New Prespektive Oxcarbazepine in the Management of Neuropath
-
Upload
rizni-fitriana -
Category
Documents
-
view
223 -
download
0
description
Transcript of 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
AKU TELAH MEMBERIKAN OBAT YANG AKU KENAL
TERHADAP PENYAKIT YANG AKU PAHAMI KEPADA PASIEN
YANG SEBAGIAN BESAR TIDAK TAHU APA-APA