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Neuropathic agents
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Neuropathic agents
Neuropathic agents
Neuropathic agents
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Neuropathic agents

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  • 1. Joshua H. Pozner, M.D.
    Mount Sinai School of Medicine
    Department of Anesthesiology
    Division of Pain medicine
    Neuropathic Agents
  • 2. Neuropathic Pain
    Pain initiated or caused by a primary lesion or dysfunction in the nervous system
    Onset secondary to viral infection, trauma, certain medications, or metabolic insults
    Typically serves no protective purpose
    Nerves that remain intact following disease or injury are often hyperactive, signaling pain in the absence of painful stimuli
    Often described as a burning in quaility
    May or may not follow a dermatomal distribution
  • 3. Neuropathic Pain States
    Diabetic painful neuropathy
    Non-diabetic painful polyneuropathy
    HIV-related distal sensory polyneuropathy
    Antiretroviral toxic neuropathy
    Post-herpetic neuralgia
    Classical trigeminal neuralgia
    Central pain
    Multiple sclerosis
    Central poststroke pain
    Spinal cord injury
    Cancer neuropathic pain
    Radiculopathy
    Phantom limb pain
    Stump pain
    Complex regional pain syndrome types I & II
  • 4. Neuropathic Agents
    Antidepressants
    Anticonvulsants
    Local anesthestics
  • 5. Antidepressants
    • 1962 case series by Kuipers
    • 6. Imipramine used in “non-articular rheumatism”
    • 7. 60-70% experienced pain relief
    • 8. 1969 double blind study by Scott
    • 9. Imipramine used in RA, OA, ankylosingspondylitis
    • 10. Significantly more pain relief than placebo
    • 11. Initially postulated that pain relief was secondary to mood elevation
    • 12. Now recognized that pain relief is likely independent of mood alteration
    • 13. Muscle relaxation, mood enhancement, improvement in sleep quality
  • Antidepressants
    Classification
    Tricyclics (TCAs)
    Selective serotonin reuptake inhibitors (SSRIs)
    Serotonin-norepinephrine reuptake inhibitors (SNRIs)
    Tetracyclics
    Monoamine oxidase inhibitors (MAOIs)
    Dopamine reuptake inhibitors (DRIs)
  • 14. TCAs
  • TCA - Mechanisms
    Seratonergic effect
    Interfere with serotonin binding and reuptake into nerve terminals
    Acts at level of descending bulbospinal pathway
    Inhibitory influence on spinal neural activity
    Evidence:
    5-HT antagonists inhibit antinociceptive effects of TCAs
    Depletion of central 5-HT systems using p-chlorophenylalanine inhibit antinociceptive effects of TCAs
  • 26. TCA - Mechanisms
    Noradrenergic effect
    Acts at level of descending bulbospinal pathway
    Inhibitory influence on spinal neural activity
    Evidence:
    Depletion of central norepinephrine systems with alpha-methyl p-tyrosine inhibits the antinociceptive actions of TCAs
    Alpha-adrenoreceptor antagonists such as phentolamine (alpha-1 and alpha-2 blocker) inhibit antinociceptive action of TCAs
    Alpha-1 blocker, prazosin + amitriptyline = antinociception
    Alpha-2 blocker, RX821002 + amitriptyline ≠ antinociception
    Suggests TCAs derive part of antinociceptive effect at the level of the alpha-2 receptor
  • 27. TCA - Mechanisms
    Opioidergic effect
    Evidence
    Naloxone has been shown to antagonize antinociceptive effect of clomipramine in rats
    Naltrindole (delta-opioid antagonist) has been shown to antagonize antinociceptive effects of TCAs
    Chronic TCA administration can modify opioid receptor densities and increase opioid levels in rats
  • 28. TCA - Mechanisms
    NMDA receptor effect
    Evidence:
    TCAs bind NMDA receptor complex
