Nerve Damage Repaired

Role of Methycobal in Nerve Role of Methycobal in Nerve RepairedRepaired► ► Neuropathic PainNeuropathic Pain

► ► Diabetic Neuropathic PainDiabetic Neuropathic Pain

► ► Post Herpetic NeuralgiaPost Herpetic Neuralgia

► ► Trigeminal NeuralgiaTrigeminal Neuralgia

► ► Management of Neuropathic Management of Neuropathic PainPain

► ► Methycobal for Nerve Methycobal for Nerve RepairedRepaired

1. Neuron Cornu Post. Medulla Spinalis.2. Talamus. 3. Korteks Lobus Parietalis Hemisfer Cerebri

Hambatan nyeri:1. Tingkat Spinal:

Neurotransmitter: GABA, serotonin, norepinefrin.

2. Tingkat Batang Otak3 Talamus : Talamotomy4. Korteks Cerebri : Hipnotisme, Sugesti.

SINAPS NYERI SINAPS NYERI

JENIS – JENIS NYERI / PAINJENIS – JENIS NYERI / PAIN

Neuropathic Pain Nociceptive Pain

Nyeri disebabkan karena kerusakan pada sistem saraf (susunan saraf perifer ataupun pusat)

Nyeri disebabkan karena adanya luka pada jaringan tubuh

(otot, tulang, kulit, viseral)

Mixed PainNyeri dengan

komponen Neuropathic

dan Nociceptive

Contoh : Contoh : Contoh :Perifer :- Diabetic Neuropathy- Post Herpetic Neuralgia- Trigeminal Neuralgia- Post Surgical Neuropathy- Post Traumatic NeuropathyCentral :- Post Stroke PainCommon descriptions :- Burning- Tingling- Hypersensitivity to touch or cold

- Low back pain with radiculopathy - Cervical radiculopathy- Cancer pain - Carpal Tunnel Syndrome

- Pain due to inflammation- Limb pain after a fracture- Joint pain in Osteoarthritis- Post Operative Visceral Pain

Common descriptions :- Aching- Sharp- Throbbing

Neuropathic Pain Nociceptive PainChronic pain (months/years) Acute pain (hours or days)

Caused by injury or disease to nerves

Caused by injury or inflammation that affects both the muscles and

joints

Mild to excruciating pain that can last indefinitely

Moderate to severe pain that disappears when the injury heals

Causes extreme sensitivity to touch –simply wearing light

clothing is painful

Causes sore, achy muscles

Sufferers can become depressed or socially withdrawn because they see no relief in sight and

may experience sleep problems

Sufferers can become anxious and distressed but optimistic

about relief from pain

Wall PD. Textbook of Pain. 4th ed; 1999; Jude EB. Clin in Pod Med and Surg.1999;16:81-97; Price SA. Pathophysiology: Clinical Concepts of Disease Processes. 5th ed; 1997: Goldman L. Cecil Textbook of Medicine. 21st ed; 2000

Perbandingan Neuropathic Pain Perbandingan Neuropathic Pain dan Nociceptive Paindan Nociceptive Pain

Woolf CJ, Mannion RJ. Neuropathic Pain: Etiology, symptoms, mechanisms, and management. Lancet, 1999;353:1959-64.

Syndrome

Symptoms

Patophysiology

Etiology

Neuropathic pain

Stimulus-independent pain

Stimulusdependent pain

Mechanisms

Nerve damage

Traumatic

Infectious

Metabolic

Hereditary Compression

Ischaemic

Th/ Pain killer, eg : gabapentin,

pregabalin

Th/ Based on etiology

Ex : Oral Anti Diabetic, Steroid, Anti biotics, etc.

Immune - mediated

Th/ nerve repaired

Methycobal – active cobalamin

Neuropathic PainPain initiated or caused by a primary lesion or dysfunction in the nervous

system

Pain initiated or caused by a primary lesion or dysfunction in the

peripheral nervous system

Peripheral Neuropathic PainPain initiated or caused by

a primary lesion or dysfunction in the central

nervous system

Central Neuropathic Pain

Klasifikasi Neuropathic Pain Klasifikasi Neuropathic Pain

Disebabkan kerusakan myelin sheet, yang berakibat :

1. impuls yang lewat akan menyebar

ke sel saraf lainnya,

sehingga timbul nyeri

2. penghantaran implus ke sel saraf

berikutnya menjadi terhambat

timbul gangguan sensorik.

