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1 神經性疼痛的處置 Management of neuropathic pain 傅進華 MD. PhD. 大林慈濟醫院慈濟大學

2 臨床常見神經痛種類糖尿病神經病變 diabetic polyneuropathy 坐骨神經痛 sciatica 三叉神經痛 trigeminal neuralgia 脊髓損傷後神經痛 spinal cord injury 帶狀泡疹後神經痛 post-herpetic neuralgia 腦中風後中樞神經痛 central pain 肌纖維疼痛 fibromyalgia

3 關於疼痛... An unpleasant sensory & emotional experience associated with actual or potential tissue damage.

4 神經痛傷害性痛糖尿病神經病變坐骨神經痛三叉神經痛 Pain post spinal cord injury 脊髓損傷後神經痛帶狀泡疹後神經痛腦中風後中樞神經痛組織發炎腫痛骨折關節炎或退化疼痛術後傷口疼痛內臟性疼痛

5 Nociceptive pain: 紅腫熱痛 histamine substance P serotonin bradykinin prostaglandin

6 神經性疼痛機轉 Mechanism of neuropathic pain

7 Neuropathic pain Positive & Negative sensory symptoms Nervous system dysfunction or damage 正向症狀 (due to excessive activity) Spontaneous pain Allodynia Hyperalgesia Dysesthesia Paresthesia 負向症狀 (due to deficit of function) Hypoesthesia Anesthesia Hypoalgesia Analgesia Numb( 麻 ),, Tingling( 輕刺 ),, Burning( 燒灼 ),, Prickling Sensation( 重刺 ) Shooting( 抽痛 ), Lancinating( 撕扯 ),, Electric-shock Pains( 電 )

8 疼痛敏感化

9 Mechanisms of Persistent Chronic Pain 慢性神經痛機轉 Neural plasticity

10 鈣離子通道 Glutamate Substance P Induced Central Sensitization Increased Pain Sensitivity

11 Reduced Descending Inhibition Induced Greater Pain Sensitivity 腦幹調控 Locus coeruleus ( 藍斑 ) Raphe nuclei ( 縫核 )

12 週邊敏感化 Peripheral Sensitization descending modulatory systems spinothalamic tract nerve injury sodium channel

13 DRG: dorsal root ganglion, NT:neurotensin RVM:rostral ventromedial medulla, NT:neurotensin PNAS July 6, 1999 中樞敏感化 Central Sensitization Threshold Responsiveness (glutamate, substance P) spinobulbospinal loop increased sensitivity to glutamate

14 慢性神經痛 Chronic Neuropathic Pain Inhibitory interneuron brainstem 腦幹 Membrane excitability 細胞過度刺激興奮 Disinhibition 減少中樞抑制 Neural plasticity 變形 Potentiation 激發 Facilitation Amplification 強化

15 中樞神經被激活 A study by Zambruno and colleagues designed to demonstrate increased cerebral activation as a result of central sensitization. Ativation area: insular area, putamen, whole median raphe, the reticular formation, the sensory cortex, and the prefrontal area.

16 糖尿病神經病變 Diabetic Peripheral Neuropathy

簡介 ~135.4 million people in the Asia Pacific region have diabetes 1 out of 4 patients with diabetes are affected by DPNP. 7.5% at baseline of DM already had neuropathy.

17 簡介 ~135.4 million people in the Asia Pacific region have diabetes 1 out of 4 patients with diabetes are affected by DPNP. 7.5% at baseline of DM already had neuropathy. 60% to 70% of diabetic patients have diabetic neuropathy Chronic sensorimotor neuropathy Autonomic neuropathy Focal and multifocal neuropathies 9 out of 10 patients with DPNP report moderate or severe pain Cause of much suffering in patients with painful neuropathy. Can lead to foot ulcerations, and amputations without proper foot care.

