive fieldsneuronal mechanisms – expansion of receptive fields changed activity of PH interneurons, thalamus – Thunberg grillchanged activity of PH interneurons, thalamus – Thunberg grill

Mechanismy NBMechanismy NB

hyperaktivace nociceptorů a vláken C, A deltahyperaktivace nociceptorů a vláken C, A delta funkční změny DRG, zadní roh, STTfunkční změny DRG, zadní roh, STT

molekulární, receptorové, synaptickémolekulární, receptorové, synaptické strukturální změnystrukturální změny

synapsesynapse populace interneuronů ZRpopulace interneuronů ZR

talamustalamus druhá vrátka, přesun k hyperaktivitě talamic relay druhá vrátka, přesun k hyperaktivitě talamic relay

neuron STTneuron STT porucha integrace tepelných x bolestivých vjemů v porucha integrace tepelných x bolestivých vjemů v

mediálním jádře - CBmediálním jádře - CB cortex – nábor nových areícortex – nábor nových areí

Peripheral Peripheral sensitizationsensitization NociceptorsNociceptors

recruitment of silent, mechano-insenzitive recruitment of silent, mechano-insenzitive nociceptorsnociceptors

acid sensing ion channelsacid sensing ion channels heat activated ion channelsheat activated ion channels CGRP, sbst PCGRP, sbst P against - anti-inflammatory mediators (ACh, against - anti-inflammatory mediators (ACh,

anandamid)anandamid) Peripheral nerve fibersPeripheral nerve fibers

expression of Na channelsexpression of Na channels high frequency firing C-fibershigh frequency firing C-fibers eecctopic source of action potentials in axon topic source of action potentials in axon

membranemembrane

Central Central sensitizationsensitization

DRG cells :DRG cells : 3 funkční stavy řízené K kanálem (tonic, plateau = 3 funkční stavy řízené K kanálem (tonic, plateau =

amplifikace, rhytmic firing = filtrace)amplifikace, rhytmic firing = filtrace) remodelaceremodelace sprouting Abeta zakončenísprouting Abeta zakončení

„„hyperalgesic“ neuronhyperalgesic“ neuron spinotalamická dráhaspinotalamická dráha

parabrachiální – „normální“ akutní bolestparabrachiální – „normální“ akutní bolest spino-retikulo-talamická – PAG – chronická bolestspino-retikulo-talamická – PAG – chronická bolest

TalamusTalamus KortexKortex

Molecular mechanismsMolecular mechanisms new channels new channels

Na, Ca alfa2 deltaNa, Ca alfa2 delta expression of new membrane receptorsexpression of new membrane receptors

sbst P, TRPV1, NK1, alfa2 adrenoreceptorsbst P, TRPV1, NK1, alfa2 adrenoreceptor mimiccroglia activationroglia activation paradoxical effects of glycin releaseparadoxical effects of glycin release macrophage activation – TNF alfa – Schwann macrophage activation – TNF alfa – Schwann

cell – NGF expressioncell – NGF expression changes of membrane properties of HEALTHY changes of membrane properties of HEALTHY

nerve fibers !nerve fibers ! efferent sympatical activationefferent sympatical activation

Paradoxical excitation by inhibitory Paradoxical excitation by inhibitory

mediators - GABA, Glycinmediators - GABA, Glycin !! !!

peripheral nerve fiber lesion - chronic peripheral nerve fiber lesion - chronic stimulation of lamina I PH Neuronsstimulation of lamina I PH Neurons

decrease of potassium transporter decrease of potassium transporter concentration KCC2 concentration KCC2 intracellular accumulation of Cl intracellular accumulation of Cl

with increase intracellular KCL with increase intracellular KCL concentration GABA a glycin produce concentration GABA a glycin produce EXCITATORY PSPs !!EXCITATORY PSPs !!

