442-MT2-Neuropathic pain

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jgiantess
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142168
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442-MT2-Neuropathic pain
Updated:
2012-03-17 22:45:08
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pharmacology
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pharmacology
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  1. TCAs for neuropathic pain
    • desipramine, nortriptyline, imipramine, doxepin, amitriptyline
    • MoA:
    • - Inhibit NE/5-HT reuptake (monoamines), thereby enhances descending inhibitory NE/5-HT systems
    • - Blocks ACh, HA receptors on nociceptive pathways -> analgesia
    • - Stimulates/potentiates opioid analgesia
    • - Blocks ion channels (Na+) in peripheral nociceptors and afferent transmission to 2nd order spinothalamic neurons
    • - Also blocks NMDA receptors
    • Use:
    • - analgesia faster than AD 6-12wks (analgesic independent of antidepressant activit)
    • - E in decreasing burning pain in hyperalgesia
    • - Dose needs to be titrated
    • - Can work for NP pts with no depression
    • - Ca also help with depression, anxiety, insomnia (co-morbidities)
    • - If >100mg or over 40yo, check EEG first
    • o Risk cardiac toxicity (SCD, MI)
    • SE: Blurred vision, Cognitive changes, Constipation, Dry mouth, **Orthostatic hypotenson (esp Ami), Sedation, Sexual dysfunction, Tachycardia, Urinary Retention
  2. SNRIs for neuropathic pain
    • venlafaxine, duloxetine
    • MoA:
    • - Dual blockage of NE + 5-HT to act on descending inhibitory pain pathways (both needed for mediating analgesia)
    • - Duloxetine: similar binding affinity to NE and 5-HT Rs ==optimal efficacy
    • - Venlafaxine: also binds Na+ channels: don’t know if that helps
    • Use:
    • - Duloxetine: start at 30mg/d, increase to 60mg in 2 weeks = tx dose already. (max 120mg/day)
    • - Venlafaxine: 150-225mg/d, need renal dose adjustment, longer to titrate
    • - Minimize SE with slow titration
    • SE:
    • - Duloxetine: N, A, D, C, insomnia, dry mouth, sleepiness, headache, fatigue, urinary retention, sweating, BP
    • - Venlafaxine: dose-dependent inc. BP + HR, agitation, tremor, N (37%) at start, sweating, headache, sleep disturbances, withdrawal effects
  3. Gabapentin for neuropathic pain
    • - After nerve injury, Ca v α2δ-1 upreg in spinal dorsal horn and DRG in NP -> modulates excitability (increase NT glutamate, sub P, calcitonin release during pain, also changes synaptic neuroplasticity in dorsal horn)
    • MoA:
    • - Structural analogs of GABA (but no effect on GABA receptors)
    • - Bind to α2δ subunit of VGCC (N-type Ca2+ channel), reduces NP
    • - Block N-type Ca2+ channel @ VGCC : decrease Ca2+ influx into presynaptic afferent terminals of superficial laminae of dorsal horn -> decrease neurotransmission, decrease hypersensitivity
    • Use:
    • - Most commonly used for NP
    • - For peripheral (PHN, PDN, TGN)
    • - For central (stroke, spinal cord injury) (esp useful for stabbing/shooting pain)
    • - Binds α2δ-1 subunit of VGCC: decreases NT (Glu, NE, Sub P) release to postsynaptic terminals in dorsal horn
    • - NP dose 900-3600mg/d (div tid-qid)
    • SE:
    • - Takes long time to titrate because of SE: e.g. dizziness, edema…
  4. Pregabalin for neuropathic pain
    • - After nerve injury, Ca v α2δ-1 upreg in spinal dorsal horn and DRG in NP -> modulates excitability (increase NT glutamate, sub P, calcitonin release during pain, also changes synaptic neuroplasticity in dorsal horn)
    • MoA:
    • - Structural analogs of GABA (but no effect on GABA receptors)
    • - Bind to α2δ subunit of VGCC (N-type Ca2+ channel), reduces NP
    • - Block N-type Ca2+ channel @ VGCC : decrease Ca2+ influx into presynaptic afferent terminals of superficial laminae of dorsal horn -> decrease neurotransmission, decrease hypersensitivity
    • Use:
    • - For PHN, PDN (also anxiety, depression, and useful in migraine, fibromyalgia)
    • - 6x more potent than GPN
    • - Binds α2δ-1subunit of VGCC: decrease NT (Glu, NE, 5-HT, DA, Sub P) release to postsynaptic terminals in dorsal horn
    • - NP dose 600mg/d (div bid-tid)
  5. Ziconotide for neuropathic pain
    • non-opioid, non-NSAID analgesic
    • MoA:
    • - block N-type VGCC reversibly
    • - prevents release of excitatory NT (Glu, Calcitonin, Substance P) in CNS
    • - promotes NE med'd descending adrenergicinhibitory pathways of pain
    • - augments inhibition by opioids (synergistic)
    • Use:
    • - only approved in US
    • - intrathecal admin only
    • SE:
    • - Sedation, dizziness, N/V, somnolence, H/A, confusion, memory impairment, slurred speech, nytagmus, double/blurry vision, urinary retention, hypotention, increase creatine kinase, gait abnormality
  6. Carbamazepine, Oxcarbazepine for neuropathic pain
    • MoA: Block VGSC (Na+) high-f firing, by decreasing ability of Na+ channels to recover from inactivation
    • Use:
    • - CBZ: trigeminal neuralgia b/c of SE limit
    • - NP dose up to200-800mg/d (div bid)
    • - OXC: being explored for use in NP now
  7. Topiramate for neuropathic pain
    • MoA:
    • - block VGSC (Na+)
    • - activates K+ current: hyperpolarizing, inhibitory
    • - enhances postsynaptic GABA-A Receptor currents
    • - limits activation of AMPA-kainate glutamate receptors
    • Use: considered 3rd line after TCA, PGB, GPN, opioids have been tried
  8. Zonisamide for neuropathic pain
    • MoA:
    • - block T-type Ca2+ currents
    • = block VGSC (Na+) ...neuronal stabilization
    • Use: proposed for migraine, PDN, TGN, PHN, phantom limb pain, post stroke central pain
  9. Lamotrigine for neuropathic pain
    • MoA:
    • - blocks VGSC (Na+) - blocks sustained repetitive firing of neurons and delays recovery
    • - acts on Na+ channels to inhibit glutamate synaptic release
    • Use: beneficial in NP from stroke, chemotherapy...3rd line
  10. Levetiracetam for neuropathic pain
    • - Binds SV2A (synaptic vesicle protein), which interacts with synaptotagmin ==antihyperalgesic/antiexcitatory
    • - Also blocks VGCC (Ca2+) --> inhibit Glu release, Glu synth and regulation.
