NEUROPATHIC PAIN

Dr.dr.Thomas Eko P. SpS(K)

Bagian/SMF Neurologi FK UNUD/ RSUP
BACKGROUND

• Pain & inflamation are normal responses in

order limitation tissue damage from injury
but if these respons excessive it can
disturb and decrease quality of life.
Charting Pain as a 5th Vital Sign
ACCOUNT NO

CLINICAL CHART HRN

NAME
CLASS DEPT WARD BED SEX/BIRTH DATE/RACE
DATE REGISTERED Paste Sticky Label
DATE
D.O.A /
P.O.D
AM PM AM PM AM PM AM PM AM PM
Time

o o
C C

4 4
0 0
T
E 39 39
M
P
E
R
38 Temperature 38
A
T
U
37 37
R
E

36 36

B 25 250

Select the
L 240
O 0 230
O 24 220
D 0 210

Pulse Rate and Blood

P 23 200
R 0 190

Pain Scale
E 22 180
S 0 170
S 21 160
U

Pressure
0 150
R 140
E 20
0 130
.

Patient is
19 120
P
U 0 110
L 18 100
S 0 90
E 17 80
. 0 70

capable of
R 16 60
E 0 50
S 15 40
P 0 30
I 14 20

Respiration Scores
R 10
A 0

using
13 9
T 8
I 0
O 12 7
N 0 6
. 11 5
P 0 4
A 10 3
I 0 2
N 90 1
0

Pain Scores
80
70
60
50
Weight
40
Bowel30
20
10
Routine
9 Sugar Albumin Acetone Blood PH
Urine8
7
6
Black5 Temperature, Pulse, Respiration, Pain Score Tick the Pain Measurement Scale that patient is capable of using.
Red 4 Blood Pressure Faces
> >

3 Numerical
2
1 Categorical
0
 Neuropathic Pain:
Issues and Challenges
 Common type of Pain
 25% to 50% of all pain clinic visits

 Under assessment and under treatment

 Interpatient variability in response to treatment
 Neuropathic pain : complex syndrome, unresponsive
to analgesic /NSAID, difficult to treat and tends
chronic.

 Rasional treatment : based on symptomatology and

pathophysiology
 Estimated Prevalence of Neuropathic Pain
In USA
Tic Douloreux

HIV-Associated Pain

Poststroke Pain

Phantom Pain

Multiple Sclerosis

Causalgia or Reflex Sympathetic Dystropy

Spinal Cord Injury

Cancer-Related Pain

Postherpetic Neuralgia

Diabetic neuropathy

Low Back Pain

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
US Prevalence (millions of cases)

Beydoun, 1999
Modifikasi Meliala, 2003
 Unadequate Pain management

 Field (1997) : “ We are clearly not doing a

good job with chronic pain”
 Watt-Wason (1999) : “Effective pain
management to be problematic in Canada
as well as internationally”
 Similar condition in Indonesia.
 Defining Pain

“An unpleasant sensory and emotional experience

associated with actual or potential tissue damage or
described in terms of
such damage.”
International Association for
International Association for
the Study of Pain (IASP), 1986

Merskey, 1986.
 Mechanism Based of Pain
Example: Example: Psychogenic
Physiologic / - Pinched Peripheral (functional)3
nociceptive1 -Mixed
- Stung by mosquito Fibromyalgia
- Irritable bowel syndrome Pain due to abnormal
Common descriptors:
Pain with inflammatory and responsiveness or function
Pain arising from
Common
Similar toNeuropathic
inflammatory paindescriptors
components of the nervous system
activation of nociceptors
Similar to neuropathic pain without neurologic deficit
or peripheral abnormality

