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YUNELDI ANWAR DEPARTEMEN NEUROLOGI FK USU

DEFINITION
Pain that persists 4 months after rash onset

or 3 month after healing of skin lesion (Dworkin 1994) most comm0nly accepted Pain persisting or recurring at the site of shingles 3 0r more months after the appearance of the HZ rash (Bowsher 1999) Presence of pain more than 1 month after the onset of zoster eruption (Rogers 1971) Persistent or recurrent pain for at least 3 months after healing or skin lesions (Rowbotham 1989)

INSIDEN DAN PREVALEN NPH


Estimasi HZ NPH berkisar 10-76% (Ragozzino 1982),

25-50% pasien HZ > 50 thn NPH (Schmader 2002) Insiden HZ di AS > satu juta kasus (Oxman 2005) Populasi immunokompeten insiden HZ berkisar 1,2 3,4 kasus/1000/thn, tetapi pada pasien usia 65 thn dan lebih tua insidennya 3,9-11,8/1000/thn (Dworkin 2001) Prevalensi NPH 30 hari sesudah onset HZ 8.0/100 kasus, dan 4,5/100 kasus setelah 60 hari onset (Choo 1997)

NYERI PADA HZ
Nyeri prodormal muncul beberapa hari

sebelum onset ruam muncul (Beutner 1995) Nyeri fase akut 4 miggu atau kurang sejak onset ruam muncul(Dworkin 1994) Fase sub akut menetap lebih dari 30 hari sesudah onset ruam tetapi kurang dari 4 bulan (Dworkin 1994) Nyeri pasca herpes (PHN) menetap lebih dari 4 bulan (Dworkin, Portenoy 1994)

SIGNs AND SYMPTOMs NPH


Nyeri terus menerus rasa terbakar dalam

(deep burning sign), seperti disayat (lancinating), disestesia (Rowbotham 1989) Nyeri berulang nyeri berdentam (throbbing pain), shock like pain, dan shooting pain Nyeri yang dibangkitkan Alodinia, hiperalgesia Defisit sensorik hpoestesia, anastesia (Fields 1998)

FAKTOR RESIKO NPH


Usia Insiden dan durasi NPH meningkat pada

usia tua (Oakes, 2004; Dworkin, 2006) Keparahan ruam dan nyeri pada fase akut Kegagalan pemakaian anti viral pada fase akut Jenis kelamin Adanya nyeri sebelum timbulnya ruam (Dworkin, 2006) Opstellen, 2002 terjadinya NPH setelah HZ (6,5%), resiko ini meningkat menjadi 11,7% pada usia 55 thn atau lebih

PATOFISIOLOGI PHN
INFEKSI PRIMER VZV

MENETAP PADA DRG (LATEN PERIOD)

Usia, kegagalan respon immun virus reaktivasi

Ganglionitis pada DRG Erupsi pada kulit (HZ) (Bowwsher 1992,Galer 2000)

NPH

Skema perubahan fungsi & struktur yg terjadi pd SSA & Neuron Kornu Dorsalis pasca lesi saraf tepi LESI SSA Aktivasi Aktifitas adrenergik Sensitisasi Interaksi antar

ektopik

nosiseptor

serabut saraf

Aktivasi tonik serabut saraf C

Fiksasi SP Pada reseptor NK1

Pelepasan glutamate/aspartate Aktivasi NMDA

Fiksasi AAE pada reseptor Metabotropik

Kenaikan Ca2+ intraseluler

Eksitoksik o.k Over stimulasi Kerusakan interneuron inhibis Penurunan inhibisi

Aktivitas NO sintase

Aktifitas PKC
Depolarisasi membran
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Kenaikan sensitivitas neuron kornu dorsalis

Management of NPH
Prevention Pharmacology therapy

= Anti depressants = Anti convulsants = Opioids = Topical medications Interventions = TENS = Epidural spinalcord stimulation = Deep brain stimulation

Guide for the Prevention and Treatment of PHN


Prevention

Shingless Prevention Study use attenuated vaccine for prevention HZ in adult > 60 years old - Reduced risk HZ 51 % in adult > 60 years and 64% in adults 60 to 80 years old - Reduced duration of PHN in individual HZ - Insidence of PHN reduce by 55 % in individual 70 79 years old (statistically significant)
Oxman MN, Levin MJ, Jhonson GR, et al. A vaccine to prevent herpes zoster and post herpeic neuralgia in olders adults. N Eng J Med 2005.;352:2271-2284.

Guide :Treatment Option 0f HZ Clinically HZ (acute/subacute)


Acetaminophen
Nonsteroidal anti inflamatory drugs (NSAIDs) Anti convulsants Gabapentin, pregebalin Anti viral Acyclovir, valacyclovir, famcyclovir (FDA

approved) 0pioids Tramadol, oxycodon, fentanyl Oral corticosteroids Methylprednisolon, prednisolon Tricyclic anti depressants (TCAs) Amitryptilin
Pilot F, Alpen BS, Vanderhoff BT. Management of herpes zoster and post herpetic neuralgia. Am Fam Phys: available at: http//www.aafp or Built /afp monograph_shingles post herpetic neuralg.

