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

Neurologist
Area of expertise

HIV specialist

Rheumatologist

Oncologist

GP

0 10 20 30 40 50 60 70
9/1/2013 7
Percentage of physicians
 Pain
 Unpleasant sensory
and emotional
experience
-Associated with
actual or
potential
tissue damage
-or described in
terms of such
damage
9/I1n/t2e0r1n3ational Association for the Study of 8
Pain (1986)
 Pain Pathway
Netter Neurology 2012

6/15/13 PPRP
9
 Physiology of Pain Perception

• Transduction Injury Brain

• Transmissio
n
• Modulation
Descending
• Perception
Pathway
Dorsal
Peripheral
Root
Nerve
Ganglion

Ascending
Pathways
C-Fiber

A-beta Fiber Dorsal

A-delta Fiber Horn
Spinal Cord
9/1/2013
10 Adapted with per1m0ission from WebMD Scientific American®
 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

Dorsal horn C-fiber terminal atrophy injury

Normal termination pattern A-fiber sprouting
Interneuron degeneration

9/1/2013
Pain hypersensibility
12
- persistent Doubell et al, 1999
Modifikasi Meliala,
 Pain Patho physiology

Adapted from Julius & Basbaum.

13
Nature92/10/0210;14313(6852):203
 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
6/15/13
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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
6/15/13 PPRP 20
 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 &
Pena
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
talaksanaan Nyeri Neuropatik 2011
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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
27
6/15/13
 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 and6J/e1971;34:50-59;
Anesthesiology. 1ns5en/.1N3eurology.1997;48:332-8;
7. Bouhassira et al.5.Pain.
Huskisson. Lancet. 1974;2:1127-31; 6. Melzack and
2004;108:248-57;
28
8. Cleeland. Ann Acad Med Singapore. 1994;23(2):129-38
Togerson.
 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 10
9
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 Unable
None
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

32
 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
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O’Connor and Dworkin Guidelines for Treatment of Neuropathic Pain
 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
α2-δLigands (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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PPRP
 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 & • Effective @ 150-225 mg/d
anxiolityc
• 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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 INDICATION
S
• Approved by BPOM
– Peripheral neuropathic pain
– Central neuropathic pain
– Epilepsy
– Generalized Anxiety Disorder (GAD)
– Fibromyalgia

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1. BP6O/M15A/p1p3roval
 Pregabalin Modulates Hyperexcited Neurons

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 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)1more predictable pharmacokinetics
6ease 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: 661–69. 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: 1274–83. 6. Ben-Menachem E. Pregabalin
pharmacology and its relevance to clinical practice. Epilepsia 2004; 45 Suppl 6: 13–18.

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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: 661–69

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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

5.9* 0.3
Dry mouth 1.8 0.1
* P<0.05 all pregabal in 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 95% very satisfied

good 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 Pregabalin, gabapentin, Tramadol, opioids, capsaicin§
of Neurological Societies TCAs, duloxetine, venlafaxine
(EFNS)1 ER, lidocaine§
The International Association Pregabalin, gabapentin, TCAs, Opioid analgesics, tramadol
for the Study of Pain duloxetine, venlafaxine,
(IASP)*2 lidocaine (topical)
The Canadian Pain Pregabalin, TCAs, gabapentin SNRIs, lidocaine (topical)
Society (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(3Sup5p0l):S3-
14.
 Recommended treatments for
central neuropathic pain
Guideline 1st line recommendations 2nd line recommendations
The European Federation Pregabalin, gabapentin, TCAs Lamotrigine, tramadol, opioids,
of Neurological Societies cannabinoids
(EFNS)1
The International Association Pregabalin, gabapentin, TCAs, Opioid analgesics, tramadol
for the Study of Pain duloxetine, venlafaxine,
(IASP)*2 lidocaine (topical)
The Canadian Pain Pregabalin, TCAs, gabapentin SNRIs, lidocaine (topical)
Society (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(3Sup5p1l):S3-
14.
 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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