第5节 脊柱肿瘤的疼痛控制
疼痛是癌症患者的常见症状。据统计，初诊癌症患者疼痛发生率约为25%，晚期癌症患者的疼痛发生率约高达75%。癌痛对机体各个系统可产生广泛影响，可导致患者出现食欲减退、乏力、失眠、焦虑、抑郁甚至自杀倾向等后果，处理不当会形成恶性循环，严重影响患者的生活质量。
一、 疼痛概述
（一） 疼痛的定义
国际疼痛学会（IASP）对疼痛的定义为：疼痛是一种令人不快的感觉和情绪上的感受，伴随着实际或潜在的组织损伤。它是一种主观的感受，而不仅仅是一种简单的生理应答，它与每个人的生理经验及以往的经历有关。
（二） 癌痛的病因
肿瘤患者出现疼痛症状的原因多种多样，大致可分为以下3类：
1. 肿瘤相关性疼痛 因肿瘤直接侵犯机体组织，肿瘤转移累及骨、脑等组织所致。
2. 抗肿瘤治疗相关性疼痛 外科手术后瘢痕痛、幻肢痛等；化疗后静脉炎、神经毒性、溃疡等；放疗后纤维化、神经损伤、放射性脊髓炎等。
3. 非肿瘤因素性疼痛 包括其他合并症、并发症等非肿瘤因素所致的疼痛。
（三） 疼痛的病理生理学分类
疼痛按发生的病理生理学机制主要分为以下两种类型：
1. 伤害感受性疼痛 是因有害刺激作用于躯体或内脏组织，使该结构发生实际或潜在的损伤而导致的疼痛。伤害感受性疼痛包括躯体痛和内脏痛。躯体性疼痛常表现为钝痛、锐痛或者压迫性疼痛；内脏痛通常表现为定位不够准确的弥漫性疼痛和 绞痛。
2. 神经病理性疼痛 是由于中枢或外周神经损伤或功能障碍引起的疼痛，临床表现为针刺样、烧灼样、电击样痛、麻木痛、麻刺痛，常伴有感觉超敏、感觉过敏或感觉异常。
（四） 癌痛的评估
疼痛是人体的主观感受，不像其他生命体征具有客观的评估依据。对疼痛的评估要求医务人员从病史采集、体格检查及辅助检查等方面收集全部临床资料进行分析，对疼痛的来源、程度、性质等要素做出一个综合判断及全面评价。癌痛评估是合理、有效进行止痛治疗的前提，也是评价疗效的重要依据。当疼痛性质、程度发生改变或出现新的疼痛时应及时重新评估，调整治疗方案，以保证癌痛评估的连续性及止痛治疗的有效性。综上所述，癌痛评估应遵循“常规、量化、全面、动态”的原则。目前临床上常用的癌痛量化评估方法有以下3种：
1. 数字疼痛量表（numeric rating scale，NRS） 此方法从0～10共11个点，表示从无痛到最痛，由患者根据自己的疼痛程度打分（图11-7）。1～3分为轻度疼痛，4～6分为中度疼痛，7～10分为重度疼痛。此表便于医务人员掌握，容易被患者理解，便于记录。是目前临床上应用较为广泛的量表。
2. 面部表情评分法 该方法用6种面部表情从微笑、悲伤至痛苦得哭泣的图画来表达疼痛程度（图11-8）。疼痛评估时要求患者选择一张最能表达其疼痛的脸谱。这种评估方法简单、直观、形象，易于掌握，特别适用于表达困难的患者，如老人、小儿，以及存在语言或文化差异或其他交流障碍的患者。
图11-7 数字疼痛量表
图11-8 面部表情评分法
3. 主诉疼痛程度分级法（verbal rating scale, VRS） 根据患者对疼痛的主诉，将疼痛程度分为轻度、中度、重度三类。
（1） 轻度疼痛：有疼痛但可忍受，生活正常，睡眠无干扰。
（2） 中度疼痛：疼痛明显，不能忍受，要求服用镇痛药物，睡眠受干扰。
（3） 重度疼痛：疼痛剧烈，不能忍受，需用镇痛药物，睡眠受严重干扰，可伴自主神经紊乱或被动体位。
二、 脊柱肿瘤疼痛的特点
当肿瘤侵犯脊柱等骨骼系统时，由于骨皮质和骨髓并非疼痛的敏感组织，所以早期常无症状，或者仅出现轻度、间歇性的疼痛。而骨膜的神经纤维分布丰富，在肿瘤发展后期，由于肿瘤的快速生长、体积增大，骨膜受牵拉，肿瘤直接侵蚀和损伤外周神经，引起神经的机械损伤、压迫和缺血，导致剧烈而持续的疼痛，发生率达50%～90%。
