1、北京大学人民医院麻醉科、疼痛医学科 冯艺,NSAID应用进展,目录,NSAID简介NSAID在慢性疼痛中的应用非癌痛、NP、癌痛新药进展,NSAID简介,传统NSAIDs类药物的疗效已被全球认可,NSAIDs世界范围使用最广泛的一类非处方药美国：1700万人日常用药；7300万张处方/年英国：2300万张处方/年, 1200万张用于60岁者英国、澳大利亚：20%的住院病人用NSAIDs 3000万人/天，60岁占 40% 5亿/年,NSAID在慢性疼痛中应用范围,炎症性肌肉骨骼痛：骨关节炎、风湿痛神经病理性疼痛癌痛,强阿片药 + NSAIDs,口服弱阿片药+NSAIDs,阿斯匹林NSAIDs,
2、J Gastroenterol (2015) 50:614625,对COX理论的修正,生理和病理状态下COX1和COX2并存COX1的生理和病理作用COX2的病理和生理作用,花生四烯酸,前列腺素,COX-2,前列腺素,血管扩张、通透性增加局部充血、水肿、疼痛增强缓激肽的致炎作用,COX-1,保证胃粘膜完整，肾、血小板功能正常,（各种组织中）,骨骼愈合、组织修复、保护血管内皮、肾血流,炎症、创伤、肿瘤刺激,生理刺激,常用非选择性NSAIDs,阿司匹林芬必得（布洛芬，iv）吲哚美辛双氯芬酸萘普生美洛昔康奈丁美酮（瑞力芬）酮洛酸（iv）氟比洛芬（凯芬，Iv）,选择性COX2抑制剂,对COX2的选择性
3、是COX1的3501200倍(万络最强）塞来昔布（西乐葆）：200mg/片帕瑞昔布：8mg罗非昔布（万络）：25mg/片（撤市）伐地考昔：撤市,不同NSAID对COX1和COX2相对特异性比,NSAIDs 作用特点,解热、镇痛、消炎（除对乙酰氨基酚）封顶（ceiling effect）效应副作用：胃肠道、血小板聚集功能、肾功能损害、心血管损伤协同阿片类药物镇痛作用，减少用量约30,NSAID在慢性疼痛中的应用,.Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spond
4、ylitis and non-radiographic axial spondyloarthritis).,39 项研究(n = 4356) 抑制剂，安慰剂良好镇痛，NSAID （）,COX2NNT: 2(1-3)均可改善活动能力(54.7改善到17.5)短期副作用差异不大连续应用可能对影像学改善有益,Cochrane Database Syst Rev. 2015 Jul 17;7:CD010952. doi: 10.1002/14651858.CD010952.pub2,NSAID与癌痛(一箭双雕),最大推荐剂量NSAID相当于510mg肠外吗啡的镇痛效能 NSAID之间无明显差异联合阿片
5、可明显改善疼痛，观察使用时间短，长效安全性待证实,Nabal M, Librada S, Redondo MJ, et al: The role ofparacetamol and nonsteroidal anti-inflammatory drugs inaddition to WHO Step III opioids in the control of pain inadvanced cancer: A systematic review of the literature.Palliat Med 26:305-312, 2012 Lancet Treatment of cancer p
6、ainVolume 377, No. 9784, p22362247, 25 June 2011,Cx reduces microvascular density in the chick-CAM assay.,PBS (Control), Cx at 500, 1000 and 2000ppm was instilled on chick chorioallantoic membranes (CAM) as described in Methods. Membranes were fixed and stained with H *: p0.0001). Scale bar: 100m.,B
7、iol Res. 2014 Jun 16;47:27. doi: 10.1186/0717-6287-47-27.Celecoxib decreases growth and angiogenesis and promotes apoptosis in a tumor cell line resistant to chemotherapy.,COX与肿瘤生长、转移的关系,Cx inhibits the growth of a murine A/J mammary tumor.,900000 tumor cells were inoculated s.c. in the flank of A/J
8、 female mice. Cx treatment and measurement of tumor development are described in the Methods section. The graph represents the tumor volume of control (n=6) and Cx-treated (n=6) mice. Cx showed an anti-tumor effect compared with control (p0.05). For bioethical reasons, the experiment was stopped at
9、19th day. Bars represent standard errors. Wilcoxon signed rank test p0.05.,Cx inhibits microvascular density of a murine A/J mammary tumor (TA3-MTXR).,Histological sections stained with Arteta were visualized at 400 in an optical microscopy and blood vessels were counted. Left panel shows a represen
10、tative section of untreated primary tumor (A) or Cx-treated (B). Blood vessels were counted (C) and a statistical significance was found (*: p0.0001). Right panel shows a representative section of untreated lung metastasis (D) or Cx-treated (E). Blood vessels were counted (F) and a statistical signi
11、ficance was found (*: p=0.0031). Blood vessels are represented by black arrows.,Cx decreases proliferation, VEGF production and promotes apoptosis of a murine A/J mammary tumor (TA3 MTXR),. Tumor samples showed a decreased proliferation in Cx-treated group (B), when compared with control group (A).
