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Management Of Different Types Of Pain
KRT Lucas Meliala
Guru Besar Luar BiasaBagian Ilmu Penyakit Saraf
Fakultas Kedokteran Universitas Gadjah Mada, Yogyakarta
Symposium Clinical UpdateYogyakarta, Januari 2011
Curriculum VitaeNama : Prof. dr. KRT. Lucas Meliala, SpKJ, SpS(K).Tempat/tanggal lahir : Membang Muda (Sumut),
22 September 1941Alamat : Jl. Nagan Lor 70, JogjakartaTelepon : (0274) 450758Fax. : (0274) 374052Mobile : 0815 687 0584E-mail : [email protected]
Pendidikan : Lulus Dokter tahun 1969, alumnus FK-UGMLulus Spesialis Saraf & Jiwa tahun 1974
alumnus FK-UI, FK-UGM, FK UnairPekerjaan : Staf Fakultas Kedokteran UGM
bagian IP Saraf sejak tahun 1968 sampai sekarangOrganisasi : 1999-2007 :
Ketua Pokdi Nyeri Perdossi Anggota IASP, ENSKetua 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
Nyeri
Adaptif
Maladaptif
Inflamasi
Nosiseptif
Fungsional
Neuropatik
Heat
Cold
Intense
ForceMechanical
Heat
Cold
PainAutonomic Response
Witdrawal Reflex
Nociceptor sensory neuron
NOCICEPTIVE PAINNoxius Pheripheral Stimuli
Spinal cord
Brain
Macrophage
NeutrophilGranulocyte
Tissue Damage
Spontaneous PainPain Hypersensitivity
Reduced Threshold : AliodynaIncreased Response : Hyperalgesia
Nociceptor sensory neuron
INFLAMANTORY PAINInflammation
Spinal cord
Mast Cell
Brain
Spontaneous PainPain Hypersensitivity
Peripheral Nerve Damage
NEUROPATHIC PAIN
Spinal cord Injury
Brain
Normal PeripheralTissue and Nerves
FUNCTIONAL PAIN
Abnormal CentralProcessing
Spontaneous PainPain Hypersensitivity
Brain
NOCICPTOR
NOCICPTOR
NOCICPTOR
PERCEPTION
MODULATION
CONDUCTION
TRANSDUCTION
PAIN – SERIES OF EVENTS
PAIN
TRANSMISSION
“Rasa sakit adalah hak istimewa kita”
Nyeri Inflamasi
• Nyeri akibat kerusakan jaringan atau proses inflamasi
• Dapat bersifat spontan atau dibangunkan
• Berguna untuk mempercepat penyembuhan
Meliala, 2004
Heat
Cold
Intense
ForceMechanical
Heat
Cold
PainAutonomic Response
Witdrawal Reflex
Nociceptor sensory neuron
NOCICEPTIVE PAIN
Noxius Pheripheral Stimuli
Spinal cord
Brain
Modifikasi Meliala, 2005
ExamplesPeripheral• Postherpetic neuralgia• Trigeminal neuralgia• Diabetic peripheral neuropathy• Postsurgical neuropathy• Posttraumatic neuropathyCentral• Poststroke painCommon descriptors2
• Burning• Tingling• Hypersensitivity to touch or cold
Examples
• Pain due to inflammation• Limb pain after a fracture• Joint pain in osteoarthritis• Postoperative visceral pain
Common descriptors2
• Aching• Sharp• Throbbing
Examples
• Low back pain with radiculopathy
• Cervical radiculopathy
• Cancer pain• Carpal tunnel
syndrome
Mixed PainPain with
neuropathic and nociceptive components
Neuropathic PainPain initiated or caused by a primary lesion or dysfunction
in the nervous system (either peripheral or
central nervous system)1
Nociceptive PainPain caused by injury to
body tissues (musculoskeletal,
cutaneous or visceral)2
PRESENTATION ACROSS PAIN STATES VARIES
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
