18. Nyeri Pasca Herpes

YUNELDI ANWARDEPARTEMEN NEUROLOGI FK USU

DEFINITIONPain 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 NPHEstimasi 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 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)

NYERI PADA HZ

SIGNs AND SYMPTOMs NPHNyeri 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 NPHUsia Insiden dan durasi NPH meningkat

pada usia tua (Oakes, 2004; Dworkin, 2006)Keparahan ruam dan nyeri pada fase akutKegagalan pemakaian anti viral pada fase

akutJenis kelaminAdanya 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)

NPH

(Bowwsher 1992,Galer 2000)

8

9

LESI SSA

Aktifitas Sensitisasi Interaksi antar ektopik nosiseptor serabut saraf

Fiksasi SPPada reseptor NK1

Fiksasi AAE pada reseptorMetabotropik

Aktivitas NOsintase

Aktivasi tonik serabut saraf C

Pelepasan glutamate/aspartate

Aktivasi NMDA

Kenaikan Ca2+intraseluler

Aktifitas PKC

Depolarisasi membran

Kenaikan sensitivitas neuron kornu dorsalis

Eksitoksik o.kOver stimulasi

Kerusakan inter-neuron inhibis

Penurunaninhibisi

Skema perubahan fungsi & struktur yg terjadi pd SSA & Neuron Kornu Dorsalis pasca lesi saraf tepi

Aktivasi adrenergik

Management of NPHPrevention Pharmacology therapy = Anti depressants = Anti convulsants = Opioids = Topical medicationsInterventions = TENS = Epidural spinalcord stimulation = Deep brain stimulation

Guide for the Prevention and Treatment of PHNPrevention 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)AcetaminophenNonsteroidal anti inflamatory drugs (NSAIDs)Anti convulsants Gabapentin, pregebalinAnti viral Acyclovir, valacyclovir, famcyclovir

(FDA approved)0pioids Tramadol, oxycodon, fentanylOral corticosteroids Methylprednisolon,

prednisolonTricyclic 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.

13

Acute Sub acute

Treatment option for PHNClinically PHNAnti convulsants : Gabapentin, pregebalin,

carbamazepin, phenytoinOpioids : Tramadol, fentanyl, oxycodonOral corticosteroids : Methylprednisolon,

prednisolonTCAs : Amitryptilin , notriptylin, desipraminTopical : Capsaicin 0,075%, Lidocain patch 5%Others : TENSFDA 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.

Primary prevention vaccination

Patient develops HZ

Patient develops PHN

Treatment option for HZ

Treatment optionn for PHN

Pain relief inadequate refer Pain specialist

PREVENTION AND TREATMENT OF PHN

Senyawa Dosis (mak) Dosis interval

Eviden

Amitriptylin

50-75 (150) 0-0-1

Gabapentin 1200-2400 (3600)

1-1-1

Pregebalin 150 (600) 1-0-1

Tramadol SR

Titrasi (600) 1-(1)-1

Capsaicin cream

- 2-5 kali/hari

Lidokain patch

-- Tempelkan setiap 4-12 jam

TERAPI FARMAKOLOGI PADA NPH (DEWASA)

Level of evidence At least 1 RCT

Several RCT or metaanalisis

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

ANTIDEPRESANInhibitors of the reuptake of

monoaminergic transmittersPotentiate effects of biogenic amines in

CNS pain modulatingBlock voltage dependent Na-channel and

alfa adrenergic reseptorSide effects orthostatic hypotension.

