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疼痛機制 The mechanism of Pain

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The slide show is my teaching material to medical students and physicans in 2006-7.

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疼痛機制 The mechanism of Pain

  1. 1. From Signal to Sufferings 從電氣訊號到疼痛
  2. 2. 台大麻醉科 孫維仁醫師
  3. 3. 千古艱難惟一死..
  4. 4. 是愛撫?還是懲罰?
  5. 5. 疼痛處理不當,會怎樣?
  6. 6. 疼痛處理得當,會怎樣?
  7. 7. Dilemma in Pain Research Nociception Pain Suffering Pain behaviors
  8. 8. Classical Approaches to Pain
  9. 9. Classical Approaches to Pain Anatomical
  10. 10. Classical Approaches to Pain Anatomical Physiological
  11. 11. Classical Approaches to Pain Anatomical Physiological Pathological
  12. 12. Classical Approaches to Pain Anatomical Physiological Pathological Psychological
  13. 13. 傷害性刺激: Nociception Damage Response
  14. 14. Transmission of Pain Injury Peri-aqueduct gray Peripheral Nerve Dorsal Root Ganglion C-Fiber A-beta Fiber A-delta Fiber Spinothalamic tract Dorsal Horn Brain Spinal Cord Somatosensory cortex Ant cingular cortex
  15. 15. Nerve Distribution
  16. 16. The Dual Pathway Pain stimulus Dorsal horn Sensory cortex Dorsal root ganglia Perception Modulation Transmission Transduction NE 5-Ht Opioid
  17. 17. Die in peace...
  18. 18. 神蹟?催眠?
  19. 19. The scope of pain 分子 生物體 社會群體
  20. 20. 分子運動 訊息傳遞 基因調節 神經系統 嬰幼期變化 c-Fos AP-1 c-Jun-pp AP-1 site Dynorphin c-Jun-ppp p CREB Immediate early gene  
  21. 21. Molecular marker of pain ms sec min hour day week month year AMPA NMDA, Sub-P, CGRP Ca, NO, PKC apoptosis ??? Neuronal Sprouting dynorphin NPY, galanin c-fos Kao & Sun, Chinese J Pain, 2003. pErk
  22. 22. medial pathway lateral pathway Damage Sensory discriminative response Emotional cognitive response Somatosensory cortex Ant cingular cortex
  23. 23. Current Dimensions of Pain Sensory Damage Response
  24. 24. Current Dimensions of Pain Sensory Emotional Damage Response
  25. 25. Current Dimensions of Pain CognitiveSensory Emotional Damage Response
  26. 26. Current Dimensions of Pain Sociobehavioral CognitiveSensory Emotional Damage Response
  27. 27. Pain-Sleep-Mood Cycle Panic, GAD, OCD Depression,and acute anxiety all associated with sleep disruption Sleep deprivation increases anxiety, stress hormones and sympathetic tone Sleep disturbance Anxiety Pain
  28. 28. 疼痛的分期 急性疼痛 慢性疼痛
  29. 29. Somatic Visceral Neuropathic 疼痛的總類
  30. 30. Mixed Type Caused by a combination of both primary injury or secondary effects Clincal Pain Nociceptive Pain Caused by activity in neural pathways in response to potentially tissue-damaging stimuli Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system Postoperative pain Cancer pain Osteoporosis Arthritis Back pain Postherpetic neuralgia Neuropathic spinal stenosis Cancer pain Myofascial pain Central post- stroke pain Phantom pain Trigeminal neuralgia Polyneuropathy (eg,diabetic, chemotherapy)
  31. 31. 孫維仁 Neuropathic Pain 代謝 缺血 遺傳 壓迫 創傷 中毒 感染 免疫 Etiology SyndromeSymptoms 自發性 經由刺 激誘導 神經性疼痛
  32. 32. normal spontaneous firing from damaged axon spontaneous firing from spinal neuron Ectopic Focus
  33. 33. 鄰近正常Aβ活化 C fiber 受損 正常Aβ神經 NGF Nerve Sprouting
  34. 34. Allodynia and Aβ Sprouting X III/ IV V I/ II AβAβ C
  35. 35. Allodynia and Aβ Sprouting X III/ IV V I/ II nociceptive neurons afferent input modulation visceral non-nociceptive neurons AβAβ C
  36. 36. 孫維仁 臨床表現 燒灼痛 觸感痛 緊繃感 尖銳感 電擊感 持續 持續 持續 持續 陣發性 時間 發作 自發性 誘發性 自發性 誘發性
  37. 37. Acute Herpes Zoster A few days…..
  38. 38. Acute Herpes Zoster A week…..
  39. 39. Sub-acute Herpes Zoster A few weeks…..
  40. 40. Post-herpetic Neuralgia A few months…..
