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PAIN EDUCATION Module 5: Neuropathic pain

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© 2013 Excerpta Medica BV

Upon completion of this training module you should have gained an increased understanding of: • • •

• • • • •

Sensory disturbances and the types of neuropathic pain (NP) The causes of NP and the mechanisms of acute and chronic pain The epidemiology, pathophysiology, risk factors, and socioeconomics of post-herpetic neuralgia (PHN) and diabetic polyneuropathy (DPN) The diagnosis of NP, including assessment, physical examination, and additional examination The treatment of NP according to the latest guidelines and the stepwise treatment algorithm First-, second-, third- and fourth-line medication according to latest guidelines and their classification Newly developed drugs for the treatment of NP The mechanism-based treatment of neuropathic pain

For additional information and further educational content related to neuropathic pain, please see Module 5 of the CME-accredited e-learning PAIN EDUCATION modules, available at www.pain-cme.net

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Learning objectives

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Definition of neuropathic pain

Neuropathic pain is the pain that arises as a direct consequence of a lesion or disease affecting the somatosensory system

References Haanpää ML, et al. Mayo Clin Proc. 2010;85:S15-25. Treede RD, et. al. Neurology. 2008;70:1630-5.

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Condition

Manifestation

Allodyna

Pain due to a stimulus that does not normally provoke pain

Paraesthesia

An abnormal sensation, which can be spontaneous or evoked

Dysaesthesia

An unpleasant abnormal sensation, which can be spontaneous or evoked

Hyperaesthesia

Increased sensitivity to stimulation

Hyperalgesia

An increased pain from a stimulus that normally provokes pain

Hypoaesthesia

Decreased sensitivity to stimulation

Anaesthesia

A loss of feeling or awareness caused by drug or other substances

Hypoalgesia

Diminished pain in response to a normally painful stimulus

Analgesia

Absence of pain in response to a stimulus that would normally be painful

Reference Vissers KC. Disabil Rehabil. 2006; 28:343-9.

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Sensory disturbances in neuropathic pain

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Classification according to the anatomical location of the lesion and underlying cause of the disorder. ● ● ● ● ● ●

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Types of neuropathic pain

Complex painful neuropathic disorders Painful peripheral neuropathy Central-pain syndrome Mixed-Pain syndrome Mononeuropathy Polyneuropathy

References Baron R. Handb Exp Pharmacol. 2009;194:3-30. Mick G et al. Pain Manage. 2012;2:71-7. Freynhagen R et.al. BMJ. 2009;339:b3002. Paster Z et al. Postgrad Med. 2010;122:91-1.

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Causes Metabolic disease Neurotropic viral disease

Examples

Peripheral

Central

Diabetes

×

×

Varicella-zoster virus (VZV) infection

×

Herpes simplex virus (HSV) infection

×

Human immunodeficiency virus (HIV) infection

× ×

Vertebral-disk herniation Mechanical nerve injury (post-surgical, post-trauma, compression)

Neurotoxicity Inflammatory and / or immunological mechanisms

Post-thoracotomy syndrome

×

Carpal tunnel syndrome (CTS)

×

Syringomyelia (compression by syrinx)

Chemotherapy

×

× ×

Multiple sclerosis

Stroke / ischaemia

Thalamic syndrome

×

Hereditary neuropathies

Amyloid neuropathy

×

Reference Zimmermann M. Eur J Pharmacol. 2001;429:23-37.

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Causes of neuropathic pain

×

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Schematic overview of molecular consequences of peripheral nerve damage

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Molecular mechanisms of neuropathic pain Nerve damage Release of TNF, IL-1 NGF

Massive influx of action potentials in the spinal cord

Antero- and retrograde axonal transport Expression of bradykinin receptors and neuropeptides

Local effect Na+ channels Cytokines Induction of COX-2

Peripheral sensitization

References Gilron I et al. CMAJ. 2006;175:265-75. Vranken JH. Cent Nerv Syst Agents Med Chem. 2009;9:71-8.

