神经病理性疼痛浙江大学医学院附属第二医院麻醉科严敏.

神经病理性疼痛浙江大学医学院附属第二医院麻醉科严敏

疼痛几个世纪以来，科学家们和哲学家们一直着迷于疼痛的起源以及它所扮演的既充当着机体重要的生理功能同样也充当着一种疾病的双重角色的研究

什么是神经病理性疼痛? 疼痛定义疼痛分类流行病学神经病理性疼痛定义神经病理性疼痛发病机制神经病理性疼痛诊断
常见神经病理性疼痛类型： DPN 、PHN DPN、PHN治疗

疼痛的定义什么是疼痛? “国际疼痛学会对疼痛的定义：疼痛是真正或潜在组织损伤或用损伤来描述的一种不愉快的感觉和情感经历。”
The Task Force on Taxonomy Committee of the International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” This definition of pain allows us to understand that pain is not only a sensory experience but also an emotion that can affect quality of life. Reference 1. Merskey H, Bogduk N, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, Wash: IASP Press; 1994: International Association for the Study of Pain (IASP) 1994 Merskey H, Bogduk N. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:

疼痛分类时间病理生理急性疼痛慢性疼痛伤害感受性疼痛神经病理性疼痛
There are a variety of approaches for classifying pain. The two that are used most frequently are based on pain duration (i.e. acute vs chronic pain) and underlying pathophysiology (i.e. nociceptive vs. neuropathic pain). 神经病理性疼痛

急性疼痛到慢性疼痛的转归1 病程 <3个月 ≥3-6个月明显组织损伤长达3-6月甚至更久2 神经系统活动增强
疼痛刺激疼痛发作病程急性疼痛慢性疼痛 <3个月 ≥3-6个月明显组织损伤神经系统活动增强损伤修复后疼痛消失机体保护功能长达3-6月甚至更久2 损伤修复后疼痛仍存在2 多不属于保护性机制3 机体健康下降3 这张幻灯介绍了在疼痛持续过程中急性和慢性疼痛特征1 关键信息点如下：急性疼痛可视为组织受损的信号，是病理状态的警告，提示患者寻求治疗或避免进一步的损伤偶发的急性疼痛可呈自限性起病后疼痛超过3-6月或于组织修复后疼痛仍存在，急性疼痛可转化为慢性疼痛2 慢性疼痛并不是机体自我保护功能，相反，它是机体健康功能的下降3 慢性疼痛可以只是伤害感受性疼痛，也可以只是神经病理性疼痛，或者两者同时存在由于慢性疼痛和急性疼痛的再发在治疗上有很大差别，区分两者十分重要参考文献： Cole BE. Pain Management: Classifying, Understanding and Treating Pain. Hosp Physician 2002;38:23-30 Turk DC, Okifuji A. Pain terms and taxonomies of pain. In: Loeser JD (ed). Bonica’s Management of Pain. 3rd ed. Philadelphia, Penn: Lippincott Williams & Wilkins; 2001:17-25 Chapman CR, Stillman M. Pathological pain. In: Kruger L (ed). Pain and Touch. 2nd ed. San Diego, Calif: Academic Press; 1996: Cole BE. Hosp Physician 2002;38:23-30 Turk DC, Okifuji A. Bonica’s Management of Pain 2001:17-25 Chapman CR, Stillman M. Pain and Touch. 1996:

伤害感受性与神经病理性疼痛的区别伤害感受性疼痛神经病理性疼痛对组织损伤产生的一种病理生理过程5 发生在损伤性刺激作用后5
Treede/p. 2/col. 1/para and continued col 2/1-2 1.Serra/p7/col.2/par1/3-6 对组织损伤产生的一种病理生理过程5 发生在损伤性刺激作用后5 疼痛感受常随刺激强度增加而增强5 机体对损伤性刺激作用后的功能性反应，是对潜在组织损伤的一种保护性信号5 非甾体类抗炎药、阿片类药物治疗有效6 神经系统损伤或功能障碍所致的疼痛1 有时无需伤害性刺激即可产生自发疼痛3 刺激强度和疼痛感受常不成比例5 对机体无益处，严重影响生活质量2 抗惊厥药、三环类抗抑郁药和一些抗精神病药物镇痛有效6 Treede/p. 1/para. 1/3-5 Two ways to classify pain, which are used most frequently, are based on duration (ie, acute vs chronic pain) and underlying pathophysiology (ie, nociceptive vs neuropathic pain).1,2 Acute nociceptive pain serves an important biologic function, as it warns of the potential for or extent of injury It serves as an “alarm” and a protective system against noxious stimuli In contrast to neuropathic pain, nociceptive pain is usually directly related to tissue damage and resolves as the underlying injury is healed Neuropathic pain is pain in the absence of adequate nociceptor stimulation and results from a lesion or disease affecting the somatosensory system, centrally or in the periphery Neuropathic pain is a symptom of aberrant somatosensory processing beyond that which could be explained by the normal plasticity of the undamaged nociceptive system Nociceptive and neuropathic pain are distinctly different, with unique diagnostic criteria and treatments 1.Serra/p7/col.2/par1/4-6 Treede/p. 1/para 1/1-6 and p. 2/col. 2/para. 1/14-16 1 徐建国等，《疼痛药物治疗学》.2007:5； 2 徐建国等，《疼痛药物治疗学》.2007:320； 3高崇荣等，《神经性疼痛诊疗学》. 2006:21； 4 倪家骧等，《慢性疼痛临床诊疗指南》.200:17； 5 徐建国等，《疼痛药物治疗学》.2007:23； 6 徐建国等，《疼痛药物治疗学》.2007:2 Serra/p. 7/abstract/10-13 References: 1. Serra J. Overview of neuropathic pain syndromes. Acta Neurol Scand Suppl. 1999;173:7-11. 2. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology. 2008;70: 10