癌性骨痛的性质多为钝痛，夜间疼痛更明显。夜间痛也是癌性骨痛与创伤及炎症性疼痛的主要区别。癌性骨痛的另外一个特点是常常伴有痛觉过敏，这与破骨细胞、肿瘤细胞或炎症细胞等分泌的生物活性物质有关，后者可降低神经细胞膜的兴奋阈值，致使神经元敏化，表现为神经病理性疼痛。
由于脊柱是人体最重要的负重骨，脊柱肿瘤易继发病理性骨折，造成脊柱不稳定。脊柱肿瘤的疼痛也常常与病理性骨折有关。脊柱病理性骨折引起疼痛的原因包括对骨膜的损伤、附着肌肉的紧张和痉挛、对脊髓的压迫等。因此在脊柱肿瘤疼痛的诊治时需结合体检及影像学检查鉴别是否存在病理性骨折。
三、 脊柱肿瘤疼痛的治疗
脊柱肿瘤疼痛的治疗方法包括：病因治疗、药物止痛治疗和非药物治疗。通常，无论是原发性或转移性脊柱肿瘤所引起的疼痛，既能控制肿瘤又能缓解疼痛的病因治疗是首选的方法。
（一） 病因治疗
1. 手术治疗 对于受累部位局限的原发性或转移性脊柱肿瘤，通过手术将肿瘤完整或部分切除，从而可以解除压迫和对神经的刺激等，去除病因，达到止痛的目的。特别值得一提的是，脊柱肿瘤导致的脊髓压迫症状，属于肿瘤急症，及时合理的神经松解减压手术是预防截瘫的有效方法。
2. 放疗 外放疗被认为是骨转移疼痛的标准治疗方法，止痛有效率为50%～90%。其止痛的作用机制为放射线抑制或杀伤肿瘤细胞，阻止骨质破坏，提高成骨细胞活性，增加胶原蛋白合成形成 新骨。
与外放疗相对应的，放射性核素内照射也可用于治疗全身多发骨转移或其他治疗没有反应的骨转移疼痛。目前临床上常用的有锶-89和钐-153等。欧洲和加拿大的研究表明，锶-89对其他治疗没有反应的骨转移疼痛缓解率为75%，20%的患者疼痛完全消失。研究发现，放射性核素缓解疼痛的结果直接来自对成骨细胞的抑制，减少引起疼痛的细胞递质的释放，而并非是对肿瘤的直接作用。
3. 化疗 一些对化疗敏感的原发性或转移性脊柱肿瘤引起的疼痛，通过化疗，可以减轻疼痛。临床上，累及骨的淋巴瘤、生殖细胞肿瘤、小细胞肺癌、Ewing肉瘤等，通过化疗后骨痛完全缓解的病例屡见不鲜。
此外，抑制破骨细胞活性的药物如双膦酸盐对破骨细胞有促进凋亡、抑制增殖作用，从而达到减轻骨痛、预防骨相关事件的疗效。近年来，地诺单抗已在国外上市，批准用于预防骨转移疼痛等骨相关事件，而且在前列腺癌及乳腺癌骨转移中显示出优于唑来膦酸的疗效。
4. 内分泌治疗 乳腺癌、前列腺癌、子宫内膜癌等激素依赖性肿瘤，骨转移灶进展缓慢且患者生存期较长，内分泌治疗能在多数患者起到减轻骨痛、延长生存期的作用。但由于内分泌治疗起效时间往往较长，应配合其他治疗方法。
（二） 药物止痛治疗
除去有效的针对肿瘤的病因治疗以外，药物止痛治疗是控制癌痛的主要手段，药物的合理应用可使80%～90%的癌痛得到较满意的缓解。因此世界卫生组织（WHO）在20世纪80年代初即建立并推行了癌痛三阶梯治疗原则。该原则要求根据轻、中、重不同程度的疼痛，单独和（或）联合应用一阶梯（非甾体类抗炎药和对乙酰氨基酚）、二阶梯（弱阿片类药）、三阶梯（强阿片类药）止痛药，配合其他辅助性药物来治疗癌性疼痛。其具体原则包括口服给药、按时给药、按阶梯给药、个体化给药，并注意具体细节。经过多年临床经验的总结，这一方案已在国际上被广泛接受。我国自20世纪90年代已经引进并推广癌痛三阶梯治疗原则。然而，临床实践中，癌痛的处理有时候远比三阶梯治疗原则的建议复杂得多。在上述背景下，美国国立综合癌症网络（NCCN）发布的成人癌痛临床实践指南以其更加细化的指导受到越来越多业内人士的重视，成为三阶梯治疗原则的发展和补充。
对于脊柱肿瘤所致的癌性骨痛，选药、用药仍遵循上述原则。止痛药物根据作用机制及临床应用可分为非阿片类药物、阿片类药物及辅助性药物。临床上可供选择的止痛药物名目繁多，要规范合理地选择药物，首先必须掌握各类止痛药物的特点。
