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 Pendidikan : ¾ Lulus Dokter tahun 1969,
Nama : Prof. dr. KRT. Lucas Meliala, SpKJ, SpS(K). alumnus FK-UGM
Tempat/tanggal lahir : Membang Muda (Sumut), ¾ Lulus Spesialis Saraf & Jiwa tahun 1974
22 September 1941 alumnus FK-UI, FK-UGM, FK Unair
Alamat : Jl. Nagan Lor 70, Jogjakarta Pekerjaan : ¾ Staf Fakultas Kedokteran UGM
Telepon : (0274) 450758 bagian IP Saraf sejak tahun 1968 sampai sekarang
Fax. : (0274) 374052 Organisasi : ¾ 1999-2007 :
Mobile : 0815 687 0584 Ketua Pokdi Nyeri Perdossi
E-mail : lucasmeliala@yahoo.com ¾ Anggota IASP, ENS
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
Pain
Autonomic Response
Witdrawal Reflex
Cold Brain

Nosiseptif Intense
Mechanical
Nociceptor
Force
sensory neuron
Heat

Cold Spinal cord

Adaptif Inflammation
INFLAMANTORY PAIN
Spontaneous Pain
Pain Hypersensitivity
Macrophage Reduced Threshold : Aliodyna
Mast Cell Increased Response : Hyperalgesia
Neutrophil
Granulocyte
Brain

Inflamasi Tissue Damage

Nociceptor
sensory neuron

Spinal cord

Nyeri NEUROPATHIC PAIN

Spontaneous Pain
Pain Hypersensitivity
Brain

Neuropatik Peripheral Nerve

Damage

Spinal cord Injury

Maladaptif FUNCTIONAL PAIN

Spontaneous Pain
NOCICPTOR Pain Hypersensitivity
Brain

Fungsional NOCICPTOR
Normal Peripheral
Tissue and Nerves
NOCICPTOR Abnormal Central
Processing
 PAIN – SERIES OF EVENTS
PERCEPTION

PAIN

MODULATION

CONDUCTION

TRANSMISSION
TRANSDUCTION
“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
 NOCICEPTIVE PAIN

Pain
Heat Autonomic Response
Witdrawal Reflex
Cold
Brain

Intense
Mechanical
Nociceptor sensory neuron
Force

Heat

Spinal cord
Cold
Noxius Pheripheral Stimuli
Modifikasi Meliala, 2005
 PRESENTATION ACROSS PAIN STATES VARIES

Neuropathic Pain Nociceptive Pain

Mixed Pain
Pain initiated or caused by a Pain with Pain caused by injury to
primary lesion or dysfunction neuropathic and body tissues
in the nervous system nociceptive (musculoskeletal,
(either peripheral or components cutaneous or visceral)2
central nervous system)1

Examples Examples Examples

Peripheral
• Postherpetic neuralgia • Low back pain with • Pain due to inflammation
• Trigeminal neuralgia radiculopathy • Limb pain after a fracture
• Diabetic peripheral neuropathy • Cervical • Joint pain in osteoarthritis
• Postsurgical neuropathy radiculopathy • Postoperative visceral pain
• Posttraumatic neuropathy • Cancer pain
Central • Carpal tunnel Common descriptors2
• Poststroke pain syndrome • Aching
Common descriptors2 • Sharp
• Burning • Throbbing
• Tingling
• Hypersensitivity to touch or cold
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
 BRAIN
PEGEL
PERIH
PANAS
PRESSURE

HEAT

CHEMICAL
Modifikasi Meliala, 2003
 NOCICEPTIVE TRANSDUCTION

H+ NaV 1.8/1.9
Na+
Heat

Heat

Heat
Capsaicin H+ PAIN
Pinch

Cold

ATP

Nociceptor Peripheral Terminal

EXAMPLE OF CHRONIC NOCICEPTIVE PAIN:
OSTEOARTHRITIS OF THE KNEE
Normal joint Osteoarthritis

Inflammation
as bones rub
together
Synovial Synovial
fluid 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 Ascending
modulation 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 Ascending
modulation input

Nociceptive afferent fiber

Perceived pain
(allodynia)
Abnormal discharges induce central sensitization

Tactile
stimuli Descending Ascending
modulation input

Intact tactile fiber

 Pathophysiological Mechanisms Of Neuropathic Pain
Aδ or Aβ fibre

C-fibre

Skin
Spinal cord dorsal horn Skin

C-fibre
C-fibre
Opioid receptor Α2-δ subunit
NMDA receptor
NE/5HT receptor
Aδ or Aβ fibre Cytokine receptor
GABA receptor AMPA/KA receptor C-fibre
α-adrenoceptor
TRPV1 receptor
AMPA/KA receptor Chemokine receptor
Chemokine receptor
Cytokine receptor
Sodium channel
Calcium Channel
(Α2-δ subunit)
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 Ascending Descending
lesion input 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 7.5% 7.7%
7 6.4%
% of patients

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
Ulkus (luka) ( tidak luka)

Nyeri perut
fungsional
Penyakit dan yang kronik
kesakitan

Penyakit SAKIT
Kesakitan
tanpa tanpa
kesakitan SAKIT penyakit
 Somatic symptoms that might be
considered in reaching a diagnosis of
fibromyalgia