神经病理性疼痛的危害导致睡眠障碍： >60%的神经病理性疼痛患者的规律性疼痛令其难以入睡，疼痛强度和睡眠障碍程度呈正相关
导致睡眠障碍： >60%的神经病理性疼痛患者的规律性疼痛令其难以入睡，疼痛强度和睡眠障碍程度呈正相关长期睡眠障碍会导致：60%的患者感觉日常生活疲惫不堪 40%的患者会伴有困倦、乏力好、精神恍惚 30%的患者出现失望、烦躁等精神障碍生活质量的下降各种功能的受损焦虑、抑郁

神经病理性疼痛患病率平均 6.7% 或每 15个成人绝对数: 3.0 2.5 4.0 2.1 (百万患者) 7.7% 7.5%
10 9 7.5% 7.7% 8 6.4% 6.0% 7 患者百分比% 6 5 平均 6.7% 或每 15个成人 4 3 2 1 英国法国德国西班牙绝对数: (百万患者) McDermott, Tölle et al. 2006, Eur J Pain

不同情况下神经病理性疼痛患病率/发病率 20–24% 患者患有糖尿病周围神经痛（PDN)1
25–50% > 50岁带状疱疹患者发展为带状疱疹神经痛（PHN） (皮疹恢复后3个月 )1 20% 手术后患者形成乳腺癌根治术后疼痛2 – 术后疼痛 – 疝修补术后等三分之一癌症患者患有神经病理性疼痛（可与伤害感受性疼痛混合存在）3 Schmader KE. Clin J Pain 2002; 18: 350– Stevens PE et al. Pain 1995; 61: 61–68. 3. Davis MP and Walsh D. Am J Hosp Palliat Med 2004; 21(2): 137–142.

伤害感受性疼痛神经病理性疼痛

神经病理性疼痛 (Neuropathic Pain, NeP)
IASP 神经病理性疼痛定义神经病理性疼痛 (Neuropathic Pain, NeP) 由于外周或中枢神经系统的损伤、病变或功能紊乱所引起的疼痛周围性神经病理性疼痛周围神经系统的原发病变或功能失调导致的疼痛中枢性神经病理性疼痛中枢神经系统的原发病变或功能失调导致的疼痛 This slide presents the current definitions of neuropathic pain from the International Association for the Study of Pain (IASP). The IASP first published its pain terms in 1979, however, neuropathic pain was not included in the list until The key talking points on this slide are as follows: The IASP’s definition of neuropathic pain as ‘pain initiated or caused by a primary lesion or dysfunction in the nervous system’ is a broad definition that encapsulates the concept that, as the nervous system is damaged, there may appear changes in the nervous system that could result in chronic pain, even in the absence of a damaging insult. Although this theory has now gained general acceptance, it was originally a revolutionary idea that repudiated the Cartesian model of nociception and pain.2 Depending on where the lesion or dysfunction occurs in the nervous system, neuropathic pain can be peripheral or central in origin. References 1. Merskey H, Bogduk N, eds. In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Seattle, Wash: IASP Press; 1994: Chong MS, Bajwa ZH. Diagnosis and treatment of neuropathic pain. J Pain Symptom Manage 2003;25(5):S4-S Cruccu G, et al. EFNS guidelines on neuropathic pain assessment. Eur J Neurol 2004;11(3): Merskey H, Bogduk N. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:

疼痛的病理生理学分类疼痛是组织损伤或潜在组织损伤引起的不愉快感觉和情感体验神经病理性疼痛混合性疼痛伤害感受性疼痛如：周围性
神经病理性疼痛和伤害感受性疼痛并存肌体组织损伤所致的疼痛 (肌肉骨骼,皮肤或内脏)2 神经系统的原发性损伤或功能障碍所致的疼痛1 如：周围性带状疱疹后神经痛三叉神经痛痛性糖尿病周围神经病术后神经病变创伤后神经病变坐骨神经痛中枢性卒中后神经痛如：腰背神经根病所致疼痛颈神经根病癌痛腕管综合征如：感染所致疼痛骨折后肢体疼痛骨关节炎的关节痛术后内脏痛 International Association for the Study of Pain. IASP Pain Terminology. Raja SN, et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed ;11-57

常见神经病理性疼痛类型： DPN 、PHN DPN、PHN治疗普瑞巴林经验分享

神经病理性疼痛机制症状神经病理性疼痛体征发病机制病理生理学改变病因神经损伤自发性疼痛刺激诱发性疼痛代谢创伤中毒缺血
遗传压迫感染免疫相关病因 This slide illustrates the concept that many different underlying causes of neuropathic pain may express as different spontaneous and stimulus-evoked pain symptoms via different pathophysiological mechanisms. The key talking points on this slide are as follows: There are many possible causes of neuropathic pain. Neuropathic pain is commonly classified according to the etiological nature of the damage to the nervous system or the anatomical distribution of the pain, although the relationship between etiology, mechanisms, and symptoms/signs is highly complex. For instance: the pain caused by diverse diseases may originate through common mechanisms one mechanism could be responsible for many different symptoms conversely, the same symptom in 2 patients may be caused by different mechanisms furthermore, more than one mechanism can operate in a single patient, and the pattern of mechanisms and symptoms within a single patient may change with time. No pain pathophysiological mechanism is an inevitable consequence of a particular disease process. Studies are needed to further define pathophysiological mechanisms of neuropathic pain. Reference 1. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999;353(9168): Additional key words: pathophysiology 神经损伤 Woolf CJ, Mannion RJ. Lancet 1999;353(9168):

