度洛西汀治疗化疗所致神经病变的研究进展（完整版）

1、度洛西汀治疗化疗所致神经病变的研究进展化疗致周围神经病变相关资料度洛西汀治疗化疗所致神经病变的文献阅读什么是化疗致周围神经病变?化疗致周围神经病变(chemotherapy-induced peripheral neuropathy, CIPN)是肿瘤病人化疗期间出现的一种常 见药物剂量-限制性不良反应。主要表现为感觉和运动异常，以及自主神经功能紊乱、感觉性共济失调，出现四肢无力、麻木、刺痛、烧灼感，戴袜套或手套样异常感等症状，偶尔还表现为运动神经症状，交感神经受累和颅神经病表现，症状可能持续数月甚至数年。CIPN常导致病人难以维持规律化疗，临床上常通过减低化疗药物剂量、延长化疗周期或停药来缓

2、解疼痛，影响治 疗效果，并且可能增加疾病复发风险，降低病人存活率。Cascella M Chemotherapy-induced peripheral neu_x0002_ropathy: limitations in current prophylactic strategies and directions forfuture research. Curr Med Res Opin, 2017, 33(6):981 984.神经毒性评定标准神经毒性评定标准参照世界卫生组织制定的抗癌药物急性以及亚急性周围神经毒性分级标准:I级：正常；感觉有-场或腱反射功能减退；hi级：感觉异常症状加重或存在

3、轻度无力现象；IV级：感觉异常严重至患者不耐受或有显著性运动障碍；患者瘫痪；V级：死亡；抗癌药物急性及亚急性毒性反应分度标准（WHO）CIPN发生机制研究进展第一种：胶质细胞活化(activation of glial cells):有研究证实，脊髓胶质细胞活化与神经病理性疼痛的发生 和发展密切相关。Preet等研究中，紫杉醇CIPN模型小鼠中脊髓神经胶质细胞较对照组显著活化。第二种：线粒体功能障碍(mitochondrial disorder):线粒体在能量代谢和自由基代谢中占据着重要地位，线粒体功能异常在CIPN发生发展中发挥举足轻重的作用。Magdalena等研究发现，顺铠通过诱导线粒体

4、p53积累和 线粒体膜去极化，引起线粒体损伤，导致线粒体功能异常，致使CIPN行为学异常。I 第三种：氧化应激(oxidative stress):氧化应激是细胞凋亡和炎症反应的重要介质。Jan等研究发现，氧化应激在CIPN发生中发挥关键作用,早期应用抗氧化酶可减轻神经元功能紊乱。第四种：离子通道改变(ionchannel change):离子通道的结构和功能正常是维持生命过程的基础，离子通道是钳类抗癌药物的毒性靶点。Juliette等研究发现，TRP离子通道亚型TRPM8和TRPA1的异常表达介导了奥沙利钳诱导冷痛觉和机械痛觉过敏,给予超级化激活通道(HCN)抑制剂伊伐布雷定后，奥沙利铀诱导

5、冷痛觉过敏明显缓解。马凯丽，程志祥.化学治疗导致周围神经病变的发生机制及防治进展J.中国疼痛医学杂志,2018,24(03):218-220+224.常见致CIPN的化疗药约30%40%化疗病人会发生CIPN奥沙利钳 急性毒性：约85%-95%的患者在数小时或数 天内出现短暂的感觉障碍；慢性毒性：当累积剂量大于 l 800mg/m2时（约8-10个周期）；顺钳成人顺钳的累积剂量达到400-700mg/m2时会出现 感觉异常；长春碱类 长春地辛的神经毒性为长春新碱的1/2,长 春花碱的神经毒性更为明显，一般发生于治疗前3个月内。紫杉类 周围神经毒性发生率为52%,多数发生在给药 后48小时内。主

6、要发生于四肢末端，被称为“手套/袜子 分布模式。；沙利 度胺外周神经毒性是沙利度胺最严重毒副反应之CIPN防治进展目前肿瘤病人在进行抗肿瘤治疗的时候，大家注意力更多集中于抗肿瘤治 疗本身，不太关注CIPN,而一旦抗肿瘤治疗结束，医务人员对CIPN关注更会减 少，再加上CIPN尚没有很好的防治方法，导致目前CIPN防治不容乐观。一 些研究发现，度洛西汀、乙酰左旋肉碱、氨磷汀、天麻素、黄茂桂枝五物汤、 细辛、延胡索乙素等药物，以及非药物治疗，如神经阻滞、电针等，对 CIPN 防治都有一定效果，但目前只有度洛西汀推荐使用，其它药物或治疗方法因循 证医学证据不足，临床可酌情应用。Hue Jung Pa

