Dr. Moch. Bahrudin, Sp.

Bagian Neurologi
Fakultas Kedokteran
Universitas Muhammadiyah Malang
 NYERI SANGAT KOMPLEKS ..

Nyeri adalah suatu pengalaman sensorik

yang multidimensional.
Nyeri memiliki komponen kognitif dan
emosional,
berkaitan dengan reflex menghindar
dan perubahan output otonom.
Patofisiologi sindroma nyeri neuropatik sangat
kompleks

Pengobatan yang efektif berdasarkan mekanisme

tidak memuaskan
RATIONALE Managing Neuropathic Pain
TOPIC :
 Definisi nyeri
 Klasifikasi nyeri
 Mekanisme nyeri
 Mekanisme nyeri neuropatik
 Assessment nyeri berdasarkan
mekanisme
DEFINISI ………
“Pain is an unpleasant sensory
and emotional experience
associated with actual or potential
tissue damage or described in
terms of such damage.”

the International Association for the Study of Pain (IASP)

Menurut IASP (International
Association for the Study of Pain) ;

NYERI NEUROPATIK
nyeri yang diawali atau disebabkan lesi
primer atau disfungsi atau gangguan
yang menetap pada sistem saraf
perifer ataupun saraf sentral
Pada praktek klinis :
Nyeri dapat dibagi atas dua, yaitu nyeri
adaptif dan maladaptif

A. Nyeri Nosiseptif
Adaptif
B. Nyeri Inflamatorik
C. Nyeri neuropatik Maladaptif
D. Nyeri Fungsional
ACUTE VS CHRONIC PAIN

CHARACTERISTIC ACUTE PAIN CHRONIC PAIN

Cause Generally known Often unknown

Duration of pain Short, Persists after healing,

well-characterized 3 months

Treatment Resolution of Underlying cause and pain

approach underlying cause, disorder; outcome is often
usually self-limited pain control, not cure
 PRAKTEK
Nociceptive Mixed Type Neuropathic
Pain Caused by a Pain
combination of both
Caused by activity in Initiated or caused by
primary injury and
neural pathways in primary lesion or
secondary effects
response to potentially dysfunction in the
tissue-damaging stimuli nervous system

CRPS*

Postherpetic
Postoperative
Arthritis neuralgia Trigeminal
pain
neuralgia
Sickle cell Neuropathic
Mechanical crisis low back pain Central post-
low back pain
Distal stroke pain
Sports/exercise polyneuropathy
injuries (eg, diabetic, HIV)
*Complex regional pain syndrome
 MEKANISME NYERI

 Transduction Injury Brain

 Transmission
 Modulation
 Perception
 Interpretation
 Behavior
Descending
Pathway

Dorsal
Peripheral Root
Nerve Ganglion

Ascending
Pathways
C-Fiber

A-beta Fiber Dorsal

Horn
A-delta Fiber
Spinal Cord
Gate control
10 ®
Nyeri muncul ...
Jika ada gangguan keseimbangan

1. Stimulasi neurotransmiter
- eksitatorik glutamat,, substansia P meningkat
- inhibitorik GABA glisin, DA, 5-HT, noradrenalin menurun

2. Jumlah dan sensivitas reseptor opioid

- menurunnya reseptor opioid

Eksitatorik Inhibitorik
 MEKANISME NYERI PERIFER
& PLASTISITAS NOSISEPTOR
Descending SIGNAL TO NOCICEPTORS
Control
fibers CNS

Satellite
Cells

Lymphocytes
Dorsal
Fibroblasts
Hom
neurons
PMN leukocytes
E, G OP

Macrophages
Glia NGF PG

CK

H+
NO BK CELL DAMAGE
and
Platelet INFLAMMATION
Autonomic
neurons
Mast cells

EFFERENT ACTIONS Byers and Bonica, 2000

Modifikasi Meliala, 2003
MEKANISME NYERI NEUROPATIK … ??

(Bridges et al. 2001) Amir, 2008)

 Normal sensory function

To brain

Noxious
Nociceptors Dorsal Pain
stimulus
Horn neuron sensation

Sensory function after nerve injury with spontaneous firing along axon

Sodium To brain
channels

Pain
No -adrenoceptors sensation
stimulus
Woolf & Mannion, 1999
Modifikasi Meliala, 2003
 the cell body

sympathetically
maintained pain

Gilron Ian, C. Peter N. Watson, Catherine M. Cahill, Dwight E. Moulin, 2006, Neuropathic pain: a practical guide for the clinician, CMAJ ; vol. 175 no. 3 265-275
Reorganisasi kornu dorsalis medula spinalis

ALLODINIA

Bridges et al. 2001, Amir, 2008

 SENSITISASI SENTRAL

Type C
fibers
GLU GLU
SP SP
Na+
Ca2+
Ca2+

Voltage-gates AMPA Type C

Ca2+ channel fibers
Ca2+
Na+(K +, Ca2+) NMDA
2+ 2+
Ca Ca Ca2+

Ca2+
IP3
Ca2+
GLU
PL-A2 SP
NO-synthase ACPD
PG5
NO Immediately early genes
(C-fos, C-jun)

Ollat H, Caesaro C.Clin Neuropharmacol, 1995

Modifikasi Meliala, 2003
 DISINHIBITION
Modification: altered conectivity and cell death

C-fiber terminal
Glu
Sprouted A fiber
terminal
Inhibitory
 GABA B Interneuron
adenosine Cell death
Glu SP
P2X
NMDA
Ca2+ Ca2+
Glu
Substance P Mg2+
BDNF
GABA B
Ca2+ PGE2
PGE2
Adenosine
NK1 Src Ca2+ Na2+ 2+
mGluR TrkB Ca2+ Na 2+Ca Ca2+