伤害感受性疼痛疼痛创伤上行通道下行调节背角脊髓背角神经元外周神经周围感受器
This slide illustrates some central and peripheral pathways by which painful stimuli are normally processed (nociceptive pain). The key talking points on this slide are as follows: Peripheral nociceptors may be activated by noxious mechanical, thermal (heat and cold) or chemical stimuli. Pain impulses are then transmitted along sensory axons, contained in peripheral nerves and dorsal roots, to the dorsal horn. Peripheral nerve fibers involved in pain include unmyelinated slowly-conducting C fibers and thinly-myelinated Adelta (A) fibers. In the superficial layers of the dorsal horn they make synaptic connection with second-order neurons that transmit the impulses through the spinal cord to the brain (ascending transmission pathway). In the brain, the thalamus and certain specific cortical areas are critical for the sensory and emotional experience of pain. Transmission and processing of pain impulses is also modulated by descending (inhibitory) and segmental controls. References 1. Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology. 10th ed. New York, NY: John Wiley & Sons; 2003. 外周神经周围感受器 Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology. 10th ed 22

生理性疼痛病理性疼痛病理性疼痛的表现：自发性疼痛（spontaneous pain ）：没有任何病理性因素状态下的疼痛
生理性疼痛病理性疼痛病理性疼痛的表现：自发性疼痛（spontaneous pain ）：没有任何病理性因素状态下的疼痛痛觉过敏或痛觉增强（hyperalgesia ）：对疼痛刺激的敏感性增加，同样的刺激引起疼痛程度的增加触诱发痛（tactile allodynia ）：非伤害性刺激如轻触就能引发痛觉尽管生理性疼痛能够起到重要的保护作用，但是在病理状态下如炎症，神经损伤，癌症，病毒感染，化疗和糖尿病，疼痛则作为一种疾病而出现。 Baron R. Clin J Pain. 2000;16(2 suppl):S12–S20 [Evidence Level B]; International Association for the Study of Pain. Available at: Accessed September 30, [Evidence Level C]

神经病理性疼痛的潜在机制外周机制中枢机制细胞膜兴奋性增高异位放电外周敏化细胞膜兴奋性增高异位放电上扬现象(Wind up)
中枢敏化去神经超敏现象正常抑制作用缺失关键信息点如下：神经病理性疼痛的定义是中枢或外周神经系统的原发性损伤或功能障碍引起的疼痛，这些损伤和/或功能障碍触发潜在机制引起神经病理性疼痛。神经痛外周机制包括细胞膜兴奋性增高(导致沿感觉神经的异常放电)和周围神经的高致敏性。神经痛中枢机制包括细胞膜兴奋性增高、 wind up、中枢敏化、去神经性超敏现象和抑制作用缺失。患者个体所感知的神经病理性疼痛并不局限于一种机制，且随着病程的进展，其机制可能发生改变，这将影响治疗方案。注意：另一种机制是A纤维的再生，A纤维本与非疼痛性触碰感的传导相关，但随着周围神经损伤，在各种神经生长因子的作用下神经纤维会凋亡和再生。在动物模型上， A纤维进入脊髓背角，脊髓背角是C型纤维感知伤害性刺激后传入的区域。在此动物实验中，当脊髓背角感知由A纤维传入的非伤害性刺激时，动物的表现与感知疼痛时一样。但人类与其是否一样尚未知晓，可能有其它机制参与其中。参考文献： Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand Suppl 1999;173:12-24 Woolf CJ, Mannion RJ. Lancet 1999;353(9168): England JD, et al. Sodium channel accumulation in humans with painful neuromas. Neurology 1996;47(1): Ochoa JL, Torebjörk HE. Paraesthesiae from ectopic impulse generation in human sensory nerves. Brain 1980;103(4): Siddall PJ, Cousins MJ. Spinal pain mechanisms. Spine 1997;22(1):98-104 Victor M, Ropper AH (Eds). Principles of Neurology. 7th ed. New York, NY: McGraw-Hill; 2001 Doubell, et al. In: Wall PD, Melzack R, eds. Textbook of Pain. 4th ed. Edinburgh, UK: Harcourt Publishers Limited; 1999 Mannion RJ, Woolf CJ. Pain mechanisms and management: a central perspective. Clin J Pain 2000;16(3 Suppl):S144-S156 Roberts MTH, Rees H. In Casey KL (Ed) Pain and Central nervous system disease. New York, NY:Raven Press, 1991. Attal N, Bouhassira D. Acta Neurol Scand Suppl 1999;173:12-24 Woolf CJ, Mannion RJ. Lancet 1999;353 (9168) : Roberts, et al. In Casey KL (Ed). Pain and central nervous system disease. 1991 25

神经生物学机制 ——神经可塑性变化病理性疼痛的机制非常复杂，但是神经可塑性是其最重要的部分，而且能够解释很大一部分的临床表现。 —— Kuner R. Central mechanisms of pathological pain, Nature Medicine, 2010 —— Gold M.S. and Gebhart G.F. Nociceptor sensitization in pain pathogenesis, Nature Medicine, 2010

神经可塑性功能可塑性结构可塑性外周可塑性变化中枢可塑性变化

神经可塑性功能可塑性分子水平：活动依赖性方式（如磷酸化）或者局限化（如胞吞或者转运）
突触水平：突触前神经递质的释放增加或者突触后受体数目的表达增加细胞水平：兴奋性增加，感受域的扩大网络水平：感受刺激的的细胞数目增加，兴奋性的扩布增加