Neuropathic PainNeuropathic Pain

• Pain disebabkan oleh kerusakan pada SSP atau SST

• Keluhan Pain biasanya : rasa geli, rasa rasa tertusuk, rasa tersengat listrik, rasa terbakar dan disertai dengan rasa kesemutan atau rasa baal.

• Pain timbul sepanjang teritori yang persarafi oleh nervus ybs (nervus, plexus, radix, spinal cord, brain)

• Biasanya kronik (e.g. postherpetic neuralgia, poststroke pain)

• Bila di terapi dengan NSAID hasilnya kurang memuaskan

What is Neuropathic Pain ? What is Neuropathic Pain ?

• Jutaan nervus saling

berhubungan di dalam tubuh :

– Nerves menghubungkan otak

dan tubuh utk berkomunikasi

– If you accidentally grab a hot

iron, nerves in your hand send

a message to the brain that

you are touching something

hot. As a result, your hand

feels a burning pain

Price SA. Pathophysiology: Clinical Concepts of Disease Processes. 5th ed; 1997

How Neuropathic Pain Occurs How Neuropathic Pain Occurs

• Jika nerves rusak atau terluka maka

fungsinya terganggu :

– Dapat mengirimkan sinyal yang salah ke

– Nervus yang rusak dapat memberitahu otak

bahwa ada rasa terbakar pada telapak kaki

walaupun tidak menapak pada suatu yang

panas.

Price SA. Pathophysiology: Clinical Concepts of Disease Processes. 5th ed; 1997

How Neuropathic Pain Happens How Neuropathic Pain Happens

Polyneuropathy is caused by the degeneration of axon terminals and results in symmetric distal sensory loss with shading to normal sensation. A compression neuropathy often results in demyelination with the axon left relatively intact. Sensory loss follows a radicular pattern. When the neuronal cell body dies the condition is called "neuronopathy." If the cell body is in the sensory ganglion the condition is often referred to as "ganglionopathy." The pattern is usually random

Axonal polyneuropathyDemyelinating NeuropathyNeuronopathy (Ganglionopathy)

• Up to 7.7 % of people in Europe have neuropathic

– 3 million people, or 7.5% in the United Kingdom

– 2.5 million people, or 6.4% in France

– 3.5 million people, or 6.0% in Germany

– 2.1 million people, or 7.7% in Spain

• It often is under-diagnosed and under-

treated

Bennett G. Hosp Pract. 1998;95-114; Patient Flow Study. Mercer

Management Consulting; July 2, 2002; Dickinson T. Trends in

Pharmacol Sci. 2003;24:555-557.

Incidence / Prevalence Incidence / Prevalence

People with neuropathic pain report:• Difficulty sleeping• A lack of energy• Drowsiness • Difficulty concentrating• Strained relationships with family and friends• An inability to work, walk, or even wear clothes as

the contact with their skin can cause an unbearable burning pain

Meyer-Rosberg K. Euro J of Pain. 2001;5:379-389; Berger A.. Pain. 2004;5(3):143-9

Emotional and Social Impact of Emotional and Social Impact of Neuropathic Pain Neuropathic Pain

Q U I ZQ U I Z

Are Men really stronger than women ?

Women produced estrogen that will increased threshold of pain

But woman report more pain throught their life time

woman feel pain in more pain of theirs body and for longer durations

Q U I ZQ U I Z

What is the type of this PAIN ?

Is it really PAIN ?