  11. Lacosamide for neuropathic pain
    • - Enhances slow inactiv. of VGSC (Na+) via shift curve to more hyperpolarized potential (less quick firing)
    • - Allows more membrane potentials to enter slow inactivation state, prolong repolarization & there are limited # of neurons avail for repol --> decrease spread of conduction
    • - Also interacts with collapsing-response mediator protein-2: modulate Glu, impact sprouting and neuroplasticity
    • - Studied in NP
  12. Opioids for neuropathic pain
    • MoA:
    • - Interact with μδκ opioid receptors, activate G-proteins
    • - G-proteins bind to N-type VGCC (Ca2+), inhibits Ca2+ currents and open Ca-dependent inwardly-rectifying K+ channels --> hyperpolarization and decrease neuronal excitability --> decreased ability of DRG sensory neurons to propagate pain signals
    • - decrease intracellular cAMP, decrease release of nociceptive NT e.g. substance P
    • Use:
    • - Ineffective by themselves, usually give GPN/TCA first, then add opioid
    • - Synergistic with ziconitide; may help reduce opioid tolerance, side effects
    • - Effect of Morphine on spinothalamic tract neuron excitability in normal vs NP states
    • o Normal rats: morphine decrease pain signal by 75%
    • o Diabetic rats: desensitized μ receptors (decreased # presynaptic opioid Rs), impaired activation of normal descending inhibitory systems…so morphine action was significantly attenuated.
    • - Also, pathological nerve damage --> “induction” of cholecystokinin (CCK)
    • o CCK antagonizes morphine effects in spinal cord…CCK antagonists found to allow greater analgesia of morphine in lab experiments
  13. Ketamine
    • MoA:
    • - Block NMDA receptor (high affinity, long-term inhib of neuronal hyperexcit.)
    • - Block VGCC (Ca) and depress VGSC (Na), attenuate hyperalgesia
    • - Alter cholinergic neurotransmission
    • - Block reuptake of NE and 5-HT
    • Use:
    • - Not used often (4th or 5th line) due to side effects
    • - Reserved for severe, hard to treat NP
    • - CRPS (complex regional pain syndrome)
    • - Postamputation pain
    • SE:
    • - Non-selective, therefore high % SE
    • - Hallucinations,dizziness, lightheadedness, nausea
  14. Lidocaine Patch/Cream/Gel
    • MoA:
    • - Block use-dependent Na channels (in tissues with high f firing APs)
    • - Reduce ectopic discharges from peripheral afferent fibres w/o numbness of treated skin
    • Use:
    • - If patch: mechanical barrier - decrease allodynia
    • - Confined location/lesion (PHN)
    • - 5% up to 3x applied qd over painful site (12 h on, 12 h off)
    • - 4 patches (1-24h) likely safe
    • Cautions:
    • - DI not likely
    • - Mostly local SE: application-site rash
  15. Capsaicin (topical 8% patch)
    • MoA:
    • - Agonist @ TRPV1 receptor on nociceptor ending.
    • - Normally, TRPV1 stim = integrated response to pH and T
    • - When activated, Na+ & Ca2+ enter cell
    • - Cause excitation (heat, burn, sting itch)
    • - @ 8%: Ca2+ also released from ER and other internal stores
    • - Ca2+ overwhelm local mechs that sequester Ca2+ --> osmotic swelling
    • - Lead to mitochondrial dysfxn
    • - Cells can’t maintain plasma membrane integrity
    • - Overstimulated nerve cells (with too many TRPV1 receptors) are killed
    • - = localized defunctionalization
    • Use:
    • - 8% patch x30-60mins
    • - Pain relief x12wks in HIV-AN and PHN
    • - Works on cutaneous nerves already damaged: already burning and numbness, capsaicin just removes burning.
    • SE: local burning, stinging, erythema…initially may be so painful that opioids are required
  16. Botulism Toxin
    • - Suppresses nociceptor sensitization
    • - Block release of excitatory NTs (CGRP, Sub P, Glu) from afferent nerve terminals
    • - Block P2X (ATP receptor) in sensory nvs
    • - Block TRPV-1 translocation in peripheral nociceptive nerve terms
    • Use: in patiets with muscle contraptures

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