PAIN EDUCATION Module 5: Neuropathic pain

PAIN EDUCATION Module 5: Neuropathic pain

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Learning objectives 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

Definition of neuropathic pain Neuropathic pain is the pain that arises as a direct consequence of a lesion or disease affecting the somatosensory system Haanpää ML, et al. Mayo Clin Proc. 2010;85:S15-25. Treede RD, et. al. Neurology. 2008;70:1630-5. 1

Sensory disturbances in neuropathic pain Condition Allodynia Paraesthesia Dysaesthesia Hyperaesthesia Hyperalgesia Hypoaesthesia Anaesthesia Hypoalgesia Analgesia Manifestation Pain due to a stimulus that does not normally provoke pain An abnormal sensation, which can be spontaneous or evoked An unpleasant abnormal sensation, which can be spontaneous or evoked Increased sensitivity to stimulation An increased pain from a stimulus that normally provokes pain Decreased sensitivity to stimulation A loss of feeling or awareness caused by drug or other substances Diminished pain in response to a normally painful stimulus Absence of pain in response to a stimulus that would normally be painful Reference Vissers KC. Disabil Rehabil. 2006; 28:343-9. 2

Types of neuropathic pain Classification according to the anatomical location of the lesion and underlying cause of the disorder. Complex painful neuropathic disorders Painful peripheral neuropathy Central-pain syndrome Mixed-Pain syndrome Mononeuropathy Polyneuropathy 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. 3

Causes of neuropathic pain Causes Examples Peripheral Central Metabolic disease Diabetes Neurotropic viral disease Varicella-zoster virus (VZV) infection Mechanical nerve injury (post-surgical, post-trauma, compression) Herpes simplex virus (HSV) infection Human immunodeficiency virus (HIV) infection Vertebral-disk herniation Post-thoracotomy syndrome Carpal tunnel syndrome (CTS) Syringomyelia (compression by syrinx) Neurotoxicity Chemotherapy Inflammatory and / or immunological mechanisms Multiple sclerosis Stroke / ischaemia Thalamic syndrome Hereditary neuropathies Amyloid neuropathy Reference Zimmermann M. Eur J Pharmacol. 2001;429:23-37. 4

Molecular mechanisms of neuropathic pain Schematic overview of molecular consequences of peripheral nerve damage Nerve damage Release of TNF, IL-1 NGF Antero- and retrograde axonal transport Expression of bradykinin receptors and neuropeptides Peripheral sensitization Gilron I et al. CMAJ. 2006;175:265-75. Vranken JH. Cent Nerv Syst Agents Med Chem. 2009;9:71-8. Local effect Na + channels Cytokines Induction of COX-2 Massive influx of action potentials in the spinal cord Intracellular molecular change Number of receptors (AMPA, NMDA, NK1) Central sensitization 5

Patients reporting pain (%) Epidemiology of post-herpetic neuralgia 100 80 60 40 20 > 1 year 6 12 months 1 6 months < 1 month 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 PHN = post-herpetic neuralgia. Gershon AA, et.al. J Clin Virol. 2010;48:S2-7. Mohamed SA, et al. Pain Clinical Updates. 1994; 2:1-8. 6

Incidence per 1,000 person-years Risk factors of post-herpetic neuralgia Risk factors in developing herpes zoster Age Impaired cell-mediated immunity Diabetes Female gender Genetic susceptibility Mechanical trauma Recent psychological stress Caucasian ethnicity 15 10 5 0 Risk factors in children < 65 year > 65 year Maternal VZV infection during late pregnancy History of primary VZV infection early in life Being immunocompromised Dworkin RH, et al. Clin Infect Dis. 2007;44:S1-26. Gershon AA, et.al. J Clin Virol. 2010;48:S2-7. 7

Pathophysiology of post-herpetic neuralgia (PHN) 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 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. 8

Epidemiology of diabetic peripheral neuropathy (DPN) 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 Schmader s findings 1 2 3 4 5 6 7 8 9 10 Pain intensity Average pain intensity among diabetics: 5.75 on a scale of 0-10 20% 6% 74% Diabetes patients Baseline patients Patients Presence of neuropathy 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 of diabetic peripheral neuropathy (DPN) Risk factors Degree and duration of hyperglycaemia 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 Zochodne DW. Muscle Nerve. 2007;36:144-66. Dyck PJ. Diabetes Care. 1999;22:1479-86. 10

Pathophysiology of diabetic peripheral neuropathy (DPN) Diabetes Hyperglycaemia Non-enzymatic glycation Polyol pathway Microvascular dysfunction and oxidative stress Axonal degeneration AGEs DPN AGEs = advanced glycation end-products; DPN = diabetic polyneuropathy. Reference Sima AA et al. Ann N Y Acad Sci. 2006;1084:235-49. 11

Neuropathic pain: signs and symptoms (1) Sensory signs / symptoms Negative Positive Reduced sensation or complete loss of sensation - Touch - Vibration - Pain - Temperature Baron R. Nat Clin Pract Neurol. 2006;2:95-106. Baron R et al. Lancet Neurol. 2010;9:807-19. 12

Neuropathic pain: signs and symptoms (2) Sensory signs / symptoms Negative Positive Non-painful Burning/ dull pain Ongoing Spontaneous sensation Painful Itching/ antcrawling Discontinuous Painful Spreading Hyperalgesia Exaggerated pain response to painful stimulus Evoked sensation Intensifying Allodynia Abnormal pain response to nonpainful stimuli such as Baron R. Nat Clin Pract Neurol. 2006;2:95-106. Baron R et al. Lancet Neurol. 2010;9:807-19. 13

Diagnosis algorithm Pain case history Physical examination Special examination Sensory system Motor system Sympathetic system Localization of pain 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 14

Localized Neuropathic Pain screening tool - algorithm 1. Does the patients history suggest a relevant nerve lesion or disease? 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? Yes No 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 15 Mick G, et al. WCN. 2013.

