摘要
目的通过本次临床研究,对神安交泰颗粒治疗失眠症苯二氮(?)类药物(benzodiazepines drugs, BZD)戒断综合征的临床有效性与安全性做出评价。方法本研究采用随机、双盲、安慰剂对照、多中心临床试验的方法,由三个医院完成。样本量为120例,采用区组随机方法,两组病例分配比例为1：1。试验组口服神安交泰颗粒,每次1袋,每日3次。对照组口服安慰剂颗粒,每次1袋,每日3次。疗程2周,随防两周。两组患者在用药前、用药第5±2天、第10±2天、第15±2天及停用试验药后14±2天各观察一次BZD的用量,修订匹兹堡睡眠质量指数(Pittsburgh sleep quality index, PSQI)量表,Zung焦虑自评量表(Self—rating Anxiety Scale, SAS),中医心肾不交证候积分表,同时观察不良反应。
结果
1.疗效性评价
此次试验共入选120例受试者,全分析数据集(full analysis set, FAS)120例,符合方案数据集(per-protocol set, PPS) 117例。
试验组60人,治疗后35人(58.33%)成功停用BZD,17人(28.33%)重新服用BZD；8人(13.33%)未停用BZD；与对照组(38.33%,30.0%,31.67%)比较,停药率有统计学差异(P<0.05)。
试验组修订PSQI临床控制40.68%,总有效率81.36%；与对照组比较(22.41%,60.34%)均有统计学差异(P<0.05),试验组优于对照组。两组修订PSQI评分治疗前后组内比较,均有统计学差异(P<0.05),治疗后指数均低于治疗前。
试验组SAS临床控制50.85%,总有效率88.14%；与对照组比较(24.14%,67.24%)均有统计学差异(P<0.05),试验组优于对照组；两组SAS标准分治疗前后组内比较,均有统计学差异(P<0.05),治疗后指数均低于治疗前。
试验组中医心肾不交证候临床控制42.37%,总有效率89.83%；与对照组比较(20.69%,48.28%)均有统计学差异(P<0.05),试验组优于对照组。两组中医心肾不交证候积分治疗前后组内比较均有统计学差异(P<0.05),治疗后分值低于治疗前。
2.安全性评价
此次临床试验期间两组临床观察未见不良事件,未发生与试验药物相关的不良作用。
结论
神安交泰颗粒治疗失眠症BZD戒断综合征安全有效,能够改善失眠症BZD戒断综合征患者的睡眠情况,减轻戒断症状,从而帮助失眠症BZD依赖患者停用BZD。试验期间未见与药物相关的不良反应发生,提示该药有较好的安全性。
Objective:To judge and reveal the clinical efficiency and safety of the treatment by Shen-An-Jiao-Tai grains on insomnia with benzodiazepines drugs withdrawal syndrome, through the study and research on this clinical trial.
Methods:Adopted randomization, double blinding, placebo controlled trial, multicenter clinical trial methods, in this trial select 120 suitable cases that were parted two groups at random, the ratio of treat group to control group was 1:1. The treat group was given the Shen-An-Jiao-Tai grains (1bag, tid), the control group was given the placebo grains (1bag, tid). The period of treatment lasted for two weeks, and follow two weeks. Before the medication, medication 5±2day、10±2day、15±2day and withdrawal 14±2day, every patient of the two groups would get evaluated according to measurement of the BZD sume information, the revised Pittsburgh sleep quality index (PSQI), Zung self-rating anxiety scale(SAS) and the disharmony of heart and kidney symptom scale; the adverse effect would also be observed and recorded.
Results:
Curative effect evaluation:After the trial there were 120 cases in full analysis set (FAS),117 cases in per-protocol set (PPS). Curative effect valued by the PPS. After treatment, in the treat group, the rate of drug withdrawal was 58.33%; in the control group, the rate of drug withdrawal was 28.33%. There were difference between two groups.
In the treat group, the total rate of the revised PSQI efficiency came to 81.36%,compared with the control group (60.34%), there were difference revised PSQI between two groups (P<0.05). It showed that the treat group had better effect than the control group. In two groups, the revised PSQI were difference between before and after the treatment (P<0.05).
In the treat group, the total rate of the SAS efficiency came to 88.14%,compared with the control group (67.24%), there were difference SAS between two groups (P<0.05),the treat group had better effect than the control group. In two groups, the SAS standard scores were difference between before and after the treatment (P<0.05), score after the therapy was lower than that before.