Sedation, urinary retension, memory loss and cardiac conduction abnormalities

Tricyclic Antidepressants:Adverse effect and DosingAdverse effects Dosing (2)DrowsinessWeight gainDry mouthConstipationUrinary hesitancyPotentially seriousCardiovascular effectsMemory impairment

Start at low dose - 1o – 25 mg Titrate by 10 – 25 mg

dayly 3 – 7 day to 75 – 150 mg/d as tolerated

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 effectsCommonly reported (generally

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

Most AE s

Fewest AEs

•Desipramin

•Nortriptylin

•Imipramin

•Doxepin

•Amiltriptylin

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 DosingAdverse Effects

Common: somnolence, dizziness 1,4

Less common: GI symptom, peripheral edema 1,3

In elderly: gait and balance problems, cognitive impairment 1

Dosing (2)Day 1: single 300 mg

doseDay 2: 600 mg divided

bidDay 3: 900 mg divided

tidTitrate up to 1800 mg

tid prn for pain reliefMax 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:DOSINGPregebalin 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 weekAfter 2-4 week, doses may be increased up to 600

mgPregebalin 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. Galer BS et al. Pain.1999;80:533-538.2. Lidoderm (lidocain patcd 5%) prescribing information 2003

Lidocaine Patch 5%Safety and Tolerability

Application Recommendation (3)

No systemic adverse effects (1)

Only common adverse effect: mild skins reactions at patch site (1)

Use with caution in patients taking oral anti arythmics (2)

Apply to intact skin to cover most painful area

Apply up to 3 patches dayly for up to 12 hours

Patches may be cut into smaller sizes

1. Rowbotham MC et al. Pain1996;65:39-44.2. Dworkin RH et al.Arch Neurol. 2003;1524-1534

3. Lidoderm (lidocain patch 5%) prescribing information 2003.

0pioid Analgesic:Mechanism of Action in Neurophatic

PrimaryBind to u-receptor in the CNS and spinal cordReduction 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

AdditionalAntinociceptive effect at peripheral terminals of

primary afferent nociceptorSupraspinal effect, including interactions with

descending pain pathway

Opioid Analgesic:Adverse effect and Dosing

Most common Adverse effect (1,2,3)

Dosing (4)

ConstipationSedationSomnolence

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

1. Watson CPN, Babul N. Neurology.1998;50:1837-1841

2. Gimbel JS, et al. Neurology. 2003;60:927-934.3. Raja SN et al.Neurology 2002.59;1015-1021.4. 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 DosingCommon Adverse Effects Dosing

Orthostatic hypotensionNauseaConstipationHeadacheSomnolence

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/dMaximum dose - 400 mg/d (100 mg q4-6h)

Combination TheraphyPossible Advantages Possible Disadvantages Decreased adverse increased adverse effects (1) effects (3,4)

Increased efficacy Increased drug – drug (1,2,4) interaction (1,4)

Difficulty in determining

cause of adverse efects(3,4)

1. Namaka M et al. Clin Ther; 2004:26.961-9792. Dwonkin RH et al. Arch Neurol. 2003,60: 1524-15343. Dwonkin RH. Schynader KE. Clin Infect Dis. 2003;36: 877-8824. Handen N, Cohen M. J Pain Symptom Manage. 2003;25: 512-517

Anti convulsan (ca-channel) Gabapentin, Pregebalin

Weak opioids Tramadol SR Naloxone SR

Antidepressants Amitriptyline

Anticonvulsant (Na-channel)

Carbamazepin, oxcarbamazepi

n

Add on therapy Lidocain topical

Capsaicin topical

TENS

+

+Limiting side effects or residual

pain

Anticonvulsant Ca-chan Gabapentin,

Pregebalin

Strong opioids Morphin , Fentanyl

Antidepressant Dulocetin, Venlafaxin

Anticonvulsant Na-chan Lamotrigin

Limiting side efect

Invasive treatment

option DBS, TENS, SCS

Algoritma pengobatan nyeri neuropatik/NPH

Combination theraphy

RESUMENyeri 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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Senyawa Dosis (mak) Dosis interval

Eviden

Amitriptylin

50-75 (150) 0-0-1

Gabapentin 1200-2400 (3600)

1-1-1

Pregebalin 150 (600) 1-0-1

Tramadol SR

Titrasi (600) 1-(1)-1

Capsaicin cream

- 2-5 kali/hari

Lidokain patch

-- Tempelkan setiap 4-12 jam

TERAPI FARMAKOLOGI PADA NPH (DEWASA)

Level of evidence At least 1 RCT

Several RCT or metaanalisis

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