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
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Pendidikan : ¾ Lulus Dokter tahun 1969, alumnus FK-UGM Prof. dr. KRT. Lucas Meliala, SpKJ, SpS(K). ¾ Lulus Spesialis Saraf & Jiwa tahun 1974 Membang Muda (Sumut), alumnus FK-UI, FK-UGM, FK Unair 22 September 1941 Pekerjaan : ¾ Staf Fakultas Kedokteran UGM Jl. Nagan Lor 70, Jogjakarta bagian IP Saraf sejak tahun 1968 sampai sekarang (0274) 450758 Organisasi : ¾ 1999-2007 : (0274) 374052 Ketua Pokdi Nyeri Perdossi 0815 687 0584 ¾ Anggota IASP, ENS
[email protected] ¾ 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
NOCICEPTIVE PAIN
Klasifikasi Nyeri
Noxius Pheripheral Stimuli Heat Cold
Nosiseptif
Pain Autonomic Response Witdrawal Reflex Brain
Intense Mechanical Force
Nociceptor sensory neuron
Heat Spinal cord
Cold
Adaptif
INFLAMANTORY PAIN Spontaneous Pain Inflammation Pain Hypersensitivity Macrophage
Reduced Threshold : Aliodyna Increased Response : Hyperalgesia
Mast Cell Neutrophil Granulocyte
Inflamasi
Brain Nociceptor sensory neuron
Tissue Damage
Spinal cord
Nyeri NEUROPATHIC PAIN Spontaneous Pain Pain Hypersensitivity Brain
Neuropatik
Peripheral Nerve Damage
Spinal cord Injury
Maladaptif
FUNCTIONAL PAIN NOCICPTOR
Fungsional
Spontaneous Pain Pain Hypersensitivity Brain
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 Pain Autonomic Response Witdrawal Reflex
Heat Cold
Brain
Intense Mechanical Force
Nociceptor sensory neuron
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
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
Nociceptive Pain Pain caused by injury to body tissues (musculoskeletal, cutaneous or visceral)2
Examples
• Low back pain with • • •
radiculopathy Cervical radiculopathy Cancer pain Carpal tunnel syndrome
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
Examples
• • • •
Pain due to inflammation Limb pain after a fracture Joint pain in osteoarthritis Postoperative visceral pain
Common descriptors2 • Aching • Sharp • Throbbing
PEGEL PERIH PANAS BRAIN
PRESSURE
HEAT
CHEMICAL Modifikasi Meliala, 2003
NOCICEPTIVE TRANSDUCTION H+
NaV 1.8/1.9 Na+
Heat Heat
Capsaicin
Heat H+ Pinch Cold ATP
Nociceptor Peripheral Terminal
PAIN
EXAMPLE OF CHRONIC NOCICEPTIVE PAIN: OSTEOARTHRITIS OF THE KNEE Normal joint
Synovial fluid
Osteoarthritis
Synovial membrane
Inflammation as bones rub together
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
Intact tactile fiber
Ascending input
Pathophysiological Mechanisms Of Neuropathic Pain Aδ or Aβ fibre
C-fibre Skin
Spinal cord dorsal horn
Skin
C-fibre Α2-δ subunit
Opioid receptor NMDA receptor NE/5HT receptor GABA receptor
Aδ or Aβ fibre
α-adrenoceptor
TRPV1 receptor AMPA/KA receptor Chemokine receptor Cytokine receptor Sodium channel Calcium Channel (Α2-δ subunit)
Cytokine receptor AMPA/KA receptor
Baron et al., 2010 Lancet Neurology 2010;9:807-19 Modifikasi Meliala, 2010
C-fibre
C-fibre
Chemokine receptor
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
% of patients
8
7.7%
7.5%
7
6.4%
6.0%
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
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
Tanpa Ulkus ( tidak luka)
Ulkus (luka)
Nyeri perut fungsional yang kronik
Penyakit dan kesakitan Penyakit tanpa kesakitan
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 • Raynaud’s 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
Stabbing, like sharp knives
Modified by Meliala 2006
Freezing, like the feet are on ice, although they feel warm to touch
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)
NOSISEPSI (NOCICEPTION)
BIOPSIKOSOSIAL (BIOPSYCHOSOCIAL)
“Rasa senang dan rasa sakit adalah kembar”
•Antidepresan •Psikotropika •Relaksasi •Spiritual •Diklofenak •Etodolac •Dexketoprofen •Celecoxib •Modalitas fisik
MECHANISTIC APPROACH TO TREATMENT OF NeP BRAIN
Beydoun, 2002
Descending Inhibitors NE/5HT Opiate receptors Peripheral Sensitization
TCAs Duloxetin SSRIs SNRIs Tramadol Opiates
Central Sensitization
PNS Na+ CBZ OXC SPINAL PHT TCA TPM LTG Mexiletine Lidocaine
CORD
Ca++ : Lyrica, GBP,OXC,LTG,LVT NMDA : Ketamine, TPM Dextromethorphan Methadone Others Capsaicin NSAIDs Cox inhibitors Levodopa
“Sukacita yang besar selalu didahului oleh penderitaan yang hebat”
Modified by MELIALA, 2006
MECHANISTIC APPROACH TO TREATMENT BRAIN
Descending Inhibition
Central Sensitization PNS
SPINAL CORD
Ectopic Discharge “Pengetahuan makin berlimpah, namun kemampuan kita untuk menilai makin tumpul”
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
PREGABALIN/gabapentin or TCAs/SNRIs (evidence level A)
Second line therapy
Opioids and lamotrigine (evidence level B)
Lack of or weak efficacy
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%)
Patients’ subjective respone
Poor (<20%)
% of Participants
100%
Antineuralgic of Choice: Peripheral Sensitization (n=207)
80% 61%
60% 40% 23%
18%
20% 7%
0% OXC/CBZ
TPM
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
TA
Other
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
Functional consequences of symptoms • Distress • Decreased activity • Isolation • Poor sleep • Increased appetite • Maladaptive illness behaviors
Dadabhoy D, Clauw DJ. Nat Clin Pract Rheumatol 2006;2:364-372.
Pharmacological therapies to improve symptoms
Nonpharmacological therapies to address dysfunction
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 9 An active form of cobalamin 9 Participates in transmethylation 9 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
Modified MELIALA, 2006
Myelin sheath
Axon
Nerve cell
Direction of degeneration
Direction of degeneration
METHYCOBAL’S EFFECT ON ECTOPIC FIRING OF DORSAL ROOT GANGLION (DOG MODEL)
Methycobal was added to the CSF solution (to make a concentration of 50 μg.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 homosisteinÆ mengurangi kerusakan saraf akibat terbentuknya reactive oxygen species • Berperan pada proteksi neuron SSP akibat glutamate-induced neurotoxicity Æ 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
Dosis
Jadwal
Aspirin
325-1000 mg
4-6 jam sekali
Kalium Diklofenak
50-200 mg
8 jam sekali
Natrium diklofenak
50 mg
8 jam sekali
Ibuprofen
200-800 mg
4-8 jam sekali
Indometasin
25-50 mg
8-12 jam sekali
Ketoprofen
25-75 mg
6-12 jam sekali
Asam mefenamat
250 mg
6 jam sekali
Naproxen
250-500 mg
12 jam sekali
Piroksikam
10-20 mg
12-24 jam sekali
Tenoksikam
20-40 mg
24 jam sekali
Meloksikam
75 mg
24 jam sekali
Celecoxib
100 mg
12 jam sekali
Nimesulfid
100 mg
12 jam sekali
Ketolorak
10-30 mg
4-6 jam sekali
Asetaminofen
500 mg
6-8 jam sekali
Tramadol
50-100 mg
8 jam sekali
Mekanisme Proteksi Nyeri C
spasme otot
Descending influences
Spinothalamic tract
Joint receptor (nociceptor)
II-IV
III-IV I
γ
B Joint dysfunction or pain
Ia α
Nociceptor α-Motoaxon γ-Motoaxon
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 Inhibit pain reflex
Pain
Ischemia
Contraction of Muscles
EPERISONE HCL
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
80.7
68.9 Stiffness
Stiff Shoulders
71.5
66.4 Rigidity
71.9
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
