New Prespektive Oxcarbazepine in the Management of Neuropath

LM

PRODUCTION

Curriculum VitaeNama : Prof. Dr. KRT. Lucas Meliala, SpKJ,

SpS(K)Tempat/tanggal lahir : Membang Muda (Sumut), 22 September 1941Alamat : Jl. Nagan Lor 70, JogjakartaTelepon : (0274) 450758Fax. : (0274) 374052Mobile : 0815 687 0584E-mail : [email protected]

Pendidikan : Lulus Dokter tahun 1969, alumnus FK-UGM Lulus Spesialis Saraf & Jiwa tahun 1974

alumnus FK-UI, FK-UGM, FK UnairPekerjaan : Staf Fakultas Kedokteran UGM bagian IP Saraf dan Jiwa sejak tahun 1968 sampai sekarangOrganisasi : 1999-sekarang : Ketua Pokdi Nyeri Perdossi Anggota IASP, ENS Ketua Governing board IPS

NEW PRESPEKTIVE NEW PRESPEKTIVE OXCARBAZEPINE IN THE OXCARBAZEPINE IN THE

MANAGEMENT OF MANAGEMENT OF NEUROPATHIC PAINNEUROPATHIC PAIN

MANADO2005

KRT. Lucas Meliala

Department of Neurology Dr. Sardjito Hospital Department of Neurology Dr. Sardjito Hospital Gadjah Mada Faculty of Medicine - YogyakartaGadjah Mada Faculty of Medicine - Yogyakarta

Spontaneous PainPain Hypersensitivity

Peripheral Nerve Damage

NEUROPATHIC PAIN

Spinal cord Injury

Brain

DEFINITION OF DEFINITION OF NEUROPATHIC PAINNEUROPATHIC PAIN

‘Pain initiated or caused by a primary lesion or dysfunction

in the nervous system’

IASPIASP

Primarly affects middle-aged and elderly patients, ie herpetic

neuralgia, diabetic painful peripheral neuropathy, trigeminal neuralgia

Treatment startegies need to take into accaunt

NEUROPATHIC PAIN

likelihood of polypharmacy for a variety of medical conditions = increased risk of drug-drug interactions

Reduced tolerability to side effects of medication

Co-morbid conditions which compromise hepatic, hematologic and/or renal functions

MULTIPLE MULTIPLE AETIOLOGIESAETIOLOGIES

Trigeminal neuralgiaPeripheral neuropathies (mono polyneuropathies)

Diabetes, post-traumatic, postherpetic, cancer

Central lesions

IASPIASP

Neuro-plasticity

Centralsensitization

AlterationOf modulatory

systems

Spinal cordAfferent fibers

Ectopicdischarge

Nerveinjury

C fiber

Abeta fiber

Ecthopicdischarge

PhenotypicalChanges

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

Ectopic Discharge

Modified by MELIALA 2004

GABA Adenosine

?

Spinal cord

Calcium channels

Hyperexcitability

Evoked spontaneous

PheripheralMechanisme

NMDAetc

NMDAetc

NMDAetc

Dickenson, 2000

Modified by Meliala, 2003

Peripheral nerve

Alteration and redistributionof channels, etc

Damaged zoneEctopic/ephaptic

impulses

TISSUE DAMAGE

INFLAMATION

SSA MI NOS

SENSITITATION

ACTIvATIONECT. DISC.

Si-Na+

DORSAL COLUMN

PgB5HTAdenosin

DESCENDINGINHIBITION

BRAIN

PAIN – NO PAIN

R-NE

AngerFearAnxietyDepression

COX2Induction

Glu SP

C-fiber terminal

GABA Badenosine

K+

NK1mGluR TrkB

VGCC NSC GABA-A GLY

GABA BAdenosine

Woolf & Mitchel, 2001Modifikasi Meliala, 2003

K+

K+K+

Glu

Ca2+

IP3

Ca2+ Na2+

Modification : altered conectivity and cell death

P2XNMDA

Ca2+

Ca2+ Na2+

Mg2+

Inhibitory InterneuronCell death

Sprouted A fiberterminal

Glu

AMPAKAI

NMDA

Ca2+ Ca2+

Mg 2+

PKC

PGE2

BDNFSubstance P

Ca2+

Src Ca2+

PGE2 PGE2

EP

PGE2PGE2

KERUSAKAN JARINGAN

INFLAMASI

SSA MI NOS

SENSITISASI

AKTIFASI

ECT. DISC.