7、rk Chemotherapy induced peripheral neuropathic pain. Korean J Anesthesiol 2014 July 67(1) :4一7神经病理性疼痛诊疗专家共识酸度洛西汀肠溶胶囊14粒/盒适应症：用于治疗抑郁症；40mg/日至60mg/日用于治疗广泛性焦虑障碍；60mg/B用于治疗慢性肌肉骨骼疼痛；起始剂量为30mg 连续1周给药，使患者适应药物治疗后增加至 60mg每日一次超说明书用药？盐酸度洛西 n月厉溶月交囊6Omg盐酸度洛西汀肠溶胶囊说明书-修改日期：2018年09月04日肿瘤患者抑郁现状国内外研究显示，大多数肿瘤化疗患者对治疗缺乏

8、信心，存在不同程度的抑郁情绪障碍。国外肿瘤患者化疗伴发 抑郁发生率为16. 3%40.1%，国内肿瘤患者化疗伴发抑郁发生率高达32.5%62.86%,抑郁促使肿瘤发生、发展、 转移和复发。 化疗是目前临床上治疗肿瘤的主要方法之一，在杀灭肿瘤细胞的同时，对机体也造成一定的创伤。化疗期间患 者承受各种躯体不适和心理困扰，其中最常见是抑郁。抑郁是一种闷闷不乐、忧愁压抑的消极心情，它主要是由疾 病过程伴随着的现实丧失或预期丧失引起。轻者表现为少言寡语、无精打釆，对外界任何事物都不感兴趣；严重的 抑郁往往导致患者自暴自弃，放弃治疗，甚至自杀。抑郁病人往往伴有生理功能紊乱，如食欲和性欲下降、睡眠紊 乱等。

9、抑郁诊断表现I以心境低落为主要特征且持续至少两周，在此期间至少有下述症状的四项: 对日常活动丧失兴趣，无愉快感；(2) 精力明显减退，无原因的持续疲乏感；(3) 精神运动性迟滞或激越；(4) 自我评价过低或自责，或有内疚感，可达妄想程度；联想困难，或自觉思考能力显著下降；(6) 反复出现想死的念头，或有自杀行为；(7)或体重明显减轻；(9)性欲明显减退。李秀，吉兆宁.肿瘤化疗患者抑郁情绪临床干预的研究进展J.中国临床药理学与治疗学,2017,22(01):110-114.欣百达3常见不良反应轻微，随治疗时间延长而逐渐减少，可逐渐耐受1度洛西汀禁忌单胺氧化酶抑制剂药14天內也应禁用本品&由于増加

10、发生五每邑胺综合征的危险，所以将蔑服用本品冶疗精稱疾病或停用本品5天内禁用JtAOIo MAO停表现为认知功能/行为改变、神经肌肉异常、植物神经功能不稳定三联征由于增加发生五軽色肢综合征的危险，所洪正在使用MAOI如利奈畔胺或静脉注射亚甲基蓝）的患者也应禁 用本品O未经泊疗的程角里青光眼临床试殓显示，度洛西汀有増抑瞳孔散大的凤险，因此，未经治疗的崔角型青光眼患者应避免使用度洛西 汀。12不良事件刺安慰剂(N=175)度洛西汀60mg/d (N=168)度洛西汀120mg/d (N=170)恶心7%42%44%I6%12%19%口干4%11%18%乏力3%13%15%多汗6%9%17%失眠5%1

11、2%10%便秘4%12%10%腹泻5%5%9%性欲械退2%11%8%厌食症2%10%9%嗜眠症2%7%10%呕吐1%5%11%镇静1%6%9%水以上列出了发生率大于5$的不良事件，数字来自1项主要的持续9周、多中心、随机.双盲、固定剂量、安慰剂对照研究，平均年龄为43.8岁(范围为218岁)，接受度洛西汀60mg/d或120mg/d治疗的患者。详细信息见说明书2开放标签延长期试验的时间段(1年户头痛焦虑乏力背痛失眠恶心头垦肢体疼痛腹泻鉛干口干30-120mg/d10.9%7.9%7.6%7.2%7.2%6.9%6.5%6.2%6.2%5.5%5.2%一项开放标签研究后虽荀店229)逬入为期4年