    Chronic administration alters NMDA binding characteristics
    Imipramine has been shown to prevent Ca2+ influx via NMDA receptor in rat brain
  • 29. TCA - Mechanisms
    Adenosine receptor effect
    Inhibit reuptake into neuronal tissue
    Adenosine has known analgesic effects both peripherally and centrally
    α1 receptor activation produces antinociception by decreasing cAMP
    Evidence:
    Adenosine receptor antagonists (i.e.: caffeine) inhibit antinociceptive effect of TCAs
  • 30. TCA - Mechanisms
    Sodium channel effect
    Local anesthetic-type mechanism
    Demonstrated in animal models
    Injection into rat sciatic notch comparable to bupivacaine
    Topical application comparable to lidocaine
    Anecdotal evidence of holding TCA tablet over sore tooth causing localized numbness
    Case studies of efficacy with 5% doxepin cream in CRPS I and with doxepin rinse in oral pain from cancer or cancer treatment
  • 31. TCA - Mechanisms
    Calcium channel effect
    Chronic treatment has been shown to increase density of L-type channels
    Antinociceptive effect nullified by nifedipine administration
  • 32. TCA - Mechanisms
    Anti-inflammatory effect
    Evidence
    Experimental model showed imipramine to reduce inflammation induced by carrageenin in rats
    Dose dependent
    Clomipramine reduces carrageenin-induced skin inflammation, PGE2 biologic activity and substance P concentration in rat inflammatory exudate
  • 33. TCA – Side Effects
    Linked to inhibitory interactions with histaminic, cholinergic muscarinic, and cholinergic nicotinic receptors
    Adverse effects
    Dry mouth
    Sedation
    Dizziness
    Lethargy
    Urinary retention
    Weight gain
    Most common antidepressants used in suicide attempts
  • 34. TCAs - Indications
    Numerous studies have demonstrated efficacy in neuropathic pain models
    Features of neuropathic pain are not dependent on the causal disease
    Has become accepted that the evidence of analgesia with specific conditions is strong enough to allow uniform use for any condition manifesting the symptoms of neuropathic pain
  • 35. TCAs - Indications
    • Postherpetic neuralgia
    • 36. Amitriptyline: arguably first line treatment (nortriptyline displays fewer side effects)
    • 37. Watson et. al: “good to excellent” pain relief in 16 of 24 pateints studied
    • 38. Max et. al: “moderate or greater” pain relief in 47% of 58 patients in RCT with amitriptyline
    • 39. Painful diabetic neuropathy
    • 40. Max et. al: desipramine is of equal efficacy to amitriptyline
    • 41. Sindrup et. al: dose-response relationship is noted
    • 42. Painful mononeuropathy
    • 43. Pain associated with spinal cord injury
    • 44. Conflicting evidence: case reports in favor; RCT show no benefit over active placebo
    • 45. Central post-stroke pain
    • 46. Case reports
  • TCAs - Indications
    • Fibromyalgia
    • 47. Conflicting evidence
    • 48. Arnold et. al meta-analysis: TCAs have positive effect on sleep, fatigue, pain, well-being, but modest improvement in stiffness and tenderness
    • 49. Osteoarthritis
    • 50. Limited evidence
    • 51. Low back pain
    • 52. Multiple RCT have demonstrated positive role in most etiologies
    • 53. Atypical facial pain
    • 54. Cancer-related neuropathic pain
    • 55. Little to no apparent efficacy (studies have been small and neuropathic pain may not have been present in isolation)
    • 56. HIV sensory neuropathy
    • 57. Little to no apparent efficacy
  • TCAs - NNT
  • 58. SSRIs
    Alaproclate
    Citalopram
    Escitalopram
    Etoperidone
    Fluoxetine
    Fluvoxamine
    Paroxetine
    Sertraline
    Zimeldine
  • 59. SSRIs
    Animal models
    Paroxetine & Fluvoxamine: dose dependent antinociception in mouse hot plate pain test (weak association fluoxetine and citalopram; none with escitalopram)