Si-Na+

KORNU DORSALIS

PgB5HTAdenosin

PengalamanKognitifBehaviourPsikologik

Inhibisi desenden

OTAK

PAIN – NO PAIN

R-NE

DISINHIBITION

Pain Message

Afferent C fibers

Pain transmitter

Neurone of theSpinothalamic tract

To the brain

-Receptor

Spinal neurone

Enkephalin

2-Receptor

Serotonin/Noradrenaline

Descending pathway

Theraupeutic Approaches of Pain Management, 2004

NO PAIN

Meliala, 2004

DESCENDING DESCENDING INHIBITIONINHIBITION

5HT

ENKAFFEREN

SP-GLUTAMATNEURON TRANSMISI

DESCENDENSBRAIN

Meliala, 2005

DESCENDING DESCENDING INHIBITIONINHIBITION

I

II

III/IV/V

Nerveinjury

Nerveinjury

Dorsal hornNormal termination pattern

C-fiber terminal atrophyA-fiber sproutingInterneuron degeneration

Pain hypersensibility - persistent Doubell et al, 1999

C-fibre

A-fibre

Aberrant connection with facilitated transmission

Structural Reorganization

I

II

III/IV/V

Modifikasi Meliala, 2003

To Brain

Negative symptoms• Neurological deficits

Sensory++Motor

cognitive

Positive symptoms•Painful symptoms

Spontaneous painAllodynia

Hyperalgesia•Non-painful symptoms

Paresthesiadysesthesia

MAIN CLINICAL MAIN CLINICAL FEATURESFEATURES

Pharmacology of painful polyneuropathy

ImipramineOptimal dose

Number needed to treat for main drug classes or drugs

TCAs

Carbamazepine

Tramadol

Gabapentin

Capsaicin

SSRIs

Phenytoln^

0 2 4 6 8

* One negative study not considered due to lack of dichotomous data; TCAs, tricyclic anti depressants; SSRIs, selective serotonin reuptake inhibitors

Adapted from Sindrup & Jensen, Neurology 2000

No. Patints

ANTICONVULSANT IN ANTICONVULSANT IN NEUROPATHIC PAINNEUROPATHIC PAIN

1942 = 1942 = Phenytoin was found to be effective in Phenytoin was found to be effective in some patient with TGN.some patient with TGN.

1962 = 1962 = Carbamazepin was also effective in Carbamazepin was also effective in treating TGNtreating TGN

CBZ : CBZ : - Drug of choice for TGN- Drug of choice for TGN

- Approved by FDA- Approved by FDA

Trigeminal neuralgia

Efficacy in 70% ofpatients within 24-48 h

But Poor tolerability (drowsiness, nausea, ataxia,

sedation)- Number needed to harm :3.4

Hypersensitivity necesstating discontinutation Numerus drug-drug interactions Modification of biological markers 20% of intial responders may become refractory

Carbamazepine is still the drug of initial choiceMcQuay et al, BMJ 1995

Difficult to use in elderly subjects due to its toxicity- Number needed to treat : 3.1 or adverse effects

McQuay et al, BMJ 1995

May interact with numerous analgesics used in combination

•Dextropropoxyfene•Other AEDS (phenytoin, lamotrigine, valproate•TCAs•Benzodiazepines•Fentanyl, Methadone

Virani et al, Pain 1997

Problems associated with the use of carbamazepine in neuropathic

pain

OXCARBAZEPINOXCARBAZEPIN

Hasil metaanalisis antara OXC & CBZ Hasil metaanalisis antara OXC & CBZ dalam trial ditemukan bahwa efektivitas dalam trial ditemukan bahwa efektivitas OXC sama dengan CBZ dengan OXC sama dengan CBZ dengan kelebihan efek samping OXC lebih kelebihan efek samping OXC lebih minimal.minimal.

Dosis 600mg/hari – 2400 mg/hariDosis 600mg/hari – 2400 mg/hari

Newly diagnosedTrigeminal neuralgia

1 studiesn=48

Oxcarbazepine &Trigeminal Neuralgia

3 double-blind randomised studiesVersus carbamazepine

Trigeminal neuralgia not responding to

(or adverse effects with) carbamazepine

1 studiesn=48

Oxcarbazepine 1050-1200 mg/dayCarbamazepine 700-900 mg/day

Oxcarbazepine 750 mg/dayCarbamazepine 500 mg/day

Oxcarbazepine &Trigeminal Neuralgia

Excellent efficacy (no pain or>50% reduction of painful attacks) in most patients within 24 h, doses of 600-2400 mg/day