12、开放标签延长期试验.评估度洛西30120mg每日一次治疗广泛性焦虑障碍的长期疗效和安全性;以上列出的安全数据星基线至1年随访期发生率大于5%的不艮事件1. Koponen H, et al. Prim Care Companion J Clin Psychiatry. 2007:9(2):100-72. 欣百达&说明书.修改日期201809月04日3. Pangallo BA, et al. Curr Med Res Opin. 2010 Nov;26(11):2643-51度洛西汀治疗说明用法用量：度洛西汀的起始剂量为每日30 mg, 一周后调整到每日60 mg （治疗神经毒性），可一次服用

13、或分两次服 用。常见不良反应有恶心、口干、出汗、乏力、焦虑、震颤等。服用要求：整粒吞服。不应咀嚼或碾碎服用；也不应打开胶囊壳，将内容物撒在食物上或与液体混合服用。因为这 些操作可能会对肠溶衣产生影响。使用本品时无须考虑饮食情况。如果忘记用药，一旦想起立即服用。如果已经接 近下次用药时间，忽略上次的漏服，直接按照以往用药时间服用正常剂量。不可同时服用两倍的剂量。药理作用：选择性抑制5-轻色胺、去甲肾上腺素再摄取，提髙二者在突触间隙的浓度，在疼痛传导途径中的下行通路发挥作用。度洛西汀联合自拟温痹方预防紫杉醇所致外周感觉神经障 碍的疗城弈析；85例紫杉醇化疗分方案治疗的患者所有患者均行紫杉醇化疗方案

14、予以治疗，共治疗6个周期。随机分为研究组42例和对照组43例ea31.0%治疗组VS对照组不作处理治疗组度洛西汀（生产企业：礼来）口服20 mg/次， 每天2次，同时采用自拟温痹方泡洗（川乌30 g.草乌30g、大血藤30 g.花椒30g、路路通30 g、桑枝30 g、当 归I g）外周感觉神经障碍的发生率69.8%（II度以上）16.7%46.5%预防性应用度洛西汀与中药泡洗能够有效降低紫杉醇化疗患者神经毒性症状发生率，减少神 经毒性对患者造成的伤害，提升患者的治疗依从性及生活质量，具有较高的临床推广价值。周向群，许小燕，诸有华，聂小萍，邵小平度洛西汀联合自拟温痹方预防紫杉醇所致外周感觉神经

15、障碍的疗效分析J.当代医学,2017,23（15）:133-135.度洛西汀治疗紫杉醇所致周围神经病变的疗效观察Successful Treatment: ty Adding Duloxetine to Pregabsrlin for Peripheral Neuropathy Inducecl by PaclitaxelA me ric*in Jku rnal of Hospice?& Pal Ifca Live? MecdicOO(O 1 -3 TBe A u cfo r(s) 20 1 2:Reprlncs nd permissioni： saiepub com/journ al sPe

16、rmi ss lons.natv DOI： 10.1 1 77/JO495K):Z/ajhipm.Mgc pub uom念 SAGEMotoya.su TaJcwnaka, MO, PhD1, HirokiPhD1,Shigerrii Matsumoto* MD 1, Shinobu 丫耳maguvhF. MO, PtiD 1 Nor*it:aLla. YosHimura, MD1 a.nd Ma.leen used to treat peripheral neuropathic pain. We report the case of a 68-year -old man wich gastr

17、ic cancer who underwent gastrectomy and then received 8 cycles of chemocherapy involving weekly adminiscraxions of pacliraxel. Undler this paclitaxel treatment, he complained of severe peripheral neuropathy, leading to a diminished quality of life. Following creacmenc with a combination of duloxetin

18、e and pregabalin, a remission of his symptoms was achievedl. Ouloxecine plus pregabalin therapy may be useful I for che peripheral neuropathy induced by pacliraxel.一位68岁的胃癌患者，他接受了胃切除术，然后接受了 8个周期的化疗，包括每周服用紫杉醇。在紫杉醇治 疗下，他抱怨严重的周围神经病变，导致生活质量下降。在联合使用度洛西汀治疗后，他的症状得到了缓解。度 洛西汀治疗紫杉醇所致周围神经病变有一定的临床应用价值。Takenaka,

