NEUROPATHIC PAIN

R3 정고운

I. Neuropathic Pain

Pain initiated or caused by a primary lesion or dysfunction of the nervous system

(eg, painful diabetic neuropathy, post-herpetic neuralgia)

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

PERIPHERAL NEUROPATHIC PAIN

Due to anatomical,chemical or biochemical changes to peripheral nervesExamples 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 primarylesion is in the CNSExamples include phantom limb pain,pain following stroke, multiple sclerosis

III. Pathophysiology

Primary afferent neuronal mechanism

Ectopic activityvotage 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

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)

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

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

Neuroimmune interaction - nerve injury → MØ → TNFα & IL1ß → ectopic activity, inflammatory hyperalgesia

- higher TNF α immuoreactivities

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

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

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

Disinhibition- inefficiency of endogenous inh. Sys.

continuous inhibitory control of brainstem↓

loss of A-δfiber induce GABAnergic inhibitory

interneuron apoptosis transynaptic neural degeneration (GABA receptor ↓, opioid receptor ↓)

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

IV. Treatment

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

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

* 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 : 100μg (transdermal)

* α2 agonist

- opioid 와 작용 비슷 - sympathetic block

→ opioid 보다 효과적

< 용량 >- clonidine : transdermal patch → systemic delivery → intraspinal delivery- intraspinal delivery : hypotension 주의

* NMDA antagonist

- NMDA ionopore : glutamate (nerve injury 시 ↑ ), Mg2+, glycine, polyamine binding → ionopore opening → Ca2+ influx

< 용량 >- ketamine : 2~6 mg/kg/d(IV), 100~500mg/d(orla)

* COX inhibitor & PG receptor antagonis

- tissue injury 시 PG release ↑ - ketorolac,parecoxib

* Na+ channel blocker

- nerve injury 시 ↑

< 용량 >- lamotrigine (choice) : ~400md/d- mexilletine : ~1200mg/d- lidocaine : 1~3mg/kg/h- non selective block

*Ca2+ channel blocker

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

*Gabapentin

- unknown mechanism

< 용량 >- starting dose : 900mg/d (#3) → 2700~3600mg/d

*Antidepressant

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