In the treat group, the total rate of disharmony of heart and kidney efficiency was 89.93%, which was compared with the control group (48.28%), and showed statistics difference (P<0.05), the treat group had better effect than the control group. In two groups, the disharmony of heart and kidney symptom scores were difference between before and after the treatment (P<0.05), score after the therapy was lower than that before.
Safety analysis:There were no untoward reactions in both treat group and control group in the clinical trial.
Conclusions:The treatment on insomnia and benzodiazepines drugs withdrawal syndrome by Shen-An-Jiao-Tai grains can have good effect on insomnia with BZD withdrawal syndrome. It can improve the sleep quality, reduce the the impact of withdrawal syndrome, as well as reduce the impact of TCM symptome. It also helps patients get rid of dependence on BZD. Safety examination finds no abnormality. During the testing period, no harmful reaction appears which point out that this medicine is relatively safe.
引文
[1]高成阁主编.精神科手册.北京：科学技术出版社,2008：317
[2]EMEA. Guideline on the Non—Clinical Investigation of Dependence Potential of Medicinal Products.2006.53-56
[3]失眠的定义、诊断及药物治疗专家共识.中华神经科杂志,2006,39(2)：141-143
[4]江帆,邱畅,李小芳.2003-2005年催眠药物用药分析[J].汕头大学医学院学报,2006,19(2)：107-108
[5]李振知.我院门诊二类精神药品应用情况与分析[J].首都医药,2007，5：26-27
[6]半个世纪的争议一苯二氮卓类药物临床应用50年.中国处方药,2003，2(3)：66-67
[7]李洪.安定依赖导致自杀1例报告[J].临床精神医学杂志,2002,12：236
[8]王庆珍,宗建强,纪青松.140例住院精神病患者苯二氮类药物使用情况分析[J].中国药物滥用防治杂志,2004,10(3)：128-129
[9]沈渔(?)主编.精神病学.第4版,北京：人民卫生出版社,1994：374
[10]刘伟,陈建军,王晓霞.苯二氮类药物依赖性与合理应用.内蒙古医学杂志,2001,33(6)530-531
[11]郭旭恒,指导：臧佩林.中医药治疗苯二氮卓类药物戒断症状的临床观察[J].辽宁中医杂志,2002,29(2)：91
[12]精神药品临床应用指导原则.卫生部公报,2007·4：35-36
[13]刘久红,郭琪.长期服用镇静催眠药产生依赖性23例[J].中国药师,2005,8(6)：520
[14]张荣华,季建林.苯二氮卓类药物的依赖及戒断.国外医学精神病学分册,2005,32(23)
82-85
[15]姜春和.精神病院门诊患者苯二氮类药物的用药评价.中国民康医学,2007,19(2)：103-104
[16]Schulz KF. Assessing allocation concealment and blinding in randomized controlled trials:why bother Evidence Based Nursing,2001,4 (1):4-6
[17]周文华,杨国栋.药物滥用的易感性.中国药物依赖性通报,1998,7：5
[18]陈彦方,顾牛范主编.新编临床精神药物手册.山东：山东科技出版社,1998：128
[19]马照红,吴琼,张衍军,等.苯二氮卓类抗焦虑药物使用与滥用的调查研究.中国民康医学.2008,20(15)：1710-1711
[20]赵忠新主编.临床睡眠障碍学[M].上海：第二军医大学出版社,2003：405-411.