PH adaptation to chronic PH adaptation to chronic nociceptive stimulationnociceptive stimulation STT neurons can have 3 functional states:STT neurons can have 3 functional states:

1.1. tonic discharge – respond by series AP to perif. stimulustonic discharge – respond by series AP to perif. stimulus2.2. rhythmic bursting – AP firing outlast the stimulusrhythmic bursting – AP firing outlast the stimulus3.3. plateau potential – spontaneous AP firing WITHOUTplateau potential – spontaneous AP firing WITHOUT

stimulation – hyperalgesic neuronstimulation – hyperalgesic neuron less then 10% neurons is normally in state 3, after less then 10% neurons is normally in state 3, after

sensitization process most of them !!sensitization process most of them !! transition of functional statestransition of functional states

is regulated by ratio of metabotrope receptors:is regulated by ratio of metabotrope receptors: NMDA + GABAb = antagonistic regulation of a common NMDA + GABAb = antagonistic regulation of a common

potassium channel of type Kir3potassium channel of type Kir3

Secondary hyperalgesia Secondary hyperalgesia is CENTRAL phenomenonis CENTRAL phenomenon

Summary Summary

Symptoms of NPSymptoms of NP

SpontaneousSpontaneous painpain pparesthesia, dysesthesiaaresthesia, dysesthesia

EvokedEvoked hyperalgesiahyperalgesia allodyniaallodynia painpain

SpontaneousSpontaneous pain pain

Lancinating painLancinating pain – – neuralgicneuralgic

Paroxysms of Paroxysms of sharp, stabbing sharp, stabbing pain pain

Peripheral Peripheral nerve:nerve:Ectopic activation , Ectopic activation , abnormal Na abnormal Na channelschannels

continuous dull continuous dull painpain

Sensitization of Sensitization of peripheral peripheral nociceptorsnociceptors

KauzalgiaKauzalgia burning painburning pain Sympatically Sympatically maintained painmaintained pain

ALODYNIA – innocuous ALODYNIA – innocuous stimulus produces painstimulus produces pain

Dynamical mechanic Dynamical mechanic A.A.

Touch stimulation by Touch stimulation by cotton swab drawn on the cotton swab drawn on the skinskin

Aß fibers Aß fibers switch to switch to nociception nociception

Static mechanic A.Static mechanic A. Blunt touch by fingerBlunt touch by finger Senzibilizace Senzibilizace C C nociceptorůnociceptorů

Cold A.Cold A. Cold stimulus perceived as Cold stimulus perceived as painfulpainful

Cold fibers C evoke Cold fibers C evoke STT activitySTT activity

Temporal Temporal summation summation

wind up – by repeated wind up – by repeated stimulusstimulus

PH = PH = NMDA NMDA activity activity increasedincreased

HYPERALGESIAHYPERALGESIA

MechanicalMechanical Increased pin prick Increased pin prick sensitivitysensitivity

increased increased sensitivity ofsensitivity of Aδ Aδ fibersfibers

ThermicThermic Pain with 46 C Pain with 46 C stimulusstimulus

vaniloid vaniloid receptor receptor sensitizedsensitized

ColdCold 25 C stimulus 25 C stimulus painfulpainful

C fibers C fibers sensitizedsensitized

Lower threshold for pain stimulation

Classification Classification of of NPNP

Peripheral x CentralPeripheral x Central Symmetrical x Asymmetrical NPSymmetrical x Asymmetrical NP EtiologicalEtiological Symptomatological – mechanism basedSymptomatological – mechanism based

Peripheral cause of NP – most frequentPeripheral cause of NP – most frequent

Focal neuropathiesFocal neuropathies Compresive neuropathy (carpal tunel)Compresive neuropathy (carpal tunel) Discogennic radix compressionDiscogennic radix compression Peripheral nerve injuryPeripheral nerve injury Postherpetic neuralgiaPostherpetic neuralgia Mononeuropathia multiplexMononeuropathia multiplex