19、 M,Iida, H. , Matsumoto, S,Yamaguchi, S,Yoshimura, N,& Miyamoto, M(2013) Successful Treatment byAdding Duloxetine to Pregabalin for Peripheral Neuropathy Induced by Paclitaxe1 American Journal of Hospice andPalliative Medicine, 30(7), 734 - 736.He巳 we report about a 60-year-old woman with metastatic

20、 breast cancer who was successfully treated for paclitaxel induced p已叩heral neuropathy with duloxetine. She was administered trastuzumab plus paclitaxel(PTX)combination therapy that was ultimately discontinued because of grade 3 peripheral neuropathy detected on day 15： according to the CTCAE (v4.0)

21、. She was administered duloxetine on day 90 after the end of the previous therapy because of the peripheral neuropathy. Thereafter, the peripheral neuropathy decreased to grade 1, which enabled PTX administration on her request. Further trials are required to confirm the efficacy of duloxetine.结论She

22、 was administered trastuzumab plus paclitaxel(PTX)combination therapy that was ultimately discontinued because of grade 3 peripheral neuropathy detected on day 157 according to the CTCAE (v4.O). Thereafter, the peripheral neuropathy decreased to grade 1, which enabled PTX administration on her reque

23、st. Further trials are required to confirm the efficacy of duloxetine.报告了一个60岁的妇女转移性乳腺癌，使用度洛西汀成功地治疗紫杉醇引起的周围神经病变。她接受了曲 妥珠单抗和紫杉醇(PTX)联合治疗，但由于第15天发现的3级周围神经病变，最终停止了治疗。由于周围神经病 变，她在治疗结束后第90天服用度洛西汀。此后，周围神经病变降至1级，使PTX能够在继续使用治疗。INagashima SA case of Paclitaxel-induced peripheral neuropathy successfully treat

24、ed with duloxetine.Gan To KagakuRyoho. 2015V42N5：617-9度洛西汀对化疗性疼痛性周围神经病变患者疼痛、功能及生活质量的影响：一项随机临床试验。二IMPORTANCE:There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy.OBJECTIVE:To determine the effect of duloxetine: 60 mg daily, on average pain severity. DESIGN, S

25、ETTING, AND PATIENTS:Randomizeds double-blind, placebo-controlled crossover trial at 8 National Cencer Institute (NCI)-funded cooperative research networks that enrolled 231 patients who were 25 years or older being treated at community and academic settings betvveen April 2008 呂nd March 2011. Study

26、 follow-up was completed July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligibility required that patients have grade 1 or higher sensory neuropathy according to the N

27、CI Common Terminology Criteria for Adverse Events and at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel other taxane, or oxaliplatin tatment. INTERVENTIONS:The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or plac

28、ebo for the first week and 2 capsules of either 30 mg of duloxetine or placebo daily for 4 additional weeks. MAIN OUTCOME MEASURESzThe primary hypothesis was that duloxetine would be more effective than placebo in decreasing chemotherapy-induced peripheral neuropathic pain. Pain severity was assesse

29、d using the Brief Pain Inventory-Short Form average painM item with 0 represent!ng no pain and 10 representing as bad as can be imagined.RE SULTS Individuals receiving duloxetine as their initial 5-week treatment reported a mea n deoreas 巳 in average pain of 1.06 (95% Ck 0.72-1.40) vs 0.34 (95% Cl,

30、0.01 0.66) among those who received placebo (P 二.003; effect size. 0.513). The observed mean difference in the average pain score between duloxetine and placebo was 0.73 (95% Cl, 0.26-1.20). Fifty-nine percent of those initially receiving duloxetine vs 38% of those initially receiving placebo report

31、ed decreased pain of any amount. CONCLUSION AND RELEVANCE:Among patients with painful chemotherapy-induced peripheral neuropathy, the use of duloxetine compared with placebo for 5 weeks resulted in a greater reduction in pain. TRIAL REGISTRATION Identifier: NCT00489411.在接受这项研究的231