18 糖尿病神經病變分類 - 1 Mononeuropathy ( 單一神經病變 ) involvement of a single nerve characteristically results in foot drop, wrist drop, or cranial nerve III, VI, or VII paralysis, sometimes, multifocal lesions Radiculopathy ( 神經根病變 ) a sensory syndrome of pain over multiple spinal nerves, mimics zoster pain Diabetic amyotrophy ( 神經肌萎縮病變 ) a rare disorder resulting in atrophy and weakness of the pelvic girdle musculature

19 糖尿病神經病變分類 - 2 Autonomic neuropathy ( 自主神經病變 ) 1.The gastrointestinal tract: gastroparesis, constipation, diarrhea 2.The cardiovascular system: orthostatic hypotension, tachycardia, alteration of heart rate control 3.The genitourinary system: impotence, urinary retention, incontinence 4.Other: abnormality in respiration, excessive sweating or dryness

20 糖尿病神經病變分類 - 3 Peripheral sensorimotor polyneuropathy ( 週邊多發性神經病變 ) 1. the most common of the diabetic neuropathies accounting for 80% of neuropathy in diabetic patients 2. numbness, tingling, or pain in the toes, feet, legs, hands, arms, and fingers (glove-sock distribution) 3. unsteadiness, weakness, wasting of the muscles of the feet or hands

21 糖尿病顱神經病變 - 通常侵犯第 3 對顱神經 ( 動眼神經 ) - 最初症狀為眼睛及前額疼痛, 接著發生眼球運動麻痺漸進性眼瞼下垂複視等現象, 但是瞳孔功能不會受影響 - 一般在幾週內會逐漸好轉 (8 週內約有 72% 的病人會自然恢復 ), 完全恢復則需 3-5 個月的時間

22 DN4 ( 糖尿病神經病變問卷 ) Douleur neuropathic DN4 questionnaire 7 questions answered by patients, 3 questions tested by doctor. DN4 (Cut off of 4) sensitivity of 80%, specificity of 92%. (Spallone V, 2012)

23 肌纖維疼痛 Fibromyalgia

24 肌纖維疼痛 Patients may present with a wide range of other symptoms - Sleep disturbance - Fatigue - Tenderness - Stiffness - Mood disorders - Flu-like aching - Headache

25 肌纖維疼痛症狀 Pain, fatigue and sleep disturbance are present in 86% of patients % 96% 86% 80 72% % 56% 52% 46% 42% 41% 32% 20 20% 0 Muscular pain Fatigue Insomnia Joint pains Restless legs Numb and tingling Impaired memory Leg cramps Headaches Impaired Nervousness Depression concentration (major depression) US data ACR Fibromyalgia Diagnostic Criteria. National Fibromyalgia Research Association Web site. Available at: Accessed October 18, 2007.

26 肌纖維疼痛原因 Exact cause of fibromyalgia is not known; central sensitization is emerging as a leading theory. Other factors involved in fibromyalgia include: Vulnerability elements, such as sex, genes, trauma, infection, abuse or other adverse experiences; Persistent stress or distress.

27 肌纖維疼痛診斷 Patient history of fibromyalgia or related conditions Personal history Family history Physical examination No evidence of synovitis, joint effusion or joint inflammation in the primary form of fibromyalgia Tender-point evaluation Differential diagnosis Osteoarthritis, rheumatoid arthritis, hypothyroidism, lupus, and Sjögren s syndrome

28 ACR 2010 criteria

29 Summary of ACR 2010 criteria WPI 7 and SS 5 WPI 7 AND SS 5 OR or WPI 3 6 AND SS 9 WPI= 3 6 and SS =9 This case definition of fibromyalgia correctly classifies 88% of cases classified by existing ACR 1990 classification criteria, but does not require a tender point examination.

30 神經性疼痛的治療什麼是你用過最強的非處方止痛藥 (pain killer)? I'm a Pain Killer.