功能可塑性分子水平：活动依赖性方式（如磷酸化）或者局限化（如胞吞或者转运）突触水平：突触前神经递质的释放增加或者突触后受体数目的表达增加细胞水平：兴奋性增加，感受域的扩大网络水平：感受刺激的的细胞数目增加，兴奋性的扩布增加

神经可塑性结构可塑性突触脊：突触脊的数目增多，形态的增大连接：轴突发芽增多或者退化减少
细胞数目：细胞的增殖（如小胶质细胞和星型胶质细胞）或者萎缩（如抑制性中间神经元）

结构可塑性突触脊：突触脊的数目增多，形态的增大连接：轴突发芽增多或者退化减少细胞数目：细胞的增殖（如小胶质细胞和星型胶质细胞）或者萎缩（如抑制性中间神经元）

外周可塑性变化伤害性感受器的敏感化——正反馈机制
伤害性刺激激活离子通道引起膜的去极化，钙离子内流，内流的钙离子引起原本储存在囊泡内的神经肽类物质以及谷氨酸盐的释放，这些物质再进一步激活膜上的受体以及增加伤害性刺激引起的化学介质的释放

PMNL, 多型核白细胞；Mast cell, 肥大细胞；TRPV1，瞬时受体电位香草酸亚型1；GPCR，G蛋白偶联受体
外周伤害性信号传导的直接或间接通路

伤害性感受器激活后引起的下游第二信使通路

伤害性感受器的敏感化伤害性感受器的敏感化——正反馈机制
伤害性刺激激活离子通道引起膜的去极化，钙离子内流，内流的钙离子引起原本储存在囊泡内的神经肽类物质以及谷氨酸盐的释放，这些物质再进一步激活膜上的受体以及增加伤害性刺激引起的化学介质的释放伤害性感受器的敏感化

中枢可塑性变化抑制作用的减弱：如中间抑制性神经元的作用降低突触前神经递质释放的增加突触后兴奋性的增加：受体数目的增加，兴奋性增加
小胶质细胞和星型胶质细胞释放神经调质的调节

病理性疼痛引起痛觉过敏的中枢机制中枢可塑性变化抑制作用的减弱：如中间抑制性神经元的作用降低突触前神经递质释放的增加
突触后兴奋性的增加：受体数目的增加，兴奋性增加小胶质细胞和星型胶质细胞释放神经调质的调节病理性疼痛引起痛觉过敏的中枢机制

介导中枢敏感化的通路及其分子机制

症状--神经病理性疼痛的问诊要点注意以下几点:1 其他相关病史疼痛的类型、位置既往史疼痛的特点
例如烧灼样、电击样、针刺样等解剖位置神经分布区域扩散区域疼痛持续的时间最近一段时间（0-10周）疼痛的平均强度对日常活动的影响程度（0-10）既往史用药史或有害因子暴露史例如：紫杉醇、放射线止痛药物服用史相关的精神及情绪障碍 1. Jensen TS, Baron R. Pain 2003;102(1-2):1-8. 42

神经病理性疼痛诊断工具诊断工具 Leeds 神经病理性疼痛症状与体征评估量表(LANSS)1 DN4 疼痛问卷2
神经病理性疼痛问卷(可用简表)3 神经病理性疼痛量表4 疼痛性质与程度疼痛VAS视觉模拟量化表5 疼痛Likert量表 McGill疼痛问卷6 简化McGill 疼痛问卷神经病理性疼痛症状评估7 疼痛评估表(BPI)8 When assessing an individual with neuropathic pain, a neurological examination, careful history-taking, and an accurate sensory examination are often sufficient to reach a diagnosis. However, many additional tools exist in the form of pain scales and questionnaires1-8 that can help in the diagnosis and assessment of neuropathic pain, as shown by the examples on this slide. The key talking points on this slide are as follows: The Leeds Assessment of Neuropathic Pain Symptoms and Signs (LANSS) scale,1 the DN4 pain questionnaire2 and the Neuropathic Pain Questionnaire,3 were developed to help differentiate neuropathic from nociceptive pain. The Neuropathic Pain scale was designed to assess the distinct qualities of neuropathic pain and also appears to be sensitive to treatment change.4 The 100 mm Visual Analog Scale (VAS) developed by Huskinsson in is one of the oldest, easiest and best validated measures to assess ongoing pain, and has been widelyused in neuropathic pain studies. The 11-point pain Likert scale is also a simple tool used by patients to rate their pain from 0 = no pain to 10 = worst possible pain, both in the clinic and in clinical studies. The McGill Pain Questionnaire (MPQ)6 and the short form of it (SF-MPQ) are frequently used self-rating instruments for pain measurement, and are also often used in drug treatment trials. One of the most recently-developed tools, the Neuropathic Pain Symptom Inventory (NPSI), assesses the type, duration and intensity of pain symptoms, and appears to be sensitive to treatment change.7 The Brief Pain Inventory (BPI) was develop to assess both the intensity of pain and the extent to which pain interferes with the patient’s life. The scale also queries the patient about pain relief, pain quality and their perception of the cause of their pain.8 References 1. Bennett M. The LANSS Pain Scale: the Leeds assessment of neuropathic symptoms and signs. Pain 2001;92(1-2): Bouhassira D, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114(1-2): Backonja MM, Krause SJ. Neuropathic pain questionnaire--short form. Clin J Pain 2003;19(5): Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology 1997;48(2): Huskisson EC. Measurement of pain. Lancet 1974;2(7889): Melzack R, Torgerson WS. On the language of pain. Anesthesiology 1971;34(1): Bouhassira D, et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004;108(3): Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23(2): 1. Bennett M. Pain 2001;92(1-2): ; 2. Bouhassira D, et al. Pain 2005;114(1-2):29-36; 3. Backonja MM. Krause SJ. Clin J Pain 2003;19(5): ; 4. Galer BS Jensen MP. Neurology 1997;48(2): ; 5. Huskisson EC. Lancet 1974;2(7889): ; 6. Melzack R, Torgerson WS. Anesthesiology 1971;34(1):50-59; 7. Bouhassira D, et al. Pain 2004;108(3): ; 8. Cleeland CS, Ryan KM. Ann Acad Med Singapore 1994;23(2):

