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摘要: 近年来,失眠的发生率日益升高,同时由于疫情的影响,越来越多的人出现了入睡困难、早醒、睡眠时间短等多种失眠问题。长期失眠会严重影响个体的工作和生活,增加罹患躯体以及精神疾病的风险,造成极大的经济和社会负担。镇静催眠药是大多数失眠患者较为常用的治疗手段,主要包括苯二氮䓬类受体激动剂、褪黑素受体激动剂、促食欲素受体拮抗剂和对睡眠具有调节作用的抗抑郁药等。然而,目前存在镇静催眠药非医疗使用和滥用的现象,主要是苯二氮䓬类受体激动剂。这种药物滥用会导致精神和躯体依赖、认知障碍、抑郁焦虑、跌倒风险和死亡风险升高等,因此国内外药品监督管理部门相继出台了有关政策以加强监管。本文对镇静催眠药的使用现状和安全性进行了综述,并提出了合理使用的思考,临床上应辩证地看待镇静催眠药的有效性和安全性,在充分、及时地解决患者失眠问题的同时,也客观、科学地评估其潜在滥用问题,以期为临床失眠药物的规范使用提供参考。Abstract: The incidence of insomnia has been increasing in recent years. In addition, due to the impact of the COVID-19 pandemic, more and more people are experiencing a variety of insomniac problems, including having difficulty in sleep initation, waking up too early, and short sleep duration. Chronic insomnia may seriously affect patients' life and work, increase their risks of developing physical and mental illnesses, and cause crushing social and economic burdens. Sedative-hypnotics, including benzodiazepine agonists, melatonin receptor agonists, orexin receptor antagonists, and antidepressants with hypnotic effects, are widely used to treat most patients suffering from insomnia. However, there is the phenomenon of the non-medical use and abuse of sedative-hypnotic drugs, especially benzodiazepine receptor agonists. The abuse of sedative-hypnotic drugs may lead to mental and physical dependence, cognitive impairment, depression and anxiety, as well as an increased risks of falls and death. Therefore, drug regulatory authorities in China and other countries have issued relevant policies to reinforce regulation. Herein, we reviewed the prevalent use and safety of sedative-hypnotic drugs and proposed suggestions concerning their appropriate use. Both the efficacy and safety of sedative-hypnotic drugs should be carefully considered so that patients suffering from insomnia receive thorough and prompt treatment and the problem of potential abuse of sedative-hypnotic drugs is assessed in an objective and scientific manner. We also hope to provide references for the standardized clinical use of insomnia drugs.
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Keywords:
- Insomnia /
- Sedative-hypnotic drugs /
- Abuse /
- Addictiveness /
- Safety /
- Appropriate use
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镇静催眠药是指能诱导睡意、促进睡眠的药物,它们对中枢神经系统有广泛的抑制作用,包括苯二氮䓬类、Z类药物、褪黑素受体激动剂、食欲素受体拮抗剂、抗抑郁药和抗组胺药(表1),不同国家对镇静催眠药的批准和用药指南存在着差异[1-3]。目前,镇静催眠药随着失眠的发生率日益升高而使用广泛,尤其是新冠疫情之下。同时,不合理使用和滥用镇静催眠的现象也日益增加。镇静催眠药的滥用一直是国内外关注的热点,不仅显著增加了个体罹患精神和躯体疾病的风险,也给家庭和社会带来了沉重的负担。因此,本文综述了镇静催眠药的国内外使用现状和滥用情况,从药物的成瘾性和人群的易感性来分别解读滥用发生的原因,总结了国内外管控政策,并提出合理使用的思考,以期为临床药物的规范使用和未来的科学研究提供理论依据。
Drug Mechanism of action The availability and indications Dose range for insomnia treatment Level of potential addiction Control policies China (NMPA) European Union (EMA) The United States (FDA) Japan (PMDA) Australia (TGA) The United Kingdom (BNF) Benzodiazepines (BZDs) Diazepam Indirect GABA agonism of BZ1 and BZ2 receptors Anxiety disorders, difficulty in sleep initiation National authorization policy Anxiety disorders, symptoms of anxiety, and convulsive disorders Anxiety, depressed mood, muscle cramps Anxiety disorders, muscle cramps and Panic attacks Insomnia associated with anxiety 5-15 mg ++ China: Diazepam, alprazolam, and temazepam are classified as second-class psychotropic drugs. America: Diazepam, alprazolam, and clonazepam are classified as List Ⅳ. England: Diazepam, alprazolam, and flunitrazepam are classified as Class C. Clonazepam Difficulty maintaining sleep National authorization