Intracellular molecular change Number of receptors (AMPA, NMDA, NK1) Central sensitization 5

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Epidemiology of post-herpetic neuralgia Patients reporting pain (%)

100 80 > 1 year

60

6–12 months 1–6 months < 1 month

40 20 0 0–19

20–29 30–39 40–49 50–59 60–69

≥ 70

Age (years)

• Primary infection (chickenpox) in 90% of children by age 15 • Latent reactivation of virus causes herpes zoster, has lifetime incidence of 10–20% • Herpes zoster patients: – 9–14% develop PHN – 20–50% of patients > 50 years of age develop PHN References Gershon AA, et.al. J Clin Virol. 2010;48:S2-7. Mohamed SA, et al. Pain Clinical Updates. 1994; 2:1-8.

PHN = post-herpetic neuralgia. 6

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Risk factors in developing herpes zoster ● Age ● Impaired cell-mediated immunity ● Diabetes ● Female gender ● Genetic susceptibility ● Mechanical trauma ● Recent psychological stress ● Caucasian ethnicity

Incidence per 1,000 person-years

Risk factors of post-herpetic neuralgia 15 10 5 0 < 65 year

> 65 year

Risk factors in children • Maternal VZV infection during late pregnancy • History of primary VZV infection early in life • Being immunocompromised

References Dworkin RH, et al. Clin Infect Dis. 2007;44:S1-26. Gershon AA, et.al. J Clin Virol. 2010;48:S2-7.

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VZV infection

Latency of VZV VZV reactivation Acute herpes zoster (shingles): skin rashes and pain

Neurological complications of VZV: PHN

VZV enters body via respiratory tract

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Pathophysiology of post-herpetic neuralgia (PHN)

Virus spreads to circulating T-lymphocytes 10–21 day incubation

Vesicular varicella rash PHN = post-herpetic neuralgia; VZV = varicella zoster virus.

Reference Gershon AA, et al. J Clin Virol. 2010;48:S2-7.

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• In 2000, there were more than 171 million diabetics worldwide • 16–50% of diabetes patients have DPN • 10–20% of DPN patients experience troublesome sensory symptoms requiring treatment

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Epidemiology of diabetic peripheral neuropathy (DPN)

Schmader’s findings 20%

6%

1

2

3

4

5

6

7

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Pain intensity • Average pain intensity among diabetics: 5.75 on a scale of 0–10

9 10

74%

Diabetes patients Baseline patients Patients Presence of neuropathy

References Boulton AJ et al. Diabetes Care. 2004;27:1458-86. Schmader KE. Clin J Pain. 2002;18:350-4. Wild S et al. Diabetes Care. 2004;27:1047-53.

DPN = diabetic polyneuropathy. 9

Risk factors ● Degree and duration of hyperglycaemia

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Risk factors of diabetic peripheral neuropathy (DPN)

– Poorly controlled glucose levels contribute to nerve damage

● Smoking – Vasoconstriction impairs blood flow to extremities

● Diabetic microvessel disease – Comorbid retinopathy and nephropathy – Probable causes: damaged and leaky vessels caused by hypoxia and ischemia References Zochodne DW. Muscle Nerve. 2007;36:144-66. Dyck PJ. Diabetes Care. 1999;22:1479-86.

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Pathophysiology of diabetic peripheral neuropathy (DPN) Diabetes Hyperglycaemia Non-enzymatic glycation

Polyol pathway

AGEs

Microvascular dysfunction and oxidative stress Axonal degeneration

DPN AGEs = advanced glycation end-products; DPN = diabetic polyneuropathy. Reference Sima AA et al. Ann N Y Acad Sci. 2006;1084:235-49.

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Neuropathic pain: signs and symptoms (1) Sensory signs / symptoms Negative

Positive

Reduced sensation or complete loss of sensation - Touch - Vibration - Pain - Temperature

References Baron R. Nat Clin Pract Neurol. 2006;2:95-106. Baron R et al. Lancet Neurol. 2010;9:807-19.

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Neuropathic pain: signs and symptoms (2) Sensory signs / symptoms Positive

Negative Spontaneous sensation

Evoked sensation Allodynia

Hyperalgesia Ongoing Non-painful Burning/ dull pain

Painful Itching/ antcrawling

References Baron R. Nat Clin Pract Neurol. 2006;2:95-106. Baron R et al. Lancet Neurol. 2010;9:807-19.