K++
K NMDA GABA-A GLY
PKC VGCC EP NSC AMPA K++
K
IP3 KAI
COX2
PGE2 PGE2
PGE2 Woolf & Mitchel, 2001
Induction Modifikasi Meliala, 2003
Possible Descriptions
of Neuropathic Pain
 Sensations  Signs/Symptoms
 numbness  allodynia:
 tingling pain from a stimulus that
 burning does not normally evoke
 paresthetic pain
 paroxysmal ○ thermal

 lancinating ○ mechanical

 electriclike  hyperalgesia:
 raw skin
exaggerated response to a
normally painful stimulus
 shooting
 deep, dull, bonelike ache
 Multiple Pathophysiologies May
Be Involved in Neuropathic Pain
 More than one mechanism of action likely involved
 Neuropathic pain may result from abnormal peripheral
nerve function and neural processing of impulses due to
abnormal neuronal receptor and mediator activity
 Combination of medications may be needed to
manage pain: topicals, anticonvulsants, tricyclic
antidepressants, serotonin-norepinephrine reuptake
inhibitors, and opioids
 In the future, ability to determine the relationship
between the pathophysiology and
symptoms/signs may help target therapy
ASSESSMENT NYERI
BERDASARKAN MEKANISME

ALLODINIA
HIPERALGESIA
ASSESSMENT NYERI BERDASARKAN
MEKANISME
What Are the Goals of
Clinical Assessment?
 Achieve diagnosis of pain
 Identify underlying causes of neuropathy
 Identify comorbid conditions
 Evaluate psychosocial factors
 Evaluate functional status (activity levels)
 Set goals
 Develop targeted treatment plan
 Determine when to refer to specialist or
multidisciplinary team (pain clinic)
Assessing the Patient With Pain

 Onset and duration

 Location/distribution
 Quality
 Intensity
 Aggravating/relieving factors
 Associated features or secondary signs/symptoms
 Associated factors
 mood/emotional distress
 functional activities
 Treatment response
Pain Treatment Continuum
Least Most
invasive invasive

Continuum not related to efficacy

Psychological/physical approaches

Topical medications

Systemic medications*

Interventional techniques*

*Consider referral if previous treatments were unsuccessful.

1.Nonpharmacologic Options
 Biofeedback
 Relaxation therapy
 Physical and occupational therapy
 Cognitive/behavioral strategies
 meditation; guided imagery
 Acupuncture
 Transcutaneous electrical nerve
stimulation
 2. Pharmacologic Treatment
Options
BRAIN Descending Modulation
Anticonvulsants
Opioids
Spinal Tricyclic/SNRI Antidepressants
CNS Cord

Dorsal Central Sensitization

PNS Horn Anticonvulsants
Opioids
NMDA-Receptor Antagonists
Peripheral Local Anesthetics Tricyclic/SNRI Antidepressants
Sensitization Topical Analgesics
Anticonvulsants
Tricyclic Antidepressants
Opioids
Beydoun, 2002, Thomson, 2005, Meliala, 2008, Jan S Purba, 2010
Pendekatan terhadap nyeri neuropatik berdasarkan
tes diagnostik dan klasifikasi berdasarkan mekanisme
FDA-Approved Treatments for
Neuropathic Pain
 Carbamazepine
 trigeminal neuralgia
 Duloxetine
 peripheral diabetic neuropathy
 Gabapentin
 postherpetic neuralgia
 Lidocaine Patch 5%
 postherpetic neuralgia
 Pregabalin*
 peripheral diabetic neuropathy
 postherpetic neuralgia

*Availability pending based upon controlled substance scheduling by the DEA.

Antidepressants in
Neuropathic Pain Disorders*
 Multiple mechanisms of action
 Randomized controlled trials and meta-analyses
demonstrate benefit of tricyclic antidepressants
(especially amitriptyline, nortriptyline, desipramine)
for postherpetic neuralgia and diabetic neuropathy
 Onset of analgesia variable
 analgesic effects independent of antidepressant activity
 Improvements in insomnia, anxiety, depression
 Desipramine and nortriptyline have fewer adverse effects

*Not approved by FDA for this use.

Tricyclic Antidepressants:
Adverse Effects
 Commonly reported AEs Fewest
(generally anticholinergic): AEs  Desipramine
 blurred vision
 cognitive changes  Nortriptyline
 constipation
 Imipramine
 dry mouth
 orthostatic hypotension
 Doxepin
 sedation
 sexual dysfunction  Amitriptyline
 tachycardia
 urinary retention Most
AEs
AEs = adverse effects.
3.Interventional Treatments
Options
 Neural blockade
 sympathetic blocks for CRPS-I and II
(reflex sympathetic dystrophy and causalgia)
 Neurolytic techniques
 alcohol or phenol neurolysis
 pulse radio frequency
 Stimulatory techniques
 spinal cord stimulation
 peripheral nerve stimulation

CRPS = complex regional pain syndrome.

TAKE HOME MESSAGE
 Neurophatic pain mechanism peripheral and
central mechanism
 Assessing Patient With Neurophatic Pain Mechanism

 “Rational” polypharmacy is often necessary

 combining peripheral and central nervous system agents
enhances pain relief
 Treatment goals include:
 balancing efficacy, safety, and tolerability
 reducing baseline pain and pain exacerbations
 improving function and QOL