    Paroxetine antinociceptive effect
    Inhibition by naloxone
    Inhibition by ondansetron (5-HT3 antagonist)
    No inhibition by ketanserin (5-HT2 antagonist)
    NNT
    Paroxetine: 5
    Fluoxetine: 15.3
  • 60. SSRIs
    Human pain studies
    PDN
    Sindrup et al.: paroxetine did produce pain relief but less than with imipramine
    Paroxetine was associated with fewer side effects
    Fibromyalgia
    Norregaard et al.: no changes observed in any pain parameter on citalopram after 8 weeks of treatment
    Caution with concomitant use of NSAIDs
    May be associated with higher incidence of gastritis/PUD
  • 61. SNRIs
    • Selectively block reuptake of norepinephrine and serotonin
    • 62. Desipramine
    • 63. Duloxetine
    • 64. 10-fold selectivity for 5-HT
    • 65. Milnacipran
    • 66. Blocks 5-HT and norepinephrine reuptake equally
    • 67. Nefazodone
    • 68. Venlafaxine
    • 69. 30-fold selectivity for 5-HT
  • SNRIs - Indications
    Painful diabetic neuropathy
    Duloxetine: first antidepressent in U.S. to have specific pain indication
    Fewer dropout rates from studies than with TCAs due to AE profile
    Favorable safety profile when used over prolonged period
    Associated with modest adverse changes in glycemia
    Fibromyalgia
    Greater likelihood of alleviating symptoms than with SSRIs
    Lower likelihood of adverse effects than with TCAs
    Arnold et al.: duloxetine significantly reduced pain, number of tender points, stiffness; improved quality of life compared with placebo (results have been reproduced with other SNRIs as well)
    Vitton et al.: RCT of 125 subjects - 37% reported 50% reduction in pain intensity with milnacipran
  • 70. Tetracyclics
    Amoxapine
    Maprotiline
    Mianserin
    Mirtazapine
    Limited evidence exists
    Less pronounced analgesic properties than with TCAs in PHN
  • 71. MAOIs
  • Dopamine Reuptake Inhibitors
    Amineptine
    Bupropion
    Also has noradrenergic activity
    Little evidence of analgesic efficacy
  • 82. Anticonvulsants
    FDA-approved pain indications for AEDs
  • 83. Anticonvulsants - Mechanisms
    Voltage-gated calcium channels
    N-type high voltage channel largely responsible for neurotransmitter release from presynaptic nerve terminals
    L-type high voltage channel found in high concentration in skeletal and smooth muscle
    T-type low-voltage channel also implicated in transmission of neuropathic pain in periphery and in spinal cord and in central pain
    α2-δ subunit
    Increased expression in DRG secondary to peripheral nerve injury in animal models
    Upregulation noted primarily in neuropathic- and inflammatory-mediated hyperalgesia
    Binding of gabapentin and pregabalin inhibits calcium influx
    Selective primarily in above pain states
  • 84. Anticonvulsants - Mechanisms
    Voltage-gated sodium channels
    Increased expression has been demonstrated in peripheral and central sensory neurons in neuropathic pain
    Na channels 1.2, 1.8, 1.9 are preferentially expressed on peripheral sensory neurons
    Role in nociception
    Greater inhibition of the channel when membrane is depolarized
    Binding of fast current of the open channel by AED is slow compared to that of local anesthetics
    Ensures that kinetic properties of normal action potential are not altered
    May also regulate excitability by blocking persistent sodium current
  • 85. Anticonvulsants - Mechanisms
    GABA modulation
    Main inhibitory neurotransmitter in CNS
    GABA-A receptors: Cl--permeable ionotropic channel pores
    GABA-B receptors: metabotropic G-protein-coupled
    Activity terminated at synapse by reuptake into nerve terminals and metabolized by GABA tramsaminase
    Activity potentiated by many AEDs
    Direct action on GABA-A receptors (benzos)
    Increase synthesis
    Inhibit reuptake
    Inhibit GABA-T
  • 86. Anticonvulsants - Mechanisms
    Glutamate modulation
    Main excitatory neurotransmitter in CNS
    Action primarily mediated through inotropic ligand-gated receptors
    NMDA – slow-gating and desensitize weakly
    Agonist action requires coagonist glycine
    Antagonized by ketamine (role in status epilepticus)
    AMPA – fast-gating and desensitize strongly
    Kainate
    Act secondarily through metabotropic G-protein-coupled receptors
  • 87. Anticonvulsants - Mechanisms
  • 88. Anticonvulsants
    Phenytoin/Fosphenytoin
    First AED to be used for neuropathic pain (trigeminal neuralgia)
    Subsequent RCTs have shown little analgesic efficacy
    Numerous drawbacks
    Highly protein-bound
    Only free drug is metabolically active
    Multiple drug-drug interactions
    Nonlinear metabolism and elimination
    AE: hypersensitivity reaction (rash, fever, LAD), hypotension, nystagmus, ataxia, encephalopathy, osteoporosis, teratogenicity
  • 89. Anticonvulsants
    Carbamazepine
    First approved for trigeminal neuralgia (later for epilepsy)
    Chemically related to TCAs
    Has been studied in PHN, PDN, poststroke pain, pain in GBS
    Nonlinear time-dependent kinetics due to autoinduction
    Half-life can shorten considerably
    38 hours after single dose to 12 hours after chronic therapy
    Often requires increase in dose after weeks of treatment
    Autoinduction quickly reversed with discontinuation
    Therapeutic range: 4-12 mg/dL
    Typically dosed twice daily
    AE: rash, neurotoxicity, diplopia, hyponatremia, agranulocytosis
    Primarily attributable to 10,11-epoxide metabolite
  • 90. Anticonvulsants
    Oxcarbazepine
    Structure similar to carbamazepine
    Modulates sodium and calcium channels
    May act at level of adenosine receptor
    Antinociception reduced with adenosine receptor antagonists
    Limited but increasing evidence of use for treatment of pain
    RCTs have shown efficacy in alleviating TGN
    Pain relief may be apparent within 24-48 hours
    Some have shown pain relief despite lack of response to carbamazepine
    May also have a role in PDN
    At therapeutic dose, metabolism is not induced nor inhibited by CYP system
    95% bioavailability
    AE: rash, hyponatremia, neurotoxicity, hypothyroidism
    Less frequent than with carbamazepine
  • 91. Anticonvulsants
    Gabapentin
    Binds α2-δ subunit of voltage-gated calcium channel
    Decreases release of monoamines
    Nonlinear kinetics
    Absorption via facilitated transport is saturable
    Bioavailability is related to dose
    Drug is not metabolized and does not induce enzymes
    Lack of drug-drug interactions
    Low protein binding
    Eliminated unchanged via kidneys
    Adjust dose in renal impairment
    Removed during HD
    Implies CRCL < 15 mL/min: dose 100-300 mg/day with supplemental dose of 100-300mg after dialysis
    Elimination half-life: 6 hours
  • 92. Anticonvulsants
    Gabapentin
    Studied in numerous pain syndromes:
    Multiple sclerosis-related central pain, CRPS I & II, migraine, TGN, HIV neuropathy, SCI, cluster HA, DPN, PHN
    May reduce opioid requirements postoperatively
    Synergistic
    Best analgesia in PDN and PHN with gabapentin-morphine combination
    Reduced doses than when either is used alone
    AE: dizziness, fatigue, somnolence, weight gain, peripheral edema
  • 93. Anticonvulsants
    Pregabalin
    Anticonvulsant, anxiolytic, and analgesic activity
    Binds α2-δ subunit of voltage-gated calcium channel
    Predictable pharmacokinetics
    High bioavailability
    Elimination half-life: 6.3 hours
    Not protein-bound
    No effect on CYP450 system
    90% excreted unchanged in urine
    Adjust dose in renal impairment
