This document summarizes neuropathic pain, including its causes, symptoms, pathophysiology, and treatments. Neuropathic pain is initiated by a primary lesion or dysfunction in the nervous system and can be peripheral or central in nature. Peripheral neuropathic pain is caused by damage to peripheral nerves, while central neuropathic pain originates in the brain or spinal cord. The pathophysiology involves abnormal neuronal excitability, sensitization of the central nervous system, and changes in ion channels. Treatments aim to reduce neuronal excitability and block sodium channels, with options including opioids, gabapentin, antidepressants, and calcium channel blockers.

1. NEUROPATHIC PAIN R3 정고운

2. I. Neuropathic Pain Pain initiated or caused by a primary lesion or dysfunction of the nervous system (eg, painful diabetic neuropathy, post-herpetic neuralgia)

3. Symptom tactile allodynia(m/c) Constant burning pain Cramping /aching Hyperpathia, hyperalgesia Hyperesthesia

4. PERIPHERAL NEUROPATHIC PAIN Due to anatomical,chemical or biochemical changes to peripheral nerves Examples include: post-herpetic neuralgia,pain in HIV infections, trigeminal neuralgia, compression by a tumour , diabetic neuropathy, sciatica, post-surgery, following chemotherapy(eg vincristine), radiation CENTRAL NEUROPATHIC PAIN Due to pathophysiological changes in the brain or spinal chord ie the primary lesion is in the CNS Examples include phantom limb pain,pain following stroke, multiple sclerosis

5. III. Pathophysiology

6. Primary afferent neuronal mechanism Ectopic activity votage gated NA+ channels 의 비정상적 증식 (neuroma) -> abnormal excitability -> spontaneous sprouts -> stimulate the connecting regenerative C-fiber -> erratic impulse generation -> transmit to the CNS -> dysesthesia, such as tingling, itching, electrifying sensitization

7. Abnormal expression of Na + channel - Increase density and up-regulation of Na channel(SNS(“sensory-nerve-specific, subtype α -Ⅲ(embryonic)) - action potential threshold ↓ & spontaneous ectopic discharge ↑ - fast recovery following inactivation - repetitive firing of injured neuron was facilitated at low threshold (ectopic impulse generation)

8. Sensory-sympathetic coupling - noradrenaline released from near by sympathetic efferent fibers binds to α adrenoreceptors on the injured afferent neuron & increased sensitivity - causalgia - sympathetic block -> pain 감소 - sympathetic stimulus -> pain 증가

9. Ca channels in injured nerve endings - entry of Ca ion into the nerve endings N- or L type calcium channel -> calcitonin gene related peptide from injured nerve endings - CCBs are effective to block neuropathic pain

10. Neuroimmune interaction - nerve injury -> MØ -> TNF α & IL1ß -> ectopic activity, inflammatory hyperalgesia - higher TNF α immuoreactivities

11. Phenotypic change - DRG neuron - A-ß fiber (non-noxious) ->substance P (pronociceptive) / neuropeptide (antinociceptive) 生

12. Pathologic interaction c C & A-ß fiber - nerve injury -> disruption of glial ensheathment -> cross-excitation ∴ A-ß fiber (tactile) ↔ C fiber (noxious)

13. Spinal mechanism Central reorganization - small-diameter aff.(C fiber) -> superficial dorsal horn (lamina I/II) -> noxious stimuli - large-diameter aff.(A-ß fiber) -> deep dorsal horn (lamina III/IV) -> tactile stimuli - nerve injury 시 C fiber degeneration & A-ß fiber growth to lamina I/II

14. Disinhibition - inefficiency of endogenous inh. Sys. continuous inhibitory control of brainstem ↓ loss of A- δ fiber induce GABAnergic inhibitory interneuron apoptosis transynaptic neural degeneration (GABA receptor ↓ , opioid receptor ↓ )

15. Central sensitization repetitive noxious stimulation leads to the increased activities of asparate & glutamte at NMDA & neurokinin 1 receptor increased inctracellular CA & activation of PKC -> activate DHC, phosphorylation of NMDA rec. -> causes decreased Mg blockade at phys. resting potential exp. Of c-fos -> neuropeptides -> central plasticity

16. IV. Treatment

18. Stimulation dependent pain (evoked pain) pph. sensitization : - local anesthetics( lidocaine patch 5%) - capsaicin abnormal exp. of Na channel - antiepileptic, anticonvulsant, anti arrhythmic, TCA(amitriptyline) central sensitization - Na channel blocker, local anesthetics

19. Stimmulous independent pain Paresthesia & dysesthesia : spont. firing of A fiber -> Na channel blocker Peripheral sensitizaion, disinhibition, causalgia -> local anesthetics, capsaicin, Na channel blocker, gabapentin, baclofen, clonidine

21. * Opiates - - C fiber 에는 효과 & A-ß fiber 에는 효과 X < 용량 > - neuropathic>>nociceptive - center ↑: effect↓ - rotation 고려 - morphine : 300mg, oxycodein : 240mg, methadone : 80mg (sustained-release) fentanyl : 100 μ g (transdermal)

22. * α 2 agonist - opioid 와 작용 비슷 - sympathetic block -> opioid 보다 효과적 < 용량 > - clonidine : transdermal patch -> systemic delivery -> intraspinal delivery - intraspinal delivery : hypotension 주의

23. * NMDA antagonist - NMDA ionopore : glutamate (nerve injury 시 ↑ ), Mg 2+ , glycine, polyamine binding -> ionopore opening -> Ca 2+ influx < 용량 > - ketamine : 2~6 mg/kg/d(IV), 100~500mg/d(orla)

24. * COX inhibitor & PG receptor antagonis - tissue injury 시 PG release ↑ - ketorolac,parecoxib

25. * Na + channel blocker - nerve injury 시 ↑ < 용량 > - lamotrigine (choice) : ~400md/d - mexilletine : ~1200mg/d - lidocaine : 1~3mg/kg/h - non selective block

26. *Ca 2+ channel blocker - L, N, P/Q, R ,T - high threshold : L(cell body & dendritie), N, P/Q, R (synaptic site) < 용량 > - ziconotide : #1 0.1 μ g/h, #2 0.2 μ g/h, #3 0.3 μ g/h, #4 0.6 μ g/h, #5 1.2 μ g/h, #6 2.4 μ g/h - non selective & dose limiting side effect

27. *Gabapentin - unknown mechanism < 용량 > - starting dose : 900mg/d (#3) -> 2700~3600mg/d

28. * Antidepressant - cathecholamine reuptake ↓ < 용량 > - by sleep disturbance & at bedtime - amitriptyline, doxepin >> nortriptyline, imipramine - starting dose : 10mg/d (>65) : 25mg/d (<65) -> 200~300mg/d