Management Of Different Types Of Pain

KRT Lucas Meliala Guru Besar Luar Biasa Bagian Ilmu Penyakit Saraf Fakultas Kedokteran Universitas Gadjah Mada, Yogyakarta
Symposium Clinical Update Yogyakarta, Januari 2011

Curriculum Vitae Nama Tempat/tanggal lahir Alamat Telepon Fax. Mobile E-mail

: : : : : : :

Pendidikan : Lulus Dokter tahun 1969, alumnus FK-UGM Prof. dr. KRT. Lucas Meliala, SpKJ, SpS(K). Lulus Spesialis Saraf & Jiwa tahun 1974 Membang Muda (Sumut), alumnus FK-UI, FK-UGM, FK Unair 22 September 1941 Pekerjaan : Staf Fakultas Kedokteran UGM Jl. Nagan Lor 70, Jogjakarta bagian IP Saraf sejak tahun 1968 sampai sekarang (0274) 450758 Organisasi : 1999-2007 : (0274) 374052 Ketua Pokdi Nyeri Perdossi 0815 687 0584 Anggota IASP, ENS lucasmeliala@yahoo.com Ketua Governing board IPS

Definisi Nyeri
Nyeri adalah pengalaman sensorik dan emosional yang tidak menyenangkan akibat kerusakan jaringan, baik aktual maupun potensial, atau yang digambarkan dalam bentuk kerusakan tersebut

Meliala et al., 2002, Pokdi Nyeri Perdossi

Klasifikasi Nyeri
Nosiseptif

NOCICEPTIVE PAIN Noxius Pheripheral Stimuli Heat Cold Intense Mechanical Force Heat Cold Spinal cord Pain Autonomic Response Witdrawal Reflex Brain Nociceptor sensory neuron

Adaptif Inflamasi Nyeri

INFLAMANTORY PAIN Spontaneous Pain Inflammation Pain Hypersensitivity

Macrophage Mast Cell Neutrophil Granulocyte Reduced Threshold : Aliodyna Increased Response : Hyperalgesia

Brain Nociceptor sensory neuron Spinal cord

Tissue Damage

NEUROPATHIC PAIN Spontaneous Pain Pain Hypersensitivity Brain

Neuropatik Maladaptif

Peripheral Nerve Damage

Spinal cord Injury FUNCTIONAL PAIN NOCICPTOR Spontaneous Pain Pain Hypersensitivity Brain

Fungsional

NOCICPTOR Normal Peripheral Tissue and Nerves NOCICPTOR Abnormal Central Processing

PAIN SERIES OF EVENTS

PERCEPTION PAIN

MODULATION CONDUCTION

TRANSMISSION
Rasa sakit adalah hak istimewa kita

TRANSDUCTION

Nyeri Inflamasi
Nyeri akibat kerusakan jaringan atau proses inflamasi Dapat bersifat spontan atau dibangunkan Berguna untuk mempercepat penyembuhan

Meliala, 2004

NOCICEPTIVE PAIN
Heat Cold Intense Mechanical Force
Nociceptor sensory neuron

Pain Autonomic Response Witdrawal Reflex Brain

Heat Cold Noxius Pheripheral Stimuli

Modifikasi Meliala, 2005

Spinal cord

PRESENTATION ACROSS PAIN STATES VARIES

Neuropathic Pain Pain initiated or caused by a primary lesion or dysfunction in the nervous system (either peripheral or central nervous system)1

Mixed Pain Pain with neuropathic and nociceptive components

Nociceptive Pain Pain caused by injury to body tissues (musculoskeletal, cutaneous or visceral)2

Examples Peripheral Postherpetic neuralgia Trigeminal neuralgia Diabetic peripheral neuropathy Postsurgical neuropathy Posttraumatic neuropathy Central Poststroke pain Common descriptors2 Burning Tingling Hypersensitivity to touch or cold

Examples

Examples

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 Postoperative visceral pain

Common descriptors2 Aching Sharp Throbbing

1. International Association for the Study of Pain. IASP Pain Terminology. 2. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57

PEGEL PERIH PANAS BRAIN

PRESSURE

HEAT

CHEMICAL
Modifikasi Meliala, 2003

NOCICEPTIVE TRANSDUCTION
H+ Heat Heat NaV 1.8/1.9 Na+

Capsaicin

Heat H+ Pinch Cold ATP

PAIN

Nociceptor Peripheral Terminal

EXAMPLE OF CHRONIC NOCICEPTIVE PAIN: OSTEOARTHRITIS OF THE KNEE

Normal joint Osteoarthritis
Inflammation as bones rub together

Synovial fluid

Synovial membrane

Joint capsule Cartilage Thinned cartilage

Nyeri Neuropatik
Nyeri yang disebabkan oleh lesi atau disfungsi pada sistem saraf
Meliala, 2004

Berbuatlah dan cintailah tanpa memperhitungkan kebahagiaanmu sendiri, dan engkau akan berbahagia sepanjang waktu

WHAT IS NEUROPATHIC PAIN?

Pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system Pain often described as shooting, electric shock-like, burning commonly associated with tingling or numbness The painful region may not necessarily be the same as the site of injury. Pain occurs in the neurological territory of the affected structure (nerve, root, spinal cord, brain) Almost always a chronic condition (e.g. postherpetic neuralgia, poststroke pain) Responds poorly to conventional analgesics

NEUROPATHIC PAIN
Spontaneous Pain Pain Hypersensitivity Brain

Peripheral Nerve Damage

Spinal cord Injury

Modifikasi Meliala, 2005

Ectopic Discharges
Nerve lesion induces hyperactivity due to changes in ion channel function

Perceived pain

Nerve lesion

Descending modulation

Ascending input

Nociceptive afferent fiber Spinal cord

Ectopic discharges

Central sensitization
After nerve injury, increased input to the dorsal horn can induce central sensitization
Perceived pain

Nerve lesion
Descending modulation Ascending input

Nociceptive afferent fiber Perceived pain (allodynia) Abnormal discharges induce central sensitization

Tactile stimuli

Descending modulation

Ascending input

Intact tactile fiber

Pathophysiological Mechanisms Of Neuropathic Pain

A or A fibre C-fibre Spinal cord dorsal horn Skin Skin

-adrenoceptor

Opioid receptor NMDA receptor NE/5HT receptor GABA receptor

C-fibre 2- subunit A or A fibre Cytokine receptor AMPA/KA receptor

C-fibre

C-fibre

TRPV1 receptor AMPA/KA receptor Chemokine receptor Cytokine receptor Sodium channel Calcium Channel (2- subunit)

Chemokine receptor

Baron et al., 2010 Lancet Neurology 2010;9:807-19 Modifikasi Meliala, 2010

EXAMPLE OF NEUROPATHIC PAIN: ULNAR NERVE LESION FOLLOWING BONE FRACTURE

Ulnar nerve

EXAMPLE OF NEUROPATHIC PAIN: ULNAR NERVE LESION FOLLOWING BONE FRACTURE

Perceived pain

Trauma leading to nerve lesion

Ascending input

Descending modulation Impulses generated within ulnar nerve

Spinal cord

Lesion

Peripheral nociceptors

Gedung-gedung makin tinggi namun sumbu amarah kita makin pendek

NEUROPATHIC PAIN PREVALENCE RANGES FROM 6.0-7.7% IN EUROPE

10 9 8 % of patients 7 6 5 4 3 2 1 0 UK France Germany Spain
Modified Meliala, 2007
Patients with axial back pain with a neuropathic component included in the survey Data on file. Pfizer Inc. Neuropathic Pain Patient Flow Survey

7.5% 6.4% 6.0%

7.7%

FUNCTIONAL PAIN
Spontaneous Pain Pain Hypersensitivity Brain

Normal Peripheral Tissue and Nerves

Abnormal Central Processing

Nyeri Fungsional
Nyeri akibat abnormalitas sistem saraf pusat, berupa peningkatan sensitivitas terhadap berbagai stimuli Dahulu dikenal dengan nyeri psikogenik

Woolf, 2004, Meliala, 2004

PENYAKIT, KESAKITAN, ATAU KEDUANYA

BERU AME

Ulkus (luka)

Tanpa Ulkus ( tidak luka)

Penyakit dan kesakitan Penyakit tanpa kesakitan

Nyeri perut fungsional yang kronik

SAKIT

Kesakitan tanpa penyakit

SAKIT

Somatic symptoms that might be considered in reaching a diagnosis of fibromyalgia

Muscle pain/weakness Fatigue/tiredness Cognitive problems Headache Abdominal pain/cramps Numbness/tingling Dizziness Insomnia Depression Constipation Nausea Nervousness Chest pain Fever Diarrhoea Dry mouth Itching Wheezing Raynauds phenomenon Hives/welts Ringing in ears Vomiting Heartburn Oral ulcers Seizures Dry eyes Loss of appetite Rash Sun sensitivity Hearing difficulties Easily bruised Hair loss Frequent urination Painful urination Bladder spasms Loss of taste Change in taste Blurred vision Shortness of breath
Wolfe et al. Arthritis Care Res 2010;62:600-610

