1. Neuropathic Pain

2. Pain Pathophysiology Nociceptive pain Nociceptive pain Neuropathic pain Neuropathic pain

3. Nociceptive Pain Sensitization and activation of “healthy” nociceptor endings and recruitment of “silent” nociceptors Sensitization and activation of “healthy” nociceptor endings and recruitment of “silent” nociceptors “Soup” of inflammatory algogenic agents, such as protons, prostaglandins, bradykinin, serotonin, adenosine, histamine, cytokines “Soup” of inflammatory algogenic agents, such as protons, prostaglandins, bradykinin, serotonin, adenosine, histamine, cytokines

4. Mechanisms of Neuropathic Pain Noninflammatory states Noninflammatory states Inflammatory states Inflammatory states

5. Pathophysiology of Neuropathic Pain Ectopic activity in the peripheral pathways, including axons and DRG Ectopic activity in the peripheral pathways, including axons and DRG CNS mechanisms CNS mechanisms

6. Neuropathic Pain: Central Mechanisms Peripheral neuropathic events can be complicated by temporary or long-term CNS changes, such as central sensitization and then reorganization of the pain pathways at the dorsal horn level

7. Neuropathic Pain and SMP Some neuropathic pains are sustained, at least in part, by sympathetic efferent activity Some neuropathic pains are sustained, at least in part, by sympathetic efferent activity – SMP Expression of alpha-adrenergic receptors on injured C-fibers may be a relevant mechanism of SMP, but others are possible Expression of alpha-adrenergic receptors on injured C-fibers may be a relevant mechanism of SMP, but others are possible Clinical findings consistent with CRPS signal an increased likelihood of SMP Clinical findings consistent with CRPS signal an increased likelihood of SMP

8. C entral sensitization Peripheral sensitization Peripheral sensitization CNS PNS CNS central nervous system CNS central nervous system “Healthy” nociceptors Normal transmission Normal transmission Central reorganization Central reorganization Abnormal nociceptors Abnormal nociceptors Physiologic state Nociceptive Pain Neuropathic Pain PNS peripheral nervous system PNS peripheral nervous system PathologicstatePathologicstate Pappagallo M. 2001.

9. Neuropathic Pain Diverse syndromes with uncertain classification Diverse syndromes with uncertain classification Mononeuropathies and polyneuropathies Mononeuropathies and polyneuropathies CRPS CRPS Deafferentation syndromes, including central pain Deafferentation syndromes, including central pain

10. Painful Mononeuropathies and Polyneuropathies Diabetic neuropathies Diabetic neuropathies Entrapment neuropathies Entrapment neuropathies Shingles and postherpetic neuralgia Shingles and postherpetic neuralgia Trigeminal and other CNS neuralgias Trigeminal and other CNS neuralgias HIV-related neuropathy HIV-related neuropathy Neuropathy due to malignant disease Neuropathy due to malignant disease Neuropathy due to rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome Neuropathy due to rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome Idiopathic distal small-fiber neuropathy Idiopathic distal small-fiber neuropathy

11. Painful Mononeuropathies and Polyneuropathies Neuropathies due to toxins: arsenic, thallium, alcohol, vincristine, cisplatinum, didioxynucleosides Neuropathies due to toxins: arsenic, thallium, alcohol, vincristine, cisplatinum, didioxynucleosides Amyloid polyneuropathy: primary and familial Amyloid polyneuropathy: primary and familial Neuropathies with monoclonal proteins Neuropathies with monoclonal proteins Vasculitic neuropathy Vasculitic neuropathy Neuropathy associated with Guillain-Barré syndrome Neuropathy associated with Guillain-Barré syndrome Neuropathy associated with Fabry’s disease Neuropathy associated with Fabry’s disease

12. Neuropathic Pain: Clinical Assessment A comprehensive diagnostic approach to patients affected by neuropathic pain A comprehensive diagnostic approach to patients affected by neuropathic pain – Medical history – Examinations: general, neurologic, regional – Diagnostic workup: imaging studies, laboratory tests, nerve/skin biopsies, electromyography/nerve-conduction velocity (EMG-NCV) studies, selected nerve blocks

13. Medical History Ask patient about complaints suggestive of Neurologic deficits: persistent numbness in a body area or limb-weakness, for example, tripping episodes, inability to open jars Neurologic deficits: persistent numbness in a body area or limb-weakness, for example, tripping episodes, inability to open jars Neurologic sensory dysfunction: touch- evoked pain, intermittent abnormal sensations, spontaneous burning and shooting pains Neurologic sensory dysfunction: touch- evoked pain, intermittent abnormal sensations, spontaneous burning and shooting pains

14. Neurologic and Regional Examinations In patients with neuropathic pain, examination should focus on the anatomic pattern and localization of the abnormal sensory symptoms and neurologic deficits