Localized Neuropathic Pain screening tool sensory examination 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 Ask the patient to rate the pain 0 = no pain/discomfort to touch 1 = uncomfortable but tolerable to touch 2 = painful 3 = extremely painful, patient cannot stand touching Pinprick Touch Touch Vibration 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 16 Mick G, et al. WCN. 2013.

Pain case history Pain case history Current medical history Occupational history Detailed past medical history incl. family history Documentation of Medication history Use of recreational drugs or alcohol Risk factors (HIV, travel, diet etc) Neuropathy 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) Motor Burning, jabbing pain, dysesthesias Cramps, fasciculations, restless legs, tightness Loss of pain or temperature sense Weakness, fatigability, hypotonia, areflexia, deformities Autonomic Hyperhidrosis, excess saliva Orthostatic hypotension, erectile dysfunction, bowel and / or bladder dysfunction Hansson P. Eur J Pain. 2002;6:47-50. Haanpää M et al. Pain. 2011;152:14-27. 17

Physical examination Tests used in physical examination of patients suspected with neuropathic pain Sensory Autonomic Motor Test Assess Test Assess Test Assess Cotton wisp Allodynia Laser doppler flow Blood flow Weakness 128-Hz tuning fork Warm / cold objects Toothpick Von Frey fibres (SWME) Reduced detection of vibration Allodynia Hyperalgesia Hyperalgesia Infra-red test Quantitative Sudomotor Axon Reflex Test (QSART) Thermoregulatory sweat test Skin temperature Sweating, heart rate, blood pressure Sweating Motor function tests Muscle symmetry Bulk Tone Fasciculations Response, reproducibility and symmetry of deep tendon reflexes Baron R. Nat Clin Pract Neurol. 2006;2:95-106. Haanpää M et al. Pain. 2011;152:14-27. 18

Treatment algorithm Stepwise approach to treating neuropathic pain 1 2 3 4 Pain assessment and diagnosis Initiate therapy for NP causing disease Pain and HR-QoL reassessment (recurrent) Second- / third- / fourth-line treatment Establish NP cause and treatment First-line medication for symptom treatment If First-line medication for symptom treatment Establish relevant comorbidities influencing NP treatment Patient evaluation for nonpharmacological treatment Substantial pain Partial pain relief No or inadequate pain relief Continue Add Other first-line possibility? Doctor patient communication: goals and treatment explanation Yes No Switch HR-QoL = health related quality of life. Attal N et al. Eur J Neurol. 2010;17:1113-e88. Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-14. 19

Treatment: first-line medication Systemic treatment Topical treatment Antidepressants Anticonvulsants Local analgesic Secondary amine TCAs SNRIs Calcium channel 2- ligands Amino amide-type Nortriptyline Desipramine Amitriptyline Duloxetine Gabapentin Pregabalin Lidocaine patch TCAs = tricyclic antidepressants; SNRI = serotonin-norepinephrine reuptake inhibitor. Reference Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-14. 20

Treatment: second-line medication Morphine Systemic treatment Strong opioid analgesics Weak opioid analgesics Oxycodone Methadone Fentanyl 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. 21

Treatment: third-line medication TCAs Bupropion Systemic treatment Antidepressant SSRI Citalopram 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. 22

Summary of treatment rationale After diagnosis Treating localized symptoms For widespread pain If there is no patient relief, or if there is insufficient pain relief In case of inadequate effect: consultation with pain specialist Causal therapy Lidocaine patch Antidepressants Weak or strong opioids Anticonvulsants Reference Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-S14. 23

Mechanism-based treatment Mechanism-based treatment approach for neuropathic pain management Pain character/ symptoms Diagnosis, e.g. Mechanisms Pain therapy with medication Affecting the nervous system / burning / shooting / concomitant neurological symptoms Diabetic polyneuropathy / post-herpetic neuralgia Formation of new channels and receptors / ectopic impulse generation (spontaneous activity) Anticonvulsives (Na + - and Ca 2 +- channel blockers) / antidepressants (especially TCAs) / topical lidocaine Neuropathy Central sensitization Reduced endogenous pain inhibition Noradrenaline and serotonin re-uptake inhibitors (antidepressants), opioids or MOR-NRI (tapentadol) 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. TCA = tricyclic antidepressant. 24

Recent clinical trials on new treatment approaches Systemic Intradermal Topical Combination therapies Antidepressants (SSRIs) Anticonvulsants MOR-NRI (dual action) Paroxetine Citalopram Escitalopram Lacosamide Tapentadol Botulinum toxin High concentration capsaicin patch Pregabalin + topical 5% lidocaine (PHN, DPN) Pregabalin + oxycodone (PHN, DPN) Gabapentin + oxycodone Gabapentin + extended release morphine Gabapentin + nortriptyline Sodium valporate + glyceryl trinitrate spray (DPN) DPN = post-herpetic neuralgia; MOR-NRI = noradrenalin reuptake inhibitor; Dworkin RH et al. Mayo Clin Proc. 2010;85 3 Suppl:S3-14. Afilalo M et al. Pain Physician. 2013;16(1):27-40. PHN = advanced glycation end-product; SSRI = selective serotonin reuptake Steigerwald I et al. Curr Med Res Opin. 2012;28(6):911-936. 25 inhibitor.

Summary 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 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 26