Anatomi Pancreas Anatomi Pancreas Pancreas menghasilkan :• Enzym – enzym pencernaan :

- amilase- tripsin- lipase

• Hormon- insulin (me ↓ glukosa darah)- glukagon (me ↑ glukosa darah)- somatostatin- polipeptida

Pulau Langerhans Pulau Langerhans

2 jam Setelah Makan, Gula Darah ↑

Pancreas mensekresi Insulin

Insulin mengubah Glukosa menjadi Glikogen(dalam darah) (di otot & hati)

Gula Darah ↓

Fisiologi Pancreas Fisiologi Pancreas

Pancreas : sekresi Insulin sedikit/tidak ada

Distribusi Nutrisi dan O2 ke jaringan terganggu

Glukosa tetap tinggi dalam darah

Fungsi otot & saraf terganggu, timbul nyeri neuropathy

Glukosa tidak dapat berubah menjadi Glikogen(dalam darah) (di otot & hati)

Patofisiologi Diabetes MellitusPatofisiologi Diabetes Mellitus

Merangsang Pancreas utk mensekresi Insulin

Distribusi Nutrisi dan O2 ke jaringan membaik

Glukosa dalam darah ↓

Fungsi otot & saraf membaik, nyeri neuropathy berkurang

Glukosa berubah menjadi Glikogen(dalam darah) (di otot & hati)

Patofisiologi Diabetes MellitusPatofisiologi Diabetes Mellitus

(Konsensus DM - PERKENI 2006)

• Usia

• Lamanya DM

• Lipotoksisitas

• Glukotoksisitas

• Faktor genetik

• Inflamasi

• Stres oksidatif

• Pola nyeri di kaki– Nyeri seperti terbakar– Nyeri seperti tertembak– Disestesia

• Keluhan penyerta yang mungkin terjadi– Rasa baal– Alodinia– Hiperalgesia

• Cenderung lebih nyeri pada malam hari

• Sensasi nyeri

• Sensasi termal

• Vibrasi

• Rasa tekanan

• Posisi

• Pemeriksaan kekuatan

• Pemeriksaan refleks

•Metabolik

•Vaskuler

•Infeksi

•Luka

•Tekanan

(Konsensus DM - PERKENI 2006)

Visual Anologue Scale (VAS)

Numeric Pain Rating Scale (NPRS)

Faces Pain Rating Scale (anak)

Long Form

KUESIONER NYERI NEUROPATIK McGILL

Short Form

Asesmen Nyeri Neuropati Diabetika

• Pada “small fiber neuropathy”:

EMG, NCV normal.

Patofisiologi Herpes Zoster Patofisiologi Herpes Zoster

Pasca infeksi Varicella Zoster

Virus Varicella Zoster dormant pada spinal ganglion sekitar tulang belakang

Pada saat imunitas tubuh ↓, virus Varicella Zoster aktif kembali menjadi virus Herpes Zoster dan menginfeksi serabut saraf mengikuti dermatom

serabut saraf yang terinfeksi mengalami kerusakan myelin dan timbul Post Herpetic Neuralgia (tidak hilang hingga 2 – 6 bulan pasca Herpes)

Patofisiologi Herpes Zoster Patofisiologi Herpes Zoster

Herpes = anggurBentuknya vesikel (berisi cairan) bergerombol seperti anggur dan disertai kemerahan

Progression of herpes zoster. A cluster of small bumps (1) turns into blisters (2). The blisters fill with lymph, break open (3), crust over (4), and finally disappear. Postherpetic neuralgia can sometimes occur due to nerve damage (5),

Treatment for Post Herpetic Treatment for Post Herpetic Neuralgia Neuralgia 1. For acute Herpes Zoster :

- Acyclovir 5 x 800 mg / day 7 days

2. For acute and cronic Post Herpetic Neuralgia :Pain killer : - Gabapentin 3 x 300 mg/day – 3 x 1200 mg/day 2 – 6 months- NSAID 1 – 2 weeks

3. For Nerve Repaired :- Methycobal injection 3 x 500 mcg / week (im)

Trigeminal Neuralgia Trigeminal Neuralgia Ada sekitar 15,000 kasus baru yang didiagnosa dlm setahun dan 90% kasus timbul pada usia di atas 40 th. Prevalensi sekitar 12 juta pasien dengan ratio ♀ : ♂ 1.5:1. Keluhan : nyeri mendadak, Stabbing (rasa tertusuk), shooting (rasa perih,panas), electric shock-like pain (rasa tersengat listrik) di sepanjang area maxillary and mandibular, sesisi. Rasa nyeri timbul spontan atau terstimuli dgn sentuhan, air dingin, mengunyah, berbicara, gerakan wajah, menyikat gigi atau stress emosional, dan berulang.