Difusse polyneuropathies :Difusse polyneuropathies : Metabolic (diabetes, etylismusMetabolic (diabetes, etylismus, amyloid polyneuropathy, hypotyreosis, , amyloid polyneuropathy, hypotyreosis,

hypovitaminosis B)hypovitaminosis B) Infection (HIV, borrelióza, herpes zoster, CMV)Infection (HIV, borrelióza, herpes zoster, CMV) Toxic (arsen, thalium, isoniazid, nitrofurantoin, metronidazol, chloramfenikol, Toxic (arsen, thalium, isoniazid, nitrofurantoin, metronidazol, chloramfenikol,

cytostatics)cytostatics) Hereditary senso-motor neuropathiesHereditary senso-motor neuropathies

Complex regional pain syndrome (RSD)Complex regional pain syndrome (RSD) Cranial neuralgias (trigeminal, glossofaryngeal…)Cranial neuralgias (trigeminal, glossofaryngeal…) Chronic vertebrogennic algic syndromeChronic vertebrogennic algic syndrome, postlaminectomic syndromes, postlaminectomic syndromes

Spinal cord disorders with NP Spinal cord disorders with NP

Multiple sclerosisMultiple sclerosis Spinal cord injurySpinal cord injury Myelopathy : Myelopathy :

Metabolical (hypovitaminoza B12, diabetes)Metabolical (hypovitaminoza B12, diabetes) VascularVascular SyringomyeliaSyringomyelia

CompressionCompression

Central NPCentral NP

Thalamic (central) pain:Thalamic (central) pain: Ischemic stroke Ischemic stroke Thalamic hemorrhageThalamic hemorrhage

Multiple sclerosisMultiple sclerosis Arnold Chiari malformationArnold Chiari malformation Neurodegeneration Neurodegeneration

Parkinson diseaseParkinson disease Alzheimer diseaseAlzheimer disease MSA, SCAMSA, SCA

Phantom painPhantom pain

Typical character of NPTypical character of NP

Continuous spontan, chronic pain - dullContinuous spontan, chronic pain - dull Evoked pain by external and internal stimuli - Evoked pain by external and internal stimuli -

lancinatinglancinating Always hypoesthesia, pain co localized Always hypoesthesia, pain co localized Pain is always projective with typical distributionPain is always projective with typical distribution Temporal summation of pain by repeated Temporal summation of pain by repeated

stimulationstimulation After-sensations, MitempfindungAfter-sensations, Mitempfindung Trophic changes – sympatic nerves over activityTrophic changes – sympatic nerves over activity

Work up of NPWork up of NP Clinical examClinical exam

symptom classificationsymptom classification sensory examinationsensory examination

distribution !distribution ! evoked symptoms of pain?evoked symptoms of pain? semiquantitasemiquantitattive examination (von Frey filaments, warm, ive examination (von Frey filaments, warm,

cold)cold) Laboratory and imagingLaboratory and imaging

etiological possibilitiesetiological possibilities Electrophysiological examinationElectrophysiological examination

assessment of NS functionassessment of NS function EMG – only thick, non-pain fibers evaluated !!EMG – only thick, non-pain fibers evaluated !! evoked potentials - SSEP and MEP – long tracts of spinal evoked potentials - SSEP and MEP – long tracts of spinal

cordcord QST, QSMAT, LEP, microneurography, R-R interval QST, QSMAT, LEP, microneurography, R-R interval

variabilityvariability

Small fiber Small fiber neuropathyneuropathy

SFNSFN

PN –80% of fibers C and A deltaPN –80% of fibers C and A delta routine examination cannot detect functionroutine examination cannot detect function EMG assess only thick fibers of light touch EMG assess only thick fibers of light touch

and vibrationand vibration clinical picture:clinical picture:

thermic hypoesthesiathermic hypoesthesia low threshold of thermic painlow threshold of thermic pain causalgia – „burning feet“causalgia – „burning feet“