DN4 问卷由医生填写神经病理性疼痛、伤害感受性疼痛鉴别诊断 2 疼痛问题（7项） 2 皮肤检查（3项）经量表验证
This slide shows the DN4 (Douleur Neuropathique en 4 questions; Neuropathic pain in 4 questions) diagnostic questionnaire, which was developed by The French Neuropathic Pain Group to differentiate neuropathic pain from non-neuropathic pain. The key talking points on this slide are as follows: The DN4 scale is based on an analysis of sensory description and examination of sensory dysfunction, and provides immediate information in the clinical setting. Patients are given 7 descriptions of different types of pain or pain-related symptoms and are asked whether their pain is associated with the characteristic or symptom described (yes/no). The presence of touch hypoesthesia, pricking hypoesthesia and brushing pain is noted (yes/no). The scale has been validated and may have utility as a diagnostic tool in both clinical practice and in clinical trials. Reference 1. Bouhassira D, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114(1-2): Additional key words: diagnosis, assessment, tool DN4: Douleur Neuropathique en 4 questions Bouhassira D, et al. Pain 2005;114(1-2):29-36;.

Diagnosis: Identifying the Type of Neuropathy
The first priority in treating neuropathic pain is to establish a diagnosis. This not only assists in determining a treatment plan, but also helps the patient understand the nature of his or her chronic pain. Diagnosis of neuropathic pain requires identifying the nerve structures that are involved. Pattern recognition is a common means of identifying the location of the deficit. Once the pattern of involvement is recognized, the next step is to identify the etiology. Mononeuropathies are usually posttraumatic or caused by entrapment neuropathies.1 Occasionally systemic disease (eg, diabetes, vasculitis) can produce a mononeuropathy.2 Mononeuropathy multiplex means that a patient has multiple mononeuropathies, usually asymmetric and involving multiple parts of the body. Causes include vasculitis, sarcoidosis, and inflammatory polyneuropathies.2 Plexopathies involve most of an extremity, often originating at the plexus.2,3 Common causes include trauma, cancer, radiation, and some systemic illnesses.3 Peripheral polyneuropathy, resulting in a “stocking-and-glove” pattern, is perhaps the pattern most easily recognized.4 It is always the result of a systemic process, such as a toxic exposure, diabetes, or alcohol.1 1. Boulton AJM, Malik RA. Diabetic neuropathy. Med Clin North Am. 1998;82: 2. Portenoy RK. Neuropathic Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Company; 1996: 3. Katz N. Neuropathic pain in cancer and AIDS. Clin J Pain. 2000;16:S41-S48. 4. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, Minn: McGraw-Hill Companies Inc; 2000:100.

临床常见神经病理性疼痛类型： DPN 、PHN 50

DPN: 什么是糖尿病周围神经痛? 糖尿病周围神经病 (DPN) 1型或2型糖尿病所继发的神经损伤诊断需排除其他病因糖尿病的常见并发症
1.Boulton/p508/col.1/par1/1-3 糖尿病周围神经病 (DPN) 1型或2型糖尿病所继发的神经损伤诊断需排除其他病因糖尿病的常见并发症神经病理性疼痛的诱发因素 1.Boulton/p508/col.1/par2/10-11 1.Boulton/p509/col.2/par6/6-8 Boulton et al. Diabet Med. 1998;15:

远端对称、多发性神经病变 (DSP) 1-2 感觉神经损伤结果手套-袜套分布为常见影响粗和细神经纤维细纤维 (A 和 C)
先出现: 疼痛与痛觉超敏后出现: 感觉异常自主神经症状诱发糖尿病足神经电生理检查可能无法检测到神经损伤 Distal symmetric polyneuropathy (DSP) is distinct from focal neuropathies such as nerve entrapment injuries that are also common among people with diabetes.1 Painful sensations are initially localized to the toes but may spread to the legs and even the hands and arms Sensory loss in the lower limbs predisposes the individual to foot injuries Small fiber pain may be described as burning, prickling, stabbing, jabbing, or tight, bandlike pressure Small-fiber neuropathy may not be evident from electrophysiologic tests Vinik. In: Diabetes and Carbohydrate Metabolism. [e-textbook] Available at: Accessed April 4, 2007. Advisory Board Meeting August 2010

远端对称、多发性神经病变 (DSP) 1-2 粗纤维 (A/) 感觉和/或运动神经往往从足部开始发病振动感觉缺失和本体感觉异常
深部咬痛/酸痛肌肉萎缩 (槌状趾 ) 可予肌电图检查诊断 Distal symmetric polyneuropathy (DSP) is distinct from focal neuropathies such as nerve entrapment injuries that are also common among people with diabetes.1 Painful sensations are initially localized to the toes but may spread to the legs and even the hands and arms Sensory loss in the lower limbs predisposes the individual to foot injuries Small fiber pain may be described as burning, prickling, stabbing, jabbing, or tight, bandlike pressure Small-fiber neuropathy may not be evident from electrophysiologic tests Vinik. In: Diabetes and Carbohydrate Metabolism. [e-textbook] Available at: Accessed April 4, 2007. Advisory Board Meeting August 2010