Effective in patients refractory to carbamazepine Well tolerated, even in patients unable to

tolerate prior carbamazepine

Intial open systematic studies

Zakrzewska & Patsalos, J Neurol Neurosurg Psychiatry 1989Farago, Eur Neurol 1987

HASIL META ANALISIS ANTARA

OXC & CBZ TERNYATA BAHWA

EFEKTIFITAS OXC sama dengan CBZ OXC sama dengan CBZ

dengan kelebihan OXC : dengan kelebihan OXC : Efek samping MinimalEfek samping Minimal Dosis : 600-1200 mg/hariDosis : 600-1200 mg/hari

Beydoun, et al., 2002

Di Jepang berbagai trial telah dilakukan untuk

pengobatan NP, dengan hasil :

Penurunan VAS sebanyak 50% Penurunan VAS sebanyak 50%

dicapai dengan pemberian dosis dicapai dengan pemberian dosis

antara 100-600 mg/hariantara 100-600 mg/hari

Ichikawa, et al, 2001

UNTUK SPINAL CORD INJURY

(TRAUMA MED.SPINALIS) Trial telah dilakukan terhadap 12 pasien Trial telah dilakukan terhadap 12 pasien

dimana gejala Alodinia terdapat pada 7 dimana gejala Alodinia terdapat pada 7 pasien.pasien.

Dosis OXC sampai dengan 1500 mg/hari hasil Dosis OXC sampai dengan 1500 mg/hari hasil : :

58% pasien penyembuhan moderat58% pasien penyembuhan moderat100% (7 dari 7 pasien dengan Alodinia) sembuh100% (7 dari 7 pasien dengan Alodinia) sembuh

Jenkins, et al, 2002

OXC PADA NYERI PASCA OXC PADA NYERI PASCA TRAUMA MEDULA SPINALISTRAUMA MEDULA SPINALIS

Dengan OXC : dosis sampai dengan Dengan OXC : dosis sampai dengan 1500mg/hari menyebabkan 1500mg/hari menyebabkan penyembuhan nyeri yang moderat penyembuhan nyeri yang moderat sampai dengan 58% dari kasus.sampai dengan 58% dari kasus.

Gejala Alodinia pemberian OXC Gejala Alodinia pemberian OXC menunjukan hasil yang sangat baik. menunjukan hasil yang sangat baik.

Khusus di Jepang berbagai trial Khusus di Jepang berbagai trial

dengan dengan

dosis 100-600mg/hari dosis 100-600mg/hari

menunjukan efektivitas OXC menunjukan efektivitas OXC

dengan dengan

penurunan VAS ± 50%penurunan VAS ± 50%

OXC PADA NYERI OXC PADA NYERI NEUROPATI DIABETIKANEUROPATI DIABETIKA

0

20

40

60

80

100

120%patients

Newly diagnosed trigeminal neuralgia

Beydoun A, Submitted

Oxcarbazepine 750 mg/day

Carbamazepine 500 mg/day

PROPORTION OF RESPONDERS IN PROPORTION OF RESPONDERS IN NEWLY DIAGNOSED TRIGEMINAL NEWLY DIAGNOSED TRIGEMINAL

NEURALGIANEURALGIA

0

20

40

60

80

100%patients

Beydoun A, Submitted

Oxcarbazepine 1050-1200 mg/day

Carbamazepine 700-900 mg/day

PROPORTION OF RESPONDERS AND PAIN FREE PROPORTION OF RESPONDERS AND PAIN FREE PATIENTS IN REFRACTORY TRIGEMINAL PATIENTS IN REFRACTORY TRIGEMINAL

NEURALGIANEURALGIA

% of patients % of pain-free patients

OXCARBAZEPIN OXCARBAZEPIN ADVANTAGE IN ADVANTAGE IN

NEUROPATIC PAINNEUROPATIC PAIN No monitoring of hematologic parameters No monitoring of hematologic parameters

requiredrequired Fewer drug-drug interactionFewer drug-drug interaction No autoinduction of metabolismeNo autoinduction of metabolisme Comparable efficacyComparable efficacy Twice-daily schedule.Twice-daily schedule. Therapeutic effect maybe detected in 24-48 Therapeutic effect maybe detected in 24-48

hourshours

Oxcarbazepine inPainful diabetic neuropathy open-label

trial

22 patients completedMean baseline VAS : 64.1

Mean 8th week VAS : 33.9

47% pain reduction

Mean oxcarbazepine dose : 393 mg twice-daily

15 responders (68%)Mean baseline VAS : 68.2

Mean 8th week VAS : 18.4

73% pain reduction

Mean oxcarbazepine dose : 359 mg twice-daily

Prospective open label trial of 36 patients with neuropathic pain refractory to gabapentine

