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Neuropathic Pain in Daily Practice

Jimbaran resto, 28 Agustus 2013

Teddy Wijatmiko ,dr.Sp.SRSUD. Dr. Wahidin Sudirohusodo

Kota Mojokerto

10.8%

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Classification of Pain

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NOCICEPTIVE AND NEUROPATHIC PAIN MAYCO-EXIST IN LOW BACK PAIN CONDITIONS

Neuropathic pain componentNociceptive 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

0 10 20 30 40 50 60 70

2010 4030 500 60 70

GP

Oncologist

Rheumatologist

HIV specialist

Neurologist

Endocrinologist

Pain specialist

Are

a o

f ex

per

tise

Percentage of physicians04/09/2023 7

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 (1986)

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Pain Pathway Netter Neurology 2012

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Physiology of Pain Perception

• Transduction• Transmission• Modulation• Perception

Injury

Descending Pathway

PeripheralNerve

Dorsal RootGanglion

C-Fiber

A-beta Fiber

A-delta Fiber

AscendingPathways

Dorsal Horn

Brain

Spinal Cord

Adapted with permission from WebMD Scientific American® Medicine.1004/09/2023 10

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Neuropathic pain mechanisms Netter 2012

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I

II

III/IV/V

Nerveinjury

Nerveinjury

Dorsal hornNormal termination pattern

C-fiber terminal atrophyA-fiber sproutingInterneuron degeneration

Pain hypersensibility - persistent Doubell et al, 1999

C-fibre

A-fibre

Aberrant connection with facilitated transmission

Structural Reorganization

I

II

III/IV/V

Modifikasi Meliala, 200304/09/2023 12

Adapted from Julius & Basbaum. Nature 2001;413(6852):203

Pain Patho physiology

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Sensitization

Primary• Tissue level

Secondary• CNS Level

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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 TheoryMelzack 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 analgesicsExample: PHN, DPN, CPSP

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PERBEDAAN SECARA UMUM NYERI NOSISEPTIK DAN NYERI NEUROPATIK :

NYERI NOSISEPTIK NYERI NEUROPATIK

- 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

- 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

Konsensus Nasional Diagnostik & Penatalaksanaan 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

LOCATE LOOKNervous system

lesion / dysfunctionSensory abnormalities,

pattern recognition

Patient verbal descriptors,Q & A

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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.Anesthesiology. 1971;34:50-59; 7. Bouhassira et al. Pain. 2004;108:248-57; 8. Cleeland. Ann Acad Med Singapore. 1994;23(2):129-38

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✔

✔

✔

✔

✔

✔ Score = 3

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ID Pain Screening

test

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

Nopain

Worst possible pain

Pain Diary (primary efficacy parameter)

Sleep Diary

0 1 2 3 4 5 6 7 8 9 10

None Unable to sleep

Select the number that best describes how your pain interfered with your sleep during the past 24 hours. (Circle one number only)

Efficacy Assessments: Daily Pain and Sleep Interference Diaries

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Management of Neuropathic Pain

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Stepwise Pharmacology Management Neuropathic Pain

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• Step 1

Assess pain and establish the diagnosis of NPEstablish and treat the cause of NPIdentify 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

Assess pain and establish the diagnosis of NPEstablish and treat the cause of NPIdentify 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 2 Initiate therapy of the disease causing NP, if applicable Initiate symptom treatment Evaluate patient for nonpharmacologic treatment

Step 3Reassess 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 3Reassess 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

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

O’Connor and Dworkin Guidelines for Treatment of Neuropathic Pain 2009

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The Inter-Relationship Between Pain, Sleep, and Anxiety / Depression

Nicholson and Verma. Pain Med. 2004;5 (suppl. 1):S9-S27; Arsenault. Canadian J Diagnosis 2010; Meyer-Rosberg K. Eur J Pain. 2001

Pain

SleepDisturbances

90%

Anxiety &Depression

45%

Functional impairment

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PENATALAKSANAAN NYERI NEUROPATIK

Konsensus Nasional Diagnostik & Penatalaksanaan NyeriNeuropatik, Pokdi Nyeri PERDOSSI, 2011

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.

Tujuan :

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Analgesic for Neuropathic Pain

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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

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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• NNT~ 4-5(~7 for SSRI)• Start & efficacius @ 60

mg/d• Antidepressant & anxiolityc• Favorable side effect profile• Limited long term data

Venlavaxine• NNT~ 4-5• Start37,5 mg/d• Increase by 37,5 mg weekly• Effective @ 150-225 mg/d

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PregabalinNNT~ 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

PhysiotherapyAcupuntureTranscutaneus 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 ® PregabalinThe 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. BPOM Approval 2008.2. FDA Approval 2007.

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44*Does not affect Ca++ influx in normal neurons

Pregabalin Modulates Hyperexcited Neurons

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The Difference

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

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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.

Pregabalin Gabapentin

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The DifferencePregabalin has predictable, linear pharmacokinetics

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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)

IncidenceDiscontinue

dIncidence

Discontinued

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

95 % very good or good

Patients

95% very satisfied or satisfied

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

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Pregabalin, Pain , Sleep and Mood

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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

1. Attal N et al. Eur J Neurol 2010;17:1113-e88.2. Dworkin RH et al. Mayo Clin Proc 2010;85(3Suppl):S3-14.

3. Moulin DE et al. Pain Res Manag 2007;12:13-21.

*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.

Guideline 1st line recommendations 2nd line recommendations

The European Federation of Neurological Societies (EFNS)1

Pregabalin, gabapentin, TCAs, duloxetine, venlafaxine ER, lidocaine§

Tramadol, opioids, capsaicin§

The International Association for the Study of Pain (IASP)*2

Pregabalin, gabapentin, TCAs, duloxetine, venlafaxine, lidocaine

(topical)

Opioid analgesics, tramadol

The Canadian Pain Society (CPS)*3

Pregabalin, TCAs, gabapentin SNRIs, lidocaine (topical)

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Recommended treatments for central neuropathic pain

1. Attal N et al. Eur J Neurol 2010;17:1113-e88.2. Dworkin RH et al. Mayo Clin Proc 2010;85(3Suppl):S3-14.

3. Moulin DE et al. Pain Res Manag 2007;12:13-21.

*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.

Guideline 1st line recommendations 2nd line recommendations

The European Federation of Neurological Societies (EFNS)1

Pregabalin, gabapentin, TCAs Lamotrigine, tramadol, opioids, cannabinoids

The International Association for the Study of Pain (IASP)*2

Pregabalin, gabapentin, TCAs, duloxetine, venlafaxine, lidocaine

(topical)

Opioid analgesics, tramadol

The Canadian Pain Society (CPS)*3

Pregabalin, TCAs, gabapentin SNRIs, lidocaine (topical)

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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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