SFNSFN

usually part of peripheral neuropathy usually part of peripheral neuropathy symptoms:symptoms: DM, etylic, HIVDM, etylic, HIV hereditary – Charcot Marie Toothhereditary – Charcot Marie Tooth

isolated SF affection possibleisolated SF affection possible SKIN BIOPSYSKIN BIOPSY EMG excludes general neuropathyEMG excludes general neuropathy LEPs abnormalLEPs abnormal

SKIN BIOPSYSKIN BIOPSY in SFN in SFN

117 patients 117 patients with NP in with NP in legslegs

44 with 44 with normal EMGnormal EMG

but: reduction but: reduction of nerve of nerve endings endings denzity in denzity in skin !!skin !!

imunofluorescence – Ab against PGP 9,5

Small x Large fiber neuropathySmall x Large fiber neuropathy

Erythromelalgia - example of SFNErythromelalgia - example of SFN

primary x secondary (DM, myeloproliferative dis.)primary x secondary (DM, myeloproliferative dis.) atacks:atacks:

red, hot, burning feetred, hot, burning feet VAS 4-10/10VAS 4-10/10 pain increase by warmpain increase by warm

mikrovascular a-v shunts in skinmikrovascular a-v shunts in skin termoregulatory hyperperfusiontermoregulatory hyperperfusion nutritive hypoperfusion, hyperkinetic hypoxynutritive hypoperfusion, hyperkinetic hypoxy

small fiber neuropathysmall fiber neuropathy increased sweating, EMG normal orincreased sweating, EMG normal or in 1/3 axonal neuropathyin 1/3 axonal neuropathy

Primary ErythromelalgiaPrimary Erythromelalgia

AD inheritanceAD inheritance painfull peripheral neuropathypainfull peripheral neuropathy zvýšenou citlivost na námahu a tepelné zvýšenou citlivost na námahu a tepelné

podnětypodněty peripheral cyanosisperipheral cyanosis manifesting form childhoodmanifesting form childhood point mutation of Na1,7 channel point mutation of Na1,7 channel chromozom 2q31-32 (gen SCN9A v r. 2004)chromozom 2q31-32 (gen SCN9A v r. 2004) memmbrane hyperexcitability of peripheral memmbrane hyperexcitability of peripheral

nerve fibersnerve fibers

Sympatically maintained painSympatically maintained pain

not a disease but pathophysiologal not a disease but pathophysiologal mechanismmechanism

part of NP symptomspart of NP symptoms no specific parameter from clinic or laboratory!no specific parameter from clinic or laboratory! typical symptomstypical symptoms

cold pressure testucold pressure testu burning, badly localized painburning, badly localized pain trophical changestrophical changes vasoparalysisvasoparalysis

Sympatically maintained painSympatically maintained pain

S. hyperactivity in peripheral nerve lesions:S. hyperactivity in peripheral nerve lesions: expression of adrenoreceptor in nerve expression of adrenoreceptor in nerve

membranemembrane synapses of S. efferent with peripheral fiberssynapses of S. efferent with peripheral fibers DiagnosisDiagnosis

ANS exam - HRV, Ewing testANS exam - HRV, Ewing test gold standard – effect of S. blockadegold standard – effect of S. blockade

TTherapy – alfa blocherapy – alfa blockerskers (prazosin, (prazosin, klonidin, tizanidin), S. ganglia blockingklonidin, tizanidin), S. ganglia blocking

Postherpetic neuralgiaPostherpetic neuralgia DR ganglionitis – VZVDR ganglionitis – VZV acute pain at least 20%, 9-15% after 1 month, 2-5% after 1 yearacute pain at least 20%, 9-15% after 1 month, 2-5% after 1 year age age >> 60-70 year prevalence 50-75% ! 60-70 year prevalence 50-75% ! risks for PHN:risks for PHN:

female genderfemale gender age over 50age over 50 trigeminus- sacral rootstrigeminus- sacral roots intensity of rash, hemorrhagic pustulasintensity of rash, hemorrhagic pustulas

all types of NP – contin. bunirng, attacks of lancinating painall types of NP – contin. bunirng, attacks of lancinating pain typical dynamic mechanical allodyniatypical dynamic mechanical allodynia secondary hyperalgesia exceeding the original exanthema !secondary hyperalgesia exceeding the original exanthema ! Therapy – resistant!Therapy – resistant!