Example:
Peripheral
Example:
Example: - Postherpetic neuralgia
- Low
- Pain due back pain with radiculopathy
to inflammation
- Trigeminal neuralgia
- Cervical
- Limb radiculopathy
pain after a fracture
Inflammatory2 - Diabetic peripheral neuropathy Neuropathic1
- Cancer
- Joint pain inpain
osteoarthritis
- Postsurgical neuropathy
- Carpal tunnel
- Postoperative syndrome
visceral pain
Pain caused by injury to - Posttraumatic neuropathy
Pain arising as a direct
body tissues Central
Common descriptors: consequence of a lesion or
(musculoskeletal, - Poststroke pain
Aching disease affecting the
cutaneous or visceral) Common descriptors
Sharp somatosensory system
Burning
Throbbing
Tingling
Hypersensitivity to touch or cold
1. Loeser JD, Treede RD. The Kyoto Protocol of IASP Basic Pain Terminology. Pain 2008;137:473-477.
2. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57.
3. Woolf CJ. Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management.. Ann Intern Med 2004;140:441-451
 Pain

Nociceptiv
e Pain

Normal
(physiological)
Nociception
Noxious
stimulation of normal tissue and
normally
functioning sensory nervous system
PSYCHOGENIC PAIN :

Pain without organic dysfunction

Psychogenic component prominent

 Nociceptive vs Neuropathic Pain
Nociceptive Pain Mixed type Neuropathic Pain
Caused by activity in neural Caused by a combination of Initiated or caused by
pathways in response to both primary injury or primary lesion or dysfunction
potentially tissue-damaging secondary effects in the nervous system
stimuli

HNP
Post-Herpetic
Arthritis Neuralgia
Post Operative Trigeminal
Pain Neuralgia

Trauma Low Back Pain

Mechanical
Low Back Pain Central Post-
Sports/Exercise Stroke Pain
Polyneuropathy
injuries (eg. diabetes, HIV)
Spectrum of pain
 Acute vs Chronic Pain

3 to 6 months
Acute Pain Chronic Pain

 Osteoarthritis
 Chronic low back pain
 Chronic headache
 Neuropathic pain
 Chronic visceral pain

Merskey, 1986.
Example of nociceptive pain:
osteoarthritis of the knee
Normal joint Osteoarthritis

Inflammation
as bones rub
together
Synovial Synovial
fluid membrane

Joint
capsule

Cartilage Thinned
cartilage
 Example of neuropathic pain:
ulnar nerve lesion following bone fracture

Ulnar nerve
 Example of co-existing pain:
herniated disc causing low back pain
and lumbar radiculopathy
 Nociceptive and neuropathic pain may
co-exist in low back pain conditions
Nociceptive pain component Neuropathic pain component
 Example of co-existing pain: herniated disc
causing low back pain and lumbar
radiculopathy
Activation of peripheral nociceptors –
cause of nociceptive pain component
Disc herniation

Lumbar
vertebra

Compression and inflammation of nerve root –

cause of neuropathic pain component
 Etiologies of Neuropathic Pain.
 Traumatic nerve injury
 Peripheral nerve
 Dorsal root or trigeminal ganglion
 Spinal cord
 Viral infection (eg, herpes zoster, HIV)
 Connective tissue/autoimmune diseases
 Peripheral ischemic disease
 Diabetes mellitus types 1 and 2
 Cerebrovascular accident
 Disk herniation and spinal stenosis
 Toxic insult
 Metabolic disorders
 Hereditary factors

Pappagallo, Clin Ther. 2003

 Easy and Simple on Neuropathic Pain

PHYSIOLOGI OF PAIN
 COMPARISON DIAMETER
SENSORIC NERVE FIBER


Somatosensory System and Pain

Modified form The cerebral cortex of man. W. Penfield &T. Rasmussen:

The Macmillan Company, New York, N.Y. 1950. 248 pp
 Emotional Cognitiv Sensory
Pain: e
Sensory
DLPF
Emotional
Cognitive Insula Amygdala C Thalamus SI

PAG
ParBr

RVM
LC
Spinal
neuro
n
Noxious
input
Spinal
neuro
n
 4
5
3

2
7

1 8

Classic Ascending and Descending Pain Pathways

Normal nerve impulses leading to
pain

Perceived pain

Noxious
stimuli
Descending Ascending
modulation input

Nociceptive afferent fiber

Spinal cord
PHYSIOLOGY OF PAIN
1. TRANSDUCTION.
Strong stimuli --- nociceptor -----> Potential
Action

2. TRANSMISSION
Convey impuls after transduction
A delta and C ---->MS ---->TH ----> corteks

3.MODULATION
Interaction between endogen analgetic system
and pain input entering dorsal horn ---> asenden

4. PERSEPSION
Final result of interaction transduction,
transmission and modulation processes.
Gabapentin
Easy and Simple on Neuropathic Pain

NEUROPATHIC PAIN
 Key Features of Neuropathic Pain
· Pain occasionally generated in · Variably associated with
response to damage to sensory sensory perturbations:
nervous system – Sensory Loss:
· Pain in areas of sensory loss -
Anaesthesia Dolorosa
· Pain in absence of a noxious
stimulus:
– Spontaneous continuous – Sensory gain:
– Spontaneous paroxysmal (lancinating) · Allodynia – pain in response to
– Evoked (stimulus dependant) pain an innocuous stimulus
· Hyperalgesia – increased
response to a painful stimulus
· Prevalence UK & France ~
7% 1

· Usually severe and chronic : 2

– Mean duration 78 months

– Mean pain intensity 6/10
1 Torrance et al 2006; Smith et al 2007; Bouhassira et al 2008 Images courtesy of Turo Nurmikko
2. Backonja & Stacey 2004
 Neuropathic pain: Positive and
34

negative sensory symptoms

Nervous system dysfunction or damage

Positive symptoms Negative symptoms

(due to excessive activity)1 (due to deficit of function)1,2

Spontaneous pain2,3 Hypoesthesia1,2

Allodynia2,3 Anesthesia1,2
Hyperalgesia2,3 Hypoalgesia1,2
Dysesthesia2,3 Analgesia1,2
Paresthesia2,3

Sensory abnormalities and pain often co-exist1,3

Each patient may have a combination of symptoms
that may change over time (even within a single etiology)

1. Baron R, Tölle TR. Curr Opin Support Palliat Care 2008;2:1-81;

2. Jensen TS et al. Eur J Pharmacol 2001;429:1-11;
3. Gilron I et al. Can Med Assoc J 2006;175:265-275.
 Symptoms of Neuropathic Pain
Stimulus-Independent Symptoms
(Symptoms Described by the Patient)
 Continuous burning pain
 Intermittent shooting, lancinating pain
 Electric shock–like pain
 Some paresthesias
 Abnormal sensations that are not unpleasant

 Some dysesthesias
 Abnormal sensations that are unpleasant
Baron, 2000; Woolf, 1999.
 Neuropathic pain descriptors

‘Electric shock-like’

‘Shooting’ ‘Burning’

‘Tingling’ ‘Numbness’

Be alert for common verbal descriptors

of neuropathic pain1,2
1. Gilron I et
et al.
al. Can
Can Med
Med Assoc
Assoc JJ 2006;175:265-275.
2. Baron R, et al. Lancet Neurol 2010;9:807-819.
 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
National Institute of Diabetes and Digestive and Kidney Diseases. Diabetic Neuropathies: The Nerve Damage of Diabetes. Available
from: http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/neuropathies.pdf. Accessed 15 Jul 2009.
 Signs of Neuropathic Pain
Stimulus-Evoked Pain (Elicited by
the Physician on Examination)

Hyperalgesia Allodynia
An increased response Pain due to a
to a stimulus that is stimulus that is
normally painful not normally painful
Easy and Simple on Neuropathic Pain

PATHOPHYSIOLOGY

Of

NEUROPATHIC PAIN
 Normal Condition

Excitatory Inhibitory
neurotransmission neurotransmission

NORMAL Balance
 Pain Phenomene...