Sub acute

Acute

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Treatment option for PHN Clinically PHN


Anti convulsants : Gabapentin, pregebalin,

carbamazepin, phenytoin Opioids : Tramadol, fentanyl, oxycodon Oral corticosteroids : Methylprednisolon, prednisolon TCAs : Amitryptilin , notriptylin, desipramin Topical : Capsaicin 0,075%, Lidocain patch 5% Others : TENS FDA approved : Gabapentin, pregebalin , lidocain

Oxman MN, Levin MJ, Jhonson GR, et al. A vaccine to prevent herpes zoster and post herpeic neuralgia in olders adults. N Eng J Med 2005.;352:2271-2284 Dwokin RH, Jonhson RW, et al. Recommendation for the management of herpes zoster. Clin Infect Dis, 2007,44: S1-S26.

PREVENTION AND TREATMENT OF PHN


Primary prevention vaccination

Patient develops HZ

Treatment option for HZ

Patient develops PHN

Pain relief inadequate refer Pain specialist

Treatment optionn for PHN

TERAPI FARMAKOLOGI PADA NPH (DEWASA)


Senyawa
Amitriptylin Gabapentin Pregebalin Tramadol SR Capsaicin cream Lidokain patch

Dosis (mak)
50-75 (150) 150 (600) Titrasi (600) --

Dosis interval
0-0-1 1-0-1 1-(1)-1 2-5 kali/hari Tempelkan setiap 4-12 jam

Eviden

1200-2400 (3600) 1-1-1

Level of evidence

At least 1 RCT Several RCT or metaanalisis

Dworkin RH 2003, Hempenstall K 2005, Sindrup SH, 1999

ANTIDEPRESAN
Inhibitors of the reuptake of monoaminergic

transmitters Potentiate effects of biogenic amines in CNS pain modulating Block voltage dependent Na-channel and alfa adrenergic reseptor Side effects orthostatic hypotension. Sedation, urinary retension, memory loss and cardiac conduction abnormalities

Tricyclic Antidepressants: Adverse effect and Dosing


Adverse effects
Drowsiness Weight gain Dry mouth Constipation Urinary hesitancy

Dosing (2)
Start at low dose

- 1o 25 mg Titrate by 10 25 mg dayly 3 7 day to 75 150 mg/d as tolerated

Potentially serious Cardiovascular effects Memory impairment


1.Bonezzi C, Demartini L. Acta Neurol Scand 1999, Suppl 173:25-35 2. Dworkin RH et al. Arch Neurol 2003,60:1524-1534

Tricyclic Antidepressants: Adverse effects


Commonly reported
Fewest AEs

(generally anticholinergic) - blurred vision - cognitive change - constipation - dry mouth - orthostatic hypotension - sedation - sexual dysfunction - tachycardy

Desipramin Nortriptylin Imipramin Doxepin Amiltriptylin

Most AE s

Gabapentin: Mechanisme of Analgesic Action


Interacts at binding site of the alfa2D

subunit of voltage-dependent Ca2+ channels Correlates with decreased Ca2+ channel function and release of neurotransmitters Decreased neurotransmitter release is associated with reduced neuronal hyperexcitability

Lauria Homer BA, Pohl RB. Expert Opin Investig Drugs 2003;12:663-672

Gabapentin: Adverse Effects and Dosing


Adverse Effects
Common: somnolence,

Dosing (2)
Day 1: single 300 mg dose Day 2: 600 mg divided bid Day 3: 900 mg divided tid Titrate up to 1800 mg tid

dizziness 1,4 Less common: GI symptom, peripheral edema 1,3 In elderly: gait and balance problems, cognitive impairment 1

prn for pain relief Max dose 1800 mg divided tid

1. Dworkin RH et al. Arch Neurol.2003;60:1524-1534 2. Neurontin (gabapentin) prescribing information.2004 3. Rowbotham MC et al. JAMA i998;280:1827-1842 4. Backonya M et al.JAMA 1998;280:1831-1836

Pregebalin: Mechanism of Analgesic Action


Interacts at alfa delta sub unit of

voltage-dependent Ca channels Correlates with decreased Ca channel function and release of neurotransmitters Decreased release of neurotransmitters leads to reduced neuronal hyperexcitability
Lauria-Horner BA, Pohl RB. Expert Opin Investig Drugs, 2003;12663-672

PREGEBALIN:DOSING
Pregebalin is approved at daily doses beginning at

- 150 mg (50 mg tid) for DPN, may be increased 300 mg (100 mg tid ) within a week - 150 mg (50 mg tid, 75 mg bid) for PHN ,may be increased to 300 mg (100 mg tid) within a week After 2-4 week, doses may be increased up to 600 mg Pregebalin is eliminated primarily by renal excretion > doses should be adjusted in patient with reduced renal function based on creatinin clearence
Lyrica (pregebalin) prescribing information, 2006

Lidocain Patch 5%: Mechanism of Analgesic Action


Reduced ectopic discharge emanating from

damaged and dysfungtional peripheral sensory nerves (1 ) Stabilizes neuronal membranes by inhibiting the ionic fluxes needed to initiate and conduct nerve impulses (2 ) Sufficient to produce analgesia without sensory block (2)
1. 2. Galer BS et al. Pain.1999;80:533-538. Lidoderm (lidocain patcd 5%) prescribing information 2003

Lidocaine Patch 5%
Safety and Tolerability
No systemic adverse effects

Application Recommendation (3)


Apply to intact skin to

(1) Only common adverse effect: mild skins reactions at patch site (1) Use with caution in patients taking oral anti arythmics (2)

cover most painful area Apply up to 3 patches dayly for up to 12 hours Patches may be cut into smaller sizes

1. 2. 3.