ID Pain Questionnaire
1. Did the pain feel like pins and needles ? Yes (+1 point) No (0 points) 2. Did the pain feel hot/burning ? Yes (+1 point) No (0 points) 3. Did the pain feel numb ? Yes (+1 point) No (0 points) 4. Did the pain feel like electrical shocks ? Yes (+1 point) No (0 points) 5. Is the pain made worse with the touch of clothing or bedsheets ? Yes (+1 point) No (0 points) 6. Is the pain limited to your joints ? Yes (-1 point) No (0 points)

ID Pain Score Card

-1 0 1 2 3 4 5 Neuropathic pain not likely Neuropathic pain less likely Neuropathic pain less likely Consider neuropathic pain Consider neuropathic pain Strongly consider neuropathic pain Strongly consider neuropathic pain

Minimum total score = -1 Maximum total score = 5

Burning, feeling like the feet are on fire

Freezing, like the feet are on ice, although they feel warm to touch

Stabbing, like sharp knives

Modified by Meliala 2006

Lancinating, like electric shocks

The task of a doctor: TO CURE IS SOMETIMES TO TREAT IS OFTEN TO COMFORT IS ALWAYS

A. Pare (1598)

PENGERTIAN MODEL NYERI

Terapi kognitif Restorasi fungsional
PERILAKU NYERI
(PAIN BEHAVIOUR)

PENDERITAAN
(SUFFERING)

Opioid Tramadol Oxcarbazepine Gabapentin Eperisone HCL Paracetamo OAINS

BYERS AND BONICA, 2001 MODIFIKASI PENULIS

NYERI
(PAIN)

Antidepresan Psikotropika Relaksasi Spiritual Diklofenak Etodolac Dexketoprofen Celecoxib Modalitas fisik

NOSISEPSI
(NOCICEPTION)

BIOPSIKOSOSIAL
(BIOPSYCHOSOCIAL)

Rasa senang dan rasa sakit adalah kembar

MECHANISTIC APPROACH TO TREATMENT OF NeP

BRAIN
Descending Inhibitors NE/5HT Opiate receptors Peripheral Sensitization

Beydoun, 2002

TCAs Duloxetin SSRIs SNRIs Tramadol Opiates

Central Sensitization
Ca++ : Lyrica, GBP,OXC,LTG,LVT NMDA : Ketamine, TPM Dextromethorphan Methadone Others Capsaicin NSAIDs Cox inhibitors Levodopa
Modified by MELIALA, 2006

PNS
Na+ CBZ OXC SPINAL PHT TCA TPM LTG Mexiletine Lidocaine

CORD

Sukacita yang besar selalu didahului oleh penderitaan yang hebat

MECHANISTIC APPROACH TO TREATMENT

BRAIN

Descending Inhibition

Central Sensitization PNS Ectopic Discharge

Pengetahuan makin berlimpah, namun kemampuan kita untuk menilai makin tumpul

SPINAL CORD

Beydoun, 2002 Modified by MELIALA 2006

Pengobatan Nyeri Neuropatik Saat ini

Ditujukan untuk mengurangi kepekaan neuron di sistema nervorum perifer dan sentral dengan memodulasi aktivitas saluran ion (GBP, PGB, CBZ) Meningkatkan mekanisme inhibisi endogen (TCA, Duloxetine, opioid, Tramadol) dan hasilnya belum memuaskan Mengapa?????
Watkins & Maier, 2002; Scholz & Woolf, 2007

EFNS guidelines for the treatment of painful polyneuropathy

Drugs with established efficacy include PREGABALIN, gabapentin, TCAs, SNRIs,, strong opioids and tramadol
Recommendations:
First line therapy Second line therapy Lack of or weak efficacy PREGABALIN/gabapentin or TCAs/SNRIs (evidence level A) Opioids and lamotrigine (evidence level B) SSRIs, capsaicin, mexiletine, oxcarbazepine and topiramate (evidence level A)

Low strength evidence Carbamazepine and valproate or safety concerns

EFNS: European Federation of Neurological Societies

OXCARBAZEPINE IN NEUROPATHIC PAIN : PROSPECTIVE OPEN-LABEL TRIAL

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

50 % patients 40 30 20 10 0 Excellent (>70%) Good (51-70%) Fair (20-50%) Poor (<20%)