Discontinuous Painful

Exaggerated pain response to painful stimulus

Spreading

Abnormal pain response to nonpainful stimuli such as

Intensifying

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Diagnosis algorithm

Pain case history

Sensory system

Physical examination

Motor system

References Gilron I, et al. CMAJ. 2006;175:265-75. Baron R. Nat Clin Pract Neurol. 2006;2:95-106. Haanpää M, et al. Pain: Clinical Updates. 2010;18:1-8

Sympathetic system

Special examination

Localization of pain

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Yes

No

1. Does the patients history suggest a relevant nerve lesion or disease?

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Localized Neuropathic Pain screening tool - algorithm

2. Is the pain distribution neuroanatomically plausible?

3. Does the neurobiological examination reveal any negative or positive sensory sign in the area of the presumably lesioned nerve?

3x yes  at least probable neuropathic pain

4. Is the most painful area circumscribed and smaller than an A4 paper? 4x yes  at least probable localized neuropathic pain Reference Mick G, et al. WCN. 2013.

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•

Start testing with a body region located far away from the painful body regions

•

Repeat every stimulation three times

•

Quantitate the response – Grade response as normal, decreased or increased

•

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Localized Neuropathic Pain screening tool – sensory examination

Touch Pinprick Vibration

Ask the patient to rate the pain 0 = no pain/discomfort to touch 1 = uncomfortable but tolerable to touch

Touch

2 = painful 3 = extremely painful, patient cannot stand touching

Pressure

Test area is the area of maximum pain as indicated by the patient Localized pain is if the test area is smaller than A4 paper Reference Mick G, et al. WCN. 2013.

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Documentation of

Pain case history • • •

Current medical history Occupational history Detailed past medical history incl. family history

Neuropathy

• • •

Medication history Use of recreational drugs or alcohol Risk factors (HIV, travel, diet etc)

Malignancy

System

Positive symptoms

Negative symptoms

Sensory (large fibre)

Paresthesias, tingling

Loss of vibration or joint position sense, areflexia, sensory ataxia, hypotonia

Sensory (small fibre)

Burning, jabbing pain, dysesthesias

Loss of pain or temperature sense

Motor

Cramps, fasciculations, restless legs, tightness

Weakness, fatigability, hypotonia, areflexia, deformities

Autonomic

Hyperhidrosis, excess saliva

Orthostatic hypotension, erectile dysfunction, bowel and / or bladder dysfunction

References Hansson P. Eur J Pain. 2002;6:47-50. Haanpää M et al. Pain. 2011;152:14-27.

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Pain case history

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Tests used in physical examination of patients suspected with neuropathic pain

Sensory

Autonomic

Test

Assess

Test

Assess

Cotton wisp

Allodynia

Laser doppler flow

Blood flow

128-Hz tuning fork

Reduced detection of vibration

Infra-red test

Skin temperature

Warm / cold objects

Allodynia

Sweating, heart rate, blood pressure

Toothpick

Hyperalgesia

Quantitative Sudomotor Axon Reflex Test (QSART)

Von Frey fibres (SWME)

Hyperalgesia

Thermoregulatory sweat test

Sweating

References Baron R. Nat Clin Pract Neurol. 2006;2:95-106. Haanpää M et al. Pain. 2011;152:14-27.

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Physical examination

Motor Test

Assess Weakness Muscle symmetry

Motor function tests

Bulk Tone Fasciculations

Response, reproducibility and symmetry of deep tendon reflexes

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Stepwise approach to treating neuropathic pain

1

2

Pain assessment and diagnosis

Initiate therapy for NP causing disease

Establish NP cause and treatment

First-line medication for symptom treatment

Establish relevant comorbidities influencing NP treatment

Patient evaluation for nonpharmacological treatment

Doctor–patient communication: goals and treatment explanation References Attal N et al. Eur J Neurol. 2010;17:1113-e88. Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-14.

3

4

Pain and HR-QoL reassessment (recurrent)

If

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Treatment algorithm

Second- / third- / fourth-line treatment

First-line medication for symptom treatment

Substantial pain

Partial pain relief

No or inadequate pain relief

Continue

Add

Other first-line possibility?