[21]张莉,董建杰,郭芳华.合理使用镇静催眠药以防产生药物依赖性.河北医学,2006,11：1201-1202
[22]张华凤编译,蔡兵校.药物依赖性的病理状态与治疗.国外医学药学分册,1999,26(4)：207-210
[23]秦小荣.苯二氮类药物依赖与戒断症状的临床和处理.中国药物滥用防治杂志,2003,9(2)： 57-60
[24]马敏,秦小荣.苯二氮卓类药物依赖与戒断的临床症状和处理.健康心理学杂志,2002,10(2)：157-159
[25]张玲.失眠症的心理治疗[J].中国临床康复,2003,7(5)：820-1
[26]Nierenbery AA, Adler LA, Peselow E, et al. Trazoclone for antidepressant associated insomnia [J].Am J psychiatry,1994,151:1069
[27]刘贤臣,唐茂芹,胡蕾,等.匹兹堡睡眠质量指数的信度和效度研究[J].中华精神科杂志,1996,29(2)：103-107
[28]石乡风纯.苯二氮卓类药物依赖性记忆障碍.精神医学,1990.32：267
[39]殷希全,喻东山,杨泰沁,等.44例阿普唑仑戒断综合征的临床特征分析.四川精神卫生,2000.13(3)：207
[30]许富春.阿普唑仑所致戒断综合征的临床特征分析.四川精神卫生,2007,20(2)：108
[31]施明.镇静催眠药依赖性失眠临床特征与从肝论治分析.上海中医药杂志,2004,38(11)：13-14
[32]刘焰刚,马福林.推拿戒除镇静类药物依赖临床体会.中国中医药信息杂志,2000,8(7)：81
[33]Romach MK, Kaplan HL, Bus-to UE, et al; A controlled trial of ondansetron, a 5-HT3 antagonist in benzodiazepine discontinuation. J Clin Psychopharmacol.1998; 18 (2):121-131
[34]Bonnafous C, et al:J Pharmacol Exp Ther.1995;273 (3):995～1000
[35]Saad SF, et al:Med Sci Res.1995; 23 (7):465～467
[36]Saad SF, et al:J Pharm Pharmacol.1997; 49(3):322～328
[37]冯春霞,黄世勋,杨洪志,等.卡马西平治疗苯二氮卓类药物戒断综合征双盲对照观察.滨州医学院学报,1998,21(1)：36-37
[38]李菊生.阿普唑仑戒断综合征60例分析.山东医药,1997,37(6)：47
[39]Katsura M. Mohri Y, Shuto K. et al. Psychological stress, but not physical stress, causes increase in diazepam binding inhibitor(DBI)mRNA expression in mouse brains[J]. Brain Res Mol Brain Res,2002,104(1):103-109
[40]李莎莎,康林,何竞等,内源性焦虑物质一苯甲二氮革结合抑制因子与物质依赖的基础研究进展.中国药物依赖性杂志,2004,13(21)2-4
[41]全世建,林杏娥,刘妮.交泰丸不同配伍比例的药效学研究[J].中药材,2006,29(2)：164-166
[42]季旭明,姜静娴,交泰丸不同配伍比例镇静安神作用研究,山东中医药大学学报2003,27(3)217-220
[43]江苏新医学院编.中药大辞典[M].上海’：上海科学技术出版社,1986：436,1031
[44]张廷模主编.中药学[M].北京：高等教育出版社,2001：316
[45]陈新谦,金有豫,汤光.新编药物学[M].第15版.北京：人民卫生出版社,2005：112
[46]Choi DS, Kim SJ, Jung MY. Inhibitory activity of berberine on DNA strand cleavage induced by hydrogen peroxide and cytochrome[J]. Biosci-Biotechnol-Biochem,2001, 65(2):452
[47]周祖玉,孙爱民,徐建国,等.黄连素对离体灌流心脏的能量保存作用[J].华西医科大学学报,2002,33(3)：431
[48]陈元,金琦.肉桂在不同剂量中的药理作用与应用,临床和实验医学杂志.2003,3(2)：183,185
[49]Preuss HG, Echard B, Polansky MM, et al. whole cinnamon and aqueous extracts ameliorate sucrose-induced blood pressure elevations in spontaneously hypertensive rats[J]. Journal of the American College of Nutrition,2006,25(2):144-150
[50]Subash Babu P, Prabuseenivasan S, Ignacimuthu S. Cinnamaldehyde-A potential antidiabetic agent[J]. Phytomedicine:international journal of phytotherapy and phytopharmacology,2007,14(1):15-22
[51]秦伯益.戒毒现状纵横谈[J].中国药物依赖性杂志,1999,8(2)：81-85
[1]瞿铭,钱文胜,邓均,等.我院精神科门诊苯二氮卓类药物使用情况调查[J].中国民康医学,2007,19：506-507
[2]苏宝兰,、孙福刚.镇静催眠药物在门诊使用情况的调查分析[J].中国民康医学,2007,19：468-469
[3]袁光辉,郑晓惠.失眠症治疗药物的研究进展[J].临床肺科杂志,2005,10：772-773
[4]王泽民.失眠症治疗药物现状调查[J].现代中西医结合杂志,2003,12：1796-1797.
