-
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
-
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
-
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…
-
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)
-
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
-
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
-
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
-
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
-
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
-
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.
-
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
-
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
-
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
-
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
-
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
-
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
|
|