Patients subjective respone

100%
% of Participants

Antineuralgic of Choice: Peripheral Sensitization (n=207)

80%
61%

60% 40%
23%

20%
7%

18%

0%
OXC/CBZ TPM TA Other
OXC=Oxcarbazepine; CBZ=Carbamazepine;TPM= Topiramate; TCA=Tricyclic Antidepressant; Other=Phenytoin,lamaotrigin,Mexiletine, Lidocaine

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

OXCARBAZEPIN ADVANTAGE IN NEUROPATIC PAIN

No monitoring of hematologic parameters required Fewer drug-drug interaction No autoinduction of metabolisme Comparable efficacy Twice-daily schedule. Therapeutic effect maybe detected in 24-48 hours

Trileptal usage by indication cumulative since launch

Psychiatric 37% Seizure 40%

Pain 23%
USA, Scott-Levin PDDA; June 2001

Multidisciplinary approach to management

Strike a balance between pharmacological and nonpharmacological approaches

Initial symptom of pain, fatigue, etc Disordered sensory processing Neuroendocrine disturbances

Pharmacological therapies to improve symptoms

Functional consequences of symptoms Distress Decreased activity Isolation Poor sleep Increased appetite Maladaptive illness behaviors

Nonpharmacological therapies to address dysfunction

Dadabhoy D, Clauw DJ. Nat Clin Pract Rheumatol 2006;2:364-372.

Management of fibromyalgia: Recommended treatment approach

Multidisciplinary therapy individualized to patients symptoms and
presentation is recommended A combination of nonpharmacological and pharmacological therapies may benefit most patients

Nonpharmacological

Pharmacological

Aerobic exercise Cognitive behavioral therapy Patient education Strength training Acupuncture* Biofeedback* Balneotherapy* Hypnotherapy*

Analgesics* Analgesic antiepileptics Antidepressants Other

*Limited evidence for efficacy exists

Mease P. J Rheumatol 2005;32:6-21; Carville et al, [published online ahead of print July 20, 2007] Ann Rheum Dis Doi:10.1136/ard.2007.071522; Goldenberg et al, JAMA 2004;292:2388-2395; Clauw et al, Best Pract Res Clin Rheumatol 2003;17:685-701; Arnold et al, Arthritis Rheum 2007;56:1336-1344

Treatments used by primary care physicians

Amitriptyline Milnacipran Fluoxetine Nortriptyline Pregabalin Tramadol Moclobemide Cyclobenzaprine Duloxetine Zolpidem
Garcia-Campayo et al. Arthritis Res Ther 2008;10:1-15.

SNRI = selective norepinephrine reuptake inhibitor. Please see Full Prescribing Information and Medication Guide available at at this presentation. Cymbalta, SavellaTM, and LYRICA are the trademarks of Lilly LLC, Forest Pharmaceuticals Inc, and Pfizer Inc, respectively.

METHYCOBAL
An active form of cobalamin Participates in transmethylation Improves synthesis of proteins, nucleic acids and phospholipids which are needed in the repair of damaged nerves.

BENEFITS ALL TYPES OF PERIPHERAL NEUROPATHIES Muscle

SEGMENTAL DEMYELINATION e.g : Diabetic neuropathy Alcoholic neuropathy Uremic neuropathy Guillain-Barre syndrome WALLERIAN DEGENERATION e.g : Spondylosis deformans Hernia of intervartebral disc Carpal tunnel syndrome Facial palsy Glaucomatous optic atrophy AXONAL DEGENERATION e.g : Drug-induced neuropathies [Vincristine, isonicotinic acid hydrazide (INH), etc] Herpes zoster Myelin sheath Axon

Nerve cell

Direction of degeneration

Direction of degeneration

Modified MELIALA, 2006

METHYCOBALS EFFECT ON ECTOPIC FIRING OF DORSAL ROOT GANGLION (DOG MODEL)

Methycobal was added to the CSF solution (to make a concentration of 50 g.ml) bathing the dorsal root ganglia During anoxia-induced ectopic firing. The firing was suppressed and the frequency (spike/sec.) dropped significantly after the addition of Methycobal