acute phase = acute phase = acycloviracyclovir + carbamazepin + opioids + carbamazepin + opioids chronic phase – anticonvulsiveschronic phase – anticonvulsives + local – capsaicin + opioids + local – capsaicin + opioids

Central PainCentral Pain

1906 Déjerine-Roussy – thalamic 1906 Déjerine-Roussy – thalamic syndromesyndrome

incomplete lesions, 1,5 - 8% incomplete lesions, 1,5 - 8% strokesstrokes

Etiology :Etiology : lacunar infarctionlacunar infarction, aart. , aart.

thalamogeniculatae thalamogeniculatae other = hemorrhage, MS plaque, other = hemorrhage, MS plaque,

gliosisgliosis rare = tumor, trauma, abscessrare = tumor, trauma, abscess

Topic of CPTopic of CP

everywhere in STTeverywhere in STT parietal pseudothalamic syndromeparietal pseudothalamic syndrome POSTEROLATERAL THALAMUSPOSTEROLATERAL THALAMUS posterior arm of capsula internaposterior arm of capsula interna dorsolateral medulladorsolateral medulla spinal cord, particularly cervical spinal cord, particularly cervical

and CC regionand CC region

Pathogenesis of CPPathogenesis of CP

disinhibition of thalamic relay neurons of disinhibition of thalamic relay neurons of STTsSTTs

posterolateral (VPL) Th nucleus and insulposterolateral (VPL) Th nucleus and insulaa denervation hypersensitivity, increased denervation hypersensitivity, increased

NMDA activity and NA channels expressionNMDA activity and NA channels expression deaferentation cortical paindeaferentation cortical pain somatosensoric cortex reorganisationsomatosensoric cortex reorganisation expansion of receptive fields (PET, SPECT)expansion of receptive fields (PET, SPECT) disturbance of central inhibitiondisturbance of central inhibition abnorm LEP x normal SSEPabnorm LEP x normal SSEP Thunberg grilThunberg gril

Character of CPCharacter of CP

dull dull ((sharpsharp))

deep deep ((superficialsuperficial)) burning (icy) burning (icy) paroxysmparoxysmss of lancinating pain of lancinating pain

spontaneousspontaneous provokedprovoked

typical is combination of several pain typestypical is combination of several pain types intensity > 50%VASintensity > 50%VAS provocation of painprovocation of pain : :

peripheral stimulationperipheral stimulation physical and psychogenic stressorsphysical and psychogenic stressors

Character of CPCharacter of CP

pain intensitypain intensity DOES NOT CORRELATE with DOES NOT CORRELATE with topical deficit !topical deficit !

pain evolves within weeks or months foll. pain evolves within weeks or months foll. stroke stroke

hemiparesis usually regressed at this timehemiparesis usually regressed at this time CP can be „healed“ by subsequent strokeCP can be „healed“ by subsequent stroke very unpleasant – suffering, strong affective very unpleasant – suffering, strong affective

componentcomponent depressions, suicidium not rare!!depressions, suicidium not rare!!

Sensory disturbance in CPSensory disturbance in CP

• always present hemi – quadrant distributionalways present hemi – quadrant distribution• can be small part -can be small part - ulnar ridge of the arm ulnar ridge of the arm, ,

cheiro-oral syndrome cheiro-oral syndrome • protopatic character (termoalgic, protopatic character (termoalgic,

propriocepce)propriocepce)• epicritical sensations spared (2 points,light epicritical sensations spared (2 points,light

toMuch, grafestesia, stereognosia)toMuch, grafestesia, stereognosia)• paresthesia, dysestesiaparesthesia, dysestesia• hyperalgesia, alodyniahyperalgesia, alodynia• atypical sensations: after sensations, atypical sensations: after sensations,