    Numerous RCTs
    Improved pain and sleep scores in PDN after one week
    Also effective in PHN, fibromyalgia
    AE: dizziness, fatigue, somnolence, weight gain, peripheral edema
  • 94. Anticonvulsants
    Topiramate
    Derivative of D-fructose
    Mechanism
    Blocks voltage-sensitive sodium channels
    Potentiates GABA at level of GABA-A receptor
    Increases opening frequency Cl- ion channels
    Blocks glutamate receptors
    Reduces activity of L-type Ca++ channels
    Linear pharmacokinetics
    Half-life: 19-25 hours
    85% bioavailability
    Mild enzyme inducer
    Indication: migraine prophylaxis
    Inhibits trigeminocervical pain transmission
    No demonstrable analgesia in PDN
    AE: paresthesias, drowsiness, cognitive effects, nephrolithiasis, weight loss
  • 95. Anticonvulsants
    Divalproex
    Mechanism:
    Inhibits GABA catabolism
    Increases synaptic release of GABA
    Sodium valproate and valproic acid in 1:1 ratio
    FDA approved for migraine prophylaxis
    Also used as acute treatment in migraine, but evidence is lacking
    Highly protein bound
    Half-life: 16 hours
    Extensively metabolized
    Lack of enzyme induction
    Multiple drug-drug interactions with other AEDs
    AE: drowsiness, tremor, nausea, weight gain, alopecia, peripheral edema, hepatotoxicity, pancreatitis, encephalopathy, teratogenicity
  • 96. Anticonvulsants
    Lamotrigine
    Fewer side effects relative to carbamazepine and phenytoin
    Little dose-dependent toxicity
    No need to monitor lab values
    No effect on liver enzymes
    55% protein-bound
    Half-life: 30 hours
    Requires slow titration (4-6 weeks)
    Serum levels reduced by enzyme-inducing drugs
    Reportedly useful in lumbar radicular pain
    RCTs have shown benefit in HIV-associated distal sensory polyneuropathy, antiretroviral toxic neuropathy, SCI pain, central poststroke pain
    AE: rash, Stevens-Johnson syndrome
  • 97. Anticonvulsants
    Others requiring further investigation to support analgesic activity:
    Levetiracetam
    Tiagabine
    May have a role in pain resulting from tonic spasm of multiple sclerosis
    Zonisamide
    May have a role in PDN
    RCTs showed improvement, but not significantly better than placebo
    Benzodiazepines
    Clonazepam has been reportedly used in chronic facial pain
  • 98. Local Anesthetics
    Uses:
    Neuropathic pain that arises from abnormally developed sodium channels at site of neuronal injury
    Persistent spontaneous ectopic discharges along an injured peripheral nerve, in neuromas, in DRG, in a central hyperexcitable state
    Repeated activation of peripheral nociceptors leading to central sensitization, resulting in hyperalgesia, allodynia
    Can block aberrant discharges at concentrations below those necessary to produce conduction blockade
  • 99. Local Anesthetics
    Lidocaine
    Binds abnormally developed sodium channels
    Reduces frequency of ectopic discharges
    Intravenous
    Meta-analysis of numerous neuropathic pain states
    Typical dose: 5mg/kg over 30-60 minutes
    Effect more consistent in patients with pain secondary to trauma, PDN, and central pain
    Also effective in PHN, stump pain
    Less effective in phantom pain than morphine
    Ineffective in HIV-related polyneuropathy
    Consider transitioning to mexilitine if positive response
    AE: nausea, vomiting, abdominal pain, diarrhea, dizziness, perioral numbness, tremor, dry mouth, metallic taste, insomia, tachycardia
  • 100. Local Anesthetics
    Lidocaine patch
    Topical application limits systemic effects
    Up to 5% of total dose applied is absorbed systemically
    Maximum plasma concentration is achieved by day 2
    Systemically absorbed lidocaine is primarily metabolized by liver
    Efficacy demonstrated in PHN – FDA approved