[5]陈彦芳主编.现代临床医学内科进展·精神分册.北京：科学技术文献出版社,2006：68-77
[6]沈渔屯(?)主编.精神病学.第4版.北京：人民卫生出版社,1994：364
[7]许启泰主编.临床药理学.郑州：郑州大学出版社2006；205
[8]许绍芬主编.神经生物学[M].上海：上海医科大学出版社,1999,166-167
[9]张荣华,季建林.苯二氮卓类药物的依赖及戒断.国外医学精神病学分册,2005,32(23)82-85
[10]Pratt JA, Brett RR, Laurie DJ. Benzodiazepine dependence:From neural circuits to gene exp expression. Pharmacol Biochem Behav,1998,59:925-934
[11]StephensDN. A glutamatergic hypothesis of drug dependence. Behav Pharmacol,1995, 6:425-446
[12]Desouza H. et al. Intansal administration of the dopaminergic agonists LDOPA amphetamine and cacaine increases dopamine activity in the neostriatum:a microdialysis study in the rat(J). J Neurochem.1997,68:233～239
[13]Koob GF. Sanna PP. Bloom FE. Neuroscience of addiction [J]. Neuro, 1998,21(3):467-76
[14]Self DW, Nestler EJ. Molecular mechanisms of drug reinforcement and addiction[J]. Annu Rev Neurosci,1995,18:463-95
[15]McBride WJ, Murphy JM, Ikemoto S. Localization of brain reinforcement mechanisms intracranial self—administration and intracranial place—conditioning studies[J]. Behav Brain Re,1999,101(2):129-52
[16]Strugstad E. Sager G. Mechanisms behind drug dependence[J]. Tidsskr Nor Lageforen,1998,118(12):1866-9
[17]王广新,蒙华庆.苯二氮草类药依赖的戒断与中枢神经递质.国外精神病学分册,2000, 27 (4) 240-243
[18]Aquilante CL, Letrent SP, Pollack GM, et al. Increased brain P-glycoprotein in morphine tolerant rats. Life Sci,2000,66:PL47—PL51
[19]Rizzi M, Caccia S, Guiso G, et al. Limbic seizures induce P-glycoprotein in rodent brain. functional implications for pharmacoresistance. J Neurosci,2002, 22:5833-5839
[20]Lazarowski A, Ramos AJ, Garcia—Rivello H, et al. Neuronal and glial expression of the multidrug resistance gene product in an experimental epilepsy model. Cell Mol Neurobiol,2004,24:77-85
[21]Lazarowski A, Massaro M, Schteinschnaider A. et al. Neuronal MDR—1 gene expression and persistent low levels of anticonvulsants in a child with refractory epilepsy. Ther Drug Monit,2004,26:44-46
[22]窦伟,赵忠新.镇静催眠药物的耐受性研究进展.中华神经科杂志,2004,37(5)：459-462
[23]王淑萍,陈虹.苯二氮卓类药物的药理作用及临床作用.天津药学,1997,11(3)：11-13
[24]赵忠新主编.临床睡眠障碍学[M].上海：第二军医大学出版社,2003：406-414
[25]Schweizer E, Richelsk. Benzodiazepine dependence and withdrawal:a review of the syndrome and its clinical mangenment, Acta Psychiatr[J]. Scand,1998,98(suppl 393):95-101.
[26]Hyttel J, Arnt J, Sanchez C. The pharmacology of citalopram [J]. Rev Contemporary Psychopharmacother,1995,6:271-285
[27]Brosen K, Naranjo CA. Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram [J]. Eur Neuropsychopharmacol,2001,11 (4):275-283
[28]鲁广秀.西酞普兰治疗血管性抑郁症疗效观察[J].中国误诊杂志,2004,4(1)97-98
[29]陈巧平,司徒鹏,李华静,等.西酞普兰治疗苯二氮卓类药物依赖的对照研究.中国误诊学杂志,2006,6(9)：1627-1629
[30]Gamble PE Peterson LG Trazodone overdose four years of experience from voluntary reports[J]. clinical chiatry 1996,47(1):6
[31]Liebowitz N. R. Trazodone for the treatment of anxiety symptom in substance abnsers. Jonmal of Chinical Psychormacology,1999,9(9):449
[32]李德东,刘玉厚.曲唑西酮替代治疗苯二氮卓类药物依赖30例临床分析.中国民康医学杂志,2005,15(12)：730
[33]孙振晓,李彦法,于相芬.曲唑酮治疗苯二氮卓类药物戒断症状临床观察.山东精神医学2003,16(2)：81-82,86
[34]张杰文,索爱琴,卢芬,等.曲唑酮治疗苯二氮卓类依赖患者疗效观察.医学论坛杂志,2006,27(17)：17-18
[35]甘伟明、朱秀花.黛力新与佐匹克隆治疗苯二氮(?)卓类药物依赖性失眠症的对照观察.中国冶金工业医学杂志,2006,23(4)：437-439
[36]Herbert Y M.Suicidality and clozapine[J]. clin Psychiatry,1996.14(2):13
[37]谭友果,张光毅,刘均富,等.氯氮平治疗苯二氮卓类依赖综合征26例临床观察.四川精神卫生,1997,10(3)：185-186
[38]De Angelis F. Pharmacol Biochem Behav.1995,52 (2):329-333
[39]Saad SF, et al. J Pharm Pharmacol.1997,49(3):322～328
[40]Saxon L, et al. Psychopharmacology (Berlin).1997,131 (2),:153～160
[41]Tsuda M, et al. Brain Research.1998,790:82～90
[42]赵宪荣,刘国,刘志香,等.热浸酸枣仁戒断治疗安眠药物依赖性成瘾42例[J].中国药师,2005,8(11)：945-946.