MitempfindungMitempfindung• syringomyelie disociated thermoalgic syringomyelie disociated thermoalgic

anestesia with normal touchanestesia with normal touch

Wallenberg syndromeWallenberg syndrome

PICA ischemiaPICA ischemia dorsolateral infarctiondorsolateral infarction ipsilateral face hypoesthesia, crossed ipsilateral face hypoesthesia, crossed

body hypoesthesiabody hypoesthesia ipsilateral bulbar palsyipsilateral bulbar palsy ipsilateral cerebellar ataxiaipsilateral cerebellar ataxia peripheral vestibular failureperipheral vestibular failure NO hemiparesis !NO hemiparesis !

Bilateral thalamic stroke in Bilateral thalamic stroke in T2 T2

weighted MRIweighted MRI

Syringomyelia, Arnold ChiariSyringomyelia, Arnold Chiari

SyringomyeliaSyringomyelia

Therapy of NPTherapy of NP

Complex + CombinedComplex + Combined

Treatment :Treatment :1.1. underlying diseaseunderlying disease2.2. NP symptoms by combination ofNP symptoms by combination of

analgesicsanalgesics anticonvulsiveanticonvulsivess antidepreantidepresssivessives

3.3. locallocal4.4. invasive proceduresinvasive procedures5.5. physical treatmentphysical treatment6.6. psychoterapypsychoterapy

Treatment planTreatment plan

Realistic – better life quality, complete Realistic – better life quality, complete pain relieve in minority of cases !pain relieve in minority of cases !

(„clinically relevant“ pain intensity decrease 45-60%, pain elimination („clinically relevant“ pain intensity decrease 45-60%, pain elimination max. 10%)max. 10%)

Measurable goals !Measurable goals ! Pain diary, pain drawing, consumption of Pain diary, pain drawing, consumption of

pain pillspain pills Informed consent – better treatment Informed consent – better treatment

adherenceadherence

AnalgesicsAnalgesics• Variable, but lower effect in comparison to nociceptive Variable, but lower effect in comparison to nociceptive

pain !!pain !!• WHO „Pain ladder“ is validWHO „Pain ladder“ is valid• but – opioid use in non-malignant painbut – opioid use in non-malignant pain

• walk on mine field !walk on mine field !• Possible substances: Possible substances: • dose acc effect, combinations possibledose acc effect, combinations possible

• paracetamol up 4 g/day, hepatotoxicityparacetamol up 4 g/day, hepatotoxicity• NSAID - better COX2 preferential (meloxicam, NSAID - better COX2 preferential (meloxicam,

nimesulid)nimesulid)• tramadol up 400 mg/daytramadol up 400 mg/day• dihydrocodein sustained release max 2x120mgdihydrocodein sustained release max 2x120mg• morphin SR 2x30-120 mgmorphin SR 2x30-120 mg• transdermal opiodstransdermal opiods

• Synergic action of fixed combination:Synergic action of fixed combination:• paracetamol 325mg-tramadol 50mg (Zaldiar) paracetamol 325mg-tramadol 50mg (Zaldiar)

NNT=3! NNT=3!

AntidepresantsAntidepresants

EBM proved – MEBM proved – Meta analysis eta analysis > > 5000 patients 5000 patients Efficacy inEfficacy in 40-70% 40-70% NNT 2-3, SSRI 6 and more!NNT 2-3, SSRI 6 and more! Analgesis Analgesis is not dependentis not dependent on antidepre on antidepresssive sive

effect effect :: good analgesia in pat. who don't score for Dep.!!good analgesia in pat. who don't score for Dep.!! effect starts early - effect starts early - 1-10 days1-10 days total dose is lowtotal dose is low increased activity of descending pain inhibiting increased activity of descending pain inhibiting

pathways (noradrenalin, serotonin) pathways (noradrenalin, serotonin)

AnticonvulsantsAnticonvulsants

Similar pathogenetic traits in pain sensitization Similar pathogenetic traits in pain sensitization and epileptogenesis and epileptogenesis