Trigeminal neuralgia juga menyebabkan chepalgia yang berat dan intermittent (hilang timbul).Trigger zones biasanya di daerah pusat wajah dan sekitar hidung dan bibir dan ukurannya kecil (1-2 mm). Penyebab Trigeminal Neuralgia karena demyelinisasi dan irritasi pada nervus trigeminal.

Anatomi Nervus V Anatomi Nervus V

- Trigeminal neuralgia (TN) = tic douloureux adalah suatu kondisi yang

mengenai nervus trigeminal (N.V).

- Nervus ini adalah salah satu nervus terbesar di kepala dan berfungsi

untuk menyalurkan impuls rabaan, tekanan, suhu, dari area wajah,

rahang, gusi, dahi, sekitar mata.

Cause of trigeminal neuralgia

- The exact cause of trigeminal neuralgia is controversial, but it is

suggested that an area of vascular compression where the

trigeminal nerve enters the brain may be the culprit.

- This compression may cause damage to the myelin sheath (the

insulating cover of a nerve fiber) that surrounds the trigeminal

nerve. Other precipitating factors include multiple sclerosis and

hypertension.

Etiologi Trigeminal Neuralgia Etiologi Trigeminal Neuralgia

- Pemeriksaan Neurologis biasanya normal.

- Yang harus dipikirkan adalah ‘sesuatu yang lebih dari sekedar’

trigeminal Neuralgia misal : multiple sclerosis atau tumor.

- MRI dgn atau tanpa kontras tetap normal jika tidak ada lesi.

- Biasanya diagnosa Trigeminal Neuralgia ditegakkan berdasarkan

anamnesa dan therapeutic trial.

- Sering terjadi pasien tidak diterapi dengan benar karena diagnosanya

sulit ditegakkan.

- Penyakit lain yang menyerupai Trigeminal Neuralgia : dental

disorders, sinus infections, temporal arteritis, migraine headaches, and

psychological disorders.

- Jika salah diagnosa maka bisa menyebabkan : ekstraksi gigi yang

tidak perlu, terapi root canals, operasi sinus, biopsi dan terapi

antibiotik.

Diagnosis Trigeminal Neuralgia Diagnosis Trigeminal Neuralgia

Treatment Trigeminal Treatment Trigeminal Neuralgia Neuralgia - Medical management : CBZ, PHT, GBP, LTG

- Mekanisme kerja dari obat obat tsb adl menghambat impuls nyeri

dengan memblok masuknya ion Natrium atau Calcium ke dalam sel.

- Surgical or radiosurgical therapy is generally only considered after

treatment with medications has failed.

Patient presents with symptoms suggestive of

neuropathic pain

DIAGNOSIS Clinical History ● Determine if manisfestations are part of common neuropathic pain syndromes

Physical Exam ● Should include a full neurological exam

Ancillary Tests

Is neuropathic pain confirme

ALTERNATIVE DIAGNOSIS

Management of

common Neuropathi

c Pain Syndromes

Based on : MIMS Neurology 2008 page A177

Management of common Neuropathic

Pain Syndromes

Painful Diabetic Peripheral Neuropathy

Postherpetic Neuralgia (PHN)

Trigeminal Neuralgia (TN)

Non-pharmacological therapy- Patient education- Optimize glycemic control- proper foot care- transcutaneous electrical nerve stimulation (TENS)- Alternative therapy: acupuncture, biofeedback, magnet therapy.

Pharmacotherapy1st line agents- TCA- Gabapentin- Pregabalin

2nd line agents- Lamotrigine- Opiods or tramadol- Serotonin-noradrenaline reuptake inhibitors (Duloxetine, Venlafaxine)

Other agents : - Capsaicin - SSRI- Oxcarbazepine - Topiramate

Non-pharmacological therapy- Patient education- Psychosocial counseling- TENS

Pharmacotherapy1st line agents- Gabapentin- lidocaine patch (preferred for eldery)- Pregabalin- TCA

2nd line agents- Opiods or tramadol

Non-pharmacological therapy- Patient education

Pharmacotherapy1st line agents- Carbamazepine- Oxcarbazepine

2nd line agents- Baclofen- Lamotrigine

Surgical intervention- Consider if refractory to monotherapy & drug combinations

Does patient have adequate pain relief in 2

Continue treatment

NoExpert referral - Consider referring the patient to a pain medicine specialist

Treatment Neuropathic Pain Treatment Neuropathic Pain

1. Based on Etiology

- Diabetic Neuropathy Oral Anti Diabetic, Insulin.