PHN: 什么是带状疱疹后神经痛? 疼痛病因 = 神经损伤定义病因带状疱疹感染皮损愈合3个月后，原皮损区仍然遗留的疼痛
患者疼痛主诉复杂、多样化持续性深部疼痛短暂、一过性触电样疼痛皮肤痛觉异常病因带状疱疹病毒感染并发症带状疱疹病毒侵及背角神经节伤及脊髓背角神经节至皮肤阶段分布疼痛病因 = 神经损伤 1.Rowbotham/p.130/col.2/par.2/1-4 1.Rowbotham/p.129/col.2/par.2/1-6 2.Edmunds/p.3076/col.1/par.1/1-21 In most patients with shingles, the disease is self-limiting, and the rash and pain disappear completely. In some patients however, the pain can persist for many years.2 PHN is a complication of herpes zoster infections (or shingles), which leads to nerve damage In patients with PHN, there is irreversible skin and sensory damage when the dorsal root ganglion and its processes are attacked by varicella zoster virus and may be severely damaged from the spinal cord to the epidermis2,3 PHN is one of the most painful conditions observed in the pain clinic4,5 Patients with PHN collectively describe 3 distinct components to their disorder1: A constant, usually deep pain A brief, recurrent shooting or shocking tic-like pain A sharp, radiating dysesthetic sensation evoked by very light touching of the skin (allodynia) 3.Rowbotham/p.129/col.1/par.1/1-17 3.Rowbotham/p.347/col.1/par.1/6-13 Bonezzi Acta Neurol Scand Suppl. 1999;173:25-35; Bowsher. Drugs Aging. 1994;5: ; Edmunds et al. Vaccine. 2001;19: ; Rowbotham. Pain. 1989;39: 4.Bonezzi/p.25/col.1/par.1/7-11 1.Rowbotham/p.129/col.2/par.2/1-6 5.Bowsher/p.413/col.1/par.1/1-6 References: Rowbotham MC, Fields HL. Post-herpetic neuralgia: the relation of pain complaint, sensory disturbance, and skin temperature. Pain. 1989;39: Edmunds WJ, Brisson M, Rose JD. The epidemiology of herpes zoster and potential cost- effectiveness of vaccination in England and Wales. Vaccine. 2001;19: Rowbotham MC, Fields HL. The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain. 1996;119: Bonezzi C, Demartini L. Treatment options in postherpetic neuralgia. Acta Neuro Scand Suppl. 1999;173:25-35. Bowsher D. Post-herpetic neuralgia in older patients: incidence and optimal treatment. Drugs Aging. 1994;5:

带状疱疹后神经痛的发病率随年龄增长而增加
* † 1.Edmunds/p.3080/fig.1 带状疱疹后神经痛的发病率(%) 1.Edmunds/p.3076/col.1/par.1-cont/18-21 The probability that an acute herpes zoster episode will result in PHN increases with increasing age.1 PHN occurs in less than 8% of zoster cases in people under age 30 but occurs in greater than 30% of cases in those older than age 801 MSGP4 (Morbidity Statistics from General Practice. 4th national study ) was a survey of general practices covering a 1% sample of England and Wales during It was conducted in order to study the pattern of disease in the community as presented to general practice including diagnoses, severity, and persistence. Doctors and nurses recorded details of face-to-face contact with patients including age, sex and diagnosis1 The second study was a retrospective study by Hope-Simpson of herpes zoster in a general practice population varying between 3,600 and 3,800 people during the period PHN was defined as pain lasting more than 1 month after the onset of zoster in the Hope-Simpson study and identified by ICD in MSGP4. The higher rates observed in the MSGP4 survey can be attributed to the inclusion of neurologic complications of zoster other than PHN1,2 1.Edmunds/ p.3077/col.1/ par.3/5-7 & 3. MSGP4/p. 1/col. 2/section1.2/para 1/1-5 and para 2/1-3 and p.2/col 1/lines 2-6 1.Edmunds/p.3080/col.2/par.1/15-18 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 年龄组美国约500,000 至 1,000,000 PHN病例 *英国研究. †MSGP4: 包括带状疱疹病毒其他相关并发症. Adapted from Edmunds et al. Vaccine. 2001;19: 2. Hope-Simpson/ p. 571/Intro/para 1/1-3 2. Hope-Simpson/p. 571/Intro/para 2/1-2 & 1.Edmunds/p. 3077/col. 1/section 2.1/lines and p. 3080/col.2/ par. 2/21-24 References: Edmunds WJ, Brisson M, Rose JD. The epidemiology of herpes zoster and potential cost-effectiveness of vaccination in England and Wales. Vaccine. 2001;19: Hope-Simpson RE. Postherpetic neuralgia. J Royal Coll Gen Prac. 1975;25:

PHN 治疗复杂 2002 年PHN调研患者疼痛程度(N=385) 满意镇痛治疗(N=385) Patients (%) 未知 2% 重度
1.Oster/p.359/fig.1 1.Oster/p.359/ col.2/par.2/1-6 未知 2% 重度 31% 轻度 28% 1.Oster/p.359/ col.2/par.2/4-6 PHN is a difficult condition to treat.1 In a survey conducted in 2002 in 385 patients ≥65 years old with persistent pain after shingles (PHN) and receiving prescription medication, only 14% were highly satisfied with their treatment A majority of patients had moderate to severe pain The survey was conducted from May to August 2002 中度 39% 1.Oster/p.359/ col.1/par.2-cont/16-17 Patients (%) 2002年385例年龄≥65 岁接受镇痛治疗的PHN患者 Adapted from Oster et al. J Pain. 2005;6: Reference: 1. Oster G, Harding G, Dukes E, Edelsberg J, Cleary PD. Pain, medication use, and health-related quality of life in older persons with postherpetic neuralgia: results from a population-based survey. J Pain. 2005;6:

DPN、PHN相关治疗手段治疗选择药物治疗神经刺激介入区域麻醉物理治疗辅助性治疗心理治疗生活方式调整
2.Belgrade/p.5/col.1/par.5/1-5 1.Ashburn/p.1867/panel 4 物理治疗辅助性治疗 Pharmacotherapy is one of the various approaches in treating DPN and PHN.1 Biofeedback, progressive muscle relaxation, hypnosis, and meditative techniques may help to reduce autonomic nervous system excitability and irritable neuronal firing2 Psychological treatment focuses on active coping skills, including education, self-management techniques, and cognitive-behavioral therapy1 Acupuncture has data supporting its effectiveness3 1.Ashburn/p.1867/panel 3 心理治疗 3.Abuaisha/p.115/abs. 生活方式调整 Ashburn and, Staats. Lancet. 1999;353: ; Abuaisha et al. Diabetes Res Clin Pract. 1998;39: References: 1. Ashburn MA, Staats PS. Management of chronic pain. Lancet. 1999;353: 2. Belgrade MJ. Following the clues to neuropathic pain. Distribution and other leads reveal the cause and the treatment approach. Postgrad Med. 1999;106:127, 3. Abuaisha BB, Costanzi JB, Boulton AJM. Acupuncture for the treatment of chronic painful peripheral diabetic neuropathy: a long-term study. Diabetes Res Clin Pract. 1998;39:

目前常用于DPN、PHN药物治疗抗癫痫药物抗抑郁药物三环类 5-羟色胺与去甲肾上腺素再摄取抑制 (SNRIs) 阿片类皮肤、外用药物

三环类抗抑郁药(TCAs): DPN研究药物剂量 (mg/d) N 时间（周） Met End Point Max et al.
2.Max/p.589/abs. DPN研究药物剂量 (mg/d) N 时间（周） Met End Point Max et al. Amitriptyline 25-150, PBO 29 12 Yes Desipramine Amitriptyline , PBO , PBO 108 14 Sindrup et al. Desipramine Clomipramine 50 or 200, PBO 50 or 75, PBO 26 6 Desipramine , PBO 20 PHN Watson et al. 12.5, PBO 24 8 , PBO 58 Graff-Radford et al. , PBO 49 Kishore-Kumar et al. Raja et al. Nortriptyline 10-160, PBO 76 3.Max/p.1250/abs. 4.Sindrup/p.683/abs. 5.Max/p.3/abs. 6.Watson/p.671/abs. 7.Max/p.1427/abs. 8.Graff-Radford/ p.188/abs. 9.KinshoreKumar/p.305 /abs. Several studies have been published utilizing TCAs.1-10 No TCA is FDA approved for painful DPN or PHN 10.Raja/p.1015/abs. References: Attal N, Cruccu G, Haanpää M, et al. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol. 2006;13: Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37: Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326: Sindrup SH, Gram LF, Skjold T, Grodum E, Brøsen K, Beck-Nielsen H. Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms: a double-blind cross-over study. Br J Clin Pharmacol. 1990;30: Max MB, Kishore-Kumar R, Schafer SC, et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain. 1991;45:3-9. Watson CP, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J. Amitriptyline versus placebo in postherpetic neuralgia. Neurology. 1982;32: Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology. 1988;38: Graff-Radford SB, Shaw LR, Naliboff BN. Amitriptyline and fluphenazine in the treatment of postherpetic neuralgia. Clin J Pain. 2000;16: Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves postherpetic neuralgia. Clin Pharmacol Ther. 1990;47: Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2002;59: These trials did not include neuropathic pain. Therefore no comparison can be made between neuropathic pain and these agents Max et al. Neurology. 1987;37: ; Max et al. N Engl J Med. 1992;326: ; Sindrup SH et al. Br J Clin Pharmacol. 1990;30: ; Max et al. Pain. 1991;45:3-9; Watson et al. Neurology. 1982;32: ; Max et al. Neurology. 1988;38: ; Graff-Radford et al. Clin J Pain. 2000;16: ; Kishore-Kumar et al. Clin Pharmacol Ther. 1990;47: ; Raja et al. Neurology. 2002;59:

阿片类: DPN研究药物 (mg/d) N 周 Met End Point Gimbel et al.
1.Gimbel/p.927/abs. 2.Watson/p.71/abs. DPN研究药物 (mg/d) N 周 Met End Point Gimbel et al. CR oxycodone (20-120, PBO) 159 6 Yes Harati et al. Tramadol (50-400, PBO) 131 Watson et al. CR oxycodone (20-80, PBO) 45 8 PHN Raja et al. CR morphine (15-240, PBO) 76 24 Watson, Babul CR oxycodone (20-60, PBO) 50 3.Watson/ p.1837/abs. 4.Harati/p.1842/abs. 5.Raja/p.1015/abs. Evidence of efficacy in painful DPN and/or PHN is available for oxycodone,1-3 tramadol,4 and morphine.5 PBO = placebo. Gimbel et al. Neurology. 2003;60: ; Harati et al. Neurology. 1998;50: ; Watson et al. Pain. 2003;105:71-78; Raja et al. Neurology. 2002;59: ; Watson and Babul. Neurology. 1998;50: References: Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology. 2003;60: Watson CPN, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105:71-78. Watson CPN, Babul N. Efficacy of oxycodone in neuropathic pain. Neurology. 1998;50: Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50: Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2002;59:

皮肤、外用药无利多卡因贴剂辣椒碱 Dermal and topical treatments.1-5
Use of dermal or topical agents may be limited in patients with allodynia or hyperalgesia, as administration itself may be painful However, the potential for systemic adverse effects is low The lidocaine patch is only FDA approved for PHN, not DPN 利多卡因贴剂辣椒碱 Physicians’ Desk Reference®. 62nd ed. 2008; Barbano et al. Arch Neurol. 2004;61: ; Biesbroeck et al. Adv Ther. 1995;12: ; Low et al. Pain. 1995;62: ; Capsaicin Study Group. Arch Intern Med. 1991;151: References: 1. Physicians’ Desk Reference®. 62nd ed. Montvale, NJ: Thomson Healthcare; 2008: 2. Barbano RL, Hermann DN, Hart-Gouleau S, et al. Arch Neurol. 2004;61: 3. Biesbroeck R, Bril V, Hollander P, et al. Adv Ther. 1995;12: 4. Low PA, Opfer-Gehrking TL, Dyck PJ, et al. Pain. 1995;62: 5. Capsaicin Study Group. Arch Intern Med. 1991;151:

神经病理性疼痛治疗效果神经病理性疼痛目前无有效疗法，期待新药上市仅22%~42%的患者对治疗表示满意
糖尿病周围神经痛DPN：早期症状单一、易诊断，而早期治疗可避免病情加重、减少并发症发生，改善患者整体情况国际最新治疗理念强调早期诊断、早期治疗，减少诊断时间，节省时间及费用

国际指南对神经病理性疼痛一线用药的推荐 2010年英国临床研究所（NICE）指南中枢、外周神经病理性疼痛唯一药物：普瑞巴林
2008年美国国家健康防止研究和质量代理之临床系统研究中心（ICSI）指南神经病理性疼痛A级推荐：三环类抗抑郁药、普瑞巴林、加巴喷丁、拉莫三嗪 2007年国家疼痛研究学会（IASP）专家共识治疗带状疱疹后神经痛一线用药：抗抑郁药、钙离子通道调节剂（普瑞巴林、加巴喷丁）、局部麻醉药 2007年加拿大疼痛学会（CPS）指南神经病理性疼痛一线用药：三环类抗抑郁药、普瑞巴林、加巴喷丁 2006年欧洲神经科学联盟（EFNS）指南痛性多发性神经病(PPN)一线用药：普瑞巴林、加巴喷丁、三环类抗抑郁药带状疱疹后神经痛（PHN）一线用药：普瑞巴林、加巴喷丁、利多卡因、三环类抗抑郁药中枢性疼痛一线用药：普瑞巴林、阿米替林、加巴喷丁 2006年美国疼痛教育学会（ASPE）指南 DPN一线用药：杜洛西丁、普瑞巴林、氧可酮、三环类抗抑郁药

目前治疗神经病理性疼痛是否有更好的方法？
诊断困难疾病机制复杂、多样化症状个体化可因伴随疾病被忽略、误诊治疗选择有限，效果欠佳 This slide describes some of the unmet needs in the management of neuropathic pain. The author reviewed the literature and identified the main areas where improvements are required to enhance the management of neuropathic pain. The key talking points on this slide are as follows: The diagnosis of neuropathic pain can be challenging. (this is also reflected in other slides within this section based on data not reviewed by the author). Some of the reasons for this are that the mechanisms that underpin neuropathic pain are complex and that symptoms vary among patients with the same underlying etiology and across pain states of different etiologies, although there are many commonly reported symptoms. Comorbid conditions, such as anxiety and depression are common and may further contribute to functional impairment and disability among patients with neuropathic pain. They are often overlooked and need to be taken into account to achieve optimal management of patients with neuropathic pain. The selection from available treatments may be sub-optimal. Inappropriate treatments are often used and this may, in part, be due to lack of understanding of which treatments are most appropriate for neuropathic pain, and which analgesics confer little benefit. Reference 1. Harden N, Cohen M. Unmet needs in the management of neuropathic pain. J Pain Symptom Manage 2003;25(5 Suppl):S12-S17 . Harden N, Cohen M. J Pain Symptom Manage 2003;25 (5 Suppl):S12-S17

思考题：疼痛概念生理性疼痛与病理性疼痛的区别神经可塑性改变在神经病理性疼痛发生中的作用临床常见神经病理性疼痛的疾病诊治

模块八参考文献 ①Miller's Anesthesia, 7ed, Ⅲ Anesthetic Parmacology, chapter 24～29 ②Miller's Anesthesia, 7ed, Ⅶ Postoperative Care, chapter 87 ③神经病理性疼痛临床诊疗学黄宇光，徐建国主编，人民卫生出版社出版 ④现代麻醉学（第三版）相关章节人民卫生出版社

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神经病理性疼痛浙江大学医学院附属第二医院麻醉科严敏.

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神经病理性疼痛 浙江大学医学院附属第二医院麻醉科 严敏.

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神经病理性疼痛浙江大学医学院附属第二医院麻醉科严敏.

Presentation on theme: "神经病理性疼痛浙江大学医学院附属第二医院麻醉科严敏."— Presentation transcript: