Neuropathic Pain

in Daily Practice
Jimbaran resto, 28 Agustus 2013

Teddy Wijatmiko ,dr.Sp.S

RSUD. Dr. Wahidin Sudirohusodo
Kota Mojokerto

1
 10.8%

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 Classification of Pain

6/15/13 PPRP 3
 NOCICEPTIVE AND NEUROPATHIC PAIN MAY
CO-EXIST IN LOW BACK PAIN CONDITIONS

Nociceptive pain component Neuropathic pain component

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 Peripheral neuropathic pain
Arch Pain 2011

Prolonged LBP 37 %
Diabetes 26%
Herper zoster 8%
Post mastectomy ~30-40%
Trigeminal neuralgia incidence 27/100.000
person-yr

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 Central neuropathic pain
Arch Pain 2011

Stroke 8 %
Multiple sclerosis 28%
Spinal cord injury 67%
Phantom limb pain incidence 1/100.000
person-yr

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 Recognition of neuropathic pain may be
challenging for many clinicians
Proportion of physicians finding it difficult to recognize
neuropathic pain

Pain specialist

Endocrinologist
Area of expertise

Neurologist

HIV specialist

Rheumatologist

Oncologist

GP

0 10 20 30 40 50 60 70

0 10 20 30 40 50 60 70
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Percentage of physicians
 Pain
Unpleasant sensory
and emotional
experience
-Associated with
actual or potential
tissue damage
-or described in
terms of such
damage

International Association for the Study of Pain

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(1986)
 Pain Pathway
Netter Neurology 2012

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 Physiology of Pain Perception

Transduction Injury Brain

Transmission
Modulation
Perception Descending
Pathway

Dorsal
Peripheral Root
Nerve Ganglion

Ascending
Pathways
C-Fiber

A-beta Fiber Dorsal

Horn
A-delta Fiber
Spinal Cord
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10 Adapted with permission from WebMD Scientific American Medicine.
 Neuropathic pain mechanisms
Netter 2012

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 Structural Reorganization
Aberrant connection with facilitated transmission

C-fibre
Nerve
injury
I I

II II

III/IV/V III/IV/V

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

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Pain hypersensibility
12
- persistent Doubell et al, 1999
Modifikasi Meliala, 2003
 Pain Patho physiology

Adapted from Julius & Basbaum.

Nature12/16/2017
2001;413(6852):203 13
 Sensitization
Primary Secondary
Tissue level CNS Level

Result in:
- treshold activation after injury
-respons to noxious stimuli
- spontaneus activity
Aguggia 2003

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 Peripheral sensitization
Core Topic in Pain 2006

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 Central sensitization
Core Topic in Pain 2006

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 Inhibitory Substance within DH
Core Topic in Pain,2006

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 Gate Control Theory
Melzack and Wall 1960
Core Topic in Pain,2006

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 Supra spinal modulation Core Topic in Pain,2006

Diagram illustrating a major descending painmodulatingpathway. Regions of the frontal lobe (F), hypothalamus(H) and amygdala (A)
project to the PAG in themidbrain. The PAG controls the transmission of nociceptiveinformation in the rostroventral medulla (RVM), DH
via relaysin the RVM and dorsolateral pontine tegmentum (DLPT). :nociceptive activation; : inhibitory (anti-nociceptive) activity
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 What is Neuropathic pain?
Definition:
Pain arising as a direct consequence of a lesion or disease
affecting the somatosensory system
Characterized by:
Pain often described as shooting, electric shock-like or burning.
The painful region may not necessarily be the same as the site
of injury.
Almost always a chronic condition (e.g. postherpetic neuralgia,
poststroke pain)
Responds poorly to conventional analgesics
Example: PHN, DPN,
CPSP

