Neuropathic PainNeuropathic PainNeuropathic PainNeuropathic Pain

Pain PathophysiologyPain PathophysiologyPain PathophysiologyPain Pathophysiology

• Nociceptive painNociceptive pain

• Neuropathic painNeuropathic pain

Nociceptive PainNociceptive PainNociceptive PainNociceptive Pain

• Sensitization and activation of “healthy” Sensitization and activation of “healthy” nociceptor endings and recruitment of nociceptor endings and recruitment of “silent” nociceptors“silent” nociceptors

• ““Soup” of inflammatory algogenic agents, Soup” of inflammatory algogenic agents, such as protons, prostaglandins, such as protons, prostaglandins, bradykinin, serotonin, adenosine, bradykinin, serotonin, adenosine, histamine, cytokineshistamine, cytokines

Mechanisms of Neuropathic Pain Mechanisms of Neuropathic Pain Mechanisms of Neuropathic Pain Mechanisms of Neuropathic Pain

• Noninflammatory statesNoninflammatory states

• Inflammatory statesInflammatory states

Pathophysiology of Neuropathic PainPathophysiology of Neuropathic PainPathophysiology of Neuropathic PainPathophysiology of Neuropathic Pain

• Ectopic activity in the peripheral pathways, Ectopic activity in the peripheral pathways, including axons and DRGincluding axons and DRG

• CNS mechanismsCNS mechanisms

Neuropathic Pain: Central Mechanisms Neuropathic Pain: Central Mechanisms Neuropathic Pain: Central Mechanisms Neuropathic Pain: Central Mechanisms

Peripheral neuropathic events can be Peripheral neuropathic events can be complicated by temporary or long-term complicated by temporary or long-term CNS changes, such as CNS changes, such as central sensitizationcentral sensitization and then and then reorganizationreorganization of the pain of the pain pathways at the dorsal horn levelpathways at the dorsal horn level

Neuropathic Pain and SMPNeuropathic Pain and SMPNeuropathic Pain and SMPNeuropathic Pain and SMP

• Some neuropathic pains are sustained, at least in Some neuropathic pains are sustained, at least in part, by sympathetic efferent activitypart, by sympathetic efferent activity– SMP SMP

• Expression of alpha-adrenergic receptors on Expression of alpha-adrenergic receptors on injured C-fibers may be a relevant mechanism of injured C-fibers may be a relevant mechanism of SMP, but others are possible SMP, but others are possible

• Clinical findings consistent with CRPS signal an Clinical findings consistent with CRPS signal an increased likelihood of SMPincreased likelihood of SMP

Central sensitization

Central sensitization

Peripheral sensitizationPeripheral sensitization

CNS CNS

PNSPNS

CNScentralnervous system

CNScentralnervous system

“Healthy” nociceptors“Healthy” nociceptors

NormaltransmissionNormaltransmission

Central reorganization Central reorganization

AbnormalnociceptorsAbnormalnociceptors

Physiologic statePhysiologic state

Nociceptive Pain Nociceptive Pain Neuropathic Pain Neuropathic Pain

PNSperipheral nervous system

PNSperipheral nervous system

Pathologic Pathologic statestatePathologic Pathologic statestate

Pappagallo M. 2001.

Neuropathic PainNeuropathic PainNeuropathic PainNeuropathic Pain

• Diverse syndromes with uncertain Diverse syndromes with uncertain classificationclassification

• Mononeuropathies and polyneuropathiesMononeuropathies and polyneuropathies

• CRPSCRPS

• Deafferentation syndromes, including Deafferentation syndromes, including central paincentral pain

Painful Mononeuropathies and Painful Mononeuropathies and PolyneuropathiesPolyneuropathies

Painful Mononeuropathies and Painful Mononeuropathies and PolyneuropathiesPolyneuropathies

• Diabetic neuropathiesDiabetic neuropathies

• Entrapment neuropathiesEntrapment neuropathies

• Shingles and postherpetic neuralgiaShingles and postherpetic neuralgia

• Trigeminal and other CNS neuralgiasTrigeminal and other CNS neuralgias

• HIV-related neuropathyHIV-related neuropathy

• Neuropathy due to malignant diseaseNeuropathy due to malignant disease

• Neuropathy due to rheumatoid arthritis, systemic Neuropathy due to rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndromelupus erythematosus, Sjögren’s syndrome

• Idiopathic distal small-fiber neuropathyIdiopathic distal small-fiber neuropathy

Painful Mononeuropathies and Painful Mononeuropathies and PolyneuropathiesPolyneuropathies

Painful Mononeuropathies and Painful Mononeuropathies and PolyneuropathiesPolyneuropathies

• Neuropathies due to toxins: arsenic, thallium, Neuropathies due to toxins: arsenic, thallium, alcohol, vincristine, cisplatinum, alcohol, vincristine, cisplatinum, didioxynucleosidesdidioxynucleosides