1. 非阿片类止痛药 主要包括非甾体类抗炎药（NSAID）和对乙酰氨基酚。NSAID类药物具有抗炎镇痛作用，而骨转移大多存在炎性反应，故其是缓解癌性骨痛的基础药；对乙酰氨基酚有解热镇痛作用，但几乎无抗炎作用。严格来说乙酰氨基酚不属于NSAID类，但为了表述方便，以下统称为NSAID类。该类药物主要作用机制在于抑制环氧化酶，从而抑制前列腺素E2的合成而产生解热镇痛的作用。常用于缓解轻度疼痛，或与阿片类药物联合用于缓解中、重度疼痛。目前常用于癌性骨痛治疗的非阿片类止痛药物包括布洛芬、双氯芬酸、对乙酰氨基酚、吲哚美辛、塞来昔布等。
使用NSAID类药物时需注意的是，用药剂量达到一定水平时，增加用药剂量并不能增强其止痛疗效，但不良反应将明显增加，这种现象被称为“天花板效应”。因此，NSAID类药物均有其每日限制剂量，如布洛芬为2 400 mg/d，对乙酰氨基酚为2 000 mg/d，塞来昔布为400 mg/d。临床上当日用剂量已达到限制性用量时，应考虑更换为阿片类止痛药；如为联合用药，则只增加阿片类止痛药用量。
NSAID类药物常见的不良反应有：消化性溃疡、消化道出血、血小板功能障碍、肾功能损伤、肝功能损伤等。其不良反应的发生，与用药剂量及使用持续时间相关。肝、肾功能不全的患者应慎用NSAID，有消化道溃疡病史及胃肠道出血史的患者应预防性给予护胃药，凝血功能有障碍者也应慎用，两种不同的NSAID类药物不宜同时使用。
2. 阿片类止痛药 是中、重度癌痛治疗的首选药物，按止痛效果可分为弱阿片类药（以可待因为代表）和强阿片类药（以吗啡为代表）。此类药物的作用机制是通过与中枢神经系统的阿片受体结合而起到镇痛、镇静的作用。
目前，临床上常用于癌痛治疗的短效阿片类药物为吗啡即释片，长效阿片类药物包括曲马多缓释片、吗啡缓释片、羟考酮缓释片、芬太尼透皮贴剂等，此外，还有阿片类与非阿片类药物制成的复合剂型。传统上，弱阿片类止痛药仅用于中度疼痛，强阿片类药仅用于重度疼痛。近年来，阿片类药物的新剂型和不断丰富的临床证据使中度疼痛的止痛药物选择更广泛，低剂量起始的强阿片类药物如吗啡、羟考酮、芬太尼等也逐渐用于中度疼痛的治疗，第二阶梯药物如可待因、曲马多的应用被弱化。对于慢性癌痛治疗，应选择纯阿片受体激动剂，如可待因、吗啡、羟考酮、氢吗啡酮、芬太尼等，尽量不选混合激动剂，如布托啡诺、喷他佐辛。长期应用阿片类止痛药时，首选口服给药途径，有明确指征时可选用透皮吸收途径给药，也可临时皮下注射用药，必要时可自控镇痛给药。
阿片类止痛药的疗效及安全性存在较大个体差异，需要逐渐调整剂量，以获得最佳用药剂量，称为剂量滴定。与NSAID类不同，阿片类药物用于止痛时没有极量限制，因此可通过滴定以获得最佳止痛效果。由于阿片类药均通过与中枢神经系统结合而发挥作用，所以在治疗癌痛时不主张将几种药物联合应用，但可以在应用缓释剂型维持的基础上，予即释吗啡处理爆发痛。
在我国，部分医护人员及患者由于担心阿片药物类“成瘾”而不敢应用足够剂量的吗啡。其实，这是认识上的误区，必须澄清。疼痛是成瘾的“天然拮抗剂”，应用阿片类药物治疗疼痛时，成瘾极少发生，据统计，其发生率小于0.04%。规范合理地应用阿片类药物是有效并且安全的，故临床医生和患者不必因担心“成瘾”而缩手缩脚。
哌替啶是常见的阿片类止痛药物之一，但对于慢性癌痛，WHO将其列为不推荐使用的药物。与吗啡相比，哌替啶的镇痛作用强度仅为吗啡的1/10。代谢产物去甲哌替啶的清除半衰期长，易在体内蓄积引起神经毒性及肾毒性。此外，因哌替啶口服吸收利用率差，多采用肌内注射给药，这本身就会增加患者的痛苦。