- Post Herpetic Neuralgia Anti Viral

- Trigeminal Neuralgia steroid

2. Pain Killer

- Anticonvulsants

- Tri Cyclic Antidepresant

- Tramadol

- Opioid

3. Nerve Repaired

- Methycobal Ampoule 3 x 500 mcg / weekBased on : MIMS Neurology 2008 page A177

Penderita Diabetic

Neuropatic Pain

Oral Anti Diabetic

-Anticonvulsants (gabapentin/pregabalin)

Vit B1,B6, B12

- Gol. Sulfonilurea- Gol. Biguanid- Gol. Glitazone

PRINSIP Therapy pada Diabetic Neuropatic PainPRINSIP Therapy pada Diabetic Neuropatic Pain

Kontrol Gula

Hilangkan Neuropati

c Pain

Memperbaiki mielin

(mielinisasi)

Struktur MethycobalStruktur Methycobal

Perbedaan bentuk struktur dengan Perbedaan bentuk struktur dengan vit. Bvit. B １２１２ lainnya: lainnya:

CyanocobalaminHydroxocobalamin DBCC

Methycobal vit.B12 aktif dengan gugus Methycobal vit.B12 aktif dengan gugus methyl (CHmethyl (CH33) )

- Methycobal adalah bentuk vit B12 aktif karena mempunyai gugus CH3.- Di dalam tubuh, semua bentuk vit. B12 akan diubah menjadi bentuk Methycobalamin sebelum digunakan dalam proses metabolisme tubuh.

B12 aktif

Jenis-jenis vit.B12 dan fungsinya Jenis-jenis vit.B12 dan fungsinya

B12 tidak aktif

（ di hepar ）

（ di serum ）

Hycobal

Memperbaiki Anemia melalui sintesa heme

Memperbaiki Neuropathy melalui sintesa asam nukleat, protein dan fosfolipid

Neuropathy Perifer

Anemia dan neuropathy yang disebabkan karena defisiensi B12 dan metabolisme yang abnormal dari B12

Anemia dan neuropathy yang disebabkan karena defisiensi B1,B6,B12 dan metabolisme yang abnormal dari B1,B6,B12

Vit ． B kompleks （ B1, B6, B12 ）

Cyanocobalamin

Hydroxocobalamin

Methycobal

Mekanisme kerja Methycobal dalam Mekanisme kerja Methycobal dalam perbaikan sel sarafperbaikan sel saraf

Methycobal is transported at high levels intoorganelles of nerve cells (Rat model)(Inada et.al.(1981):Symposium on Nervous System and MethylB12, Hakone, Japan)

Methycobal enhances synthesis of nucleic acidsand proteins in nerve cells (Mouse model)(Nakazawa et.al. (1970): Vitamin, 42(5), 275)

Methycobal stimulates axonal transport(Rat model)Takenaka et.al.: Prog. Med. 2 （ 10 ） ,149-152 （ 1982 ）Saito et.al.: Hakone Symposium “Nervous System and Methyl B12”: p 75, 1981

Promotes myelinization- Synthesis of Lipids(in vitro)(Yonezawa T. et al.: Hakone Symposium “Nervous System and Methyl B12”, p49-53, 1981 ）Nakazawa T. et.al.: Hakone Symposium “Nervous System and Methyl B12”, 54-60, 1981)

Methycobal stimulates axonal regeneration(Rat)Onishi A. et.al.:Clinical Pharmacology 18(2): 387 (1987)

Accelerates early recovery of synapticTransmissionShibuya et. al: Symposium on Nervous System and MethylB12”, Hakone, Japan. 1981)

Restores diminished neurotransmitter levelsSasaki et. al. Pharmacol.Biochem.Behav.,43,635-639 （ 1992 ）

Sintesa asam nukleat dan protein Sintesa asam nukleat dan protein (Biochemical action - 1)(Biochemical action - 1)