• Muscle pain/weakness • Fever • Loss of appetite

• Fatigue/tiredness • Diarrhoea • Rash
• Cognitive problems • Dry mouth • Sun sensitivity
• Headache • Itching • Hearing difficulties
• Abdominal pain/cramps • Wheezing • Easily bruised
• Numbness/tingling • Raynaud’s phenomenon • Hair loss
• Dizziness • Hives/welts • Frequent urination
• Insomnia • Ringing in ears • Painful urination
• Depression • Vomiting • Bladder spasms
• Constipation • Heartburn • Loss of taste
• Nausea • Oral ulcers • Change in taste
• Nervousness • Seizures • Blurred vision
• Chest pain • Dry eyes • 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 Neuropathic pain not likely
0 Neuropathic pain less likely
1 Neuropathic pain less likely
2 Consider neuropathic pain
3 Consider neuropathic pain
4 Strongly consider neuropathic pain
5 Strongly consider neuropathic pain

Minimum total score = -1

Maximum total score = 5
 Freezing, like the feet are on ice,
Burning, feeling like the feet are on fire 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 PERILAKU NYERI

•Restorasi fungsional (PAIN BEHAVIOUR)
•Antidepresan
PENDERITAAN •Psikotropika
(SUFFERING)
•Relaksasi
NYERI •Spiritual
•Opioid (PAIN)
•Tramadol
•Oxcarbazepine
•Diklofenak
•Gabapentin
NOSISEPSI •Etodolac
•Eperisone HCL
(NOCICEPTION) •Dexketoprofen
•Paracetamo
•Celecoxib
•OAINS
•Modalitas fisik
BYERS AND BONICA, 2001
MODIFIKASI PENULIS BIOPSIKOSOSIAL
(BIOPSYCHOSOCIAL)

“Rasa senang dan rasa sakit adalah kembar”

 MECHANISTIC APPROACH TO TREATMENT OF NeP

Beydoun, 2002 BRAIN

TCAs
Duloxetin
Descending
Inhibitors SSRIs
NE/5HT SNRIs
Opiate receptors Tramadol
Opiates
Peripheral
Sensitization Central Sensitization
PNS Ca++ : Lyrica, GBP,OXC,LTG,LVT
Na+ NMDA : Ketamine, TPM
CBZ Dextromethorphan
OXC Methadone
PHT SPINAL CORD
Others
TCA
Capsaicin
TPM
NSAIDs
LTG
Cox inhibitors
Mexiletine
Levodopa
Lidocaine
Modified by MELIALA, 2006

“Sukacita yang besar selalu didahului oleh penderitaan yang hebat”

 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:

PREGABALIN/gabapentin or TCAs/SNRIs
First line therapy
(evidence level A)

Second line therapy Opioids and lamotrigine (evidence level B)

Lack of or SSRIs, capsaicin, mexiletine, oxcarbazepine and

weak efficacy 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 Good Fair Poor
(>70%) (51-70%) (20-50%) (<20%)
Patients’ subjective respone
 Antineuralgic of Choice: Peripheral
Sensitization (n=207)
100%
% of Participants

80%
61%
60%

40%
23% 18%
20%
7%
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 Seizure
37% 40%

Pain
23%
USA, Scott-Levin PDDA; June 2001
 Multidisciplinary approach to
management
• Strike a balance between pharmacological and non-
pharmacological approaches

Initial symptom of pain, fatigue, etc Pharmacological therapies to

• Disordered sensory processing improve symptoms
• Neuroendocrine disturbances

Functional consequences of symptoms

• Distress
• Decreased activity Nonpharmacological therapies
• Isolation to address dysfunction
• Poor sleep
• Increased appetite
• Maladaptive illness behaviors

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 • Analgesics*
• Cognitive behavioral therapy • Analgesic antiepileptics
• Patient education • Antidepressants
• Strength training • Other
• Acupuncture*
• Biofeedback*
• Balneotherapy*
• Hypnotherapy*

*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
Garcia-Campayo et al. Arthritis Res Ther 2008;10:1-15.
• 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.
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
Myelin sheath Axon
SEGMENTAL DEMYELINATION
e.g :
Diabetic neuropathy
Alcoholic neuropathy
Uremic neuropathy
Guillain-Barre syndrome Nerve cell

WALLERIAN DEGENERATION
e.g : Direction of degeneration
Spondylosis deformans
Hernia of intervartebral disc
Carpal tunnel syndrome
Facial palsy
Glaucomatous optic atrophy

AXONAL DEGENERATION
e.g :
Drug-induced neuropathies Direction of degeneration
[Vincristine, isonicotinic
acid hydrazide (INH), etc]
Herpes zoster

Modified MELIALA, 2006

 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 spasme otot
C Descending influences
Spinothalamic Joint receptor (nociceptor)
tract
II-IV

B Joint dysfunction
III-IV or pain
I Ia

α
γ Nociceptor

α-Motoaxon A Muscle pain

γ-Motoaxon 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

Pain
Ischemia

EPERISONE HCL
Pain
Ischemia
Ischemia

Improves circulation Pain Stimuli

Modifikasi Meliala, 2005

IMPROVEMENT RATES WITH EPERISONE

77.5
77.5
Dizziness
Headache
65.4
Tinnitus

Cervical Pain 71.9

80.7
68.9
Stiff Shoulders
Stiffness

71.5
66.4
Lumbago
Rigidity

Difficulty in Going Up 55.2

and Down Stairs

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