  41. 41. 孫維仁 Natural Course of Herpes Zoster Burning Tactile-allodynia Tightness Pin-pricking Shooting Acute ChronicSub-acute Peripheral CentralPeripheral+CentralSensitization
  42. 42. 孫維仁 Central Sensitization Normal
  43. 43. 孫維仁 Central Sensitization Normal
  44. 44. 孫維仁 Central Sensitization Normal
  45. 45. 孫維仁 Central Sensitization Normal Sensitized
  46. 46. 孫維仁 Central Sensitization Normal Sensitized
  47. 47. 孫維仁 Central Sensitization Normal Sensitized
  48. 48. 孫維仁 Central Sensitization Normal Sensitized
  49. 49. 孫維仁 Definition "Stimulus – threshold – modality "Response – pain intensity Hyperalgesia HypesthesiaAllodynia
  50. 50. 孫維仁 Definition "Stimulus – threshold – modality "Response – pain intensity    Hyperalgesia HypesthesiaAllodynia
  51. 51. 孫維仁 Definition "Stimulus – threshold – modality "Response – pain intensity       Hyperalgesia HypesthesiaAllodynia
  52. 52. 孫維仁 Definition "Stimulus – threshold – modality "Response – pain intensity          Hyperalgesia HypesthesiaAllodynia
  53. 53. Threshold vs ResponsePainIntensity 10 8 6 4 2 0 Stimulus Intensity Hyperalgesia InjuryAllodynia Normal Hyperpathia
  54. 54. 孫維仁 Targeted Approach Mechanisms Signs and Symptoms Treatment 對症下藥 對病下藥
  55. 55. Management of Neuropathic Pain • Pharmaceuticals Antidepressants Anticonvulsants Local anesthetics NSAID’s/COX 2’s Opioids α-adrenergic agents Topical agents • Nerve blocks – Sympathetic – Somatic • Interventional therapies – Spinal cord stimulation – Intrathecal opioids – Neuro-lesioning • Complementary – Acupuncture – Biofeedback/hypnosis • Psycho-social consulting
  56. 56. Pain Treatment Continuum Least invasive Most invasive Psychological/physical approaches Topical medications Oral medications* *Consider referral if previous treatments are unsuccessful. Injections* Interventional techniques* Continuum not related to efficacy.
  57. 57. 鴉片類止痛劑
  58. 58. mu-Agonist Efficacious dose-dependent no ceiling Reliable Predictable
  59. 59. NSAID mu-opioid
  60. 60. 藥理作用 藥品 μ κ 效價 管制 Agonist Morphine ++ 1 I Demerol ++ 1/8 II Fentanyl ++ 100 II Tramadol + + 1/10 III Propoxyphene + 1/3 IV Codeine + 1/12 III Partial Agonist Buprenorphine + 60 III Agonist Antagonist Nalbuphine - + 1 III Butorphanol - + 10 IV Antagonist Naloxone -- -- Pharmacodynamic Profiles
  61. 61. Adjuvants ✓ 便秘 ✓ 小便滯留 ✓ 暈眩 ✓ 噁心嘔吐 ✓ 皮癢 ✓ 呼吸抑制 Laxatives & stimulants (peripheral opioid Ant) Alfa-1 blocker Ritalin Novamine/Haldol/Remeron Nalbuphine/ Butophanol Nalbuphine/ Butophanol
  62. 62. WHO止痛階梯
  63. 63. WHO止痛階梯 非嗎啡類 止痛藥 Step I
  64. 64. WHO止痛階梯 非嗎啡類 止痛藥 Step I 弱效嗎啡類 止痛藥 Step II
  65. 65. WHO止痛階梯 非嗎啡類 止痛藥 Step I 弱效嗎啡類 止痛藥 Step II 強效嗎啡類 止痛藥 Step III
  66. 66. WHO止痛階梯 非嗎啡類 止痛藥 Step I 弱效嗎啡類 止痛藥 Step II 強效嗎啡類 止痛藥 Step III 九成治癒率
  67. 67. 孫維仁 Therapeutic TOXIC 「低量開始,緩慢加量」 SerumLevel
  68. 68. 鎮痛消炎劑
  69. 69. 孫維仁 Analgesic Action of NSAID
  70. 70. 孫維仁 Analgesic Action of NSAID Arachidonic acid Prostaglandins
  71. 71. 孫維仁 Analgesic Action of NSAID COX 1 COX 2 Arachidonic acid Prostaglandins
  72. 72. 孫維仁 Analgesic Action of NSAID COX 1 COX 2 peripheral central nociceptor activation neuronal sensitization Arachidonic acid Prostaglandins
  73. 73. 孫維仁 Analgesic Action of NSAID COX 1 COX 2 peripheral central nociceptor activation neuronal sensitization NSAID Arachidonic acid Prostaglandins
  74. 74. 孫維仁 Inflammation or Pain COX-2 Prostaglandins COX-1 InflamedNormal NSAID COX-2 specific inhibitor COX-1 COX-1 Inflammation, pain COX-1
  75. 75. 孫維仁 COX-2 NSAID on COX-1/2 COX-1 N-terminal Carboxylic group of NSAID forms “salt bridge” with Arginine at 120 C-terminal containing active sites Arachidonic Acid NSAID (flurbiprofen) phenyl group binds to hydrophobic channel N-terminal Carboxylic group of NSAID forms “salt bridge” with Arginine at 120 C-terminal containing active sites Arachidonic Acid NSAID (flurbiprofen) phenyl group binds to hydrophobic channel Kurumbail et al. Nature. 1996; 384: 644-648
  76. 76. 孫維仁 Specific COX-2 Inhibitor - “Side Pocket” Hydrophilic “side pocket” N-terminal C-terminal containing active sites Arg 513, Hist 90 – forms hydrogen bonds with oxygen in sulfonamide side chain Specific COX-2 inhibitor – phenyl group binds to hydrophobic channel Arachidonic Acid Arg 120 Kurumbail et al. Nature 1996; 384: 644-648
  77. 77. 抗憂鬱劑
  78. 78. Antidepressants in Multiple mechanisms of action RCTs and meta-analyses demonstrate benefit of amitriptyline, nortriptyline, desipramine Variable onset of analgesia Independent of antidepressant activity Improvements in insomnia, anxiety, depression *Not approved by FDA for this use.