Glutamate,
GABA
CCK, Glycine,
substans P DA,
5-HT,
nor Adrenaline
MECHANISM of NP
I. Peripheral Mechanisme
1. Ectopic Discharges
2. Peripheral Sensitization
3. Abnormal interaction nerve fiber
4. Sympathetic Maintain Pain

II. Central Mechanism

1. Central Sensitization
2. Loss of inhibitory controls
3. Structural Reorganization
 Nerve Lesion

Wallerian Degeneration
Johnson, 2000
The Triad
Immune & glial reaction
Immune & glial reaction
 Immune & glial reaction

T lymphocyte

Schwann cell
Injured axon

Macrophage
Mast cell

Scholz & Woolf, 2007; modified by Meliala, 2008

Immune & glial reaction

Macrophage Matrix
metalloproteases Chemokines receptors
(MMP) (CCR2, CCR1, dan CCR5)

Chemokines
(CCL2,CCL3)
Schwann cell
Injured axon

T lymphocyte
Mast
cell

Scholz & Woolf, 2007; modified by Meliala, 2008

 Ectopic Discharge
Injured nerve fibers develop increased expression of Na+ channels

Primary excitatory afferent nerve fiber

Na+ channel
expression
increased

Conduction frequency amplified

Na+ = sodium ion. England et al. Neurology 1996;47:272-76. Ochoa et al. Brain. 1980;103:835-853
Taylor. Curr Pain Headache Rep. 2001;5:151-161. Sukhotinsky et al. Eur J Pain. 2004;8(2):135-43
 I.1.Ectopic Discharge
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
No Pain
stimulus -adrenoceptors sensation

Woolf & Mannion, 1999

Modifikasi Meliala, 2003
 I.2.Peripheral Sensitization
Primary afferent nerve fibers Dorsal horn
neurons
NGF

NGF

NGF
Neuropeptide release

NGF

Innocuous stimulus

Pain sensation

Woolf and Mannion. Lancet 1999;353:1959-1964

 I.3. Abnormal interaction
nerve fiber

* Ephatic Crosstalk:
Nerve lesion  loss of glia isolation
 short circuit
Lesion Aβ activated Aδ  allodynia
Mechanistic Implications of Hyperalgesia and Allodynia
I.4. Sympathetic Maintain Pain

NA Regenerating
 sprouts

Primary afferent fiber


NA

NA

Pre-ganglionic
sympathetic fiber
Post-ganglionic
sympathetic fiber
Attal, 1999
Modifikasi Meliala, 2003
 II.1. CENTRAL SENSITIZATION
MECHANISMS OF WIND-UP

Type C
fibers
GLU GLU
SP SP
Na+
Ca2+
Ca2+ Mg 2+
Voltage-gates AMPA Type C
Ca2+ channel fibers
Ca2+
NaCa
+
(KCa+, Ca2+) NMDA
2+ 2+
Ca2+

Ca2+
IP3
Ca2+
GLU
NO-synthase
PL-A2 ACPD SP

PG5
NO Immediately early genes
(C-fos, C-jun)

Ollat H, Caesaro C.Clin Neuropharmacol, 1995

Modifikasi Meliala, 2003
 Pharmacology of Central
Sensitisation

NK1
Substance P
AMPA

Glutamate NMDA
Ca++ Mg++

NOS
COX

BDNF Phosphorylation

trkB
 II.2. Loss of inhibitory controls
Loss of descending modulation causes exaggerated pain due to an imbalance between
ascending and descending signals

Exaggerated pain
perception

Noxious
stimuli
Loss of
Ascending
descending
input
modulation

Nociceptive afferent fiber

Spinal cord
 II.3. Structural Reorganization
Aberrant connection with facilitated transmission

C-fibre
To Brain
Nerve
injury
I I

II II

III/IV/V III/IV/V

A-fibre
Nerve
C-fiber terminal atrophy injury
Dorsal horn A-fiber sprouting
Normal termination pattern Interneuron degeneration