• Amyloid polyneuropathy: primary and familialAmyloid polyneuropathy: primary and familial

• Neuropathies with monoclonal proteinsNeuropathies with monoclonal proteins

• Vasculitic neuropathyVasculitic neuropathy

• Neuropathy associated with Guillain-Barré Neuropathy associated with Guillain-Barré syndromesyndrome

• Neuropathy associated with Fabry’s diseaseNeuropathy associated with Fabry’s disease

Neuropathic Pain: Clinical AssessmentNeuropathic Pain: Clinical AssessmentNeuropathic Pain: Clinical AssessmentNeuropathic Pain: Clinical Assessment

• A comprehensive diagnostic approach to A comprehensive diagnostic approach to patients affected by neuropathic painpatients affected by neuropathic pain– Medical historyMedical history

– Examinations: general, neurologic, regional Examinations: general, neurologic, regional

– Diagnostic workup: imaging studies, Diagnostic workup: imaging studies, laboratory tests, nerve/skin biopsies, laboratory tests, nerve/skin biopsies, electromyography/nerve-conduction velocity electromyography/nerve-conduction velocity (EMG-NCV) studies, selected nerve blocks (EMG-NCV) studies, selected nerve blocks

Medical HistoryMedical HistoryMedical HistoryMedical History

Ask patient about complaints suggestive of Ask patient about complaints suggestive of • Neurologic deficits:Neurologic deficits: persistent numbness persistent numbness

in a body area or limb-weakness, for in a body area or limb-weakness, for example, tripping episodes, inability to example, tripping episodes, inability to open jars open jars

• Neurologic sensory dysfunction:Neurologic sensory dysfunction: touch- touch-evoked pain, intermittent abnormal evoked pain, intermittent abnormal sensations, spontaneous burning and sensations, spontaneous burning and shooting painsshooting pains

Neurologic and Regional ExaminationsNeurologic and Regional ExaminationsNeurologic and Regional ExaminationsNeurologic and Regional Examinations

In patients with neuropathic pain, In patients with neuropathic pain, examination should focus on the anatomic examination should focus on the anatomic pattern and localization of the abnormal pattern and localization of the abnormal sensory symptoms and neurologic deficitssensory symptoms and neurologic deficits

Neuropathic Pain: Clinical CharacteristicsNeuropathic Pain: Clinical CharacteristicsNeuropathic Pain: Clinical CharacteristicsNeuropathic Pain: Clinical Characteristics

• Burning, shooting, electrical-quality painBurning, shooting, electrical-quality pain

• May be aching, throbbing, sharpMay be aching, throbbing, sharp

• Neuropathic sensations: dysesthesias, Neuropathic sensations: dysesthesias, paresthesiasparesthesias

Neuropathic SensationsNeuropathic SensationsNeuropathic SensationsNeuropathic Sensations

• Paresthesias:Paresthesias: abnormal; spontaneous, abnormal; spontaneous, intermittent, painless intermittent, painless

• Dysesthesias:Dysesthesias: abnormal; spontaneous or abnormal; spontaneous or touch-evoked, unpleasanttouch-evoked, unpleasant

Neuropathic Pain: Evoked DysesthesiasNeuropathic Pain: Evoked DysesthesiasNeuropathic Pain: Evoked DysesthesiasNeuropathic Pain: Evoked Dysesthesias

• Allodynia:Allodynia: pain elicited by a nonnoxious stimulus pain elicited by a nonnoxious stimulus (clothing, air movement, touch)(clothing, air movement, touch)– Mechanical (induced by light pressure)Mechanical (induced by light pressure)

– Thermal (induced by a nonpainful cold or warm Thermal (induced by a nonpainful cold or warm stimulus) stimulus)

• Hyperalgesia:Hyperalgesia: exaggerated pain response to a exaggerated pain response to a mildly noxious (mechanical or thermal) stimulusmildly noxious (mechanical or thermal) stimulus

• Hyperpathia:Hyperpathia: delayed and explosive pain delayed and explosive pain response to a noxious stimulusresponse to a noxious stimulus

Primary HyperalgesiaPrimary HyperalgesiaPrimary HyperalgesiaPrimary Hyperalgesia

• Present in the primary zone, at the location Present in the primary zone, at the location of injury of injury

• Characterized by pinprick hyperalgesia + Characterized by pinprick hyperalgesia + warm and heat hyperalgesia + static warm and heat hyperalgesia + static mechanical allodynia (tenderness)mechanical allodynia (tenderness)

• Indicative of PNS sensitizationIndicative of PNS sensitization

Secondary HyperalgesiaSecondary HyperalgesiaSecondary HyperalgesiaSecondary Hyperalgesia