Yes No

Switch HR-QoL = health related quality of life. 19

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Treatment: first-line medication Nortriptyline Systemic treatment

Secondary amine TCAs

Antidepressants

Anticonvulsants Topical treatment Local analgesic

Desipramine Amitriptyline

SNRIs

Duloxetine

Calcium channel 2- ligands

Gabapentin

Amino amide-type

Lidocaine patch

Pregabalin

TCAs = tricyclic antidepressants; SNRI = serotonin-norepinephrine reuptake inhibitor. Reference Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-14.

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Morphine Strong opioid analgesics Systemic treatment

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Treatment: second-line medication Oxycodone Methadone Fentanyl Weak opioid analgesics

Tramadol

Analgesics may be considered as first-line medication: • • • • •

If NP patients do not respond to other first line medications If patients have acute NP If patients have NP due to cancer If patients have episodic exacerbations of severe NP If prompt pain relief is required when titrating one of the first-line medications

Reference Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-14.

NP = neuropathic pain.

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TCAs Antidepressant Systemic treatment

Bupropion

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Treatment: third-line medication Citalopram SSRI

Paroxetine Carbamazepin

Anticonvulsants

Lamotrigine Oxcarbazepin Topiramate Valproic acid

SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant. Reference Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-14.

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After diagnosis

Causal therapy

Treating localized symptoms

For widespread pain

Lidocaine patch

If there is no patient relief, or if there is insufficient pain relief

Antidepressants

In case of inadequate effect: consultation with pain specialist

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Summary of treatment rationale

Weak or strong opioids

Anticonvulsants

Reference Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-S14.

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Mechanism-based treatment approach for neuropathic pain management Pain character/ symptoms

Diagnosis, e.g.

Affecting the nervous system / burning / shooting / concomitant neurological symptoms

Diabetic polyneuropathy / post-herpetic neuralgia

Mechanisms

Pain therapy with medication Formation of new channels and receptors / ectopic impulse generation (spontaneous activity)

Anticonvulsives (Na+- and Ca2+channel blockers) / antidepressants (especially TCAs) / topical lidocaine

Central sensitization

Noradrenaline and serotonin re-uptake inhibitors (antidepressants), opioids or MOR-NRI (tapentadol)

Neuropathy

Reduced endogenous pain inhibition

References Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-14. Dworkin RH et al. Pain. 2007;132:237-51. Woolf CJ. Life Sci. 2004;74:2605-10. Hans G et al. Clin Pharmacol. 2010;2: 65–70. Kress H. Eur J Pain. 2010;14(8):781-783.

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Mechanism-based treatment

TCA = tricyclic antidepressant. 24

Antidepressants (SSRIs)

Paroxetine Citalopram Escitalopram

Anticonvulsants

Lacosamide

MOR-NRI (dual action)

Tapentadol

Systemic

Intradermal

Botulinum toxin

Topical

High concentration capsaicin patch

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Recent clinical trials on new treatment approaches

Pregabalin + topical 5% lidocaine (PHN, DPN) Pregabalin + oxycodone (PHN, DPN) Combination therapies

Gabapentin + oxycodone Gabapentin + extended release morphine Gabapentin + nortriptyline Sodium valporate + glyceryl trinitrate spray (DPN)

References Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-14. Afilalo M et al. Pain Physician. 2013;16(1):27-40. Steigerwald I et al. Curr Med Res Opin. 2012;28(6):911-936.

DPN = post-herpetic neuralgia; MOR-NRI = noradrenalin reuptake inhibitor; PHN = advanced glycation end-product; SSRI = selective serotonin reuptake inhibitor.

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  

Neuropathic pain is a severe and disabling disorder usually occurring as a consequence of a lesion or disease of the nervous system Neuropathic pain is classified according to anatomical location of the lesion and underlying causes Signs and symptoms of neuropathic pain can be

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Summary

– Negative: reduced or loss of sensation – Positive: spontaneous or evoked sensation including abnormal responses to (non-)painful stimuli





In the diagnosis of neuropathic pain, physical examination includes tests of the sensory, motor, sympathetic and autonomic system to assess the positive and negative symptoms Treatment of neuropathic pain includes: – Causal therapy and local analgesic (e.g. lidocaine patch) – Widespread pain: antidepressants/anticonvulsants – No or insufficient relief: weak or strong opioid analgesics (e.g. tramadol or morphine)



Effective management of neuropathic pain requires a mechanism-based approach

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