Rowbotham MC et al. Pain1996;65:39-44. Dworkin RH et al.Arch Neurol. 2003;1524-1534 Lidoderm (lidocain patch 5%) prescribing information 2003.

0pioid Analgesic:
Mechanism of Action in Neurophatic
Primary
Bind to u-receptor in the CNS and spinal cord Reduction of C fibre-mediated nociceptive transmission in spinal

cord by

-- Presynaptic inhibition of neurotransmitter release


-- Post synaptic inhibition of evoked activity -- Post synaptic disinhibition of inhibitory interneuron

Additional
Antinociceptive effect at peripheral terminals of primary afferent

nociceptor Supraspinal effect, including interactions with descending pain pathway

Opioid Analgesic: Adverse effect and Dosing


Most common Adverse effect (1,2,3)
Constipation Sedation

Dosing (4)
Begin with short acting oral

opioid - Equianalgesic to oral morphine


sulfate 5-15 mg q4h prn After 1 or 2 wk, convert to long acting opioid

Somnolence

1. 2. 3. 4.

Watson CPN, Babul N. Neurology.1998;50:1837-1841 Gimbel JS, et al. Neurology. 2003;60:927-934. Raja SN et al.Neurology 2002.59;1015-1021. Dworkin RH et al. Arch Neurol. 2003;60:1524-1534.

Tramadol: Mechanism of Analgesic Action


Opioid Component - Mayor metabolite binds to u-opioid receptors Non opioid component - Inhibit reuptake of norepinephrin and serotinin

Ralfa RB et al. J. Pharmacol Exp Ther; 1992, 280; 275-285.

Tramadol: Adverse Effects and Dosing


Common Adverse Effects
Orthostatic hypotension Nausea Constipation Headache Somnolence

Dosing
Start at low dose 25 mg qam Titrate

- q3d by 25 mg in divided dose to 100 mg/d as tolerated - then q3d by 50 mg as tolerat to 200 mg/d Maximum dose - 400 mg/d (100 mg q4-6h)

Combination Theraphy
Possible Advantages

Decreased adverse effects (1) Increased efficacy


(1,2,4)

Possible Disadvantages increased adverse effects (3,4) Increased drug drug interaction (1,4) Difficulty in determining cause of adverse efects(3,4)

1. 2. 3. 4.

Namaka M et al. Clin Ther; 2004:26.961-979 Dwonkin RH et al. Arch Neurol. 2003,60: 1524-1534 Dwonkin RH. Schynader KE. Clin Infect Dis. 2003;36: 877-882 Handen N, Cohen M. J Pain Symptom Manage. 2003;25: 512-517

Combination theraphy
Anti convulsan (cachannel) Gabapentin, Pregebalin Anticonvulsant (Na-channel) Carbamazepin, oxcarbamazepin Antidepressants Amitriptyline

Weak opioids Tramadol SR Naloxone SR

+ +

Add on therapy Lidocain topical Capsaicin topical

Limiting side effects or residual pain TENS

Anticonvulsant Ca-chan Gabapentin, Pregebalin Anticonvulsant Na-chan Lamotrigin

Antidepressant Dulocetin, Venlafaxin Strong opioids Morphin , Fentanyl

Limiting side efect

Algoritma pengobatan nyeri neuropatik/NPH

Invasive treatment option DBS, TENS, SCS

RESUME
Nyeri pasca herpes nyeri yang menetap selama

4 bulan sesudah munculnya ruam atau 3 bulan sesudah sembuhnya lesi dikulit Mekanisme timbulnya nyeri lesi pada sistem saraf aferen yang dapat menimbulkan sensitasi perifer dan sentral Penatalaksanaannya mulai dari prevensi primer, pemelihan obat-obatan pada fase akut, subakut dan neuralgia pasca herpes Saat ini obat lini pertama pada NPH adalah anti depresan, anti konvulsan dan anastetik topikal

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TERAPI FARMAKOLOGI PADA NPH (DEWASA)


Senyawa
Amitriptylin Gabapentin Pregebalin Tramadol SR Capsaicin cream Lidokain patch

Dosis (mak)
50-75 (150) 150 (600) Titrasi (600) --

Dosis interval
0-0-1 1-0-1 1-(1)-1 2-5 kali/hari Tempelkan setiap 4-12 jam

Eviden

1200-2400 (3600) 1-1-1

Level of evidence

At least 1 RCT Several RCT or metaanalisis

Dworkin RH 2003, Hempenstall K 2005, Sindrup SH, 1999