32、名患者中，115人被分配到A组(度洛西汀第一组，安慰剂第二组)和116名B组(安慰剂第一组，度洛西 汀第二组)。第一周每日服用多洛西汀30毫克或安慰剂1粒z每日30毫克多洛西汀或安慰剂2粒z共4周。Takenaka, M,Iida, H. , Matsumoto, S. , Yamaguchi, S,Yoshimura, N. , & Miyamoto, M. (2013). Successful Treatment byAdding Duloxetine to Pregabalin for Peripheral Neuropathy Induced by Paclitaxel America

33、n Journal of Hospice andPalliative Medicine, 30(7), 734 - 736.Initial treatment periodCrossover treatment periodpoos UF匚e乞63666774Conclusion and Relevance Among patients with painful chemotherapy-induced : ipheral neuropathy, theDuEhefirst(c peripheral neuropathy, the use of duloxetine compared with

34、 placebo for 5 weeks re-| Placebo first(gro suited in a greater reduction in pain.)接受辰/口3/口/口 口U/SVS0用叶刀P4H氐十4L1旦Hd亚权冋。7T畑兀攻乂夕:感別卮VQ 址L空7用叶刀P丰土禾十口”5列为38% ,开始先接受度洛西汀患者组同比比例则达59%0在疼痛性化疗所致周围神经病变患者中，与安慰剂相比，使用度洛西汀5周后疼痛减轻更大。Takenaka, M,Iida, H,Matsumoto, S,Yamaguchi, S,Yoshimura, N,& Miyamoto, L (2013) Su

35、ccessful Treatment byAdding Duloxetine to Pregabalin for Peripheral Neuropathy Induced by Paclitaxe1. American Journal of Hospice andPalliative Medicine, 30(7), 734 - 736.本研究旨在评价度An even higher dosage of duloxetine might be useful forUsefulness ofNeuropathy rthose cases in our study that did not suf

36、fer adverse effects at the dosage used; however, the higher maintenance dosage of duloxetine (20 mg/day versus 40 mg/day) was not associated with improved effectiveness. Duloxetine isAKIKO OTASEIJI MAITOMOM1 EGAWA-TAb2Department of结果25例患者中，14例（f 紫杉醇或卡铠的累积剂量、阴approved as a first-line age nt for diabe

37、tic peripheral neuropathy with pregabalin. The maintenance dosage recommended is a dose of 60 mg /day (19). In some previous studies, patients were administered a dosage o 50 mg/day duloxetine for their CIPN (15, 16). In our study :he majority of patients (18/25) receivejl only the minimun dosage of

38、 20 mg/day.SR out of theponders in 銚noeffects with their dosages (20 mg/day: n二4; 40 mg/day: n=2). It is possible that an increased dosage of duloxetine would have been beneficial, if it had been attempted. Future studies might作为一种选择，度洛西刀 try titrating upward to where adverse effects are noted in th

39、e 龄、肿瘤的来源、化疗方案或 lnd!yidu!lPnt：then backhlg 3Way a tolerable dose.庁效及不良反应。I Peripheraler PatientsWADA1,OBE1,DASH! KIMURA1mka, Japan龄、肿瘤来源、化疗方案、O神经病变，而不论患者的年Otake, A ； Yoshino, K ； Ueda, Y ； Kimura, T. Usefulness of duloxetine for Pac1itaxe1-induced peripheral neuropathy treatment in gynecological can

40、cer patients.Anticancer Res.2015 Jan ；35(1) :359-63目前肿瘤病人的治疗手段逐渐增多，幸存者数量正在增加，延缓和控制CIPN迫在眉睫。虽然化疗药物 抗肿瘤作用机制很明确，但导致CIPN发生机制可能不同，从而导致CIPN的发生发展具有不可预测性 ,症状的发生、严重程度和持续时间个体差异很大。目前关于度洛西汀可有效缓解CIPN的报道较少，虽部分实验证实了度洛西汀的有效性，但样本量小，试 验方法有一定得局限性，因此关于度洛西汀对CIPN的疗效还有待进一步研究。现有的文献支持中，对于度洛西汀治疗依然是推荐60mg,起始30mg周后增量60mg维持五周对神经毒性能达到最好的缓解效果。Cascella M Chemotherapy-induced peripheral neu_x0002_ropathy future research. Curr Med Res Opin, 2017, 33(6)：981984.抗癌药物急性及亚急性毒性反应分度标准(WHO)ions in current prophylactic strategies and directions for马凯丽，程志祥.化学治疗导致周围神经病变的发生机制及防治进展J.