[43]孙波,赵洪霞,于立江,等.阿普唑仑依赖及戒断综合征一例报告[J].山东精神医学,1999,12(2),24
[44]秦小荣.苯二氮类药物依赖与戒断症状的临床和处理.中国药物滥用防治杂志,2003,9(2)：57-60
[45]郭旭恒,指导：臧佩林.中医药治疗苯二氮卓类药物戒断症状的临床观察[J].辽宁中医杂志,2002,29(2)：91
[46]施明.镇静催眠药依赖性失眠临床特征与从肝论治分析.上海中医药杂志,2004,38(11)：13-14
[47]胡玲香,李雪青,薛斌.药物依赖与脾脏关系的中医理论.中国中医基础医学杂志,2004,10(11)：10,16
[48]张悦,刘绍惠,侯悦春.针刺治疗药物依赖性失眠.中国针灸,2002,22(3)：185
[49]董应忠.黄连阿胶合补肝汤对阿普唑仑戒断症状的影响.中国民康医学,2007,19(9)775
[50]刘焰刚,马福林.推拿戒除镇静类药物依赖临床体会.中国中医药信息杂志,2000,8(7)：81
[51]阮经文,郑沛仪.针灸治疗药物依赖型失眠患者的疗效分析.中国康复医学杂志,2002,17(3)：167-168
[52]李培宏,李启勇.推拿治疗药物依赖性失眠症46例.云南中医学院学报,2000,23(3)：31-32
[53]熊佐玲,沈涛群.中药协助戒断苯二氮卓类安眠药的临床观察.江西中医药,2007,7：54
[54]施蕾,朱国庆,王敏,等.中西医结合治疗安定类药物依赖型失眠症28例[J].安徽中医学院学报,1998,17(1)：12-13
[55]杨东东.安神调和法治疗苯二氮卓类药物戒断综合征的临床研究.中国中医药信息杂志2006,13(10)：60-61
[56]孙增华.镇静催眠剂引起依赖综合征诊治体会.江苏中医,1997,18(8)：9-10
[57]李晓光,牟苒苒.中西医结合治疗安定类药物依赖型失眠症疗效观察[J].山东医药,2004,44(5)：70
[58]朱国庆,施蕾,王敏,等.中西医结合治疗安定类药物依赖型失眠症28例[J].安徽中医学院学报,1998,17(1)：12-13
[59]付慧鹏,于海亭,霍军,等.中西医结合治疗失眠症53例疗效观察[J].新中医,2004,36(12)：40-41
[60]徐志明,李铭.戒断中应用中药辅助治疗的临床观察[J].云南中医学院学报,1999,22(2)：25-28
[61]薛明翠.绿茶和酸枣仁治疗不寐症39例[J].湖北中医杂志,2000,22(5)：35
[62]张淑娟,蔡晓瑾.安定依赖62例分析.中国临床医生杂志,2007,35(1)：52-53
[63]王艳铭.浅析镇静催眠药的合理应用.中华临床医学研究杂志,2006,12(9)：1225-1226
[64]苏卫东.苯二氮卓类药物依赖的治疗[J].江苏药学与临床研究,2001,9(2)：54
[65]秦晓霞,丁宝坤,彭淼.苯二氮类药物的依赖及防治对策.临床精神医学杂志,1999,9(4)：224-225
[66]秦晓霞.9例苯二氮类药物依赖病人的临床报告.中国药物依赖性杂志,1999,8(4)：296-297
[67]苯二氮卓类药物使用原则.卫生部公报,2007,4：57-59
[68]张莉,董建杰,郭芳华.合理使用镇静催眠药以防产生药物依赖性.河北医学,2006,12(11)：1201-1202
[69]半个世纪的争议-苯二氮卓类药物临床应用50年.中国处方药,2003,2(3)：66-67
[70]杨秀双,陶国有,姜云,等.中西医结合治疗药物依赖后失眠的对照研究.中国实用神经疾病杂志,2008，11(8)：125-126
[71]秦伯益.戒毒现状纵横谈[J].中国药物依赖性杂志,1999,8(2)：81-85