Initated on 150 mg or 300mg oxcarbazepine at bedtime and titrated to maximum dose of 1200 mg/day

Nearly 66% of patients experienced > 50% improvement in symptoms

Oxcarbazepine was well tolerated : 4 patient had edema and 1 had a skin rash

Oxcarbazepine inneuropathic pain

0

10

20

40

%patients

Royal M et all, AAPM 17th Annual Meeting Feb 2001

Oxcarbazepine in neuropathic pain :Oxcarbazepine in neuropathic pain :Prospective open-label trialProspective open-label trial

Excellent

Patients’ subjective respone

30

50

Good Fair Poor(>70%) (51-70%) (20-50%) (<20%)

Antineuralgic of Choice: Peripheral Sensitization (n=207)

7%

18%23%

61%

0%

20%

40%

60%

80%

100%

OXC/CBZ TPM TA Other

% o

f P

arti

cip

ants

R. Harden et al.The Journal of Pain, Vol.3 Nr.2 Suppl.1April 2002

OXC=Oxcarbazepine; CBZ=Carbamazepine;TPM= Topiramate;TCA=Tricyclic Antidepressant; Other=Phenytoin,lamaotrigin,Mexiletine, Lidocaine

VGCC

VGSC

VGSC

VGSC

CBZOXCLTG

GLUTAMATE

PEPTIDES

Altered Properties

Altered Activity

Rowbotham et al, 2000

+

Ca++

NMDA ++

AMPAKainate

Hyperexitability

OpioidsGABA

VGSC

CBZOXCLTG

Na+

Modifikasi Meliala, 2003

Ca2+

Ca2+

Ca2+Na2+

Na+

Mg2+

FT-NPBRAINPAINPAINN0 PAINNO PAIN

ADENYLCYCLASE

cAMPATP

PKA

GIGs

A2 1a

-+

+

HYPERALGESIAPGI2

8(R), 15(S) ADEN 5-HTPGE2 diHETE

ANALGESIAADEN

A1

P

GsADENYL

CYCLASE

ATP cAMP

PKA

Levine & Reichling, 1999Modifikasi Meliala, 2003

INTRACELLULAR SECOND MESSENGERMECHANISM OF NOCICEPTOR SENSITIZATION

GI

Na 2+

OXC

CBZOPOID

Na 2+

OXCARBAZEPIN OXCARBAZEPIN ADVANTAGE IN ADVANTAGE IN

NEUROPATIC PAINNEUROPATIC PAIN No monitoring of hematologic parameters No monitoring of hematologic parameters

requiredrequired Fewer drug-drug interactionFewer drug-drug interaction No auto induction of metabolismsNo auto induction of metabolisms Comparable efficacyComparable efficacy Twice-daily schedule.Twice-daily schedule. Therapeutic effect maybe detected in 24-48 Therapeutic effect maybe detected in 24-48

hourshours

29% of patients reported at leas one adverse effect with oxcarbazepine compared with 44% for carbamazepine

9% presented with severe adverse effects (vomiting, nausea, vertigo, and fatigue) with oxcarbazepine (one study)

Adverse Effects

Adverse Effects

Dizziness

Nausea

Somnolence

Ataxia OxcarbazepineCarbamazepine

No. patients

Fatigue

Vertigo

0 5 10 15 20

Beydoun A, Submitted

Conclusions and implications for use of oxcarbazepine in trigeminal

neuralgia

Oxcarbazepine is highly effective in newly diagnosed and refractory trigeminal neuralgia

Oxcarbazepine appears safe and well tolerated

Oxcarbazepine is at least as effective as carbamazepine

Up to 80% responders (1200 mg/day) in patients refractory to carbamazepine

Trend towards better tolerance of oxcarbazepine

Oxcarbazepine may be recommended in the treatment of trigeminal neuralgia, especially in patients unable to tolerate or refractory to carbamazepine

Potential efficacy in neuropathic pain

Should be safer and better tolerated, notably in elderly patients who cannot tolerate carbamazepine

Oxcarbazepine :Potential role in neuropathic

pain

Oxcarbazepine is safe and effective in the treatment of trigeminal neuralgia

Placebo-controlled and active-controlled double-blind studies are warranted to

confirm its efficacy and safety in other neuropathic pains

CONCLUSIONS

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