Atsuta et.al Methycobal Forum 1993; 101-103

Metilkobalamin: Kesimpulan
Metilkobalamin adalah bentuk aktif Vit B12, siap digunakan tubuh dalam reaksi metilasi homosistein membentuk metionin Reaksi metilasi berperan pada pembentukan DNA, protein yang penting untuk saraf, pembentukan mielin dan transpor aksonal Metilkobalamin berperan pada regenerasi saraf yang mengalami kerusakan, misalnya pada, nyeri neuropatik, neuralgia nervus kranialis, peripheral nerve injury, vertigo dan tinitus dengan mengurangi ectopic discharge

Kesimpulan
Metilkobalamin berperan pada penurunan kadar homosistein mengurangi kerusakan saraf akibat terbentuknya reactive oxygen species Berperan pada proteksi neuron SSP akibat glutamate-induced neurotoxicity proteksi neuron pada stroke, cedera serebral, Alzheimer, Parkinson, Hipoglikemia dan Status epileptikus Secara umum sediaan oral maupun injeksi cukup aman dengan kejadian efek samping yang kecil

ANALGESIC MEDICATIONS ON INFLAMATORY PAIN

PRIMARY ANALGESICS Acetaminophen Prostaglandin synthesis inhibitors Salicylates Traditonal NSAIDs COX-2-selective NSAIDs (coxibs) Tramadol Opioids Traditional Mixed ADJUVANT MEDICATIONS Antidepressants Anticonvulsants Local anesthetics Muscle Relaxant Miscellaneous agents

Clinical Experience
NSAID dipergunakan > 40 th sampai sekarang masih terbaik Khusus : Nyeri dengan inflamasi
Dionne et al, 2010 In Mogill J (Ed) Pain 2010, Clinical Pharmacology et Nonsteroidal Antiinflammatory Drugs, 217-223

Analgetik Yang Paling Sering Digunakan

Nama Obat Aspirin Kalium Diklofenak Natrium diklofenak Ibuprofen Indometasin Ketoprofen Asam mefenamat Naproxen Piroksikam Tenoksikam Meloksikam Celecoxib Nimesulfid Ketolorak Asetaminofen Tramadol Dosis 325-1000 mg 50-200 mg 50 mg 200-800 mg 25-50 mg 25-75 mg 250 mg 250-500 mg 10-20 mg 20-40 mg 75 mg 100 mg 100 mg 10-30 mg 500 mg 50-100 mg Jadwal 4-6 jam sekali 8 jam sekali 8 jam sekali 4-8 jam sekali 8-12 jam sekali 6-12 jam sekali 6 jam sekali 12 jam sekali 12-24 jam sekali 24 jam sekali 24 jam sekali 12 jam sekali 12 jam sekali 4-6 jam sekali 6-8 jam sekali 8 jam sekali

Mekanisme Proteksi Nyeri

C

spasme otot
Joint receptor (nociceptor)

Descending influences

Spinothalamic tract

II-IV
B Joint dysfunction or pain

III-IV I
-Motoaxon -Motoaxon

Ia

Nociceptor A Muscle pain

PAIN NO PAIN
Muscle spindle

Eperison

Eperisone HCl (Myonal )

Golongan antispasmodik, banyak dipakai nuntuk efek muscle relaxant Insidensi sedasi kecil, dibanding obat lain yang segolongan
Mempermudah aplikasi klinis, untuk pasien yang membutuhkan terapi tanpa mempengaruhi alertness

Efek samping yang timbul biasanya jarang terjadi

SITES OF ACTION OF EPERISONE IN THE VICIOUS CYCLE OF HYPERTONIA

Relaxes hypertonia
Contraction of Muscles

Inhibit pain reflex

Ischemia

EPERISONE HCL

Pain

Pain

Ischemia Ischemia

Improves circulation

Pain Stimuli

Modifikasi Meliala, 2005

IMPROVEMENT RATES WITH EPERISONE

77.5 Dizziness 77.5 Headache 65.4 Tinnitus

Cervical Pain

71.9

68.9 Stiffness

80.7 Stiff Shoulders

66.4 Rigidity

71.5 Lumbago Difficulty in Going Up and Down Stairs 55.2

53.9 Difficulty in Walking

Modifikasi Meliala, 2005

Myonal: Kesimpulan
Relaksasi otot skelet yang mengalami hipertonus Memperbaiki aliran darah intramuskuler Mengurangi sensitivitas muscle spindle melalui neuron motorik Vasodilatasi dan augmentasi aliran darah Aksi analgesik dan inhibisi refleks nyeri di medula spinalis

Simpulan
Pemahaman mekanisme nyeri sangat bermanfaat dalam penatalaksanaan nyeri

SEMOGA TIDAK NYERI SALAM