    Has also been used in myofascial pain, LBP, OA, PDN
    10 x 14cm, 700mg, nonwoven polyethylene backing
    Maximum of three patches to intact skin
    12 hours on, 12 hours off
    Those who are responsive feel relief within days
    Some have delayed relief – trial period of 2 weeks recommended
    1/3 report continued pain relief when patch is not applied
    Minimal AE (skin irritation); minimal drug-drug interactions; may be used indefinitely
  • 101. Local Anesthetics
    Mexilitine
    Oral bioavailable analogue of lidocaine
    Most effective in neuropathic pain due to PDN, trauma and central pain
    Has also been used in postoperative pain
    600mg night before breast cancer surgery and for 10 days reduced analgesic requirements from postoperative days 2-10
    AE: similar to lidocaine; more nausea, fewer CNS symptoms; fever, eosinophilia, lymphocytosis, liver dysfunction
    90% bioavailable
    40% protein-bound
    Eliminated primarily by hepatic metabolism
    Caution in liver dysfunction
    Half-life: 6.7-17.2 hours
    Lack of predictable dose-response relationship
    Titrate over days to weeks
  • 102. Ketamine
    Mechanisms
    Non-competitive NMDA receptor antagonist
    Inhibition of voltage gated Na+ and K+ channels
    Inhibition serotonin, dopamine reuptake
    Formulations
    Injectable, oral, topical, intrathecal, epidural
    May be useful in instances in which “wind-up” is presumed to have already occurred
    Evidence for efficacy is moderate to weak
    Described uses
    Central pain
    Complex regional pain syndromes
    Fibromyalgia
    Ischemic pain
    Phantom limb pain
    Postherpetic neuralgia
    Cancer pain
    AE: psychomimetic reactions, sensorimotor disturbances, hyperactivity
  • 103. Capsaicin
    Mechanisms
    Causes neurotoxic cellular degeneration of primary afferent nociceptors
    Results in activation, desensitization, and occasionally, destruction of lightly myelinated or unmyelinated primary afferent fibers
    Uses
    Possible clinical role for topical capsaicin at high doses
    Applications of 5-10%
    PHN
    HIV associated neuropathy
    Arthritic pain; LBP; post-surgical pain
    At low doses, compliance may be a problem because prolonged and frequent applications are required, and application is marked by intense initial burning effects
  • 104. Clonidine
    Mechanisms
    Alpha-2 adrenergic agonist
    Increases GABA-A activity
    Stimulates cholinergic interneurons in the spinal cord when given intrathecally and epidurally
    Sites of action: periphery, supraspinal CNS, spinal cord
    Most data reflect the effectiveness of the intrathecal and epidural administration of clonidine
    Newer data may support efficacy in various neuropathic pain states with use of oral and topical administration
    Diabetic neuropathy
    Postherpetic neuralgia
    Dose should be tapered to avoid rebound hypertension
    AE: sedation, hypotension, dry mouth, dizziness, constipation, orthostasis, sexual dysfunction
  • 105. Botulinum Toxin
    Neurotoxin with affinity for cholinergic synapses
    Endocytosed into motor neuron terminal
    Inhibits exocytosis of synaptic vesicles containing acetylcholine
    Role in pain modulation
    Inhibits exocytosis of other neuropeptides such as substance P
    In vitro: reduces stimulated release of CGRP
    Decreases the inflammatory response and release of glutamate induced by SQ formalin in mice paws
    Reduced activity of dorsal horn neurons
    May mitigate peripheral and central sensitization
    Uses
    PDN
    TGN
    PHN
    Migraine
  • 106. Conclusion
    Complex chronic pain state
    Numerous etiologies
    Difficult to treat
    Multimodal/multiagent approach
    Trial and error

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