  79. 79. Tricyclic Antidepressants for Neuropathic Pain Disorders Start at 10-25 mg at bedtime increase every few days as tolerated to a target dose of 50 mg if no effect at 2 wk, continue to increase may need ≥150 mg Can split dose to reduce side effects Expect partial effect use multiple agents Consider preprescription cardiac evaluation
  80. 80. Tricyclic Antidepressants: Adverse Effects (AEs) • Commonly reported AEs (generally anticholinergic): – blurred vision – cognitive changes – constipation – dry mouth – orthostatic hypotension – sedation – sexual dysfunction – tachycardia – urinary retention • Desipramine • Nortriptyline • Imipramine • Doxepin • Amitriptyline Fewest AEs Most AEs
  81. 81. Pharmacodynamic profiles Receptor 5-HT NE clinical actions antidepression anxiolysis antidepression enhanced drive side effect nausea,vomiting GI symptoms headache tachycardia tremor sympathomimetic
  82. 82. Clinical Manifestation Receptor 5-HT1 5-HT2 5-HT3 action antidepression anxiolysis side effect insomnia agitation nervousness sexual disorder nausea vomiting GI symptoms headache
  83. 83. Effect of mirtazapine on aminergic neurons NA cell body 5-HT cell body presynaptic NA neuron α2-autoreceptor presynaptic 5-HT neuron postsynaptic 5-HT neurons 5-HT1 5-HT2 5-HT3 postsynaptic NA neuron noradrenaline serotonin α2-heteroreceptor Remeron vesicle α2-autoreceptor α1-adrenoreceptor
  84. 84. Remeron Sleep improvement ! via block 5-HT2 receptors You need to know !
  85. 85. 抗癲癇製劑
  86. 86. Gabapentin α2δ GABA
  87. 87. Gabapentin α2δ GABA
  88. 88. Clinical Applications Neuropathic Pain Post-herpetic neuralgia Diabetic painful neuropathy Trigeminal neuralgia Acute herpes zoster Acute HIVD Sleep disorder
  89. 89. 介入性止痛術
  90. 90. Epidural Injection Inter-laminar Trans-foraminal
  91. 91. Headache inflammatory pain spasticity-induced pain Botulinum and Analgesia Migraine ++ Tension-type ??
  92. 92. 疼痛病患問題的特質 痛覺感受的異常性 生理狀況的脆弱性 心理問題的複雜性 疾病進展的多樣性 藥物反應的不定性
  93. 93. Delimma of Pain Management Analgesia Side effect Pain Sufferings Treatment
  94. 94. 療效 副 作 用 止痛越強=副作用越強?
  95. 95. 嗜血的殺手?
  96. 96. 還是,混口飯吃?
  97. 97. The Strategy Mechanisms Signs and Symptoms Treatment 對症下藥 對病下藥
  98. 98. 慢性疼痛治療原則  Nociceptive -- somatic origin -- visceral origin  Non-nociceptive -- somatic origin -- visceral origin -- neuropathic origin Opioids!! Adjuvant! Nerve block!
  99. 99. From Signal to Cells
  100. 100. spinal cord From Signal to Cells
  101. 101. spinal cord dorsal horn From Signal to Cells
  102. 102. spinal cord dorsal horn Sensory neuron From Signal to Cells
  103. 103. spinal cord dorsal horn Sensory neuron From Signal to Cells
  104. 104. From Damage to Sufferings Damage Response
  105. 105. From Damage to Sufferings Damage Response Anatomical Physiological Pathological Psychological
  106. 106. From Damage to Sufferings Damage Response Anatomical Physiological Pathological Psychological Sociobehavioral CognitiveSensory Emotional

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