Pain hypersensibility - persistent Doubell et al, 1999

Modifikasi Meliala, 2003
Example of neuropathic pain

Perceived pain

Trauma
leading
to nerve Ascending Descending
lesion input modulation

Impulses generated
within ulnar nerve
Spinal cord

Lesion

Peripheral
nociceptors
 Example of co-existing pain: herniated disc causing
low back pain and lumbar radiculopathy
Constant ache, throbbing Shooting, burning
pain in the low back pain in the foot
Patient presents
with both types
of pain

Lesion

Activation
of local Ectopic discharges
nociceptors from nerve
root lesion
 Life is easy ---- if difficult, it means :

Your expectation greater than your capability

 Diagnosis of NP
1. Pain Assessment
Anamnesis  Basic seven
2. Physical Examination
3. Special Investigation
 Pain Assessment
Pain scale :
0-10 Numeric Pain Intensity Scale

0 1 2 3 4 5 6 7 8 9 10

Wong-Baker FACES Pain Rating Scale

0 2 4 6 8 10
No hurt Hurts a Hurts a Hurts even Hurts a Hurt
little bit little more more whole lot worst

Pain Intensity : 1-3 mild ; 4-6 moderate ; 7-10 severe pain

 VISUAL ANALOG SCALE (VAS)

NUMERIC PAIN RATING SCALE (NPRS)

Faces Pain Rating Scale (for children)

 Simple Bedside Tests: Allodynia
Type of Allodynia Assessment Expected Response
Mechanical Manual light pressure Dull pain
static of skin

Mechanical Light manual pinprick Sharp, superficial

punctate with sharp stick pain

Mechanical Stroke skin with brush, Sharp, burning,

dynamic gauze, or cotton superficial pain

Thermal warm Contact skin with Painful, burning

objects at 40°C sensation

Thermal cold Contact skin with Painful, burning

objects at 20°C sensation
Baron, 2000.
 Simple Bedside Tests:
Hyperalgesia
Type of
Hyperalgesia Assessment Expected Response
Mechanical Manual pinprick Sharp, superficial
pinprick of skin with safety pin pain

Thermal cold Contact skin with Painful, burning

coolants (acetone) sensation

Thermal heat Contact skin with Painful, burning

objects at 46°C sensation

Baron, 2000.
Easy and Simple on Neuropathic Pain

MANAGEMENT
of
NEUROPATHIC PAIN
 Neuropathic Pain:
Approach to treatment
Diagnosis

Treat underlying condition/symptomatic treatment

Prevention
(if applicable)
Reduce Pain

Improve Improve
physical overall quality
functioning Reduce of life
Psychological
distress
 Neuropathic Pain:
Treatment algorithm
NEUROPATHIC PAIN

Surgical management Nerve blocks

Medical Management

Membrane stabilizing Drugs that enhance

agents dorsal horn inhibition

Corticosteroids Antidepressants GABA-B agonist

Antikaovulsant

Antikonvulsant
Antiarrhythmics

M. Sam Chong and ZH Bajwa, J Pain Symptom Manage, May 2003

The task of a doctor:
 TO CURE IS SOMETIMES
 TO TREAT IS OFTEN
 TO COMFORT IS ALWAYS
A. Pare (1598)
MECHANISM: PAIN TRANSFORMATION
FROM ACUTE to CHRONIC

Noxious stimulus
↓
Tissue damage
↓
ACUTE PAIN (Nociceptive)
← Repetitive stimuli
Peripheral Sensitization
↓
Central Sensitization
↓
CHRONIC PAIN (Neuropathic)
 FROM ACUTE PAIN TO CHRONIC PAIN
WHY DOES IT DEVELOP ?

Continuum of Pain:
≥ 3-6 months

ACUTE PAIN CHRONIC PAIN

● Inadequate pain Tx
● “Yellow flags”
 FROM ACUTE PAIN TO CHRONIC PAIN
HOW TO PREVENT ?