阿片类药物的不良反应主要包括：便秘、恶心、呕吐、嗜睡、尿潴留、过度镇静、呼吸抑制等。应把预防和处理阿片类止痛药不良反应作为止痛治疗计划的重要组成部分。恶心、呕吐、嗜睡等大多出现在未使用过阿片类药物的患者用药1周内。初用阿片类药物时，可考虑同时给予甲氧氯普胺（胃复安）等止吐药预防恶心、呕吐，症状缓解则可停用止吐药。便秘症状通常会持续发生于阿片类药物止痛治疗全过程，多数患者需使用缓泻剂防治便秘。阿片类药物对输尿管平滑肌有兴奋收缩作用，可引起尿潴留，如发生尿潴留，可换用另一种阿片药。过度镇静是药物过量的最初表现，进一步会发展为呼吸抑制。事实上，规范应用阿片类药物，可极少出现呼吸抑制。出现过度镇静时，阿片类药物应减量或暂停使用，并予吸氧、唤醒治疗；有明显呼吸抑制者，可使用阿片类受体拮抗药纳洛酮静推解救。
3. 辅助性药物 辅助性药物能够增强止痛药物的疗效，或产生直接镇痛作用，可用于癌痛三阶梯的任何一个阶段。如前所述，脊柱肿瘤导致的疼痛常与局部炎症水肿有关，而且常常合并神经病理性疼痛，因此需要用到的辅助用药包括治疗神经病理性疼痛的药物以及具有抗炎作用的糖皮质激素等。
（1） 三环类抗抑郁药：为治疗神经病理性疼痛的常用药物，用于脊柱肿瘤所致的麻木样痛、灼痛，该类药物也可以改善情绪、改善睡眠，如阿米替林、度洛西汀、文拉法辛等。
（2） 抗惊厥类药物：用于脊柱肿瘤所致的撕裂痛、放电样疼痛及烧灼痛，代表药物如卡马西平、加巴喷丁、普瑞巴林。加巴喷丁100～300 mg口服，每日1次，逐步增量至300～600 mg，每日3次，最大剂量为3 600 mg/d；普瑞巴林75～150 mg，每日2～3次，最大剂量为600 mg/d。
（3） 糖皮质激素：此类药物本身不具有镇痛作用，但能提高吗啡等药物的镇痛作用，这可能与其抑制炎性细胞因子的合成、减轻肿瘤周围水肿的作用有关。在脊柱肿瘤导致脊髓压迫时，糖皮质激素应尽可能在诊断后24小时内给药。放疗同时给予地塞米松可减少疼痛“闪耀”的发生。但与NSAID类药物合用时应慎重，因可加重其不良反应。代表药物如地塞米松、泼尼松等。
（4） 肌松剂：这类药物主要用于缓解由于肌肉痉挛引起的疼痛。当脊柱肿瘤导致的疼痛合并束带感或紧绷感时可联合应用肌松剂，如盐酸乙哌立松、氯唑沙宗、巴氯芬等。使用过程中如出现困倦、呼吸困难、四肢无力、站立不稳等症状时，应减少用量或停止用药。
（5） 抗焦虑药：可缓解癌症患者的焦虑，同时具有镇静、镇痛作用，可辅助阿片类药治疗疼痛，如地西泮、阿普唑仑、劳拉西泮等。
（6） 中医中药：传统的中医药对某些疼痛的治疗有独特的方法和疗效，可根据患者的病情适当地选择中药内服或外敷。
（三） 非药物治疗
用于癌痛治疗的非药物治疗方法主要有：介入治疗、针灸等物理治疗、心理治疗等。癌痛的介入治疗方法包括神经阻滞、神经毁损、经皮椎体成形术（percutaneous vertebroplasty，PVP）、射频消融术等。合理应用非药物治疗可以减少止痛药物的使用剂量并增强止痛疗效。
PVP是脊柱肿瘤疼痛最常用的介入治疗方法，是在影像设备监视下，通过椎弓根或椎弓根外途径，将骨水泥直接注射到病变椎体内，利用骨水泥重建椎体形态，重塑椎体的生理功能。同时，利用骨水泥硬化过程中产热和释放单体化学物质的特性杀死肿瘤细胞，破坏病变组织内的神经末梢，缓解和解除由于椎体病理性骨折、肿瘤破坏和肿瘤产生的细胞因子对病变椎体内神经末梢刺激导致的疼痛。据文献报道，其近期止痛有效率为70%～95%。适应证为常规止痛无效的椎体溶骨性转移导致的骨痛（无论是否合并压缩性骨折），禁忌证包括椎管狭窄、神经根性疼痛、椎体后壁破坏、感染、凝血障碍等。
（姚阳 孙元珏 郑水儿 林峰 何爱娜
胡海燕 李洪涛 沈赞 张剑军 闵大六）
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