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 PERBEDAAN SECARA UMUM
NYERI NOSISEPTIK DAN NYERI NEUROPATIK :
NYERI NOSISEPTIK
- Terlokalisasi pada tempat
cedera.
- Sensasi sesuai stimulus, misalnya
jika terbakar akan terasa panas, jika
tertusuk pisau maka lesi seperti
ditikam dan lain-lain.
- Akut, mempunyai batas waktu. Nyeri
menghilang setelah cedera sembuh.
- Memiliki fungsi protektif
Konsensus Nasional Diagnostik & Penatalaksanaan Nyeri Neuropatik 2011
6/15/13
NYERI NEUROPATIK
- Nyeri di bagian distal dari lesi atau
disfungsi saraf.
- Sensasi tidak selalu sesuai stimulus,
rasa panas, berdenyut, ngilu, kaku.
- Kronis, persisten setelah cedera
menyembuh.
- Tidak memiliki fungsi protektif
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 Low back pain, diabetic neuropathy, & post herpetic
neuralgia are the most common type of pain with NeP

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 Neuropathic Pain
Signs and Symptoms

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Your Patients may be suffering NeP if they
have following characteristic

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 Diagnosing
Neuropathic Pain

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 The 3L Approach to Diagnosis

LISTEN
Patient verbal descriptors,
Q&A

LOCATE LOOK
Nervous system Sensory abnormalities,
lesion / dysfunction pattern recognition
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 Examples of Tools Used in the Diagnosis
and Assessment of Neuropathic Pain
Diagnostic aids
ID Pain Screening
Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Scale1
DN4 Pain Questionnaire2
Neuropathic Pain Questionnaire (also available in short-form)3
Neuropathic Pain Scale4

Pain intensity and characteristics

Numerical Pain Scale / Faces Pain Rating Scale9,10
Pain Visual Analog Scale5
Pain Likert Scale
McGill Pain Questionnaire6
Short-form McGill Pain Questionnaire derived
Neuropathic Pain Symptom Inventory7
Brief Pain Inventory (BPI)8
1. Bennett. Pain. 2001;92:147-57; 2. Bouhassira et al. DN4; 3. Backonja and Krause Clin J Pain. 2003;19:315-6;
4. Galer and Jensen. Neurology.1997;48:332-8; 5. Huskisson. Lancet. 1974;2:1127-31; 6. Melzack and Togerson.
6/15/13
Anesthesiology. 1971;34:50-59; 7. Bouhassira et al. Pain. 2004;108:248-57;
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8. Cleeland. Ann Acad Med Singapore. 1994;23(2):129-38
 ID Pain
Screening
test

Score = 3

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 Efficacy Assessments:
Daily Pain and Sleep Interference Diaries
Pain Diary (primary efficacy parameter)
Select the number that best describes your neuropathic pain
during the past 24 hours. (Circle one number only)
0 1 2 3 4 5 6 7 8 9 10

Worst
No possible
pain pain

Sleep Diary
Select the number that best describes how your pain interfered with your sleep
during the past 24 hours. (Circle one number only)
0 1 2 3 4 5 6 7 8 9 10

None Unable
to sleep

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Management of Neuropathic Pain

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 Stepwise Pharmacology
Management Neuropathic Pain
Step 1

Assess pain and establish the diagnosis of NP

Establish and treat the cause of NP
Identify relevant comorbidities (e.g., cardiac, renal, or
hepatic disease, depression, gait instability)
Explain the diagnosis and treatment plan to the
patient, and establish realistic expectations

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 Step 2
Initiate therapy of the disease causing NP, if applicable
Initiate symptom treatment
Evaluate patient for nonpharmacologic treatment

Step 3
Reassess pain and health-related QoL frequently
If substantial pain relief (e.g., average pain reduced to NRS 3/10)
and tolerable side effects, continue treatment.
If partial pain relief add 1 of the other first-line medications
If no or inadequate pain relief switch to an alternative first-line
medication

Step 4
If trials of first-line medications alone and in combination fail,
consider second-line medications or referral to a pain specialist or
multidisciplinary pain center
6/15/13and Dworkin
OConnor PPRP
Guidelines for Treatment of Neuropathic Pain 2009 33
 The Inter-Relationship Between Pain,
Sleep, and Anxiety / Depression

Pain

Functional
impairment

Anxiety & Sleep

Depression Disturbances
45% 90%
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Nicholson and Verma. Pain Med. 2004;5 (suppl. 1):S9-S27; Arsenault. Canadian J Diagnosis 2010; Meyer-Rosberg K. Eur J Pain. 2001
 PENATALAKSANAAN NYERI
NEUROPATIK
Tujuan :
Meningkatkan kualitas hidup pasien dengan melakukan
pendekatan secara holistik, berupa pengobatan terhadap
pain triad, yaitu nyeri, gangguan tidur dan gangguan mood
( ansietas, depresi dan obsesi konvulsi ) yang dilakukan oleh tim
multidisiplin.

Konsensus Nasional Diagnostik & Penatalaksanaan Nyeri

Neuropatik, Pokdi Nyeri PERDOSSI, 2011

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 Analgesic for Neuropathic Pain
First Line (TCA, SSNRi, Calcium Channel
2-Ligands (Gabapentin and Pregabalin)
Topical Lidocain

Second Line : Opioid analgesic, Tramadol

Third line : bupropion, citalopram, and

parox- etine,

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 EFNS recommendation 2010
Diabetic NP Duloxetin,Gabapentin, pregabalin,
TCA, venlavaxine

PHN Gabapentin, pregabalin,

TCA, lidocain plester

TN Carbamazepin, oxcarbazepine

Central pain Gabapentin, pregabalin,

TCA

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 Tricyclic antidepressants (TCAs)
40-60% effiacy for partial relief (NNT~ 2.5-3)
Starts 10-25 mg/d and 10-25 mg each w
best effect 50-150 mg/d
Mechanism : NE & 5 HT reuptake blockade
Anticholinergic effects

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 Selective Serotonin-Norepinephrine
Reuptake Inhibitors (SNRIs)
Duloxetine Venlavaxine
NNT~ 4-5(~7 for SSRI) NNT~ 4-5
Start & efficacius @ 60 Start37,5 mg/d
mg/d Increase by 37,5 mg weekly
Antidepressant & anxiolityc Effective @ 150-225 mg/d
Favorable side effect profile
Limited long term data

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 Pregabalin
NNT~ 3.5-4.5

Despite advance in research and clinical trial,

a considerable number of individuals do not
get relief
NNT~3-5 for most drugs

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 Non-Pharmacological Treatment
Should be considered whenever appropriate 1
Complementary to drug therapy ,Include 2

Physiotherapy
Acupunture
Transcutaneus electrical nerve stimulation
(TENS)
1.Gilron, Can Med Assoc J, 2006;175;265-275
2. Bennet MI, Pain Clinical Update, 2010; 18 :1-6

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 Provelyn Pregabalin
The Advance Treatment
for Pain Triad
in Neuropathic Pain

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 INDICATIONS

Approved by BPOM
Peripheral neuropathic pain
Central neuropathic pain
Epilepsy
Generalized Anxiety Disorder (GAD)
Fibromyalgia

1. 6/15/13
BPOM Approval 2008. 43
2. FDA Approval 2007.
 Pregabalin Modulates Hyperexcited Neurons

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*Does not affect Ca++ influx in normal neurons
 The Difference
Pregabalin Gabapentin

Pregabalin is different molecule from gabapentin1

Pregabalin is rapidly absorbed 1 fast pain relief 4,5
Pregabalin plasma concentration is proportional to dose (high
bioavailability)1more predictable pharmacokinetics
6ease to use in clinical practice6

References: 1. Bockbrader HN et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 2010; 49: 66169. 2. Provelyn
Product Information. 3. Nepatic Product Information. 4. Lesser H et al. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 2004; 63:
2105. 5. Dworkin RH et al. Pregabalin in the treatment of postherpetic neuralgia: A randomized, placebo-controlled trial. Neurology 2003; 60: 127483. 6. Ben-Menachem E. Pregabalin
pharmacology and its relevance to clinical practice. Epilepsia 2004; 45 Suppl 6: 1318.

