Neuropathic agents


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Neuropathic agents

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