ACUTE PAIN CHRONIC PAIN

☻ Aggressive pain treatment

“Analgesic Dosing Ladder”

☻ Psychological therapy for “yellow flags”

 2. ELIMINATION OF “YELLOW FLAGS”

▪ YELLOW FLAGS are psychosocial

disorders as risk factors for the development of
chronic pain. eg. Perception, memory,
behavior.

▪ Method: relaxation, cognitive behaviour

therapy.
 MANAGEMENT OF CHRONIC NEUROPATHIC
PAIN
ACUTE PAIN (< 3–6 months)

Prevent transformation to chronic pain

●Aggressive pain treatment (Curative model)
●Eliminating “yellow flags”
CHRONIC PAIN (> 3-6 months)

Chronic disability

Dysfunction Whole-patient management

Tx Pain, Sleep disorder, Mood changes
(Palliative model)
↓QOL + Socioeconomic loss
The inter-relationship between pain, sleep
and anxiety/depression
Pain

Functional
impairment

Anxiety and Sleep

depression disturbance
 Neuropathic Pain:
Whole-Patient Management
Multidisciplinary team approach
 Physician
 Nurse
 Pharmacist
 Therapists
 Psychologist/
psychiatrist
 Easy and Simple on Neuropathic Pain

PHARMACOLOGIC THERAPY
of NP
MECHANISM APPROACH
WHO ANALGESIC LADDER 1996

Freedom from pain

Opioid for moderate to severe pain Step 3
+/- Adjuvant
Persisting Pain
Opioid for mild to moderate pain Step 2
+/- Non opioid , +/- Adjuvant
Persisting Pain
Step 1
Non opioid +/- Adjuvant
 Chronic Pain: Intervention
Therapy Methode

Analgesic Nerve Block Alternative

Analgesic Ireversible
•NSAID •Operasi
-Parasetamol •Destruction •Stimulator
- opioid •Accupuncture
•Hypnosis
•Adjuvant analgesic Reversible •Psychology
•Antidepressant •Local Anesthesi
•Antikonvulsan  steroid
•etc  opioid

(McQuay
(McQuay &
& Moore,
Moore, 1999)
1999)
 MECHANISTIC APPROACH TO TREATMENT

Beydoun, 2002 BRAIN

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

Modified by MELIALA 2006

 MECHANISTIC APPROACH TO TREATMENT

BRAIN

Beydoun, 2002

Descending
Inhibition

Central Sensitization

PNS
SPINAL CORD

Ectopic Discharge

Modified by MELIALA 2006

 STANDARD THERAPY FOR
SEVERAL NEUROPATHIC PAIN CONDITION
POST- DIABETIC PHANTOM
Neuropatic TRIGEMINAL
HERPETIC Cancer pain
NEUROPATHY NEURALGIA
NEURALGIA LIMB
Pregabalin Pregabalin Epidural - Gabapentin Carbamazepin
Gabapentin Lignocaine Opioids Oxcarbazepin
Gabapentin
Paracetamol Epidural-local Gabapentin
Carbamazepin
Carbamazepin Narcotic- anestesi Valproic acid
Oxcarbazepin
Oxcarbazepin Analgetic Epidural Phenytoin
Duloxetin NSAID -Clonidin Lamotrigine
Amitriptilin
-blockers Carbamazepin Baclofen
Despiramin Amitriptilin
Tricyclic Oxcarbazepin
Mexiletine Imipramine
-antidepressant Amitriptilin
Capsaicin Despiramin
Calcitonin Amantadine (IV)
Aciclovir Phenytoin
Ketamine Capsaicin
Capsaicin Tramadol
Carbamazepin
Lignocain Capsaicin
Oxcarbazepin
High dose oral Topical- Clonidine
opioids Morphin, Mexiletine
Oxycodone, Citalopram