31 神經性痛藥物可能作用點 NEJM 2003

32 SNRI and TCA increase the descending pain-suppressing pathways ( 抗憂鬱劑 ) 2 1

Mechanism of Antidepressants, Opioids and α2δ calcium blockes in NeP 踩煞車 Dampens Pain Perception 阻斷 Blocks TCAs and SNRIs are believed to dampen pain signals by increasing availability of

33 Mechanism of Antidepressants, Opioids and α2δ calcium blockes in NeP 踩煞車 Dampens Pain Perception 阻斷 Blocks TCAs and SNRIs are believed to dampen pain signals by increasing availability of norepinephine and serotonin within the descending pathway 2 Descending Pathway Pain Stimulus Ascending Pathway Some opioids are believed to work in the brain to block pain perception 1 減少刺激 Reduces The ion channel blockers are believed to work in the cortex and prior to the ascending pathway to reduce release of pain-related neurotransmitters TCA: tricyclic antidepressant SNRI: serotonin-norepinephrine reuptake inhibitor 1. Way WL, et al. In: Basic & Clinical Pharmacology, 8th ed. New York, NY: Lange Medical Books/McGraw-Hill; 2001: Smith T, et al. Vasc Health Risk Manag 2007;3(6):

34 Pharmacological treatments for NeP: Hypothesized mechanisms of action Predominant mechanism Binding to α2δ subunit of voltage-dependent calcium channels with reduced release of transmitters Dual serotonin/noradrenaline reuptake inhibition μ-opioid (or К 2 -opioid) receptor agonist Voltage-gated sodium channel inhibition Voltage-gated sodium-channel block; inhibition of glutamate release via activity at AMPA/kainate receptors Increase of GABA levels in brain and potentiation of GABA-mediated responses NMDA (N-methyl-D-aspartate) antagonists DPNP, Diabetic peripheral neuropathic pain Venlafaxine is not approved for the treatment of neuropathic pain. Drugs pregabalin, gabapentin amitriptyline, duloxetine, imipramine, venlafaxine oxycodone; tramadol (also has monoamine reuptake inhibition) lamotrigine, carbamazepine, oxcarbazepine topiramate valproate memantine; dextromethorphan (weak) 1. Zin CS, et al. CNS Drugs 2008;22: Attal N, et al. Eur J Neurol 2010;17:1113-e88.

36 AAN (American Academy of Neurology) Guidelines Neurology 2011

37 EFNS (Europ) Guidelines on Pharmacological Treatment of Neuropathic Pain (2010 revision) Pain condition Painful polyneuropathies (e.g. DPNP) Postherpetic neuralgia (PHN) Recommendations for 1 st -line Duloxetine Gabapentin Pregabalin Tricyclic antidepressant Venlafaxine ER Gabapentin Pregabalin Tricyclic antidepressant Lidocaine plasters (elderly) Recommendations for 2 nd - or 3 rd -line Opioids Tramadol Capsaicin Opioids Trigeminal neuralgia Oxcarbazepine Surgery Carbamazepine Central pain Gabapentin Cannabinoids (MS) Pregabalin Tricyclic antidepressant Lamotrigine Opioids Tramadol (SCI) Attal et al. Eur J Neurol. 2010;17(9):1113-e88

38 Deactivation of the thalamocortical network is essential to sleep. But these systems are ativated by pain. REM NREM waking sleep and pain

39 總結神經性疼痛的種類 : 糖尿病神經病變三叉神經坐骨神經帶狀砲疹腦中風或脊髓損傷肌纖維疼痛神經性疼痛的機轉 : 鈣及鈉離子傳輸腦幹血清素及腎上腺素周邊及中樞神經敏感化神經性疼痛的藥物治療 : 離子通道阻斷劑 :pregabalin, gabapentin, depakine, tegretol 抗憂鬱劑 :TCAs, SNRIs μ-opioid (or К 2 -opioid): Tramadol Lidocaine, Capsaicin...

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<4D6963726F736F667420576F7264202D2030383132C3C4B0542DAA76C0F8AF70AF6CABE1AFABB867B568ADD7A7EF> 老人帶狀皰疹後神經痛江文心林珍芳一前言帶狀疱疹 (herpes zoster) 俗稱皮蛇 (shingles), 引起的病毒就是引起水痘的病毒 varicella-zoster virus(vzv), 水痘痊癒後少量病毒潛伏在體內感覺神經的背根神經節 (dorsal root ganglia)