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Neuropathic agents
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
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
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
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
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