HEAT
CHEMICAL
PRESSUREBRAINPANASPEGELPERIH
Modifikasi Meliala, 2003
Na+
Nociceptor Peripheral Terminal
H+
Heat
Pinch
Cold
ATP
Heat
HeatH+Capsaicin
NOCICEPTIVE TRANSDUCTION
NaV 1.8/1.9
PAIN
EXAMPLE OF CHRONIC NOCICEPTIVE PAIN: OSTEOARTHRITIS OF THE KNEE
Normal joint Osteoarthritis
Synovial membrane
Cartilage
Synovialfluid
Jointcapsule
Inflammationas bones rub
together
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
Spontaneous PainPain Hypersensitivity
Peripheral Nerve Damage
NEUROPATHIC PAIN
Spinal cord Injury
Brain
Modifikasi Meliala, 2005
Ectopic DischargesNerve lesion induces hyperactivity due to changes in ion channel function
Ectopic discharges
Nerve lesion
Spinal cordNociceptive afferent fiber
Descendingmodulation
Ascendinginput
Perceived pain
Intact tactile fiber
Central sensitizationAfter nerve injury, increased input to the dorsal horn can induce central sensitization
Perceived pain
Ascendinginput
Descendingmodulation
Nerve lesion
Nociceptive afferent fiber
Tactilestimuli
Perceived pain(allodynia)
Ascendinginput
Descendingmodulation
Abnormal discharges induce central sensitization
Pathophysiological Mechanisms Of Neuropathic Pain
Lancet Neurology 2010;9:807-19 Modifikasi Meliala, 2010
Spinal cord dorsal horn
C-fibre
Skin
Aδ or Aβ fibre
Skin
C-fibre
C-fibre
C-fibre
Aδ or Aβ fibre
Opioid receptorNMDA receptorNE/5HT receptorGABA receptorα-adrenoceptorTRPV1 receptorAMPA/KA receptorChemokine receptorCytokine receptorSodium channelCalcium Channel(Α2-δ subunit)
Α2-δ subunit
Chemokine receptor
Cytokine receptorAMPA/KA receptor
Baron et al., 2010
EXAMPLE OF NEUROPATHIC PAIN:ULNAR NERVE LESION FOLLOWING BONE FRACTURE
Ulnar nerve
Peripheral nociceptors
Ascendinginput
Descendingmodulation
EXAMPLE OF NEUROPATHIC PAIN:ULNAR NERVE LESION FOLLOWING BONE FRACTURE
Trauma leadingto nerve lesion
Perceived pain
Impulses generatedwithin ulnar nerve
Spinal cord
Lesion
“Gedung-gedung makin tinggi namun sumbu amarah kita makin pendek”
NEUROPATHIC PAIN PREVALENCE RANGES FROM 6.0-7.7% IN EUROPE
0123456789
10
UK France Germany Spain
% o
f pat
ient
s
Patients with axial back pain with a neuropathic component included in the surveyData on file. Pfizer Inc. Neuropathic Pain Patient Flow Survey
7.5%6.4%
6.0%
7.7%
Modified Meliala, 2007
Normal PeripheralTissue and Nerves
FUNCTIONAL PAIN
Abnormal CentralProcessing
Spontaneous PainPain Hypersensitivity
Brain
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
SAKIT
SAKITPenyakittanpa
kesakitan
Penyakit dankesakitan
Kesakitantanpa
penyakit
Ulkus (luka)Tanpa Ulkus ( tidak luka)
Nyeri perutfungsional yang kronik
BERU A M E
Somatic symptoms that might be considered in reaching a diagnosis of
fibromyalgia
Wolfe et al. Arthritis Care Res 2010;62:600-610
• 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
ID Pain Questionnaire1. 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 Neuropathic pain not likely0 Neuropathic pain less likely1 Neuropathic pain less likely2 Consider neuropathic pain3 Consider neuropathic pain4 Strongly consider neuropathic pain5 Strongly consider neuropathic pain