John M. Scott et al: Lancet: 337,1981

Deoxyuridine monophosphateDeoxyuridine monophosphate （（ d-UMPd-UMP ））Thymidine monophosphateThymidine monophosphate （（ d-TMPd-TMP ））ThymineThymine

DNADNA

CHCH33-- TransmethylationTransmethylation

5,10 methylenetetrahydrofolic acid5,10 methylenetetrahydrofolic acid

5 methyltetrahydrofolic acid5 methyltetrahydrofolic acid

Dihydrofolic acidDihydrofolic acid

Tetrahydrofolic acidTetrahydrofolic acid（（ THFTHF ））

MethionineMethionine

Methionine synthetaseMethionine synthetase

HomocysteineHomocysteine

S-adenosylhomocysteineS-adenosylhomocysteine S-adenosylmethionineS-adenosylmethionine

MecobalaminMecobalamin

Methycobal mengaktivasi sintesa DNA di sel saraf dan membantu sintesa protein

Shinichi Tashiro : Hakone Symposium “The Nervous System and Methyl B12” p.30, 1981.

Methycobal mensintesa lecithin, komponen utama dari selubung myelin

Transmethylation

Ethanolamine Choline

CephalinLecithin

S-adenosylhomocysteine S-adenosylmethionine

Methionine Homocysteine

Mecobalamin

S-adenosylhomocysteine S-adenosylmethionine

Methionine Homocysteine

Mecobalamin

Sintesa fosfolipid Sintesa fosfolipid (Biochemical action - 2)(Biochemical action - 2)

Distribusi Methycobalamin pada Cerebro Distribusi Methycobalamin pada Cerebro Spinal FluidSpinal Fluid

Nobuo Tanaka et al. : Hakone Symposium "The Nervous System and Vitamin B12" P.5,1981.

Tujuan

Metode

Mengevaluasi distribusi Methycobalamin pada Cerebro Spinal Fluid

CH3B12 1000μg

CNB12 1000μg1x pemberian IM

Sebelum 1 jam 3 jam 6 jam 12 jam

CH3B12

32.4+/-6.7N=17

Konsentrasi Methycobalamin lebih tinggi daripada cyanocobalamin dalam CSF

Haruto Uchino et al. :Vitamins 42(3):198,1970.

Haruto Uchino et al. :Kyoto Symposium "Peripheral Neuropathy and Methycobal," p.1,1978.

Metode

0.9%CNB12

Serum Cerebro Spinal Fluid

73.2% CH3 B12

Methycobalamin

DBCC25.9

Perbandingan konsentrasi vit. B12 di dalam serum dan Cerebro

Spinal Fluid pada orang sehat.

Konsentrasi Methycobalamin lebih tinggi daripada vit B12 lainnya di serum dan CSF

Distribusi Methycobalamin dalam serum Distribusi Methycobalamin dalam serum dan Cerebro Spinal Fluiddan Cerebro Spinal Fluid

Ampoule

The ready to use - Active Cobalamin The ready to use - Active Cobalamin

for Nerve Damage Repaired for Nerve Damage Repaired

Garis robek

Masing-masing ampul Methycobal Injeksi dikemas dalam bungkus aluminium bag agar terlindung dari cahaya dan dirancang dengan garis tempat merobek tepat pada leher ampul, sehingga badan ampul tetap berada di dalam agar tidak terpapar cahaya.

Methycobal merupakan preparat yang light sensitive

Methycobal merupakan obat dan di cover oleh asuransi kesehatan

DosageRoute of

AdministrationUse for

Ampoule 500 mcg 3 times/week i.m. or i.v. Hospitalized Patients

Capsules 500 mcg 3 times/day per oral out patients

follow byfollow by

Special cover design to protect from light, both capsules & ampoules

Small capsule, easy to swallow

Contain 1 ml, more convenient, no pain in injection

Active Cobalamin for Nerve Damage RepairedActive Cobalamin for Nerve Damage Repaired

Covered by insurance because it’s drug

Original product with affordable price

√√

Blister dengan warna gelap untuk melindungi kapsul dari cahaya

Tercantum no. reg untuk membedakan dengan product palsu

Available on Jan 09

‘ Methycobal jacket ‘ untuk melindungi botol infus dari cahaya pada pemberian Methycobal ampul perdrip

Nerve Damage Repaired

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