Analgetic effect proved in animal and RCT Analgetic effect proved in animal and RCT studies as wellstudies as well

But not in all antiepileptics !But not in all antiepileptics ! I. vs. III. generation anti-EP :I. vs. III. generation anti-EP :

similar efficacysimilar efficacy new drugs:new drugs:

better tolerance, less interaction, no hepatic inductionbetter tolerance, less interaction, no hepatic induction phpharmakoeconomicsarmakoeconomics

AnticonvulsantsAnticonvulsants• carbamazepincarbamazepin – sharp lancinating pain (PHN, TN) – sharp lancinating pain (PHN, TN)

• slow up titration ! , max 1200 mg/dslow up titration ! , max 1200 mg/d• cave toxoalerg.exanthema, central toxicitycave toxoalerg.exanthema, central toxicity• hepatic enzyme inductor – many interactions hepatic enzyme inductor – many interactions

• gabapentingabapentin – well tolerated, RCT proved efficacy in DPN, PHN, TN – well tolerated, RCT proved efficacy in DPN, PHN, TN• 1200-2400 mg, no metabolism, no interactions !1200-2400 mg, no metabolism, no interactions !

• clonazepam, valproate clonazepam, valproate • Back-up possibilities: Back-up possibilities: more SE and interactions slow titration is and interactions slow titration is

a rule!a rule!• lamotrigine lamotrigine 50-100-400mg (rash, central toxicity, blocks 50-100-400mg (rash, central toxicity, blocks

metabolism of valproate )metabolism of valproate )• topiramate topiramate 50-100-400mg (central toxicity, leukopenia, nefrolithiaza)50-100-400mg (central toxicity, leukopenia, nefrolithiaza)• phenytoinphenytoin 2x100mg (nausea, vertigo, bradykardia, heart conduction 2x100mg (nausea, vertigo, bradykardia, heart conduction

blocker, gingival hyperplasia, potentn hepatic enzyme inductor)blocker, gingival hyperplasia, potentn hepatic enzyme inductor)

Pharmacotherapy of Pharmacotherapy of

painpain

Na channels blocking

Ca channels blocking

Descendant inhibition enhancement

Local treatmentLocal treatment

local anesthetics – „lidocain patch“local anesthetics – „lidocain patch“ adhesive plasters, creams, local adhesive plasters, creams, local

injectionsinjections capsaicincapsaicin – Zostrix – Zostrix

sbst P agonist, analg. through destruction of C fiber sbst P agonist, analg. through destruction of C fiber endings endings

PHNPHN local forms of NSAIDlocal forms of NSAID

Adjuvant treatmentAdjuvant treatment

CortiCorticosterocosteroidsids MyorelaxanciaMyorelaxancia Vitamins BVitamins B Thioctic acidThioctic acid

ImportantImportant ! !

treat not only NP, but also BYSTANDER pain:treat not only NP, but also BYSTANDER pain: vertebral pain due to failed movement regimevertebral pain due to failed movement regime movement apparatus – pain form shortened movement apparatus – pain form shortened

tendons, musclestendons, muscles complication of immobility, sphincter functionscomplication of immobility, sphincter functions disorders of sleep and depression !!disorders of sleep and depression !!

Invasive treatmentInvasive treatmentAlgesiology, Center of painAlgesiology, Center of pain local nerve blockadeslocal nerve blockades epidural anesthesiaepidural anesthesia

single blockadesingle blockade long terms catheters (mo+steroids)long terms catheters (mo+steroids)

Spinal cord stimulationSpinal cord stimulation electrical stimulation of Post.Tractselectrical stimulation of Post.Tracts very potent modality in resistent NPvery potent modality in resistent NP

Last resort – pain surgeryLast resort – pain surgery destruction avoideddestruction avoided stimlation methods – motor cortex stimul in intractable stimlation methods – motor cortex stimul in intractable

deafferentation paindeafferentation pain