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 The Difference
Pregabalin has predictable, linear pharmacokinetics

Steady state minimum plasma drugs concentration

Bockbrader HN et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin
Pharmacokinet 2010; 49: 66169

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Most Frequent Adverse Events and Discontinuations
in Peripheral Neuropathic Pain Studies (% of Patients)

Placebo (n=764) Pregabalin (n=1556)

Discontinue Discontinue
Incidence Incidence
d d
Dizziness 6.4 0.3 21.7* 3.1

Somnolence 3.8 0.1 13.8* 2.6

Peripheral edema 1.8 0.1 9.5* 0.8

Infection 4.8 0.1 6.2 0.1

Dry mouth 1.8 0.1 5.9* 0.3

* P<0.05 all pregabalin vs. placebo

Those occurring in 5% of pregabalin-treated patients and with higher frequency with pregabalin
than placebo
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 Overall assesment by physicians and
patients of the tolerability of pregabalin
Physicians Patients

95 % very good or good 95% very satisfied or

satisfied

Mallison R et al, MMW Forschr Med 2007;149;46

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 Pregabalin, Pain , Sleep and Mood

After 12 weeks, significant improvements in pain,

associated symptoms of anxiety, depression and sleep
disturbances, general health; and level of disability
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 Recommended treatments for
peripheral neuropathic pain
Guideline 1st line recommendations 2nd line recommendations
The European Federation of Pregabalin, gabapentin, TCAs, Tramadol, opioids, capsaicin
Neurological Societies duloxetine, venlafaxine ER,
(EFNS)1 lidocaine
The International Association Pregabalin, gabapentin, TCAs, Opioid analgesics, tramadol
for the Study of Pain (IASP)*2 duloxetine, venlafaxine, lidocaine
(topical)
The Canadian Pain Society Pregabalin, TCAs, gabapentin SNRIs, lidocaine (topical)
(CPS)*3

*Guidelines did not distinguish between peripheral and central neuropathic pain.
For focal neuropathy, such as postherpetic neuralgia.

TCAs, tricyclic antidepressants; ER, extended release; SNRIs, serotonin-norepinephrine reuptake inhibitors.
Venlafaxine is not approved for the treatment of neuropathic pain.

1. Attal N et al. Eur J Neurol 2010;17:1113-e88.

6/15/13 2. Dworkin RH et al. Mayo Clin Proc 2010;85(3Suppl):S3-14.
50
3. Moulin DE et al. Pain Res Manag 2007;12:13-21.
 Recommended treatments for
central neuropathic pain
Guideline 1st line recommendations 2nd line recommendations
The European Federation of Pregabalin, gabapentin, TCAs Lamotrigine, tramadol, opioids,
Neurological Societies cannabinoids
(EFNS)1
The International Association Pregabalin, gabapentin, TCAs, Opioid analgesics, tramadol
for the Study of Pain (IASP)*2 duloxetine, venlafaxine, lidocaine
(topical)
The Canadian Pain Society Pregabalin, TCAs, gabapentin SNRIs, lidocaine (topical)
(CPS)*3

*Guidelines did not distinguish between peripheral and central neuropathic pain.
TCAs, tricyclic antidepressants; ER, extended release; SNRIs, serotonin-
norepinephrine reuptake inhibitors.
Venlafaxine is not approved for the treatment of neuropathic pain.

1. Attal N et al. Eur J Neurol 2010;17:1113-e88.

6/15/13 2. Dworkin RH et al. Mayo Clin Proc 2010;85(3Suppl):S3-14.
51
3. Moulin DE et al. Pain Res Manag 2007;12:13-21.
 Conclusion
NeuP is pain arising as a direct
consequence of a lesion or disease
affecting the somatosensory system
5 Characteristics of NeuP: Electric shocks,
Painful cold, Pins & needles, Burning,
Itching.
Approach for NeuP with Pain Triad
Pregabalin (Provelyn ) recommended
treatment for peripheral & central NeuP
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 Maturnuwun

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