12、Relative expression is represented (C) (*: p0.0001) VEGF expression was reduced in treated group (E) when it was compared with control group (D). Relative expression is represented (F) (*: p=0.0178). Apoptotic nuclei of lung sections were labeled with a TUNEL assay and treated group (H) showed an in
13、creased apoptotic nuclei/field when it was compared with control group (G). Apoptotic nuclei per field are represented (I) (*: p200mg/D可能AMI 使心血管心事件发生危险增加2.5倍罗非昔布：可产生活性代谢产物，改变细胞膜脂质结构， 25mg/D可能 AMI 25mg/D一定 AMI,FDA CDER 2005 Meeting DocumentsHermann M et al Circulation 2003Widlansky Hypertension 2003
14、,年罗非下市！,COX2抑制剂的胃肠安全性,提高对正常胃肠的安全性，罗非昔布较塞来昔布好Vioxx gastointestinal outcomes research studyCelecoxib long-term arthritis safety study, CLASS预防复发性出血：塞来昔布双氯芬+奥美拉唑 Francis KL. N Engl J Med 2002；347：2104-10恶化已存在的、活动期肠道溃疡病 Matuk Inflamm Bowel Dis. 2004 Jul;10(4):352-6.,NSAIDs对心血管系统影响,非选择性不良反应包括水肿、高血压、AMI等
15、可能增加AMI危险性总体相对危险1.12奈普生1.06吲哚美辛1.71布洛芬1.11美洛昔康1.37FDA CDER 2005 Meeting Documents增加严重心血管不良反应可能是NSAID（除阿司匹林）的一种类效应！,所有NSAID类药物均有心血管风险,未用NSAIDs,布洛芬,萘普生,罗非昔布25 mg,其它 NSAIDs,消炎痛,双氯芬酸,校正后比值比 (95% 可信区间),1.00(对照),0.86 (0.69-1.07),1.09 (0.99-1.21),1.18 (1.04-1.35),3.15 (1.14-8.75),1.16 (1.04-1.30),1.33 (1.0
16、9-1.63),1.69 (0.97-2.93),罗非昔布25 mg,1.29(0.93-1.79),AMI=急性心梗; SCD=心源性猝死.对年龄、性别、健康计划区域、病史、吸烟情况和医疗措施应用校正。Graham DJ, Campen D, Hui R, et al. Lancet. 2005.,第二类新药:非口服制剂,静脉: 氟比洛芬酯(凯纷)经皮肤:吲哚美辛、双氯芬酸经粘膜:双氯芬酸,吲哚美辛,吲哚美辛喷雾制剂治疗放化疗后口腔黏膜炎效果,开始使用一天后VAS：10分降至5.40.6起效时间：231 分钟持续时间：22510 分钟每日最大使用量：12mg/天，约为口服吲哚美辛剂量75mg
17、/天的1/6未见不良有害主诉,第三类新药：NSAID复合胃粘膜保护剂,Sources: Gastric Ulcer Data Cochrane Review 2011 update 4; CV Risk Data CNT 2013 3.,第四类：微颗粒与传统NSAID的等效剂量,Pain Medicine 2013; 14: S11S17Wiley Periodicals, Inc. Pain Medicine 2013; 14: S11S17,在安全性和有效性方面找到一个平衡点,增效减副,在研新药,透明脂酸NSAID：关节腔内注射液，II期阶段NONSIAD：III期完成，FDA未批准H2SNSAID：FDA未批准,最新尝试：n-3 PUFA based NSAIDs,利用n-3 PUFA 的胃肠、心血管、肾脏保护作用纠正NSAID引起的紊乱 保护全胃肠道协同对抗关节炎,应用NSAID注意事项,NSAIDs和剂量的个体化避免同时服用两种或两种以上NSAIDs饭后服药或使用肠溶制剂（除COX2抑制剂）如口服肠胃不能耐受时，可选用另外途径给药，如外涂、塞肛或肌注尽量避免长期大量使用,2015.11.27,