Minimum total score = -1Maximum total score = 5
Burning, feeling like the feet are on fire
Stabbing, like sharp knives Lancinating, like electric shocks
Freezing, like the feet are on ice, although they feel warm to touch
Modified by Meliala 2006
• TO CURE IS SOMETIMES• TO TREAT IS OFTEN• TO COMFORT IS ALWAYS
The task of a doctor:
A. Pare (1598)
PERILAKU NYERI(PAIN BEHAVIOUR)
PENDERITAAN(SUFFERING)
NYERI(PAIN)
BIOPSIKOSOSIAL(BIOPSYCHOSOCIAL)
NOSISEPSI(NOCICEPTION)
PENGERTIAN MODEL NYERI
BYERS AND BONICA, 2001MODIFIKASI PENULIS
•Terapi kognitif•Restorasi fungsional
•Opioid•Tramadol
•Oxcarbazepine•Gabapentin
•Eperisone HCL•Paracetamo
•OAINS
•Antidepresan•Psikotropika•Relaksasi•Spiritual
•Diklofenak•Etodolac•Dexketoprofen•Celecoxib•Modalitas fisik
“Rasa senang dan rasa sakit adalah kembar”
MECHANISTIC APPROACH TO TREATMENT OF NeP
BRAIN
SPINAL CORD
PNSCentral SensitizationCa++ : Lyrica, GBP,OXC,LTG,LVTNMDA : Ketamine, TPM
DextromethorphanMethadone
OthersCapsaicinNSAIDsCox inhibitorsLevodopa
DescendingInhibitorsNE/5HTOpiate receptors
PeripheralSensitization
Na+CBZOXCPHTTCATPMLTGMexiletineLidocaine
TCAsDuloxetinSSRIsSNRIsTramadolOpiates
Beydoun, 2002
Modified by MELIALA, 2006
“Sukacita yang besar selalu didahului oleh penderitaan yang hebat”
MECHANISTIC APPROACH TO TREATMENT
BRAIN
SPINAL CORDPNS
Central Sensitization
Beydoun, 2002
Modified by MELIALA 2006
Ectopic Discharge
Descending Inhibition
“Pengetahuan makin berlimpah, namun kemampuan kita untuk menilai makin tumpul”
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 ofpainful polyneuropathy
• Drugs with established efficacy include PREGABALIN, gabapentin, TCAs, SNRIs,, strong opioids and tramadol
EFNS: European Federation of Neurological Societies
First line therapy PREGABALIN/gabapentin or TCAs/SNRIs (evidence level A)
Second line therapy Opioids and lamotrigine (evidence level B)
Lack of orweak efficacy
SSRIs, capsaicin, mexiletine, oxcarbazepine and topiramate (evidence level A)
Low strength evidence or safety concerns Carbamazepine and valproate
Recommendations:
0
10
20
40
%patients
Royal M et all, AAPM 17th Annual Meeting Feb 2001
OXCARBAZEPINE IN NEUROPATHIC PAIN :PROSPECTIVE OPEN-LABEL TRIAL
Excellent
Patients’ subjective respone
30
50
Good Fair Poor(>70%) (51-70%) (20-50%) (<20%)
Antineuralgic of Choice: Peripheral Sensitization (n=207)
7%
18%23%
61%
0%
20%
40%
60%
80%
100%
OXC/CBZ TPM TA Other
% o
f Par
ticip
ants
R. Harden et al.The Journal of Pain, Vol.3 Nr.2 Suppl.1April 2002
OXC=Oxcarbazepine; CBZ=Carbamazepine;TPM= Topiramate;TCA=Tricyclic Antidepressant; Other=Phenytoin,lamaotrigin,Mexiletine, Lidocaine
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
Psychiatric37%
Seizure40%
Pain23%
USA, Scott-Levin PDDA; June 2001
Multidisciplinary approach to management
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
Dadabhoy D, Clauw DJ. Nat Clin Pract Rheumatol 2006;2:364-372.
Nonpharmacological therapiesto address dysfunction
• Strike a balance between pharmacological and non-pharmacological approaches
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
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
Nonpharmacological
• Aerobic exercise• Cognitive behavioral therapy• Patient education• Strength training• Acupuncture* • Biofeedback* • Balneotherapy*• Hypnotherapy*
Pharmacological• Analgesics*• Analgesic antiepileptics• Antidepressants• Other
*Limited evidence for efficacy exists
Treatments used by primary care physicians
• Amitriptyline• Milnacipran• Fluoxetine• Nortriptyline• Pregabalin• Tramadol• Moclobemide• Cyclobenzaprine• Duloxetine• Zolpidem
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.
Garcia-Campayo et al. Arthritis Res Ther 2008;10:1-15.
METHYCOBAL
An active form of cobalamin
Participates in transmethylation
Improves synthesis of proteins, nucleicacids and phospholipids which are needed in the repair of damaged nerves.
BENEFITS ALL TYPES OF PERIPHERAL NEUROPATHIES
Nerve cell
Myelin sheath AxonMuscle
SEGMENTAL DEMYELINATIONe.g :Diabetic neuropathyAlcoholic neuropathyUremic neuropathyGuillain-Barre syndrome
WALLERIAN DEGENERATIONe.g :Spondylosis deformansHernia of intervartebral discCarpal tunnel syndromeFacial palsyGlaucomatous optic atrophy
AXONAL DEGENERATIONe.g :Drug-induced neuropathies[Vincristine, isonicotinicacid hydrazide (INH), etc]Herpes zoster
Direction of degeneration
Direction of degeneration
Modified MELIALA, 2006
METHYCOBAL’S EFFECT ON ECTOPIC FIRING OF DORSAL ROOT GANGLION (DOG MODEL)
Atsuta et.al Methycobal Forum 1993; 101-103
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 additionof Methycobal
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, 2010In Mogill J (Ed) Pain 2010, Clinical Pharmacology et Nonsteroidal Antiinflammatory Drugs, 217-223
Nama Obat Dosis JadwalAspirin 325-1000 mg 4-6 jam sekali
Kalium Diklofenak 50-200 mg 8 jam sekaliNatrium diklofenak 50 mg 8 jam sekali
Ibuprofen 200-800 mg 4-8 jam sekaliIndometasin 25-50 mg 8-12 jam sekaliKetoprofen 25-75 mg 6-12 jam sekali
Asam mefenamat 250 mg 6 jam sekaliNaproxen 250-500 mg 12 jam sekali
Piroksikam 10-20 mg 12-24 jam sekaliTenoksikam 20-40 mg 24 jam sekaliMeloksikam 75 mg 24 jam sekaliCelecoxib 100 mg 12 jam sekaliNimesulfid 100 mg 12 jam sekaliKetolorak 10-30 mg 4-6 jam sekali
Asetaminofen 500 mg 6-8 jam sekaliTramadol 50-100 mg 8 jam sekali
Analgetik Yang Paling Sering Digunakan
Mekanisme Proteksi Nyeri spasme otot
I
γα
II-IV
III-IV
Ia
Joint receptor (nociceptor)
Joint dysfunctionor pain
Nociceptor
Muscle painA
B
Muscle spindle
γ-Motoaxon
α-Motoaxon
Descending influencesCSpinothalamic
tract
I
γα
Eperison
PAINNO PAINNO PAIN
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
Contraction of Muscles
Ischemia
Pain Stimuli
Pain
Ischemia
Pain
Isch
emia
Pain
Relaxes hypertonia
Inhibit pain reflex
Improves circulation
EPERISONE HCL
Modifikasi Meliala, 2005
Difficulty in Walking
Difficulty in Going Upand Down Stairs
Lumbago
Stiff Shoulders
Cervical Pain
Tinnitus
HeadacheDizziness
Stiffness
Rigidity
77.577.5
65.4
71.9
80.7
71.5
55.2
53.9
68.9
66.4
IMPROVEMENT RATES WITH EPERISONE
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
SimpulanPemahaman mekanisme nyeri
sangat bermanfaat dalam penatalaksanaan nyeri
SEMOGA TIDAK NYERISALAM