15. Neuropathic Pain: Clinical Characteristics Burning, shooting, electrical-quality pain Burning, shooting, electrical-quality pain May be aching, throbbing, sharp May be aching, throbbing, sharp Neuropathic sensations: dysesthesias, paresthesias Neuropathic sensations: dysesthesias, paresthesias

16. Neuropathic Sensations Paresthesias: abnormal; spontaneous, intermittent, painless Paresthesias: abnormal; spontaneous, intermittent, painless Dysesthesias: abnormal; spontaneous or touch-evoked, unpleasant Dysesthesias: abnormal; spontaneous or touch-evoked, unpleasant

17. Neuropathic Pain: Evoked Dysesthesias Allodynia: pain elicited by a nonnoxious stimulus (clothing, air movement, touch) Allodynia: pain elicited by a nonnoxious stimulus (clothing, air movement, touch) – Mechanical (induced by light pressure) – Thermal (induced by a nonpainful cold or warm stimulus) Hyperalgesia: exaggerated pain response to a mildly noxious (mechanical or thermal) stimulus Hyperalgesia: exaggerated pain response to a mildly noxious (mechanical or thermal) stimulus Hyperpathia: delayed and explosive pain response to a noxious stimulus Hyperpathia: delayed and explosive pain response to a noxious stimulus

18. Primary Hyperalgesia Present in the primary zone, at the location of injury Present in the primary zone, at the location of injury Characterized by pinprick hyperalgesia + warm and heat hyperalgesia + static mechanical allodynia (tenderness) Characterized by pinprick hyperalgesia + warm and heat hyperalgesia + static mechanical allodynia (tenderness) Indicative of PNS sensitization Indicative of PNS sensitization

19. Secondary Hyperalgesia Present in the zone surrounding an injury Present in the zone surrounding an injury Characterized by dynamic mechanical allodynia + cold hyperalgesia Characterized by dynamic mechanical allodynia + cold hyperalgesia Indicative of CNS sensitization Indicative of CNS sensitization

20. Diagnostic Workup: Lab Tests Complete blood cell count with differential, erythrocyte sedimentation rate, chemistry profile Complete blood cell count with differential, erythrocyte sedimentation rate, chemistry profile Thyroid-function tests, vitamin B 12 and folate, fasting blood sugar, and glycosylated hemoglobin Thyroid-function tests, vitamin B 12 and folate, fasting blood sugar, and glycosylated hemoglobin Serum protein electrophoresis with immunofixation Serum protein electrophoresis with immunofixation Lyme titers, hepatitis B and C, HIV screening Lyme titers, hepatitis B and C, HIV screening Antinuclear antibodies, rheumatoid factor, Sjögren’s titers (SS-A, SS-B), antineutrophil cytoplasmic antibody Antinuclear antibodies, rheumatoid factor, Sjögren’s titers (SS-A, SS-B), antineutrophil cytoplasmic antibody

21. Diagnostic Workup: Lab Tests Cryoglobulins Cryoglobulins Antisulfatide antibody titers, anti-HU titers Antisulfatide antibody titers, anti-HU titers Heavy metals serum and urine screens Heavy metals serum and urine screens Cerebrospinal fluid study for demyelinating diseases and meningeal carcinomatosis Cerebrospinal fluid study for demyelinating diseases and meningeal carcinomatosis

22. Diagnostic Workup: Electrophysiologic Studies EMG-NCV and QST To localize pain-generator/nerve or root lesion To localize pain-generator/nerve or root lesion To rule out To rule out – Axonal vs focal segmental demyelination – Underlying small-fiber or mixed polyneuropathy

23. BiopsiesBiopsies Nerve (eg, sural nerve): to diagnose vasculitis, amyloidosis, sarcoidosis, etc. Nerve (eg, sural nerve): to diagnose vasculitis, amyloidosis, sarcoidosis, etc. Skin: to evaluate density of unmyelinated fibers within dermis and epidermis Skin: to evaluate density of unmyelinated fibers within dermis and epidermis

24. Neuropathic Pain: Management Pharmacotherapy Pharmacotherapy – Nonopioid – Opioid – Adjuvant analgesics Interventional Interventional – Neural blockade (eg, sympathetic nerve blocks) – Neurostimulatory techniques (eg, spinal cord stimulation) – Intraspinal infusion

25. Neuropathic Pain: Pharmacologic Therapies Gabapentin, carbamazepine, lamotrigine, and newer AEDs Gabapentin, carbamazepine, lamotrigine, and newer AEDs Antidepressants Antidepressants Opioid analgesics Opioid analgesics Lidocaine (transdermal, intravenous [IV]), mexiletine Lidocaine (transdermal, intravenous [IV]), mexiletine Alpha-2 adrenergic agonists Alpha-2 adrenergic agonists

26. Neuropathic Pain: Management Rehabilitative approaches Rehabilitative approaches Psychologic interventions Psychologic interventions

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