• Present in the zone surrounding an injuryPresent in the zone surrounding an injury

• Characterized by dynamic mechanical Characterized by dynamic mechanical allodynia + cold hyperalgesiaallodynia + cold hyperalgesia

• Indicative of CNS sensitization Indicative of CNS sensitization

Diagnostic Workup: Lab TestsDiagnostic Workup: Lab TestsDiagnostic Workup: Lab TestsDiagnostic Workup: Lab Tests

• Complete blood cell count with differential, Complete blood cell count with differential, erythrocyte sedimentation rate, chemistry profileerythrocyte sedimentation rate, chemistry profile

• Thyroid-function tests, vitamin BThyroid-function tests, vitamin B1212 and folate, fasting and folate, fasting

blood sugar, and glycosylated hemoglobinblood sugar, and glycosylated hemoglobin

• Serum protein electrophoresis with immunofixationSerum protein electrophoresis with immunofixation

• Lyme titers, hepatitis B and C, HIV screeningLyme titers, hepatitis B and C, HIV screening

• Antinuclear antibodies, rheumatoid factor, Sjögren’s Antinuclear antibodies, rheumatoid factor, Sjögren’s titers (SS-A, SS-B), antineutrophil cytoplasmic titers (SS-A, SS-B), antineutrophil cytoplasmic antibodyantibody

Diagnostic Workup: Lab TestsDiagnostic Workup: Lab TestsDiagnostic Workup: Lab TestsDiagnostic Workup: Lab Tests

• CryoglobulinsCryoglobulins

• Antisulfatide antibody titers, anti-HU titersAntisulfatide antibody titers, anti-HU titers

• Heavy metals serum and urine screensHeavy metals serum and urine screens

• Cerebrospinal fluid study for demyelinating Cerebrospinal fluid study for demyelinating diseases and meningeal carcinomatosisdiseases and meningeal carcinomatosis

Diagnostic Workup: Electrophysiologic Diagnostic Workup: Electrophysiologic StudiesStudies

Diagnostic Workup: Electrophysiologic Diagnostic Workup: Electrophysiologic StudiesStudies

EMG-NCV and QSTEMG-NCV and QST

• To localize pain-generator/nerve or root To localize pain-generator/nerve or root lesion lesion

• To rule outTo rule out– Axonal vs focal segmental demyelinationAxonal vs focal segmental demyelination

– Underlying small-fiber or mixed Underlying small-fiber or mixed polyneuropathy polyneuropathy

BiopsiesBiopsiesBiopsiesBiopsies

• Nerve (eg, sural nerve):Nerve (eg, sural nerve): to diagnose to diagnose vasculitis, amyloidosis, sarcoidosis, etc.vasculitis, amyloidosis, sarcoidosis, etc.

• Skin:Skin: to evaluate density of unmyelinated to evaluate density of unmyelinated fibers within dermis and epidermisfibers within dermis and epidermis

Neuropathic Pain: ManagementNeuropathic Pain: ManagementNeuropathic Pain: ManagementNeuropathic Pain: Management

• PharmacotherapyPharmacotherapy– NonopioidNonopioid

– OpioidOpioid

– Adjuvant analgesicsAdjuvant analgesics

• InterventionalInterventional– Neural blockade (eg, sympathetic nerve blocks)Neural blockade (eg, sympathetic nerve blocks)

– Neurostimulatory techniques (eg, spinal cord Neurostimulatory techniques (eg, spinal cord stimulation)stimulation)

– Intraspinal infusionIntraspinal infusion

Neuropathic Pain:Neuropathic Pain:Pharmacologic TherapiesPharmacologic Therapies

Neuropathic Pain:Neuropathic Pain:Pharmacologic TherapiesPharmacologic Therapies

• Gabapentin, carbamazepine, lamotrigine, Gabapentin, carbamazepine, lamotrigine, and newer AEDsand newer AEDs

• AntidepressantsAntidepressants

• Opioid analgesicsOpioid analgesics

• Lidocaine (transdermal, intravenous [IV]), Lidocaine (transdermal, intravenous [IV]), mexiletinemexiletine

• Alpha-2 adrenergic agonistsAlpha-2 adrenergic agonists

Neuropathic Pain: ManagementNeuropathic Pain: ManagementNeuropathic Pain: ManagementNeuropathic Pain: Management

• Rehabilitative approachesRehabilitative approaches

• Psychologic interventionsPsychologic interventions

ConclusionsConclusionsConclusionsConclusions

• More effective medical therapies for More effective medical therapies for neuropathic pain are becoming available neuropathic pain are becoming available and physicians should use them to limit and physicians should use them to limit unnecessary suffering, with the ultimate unnecessary suffering, with the ultimate goal of significantly improving patients’ goal of significantly improving patients’ quality of lifequality of life