policy Not approved Insomnia Severe insomnia Not available 0.5-2 mg ++ Estazolam Difficulty initiating sleep, difficulty maintaining sleep National authorization policy Short-term management of insomnia Insomnia and anaesthetic premedication Not available Not available 0.5-4 mg + Temazepam Not available National authorization policy Short-term treatment of insomnia Not available Short-term treatment of insomnia Short-term treatment of insomnia 7.5-40 mg ++ Lorazepam Difficulty maintaining sleep, anxiety disorders National authorization policy Insomnia and anxiety Somatic symptoms in psychosomatic diseases Insomnia due to anxiety, anxiety, and anaesthetic premedication Short-term treatment of insomnia associated with anxiety 1-4 mg + Triazolam Difficulty initiating sleep, difficulty maintaining sleep or early morning awakening National authorization policy Short-term treatment of insomnia Insomnia Not available Not available 0.125-0.5 mg ++ Z-drugs Zopiclone Indirect GABA agonism of BZ1 receptor Difficulty maintaining sleep National authorization policy Not approved Insomnia and anaesthetic premedication Short-term treatment of insomnia Short-term treatment of insomnia 3.75-10 mg + China: Zopiclone and zolpidem are classified as second-class psychotropic drugs. Eszopiclone Difficulty maintaining sleep, difficulty maintaining sleep or early morning awakening Not available Insomnia Insomnia Not available Not available 1-3 mg + Zaleplon Difficulty maintaining sleep Insomnia characterized by difficulty in sleep initiation Short-term treatment of insomnia Not available Not available Not available 5-10 mg + Zolpidem Difficulty maintaining sleep Insomnia Short-term treatment of insomnia characterized by difficulties with sleep initiation Insomnia (except for insomnia associated with schizophrenia or manic depressive) Short-term treatment of insomnia Short-term treatment of insomnia 5-10 mg (6.125-12.5 mg extended release) + Melatonin and melatonin agonists Melatonin Melatonin agonism of MT1, MT2, and MT3 receptors Not approved 2 mg modified release for short-term treatment of primary insomnia characterized by poor quality of sleep in patients aged 55 or over Not approved Not available The improvement of sleep quality and morning alertness in patients over 55 with poor quality of sleep The short-term treatment of insomnia in adults 55 years and over and jetlag 2 mg No None Tasimelteon Melatonin agonism of MT1 and MT2 receptors Not approved Not available Non-24-hour sleep-wake rhythm disorder and jetlag Not available Not available Not available Not available No Ramelteon Not approved Not approved Insomnia characterized by difficulty with sleep initiation Insomnia characterized by difficulty with sleep initiation Not available Not available 8 mg No Orexin receptor antagonists Suvorexant Orexin antagonism of OX1 and OX2 receptors Not yet approved (ongoing application) Not approved Insomnia characterized by difficulties with sleep initiation and/or sleep maintenance Insomnia Insomnia Not available 5-20 mg Low None Lemborexant Not approved (Phase Ⅲ clinical trial) Not approved Insomnia characterized by difficulties with sleep initiation and/or sleep maintenance Insomnia, dose increase should be determined carefully Insomnia characterized by difficulties with sleep onset and/or sleep maintenance Not available 5-10 mg No Daridorexant Not approved Not available Insomnia characterized by difficulties with sleep initiation and/or sleep maintenance Not available Not available Not available 25-50 mg No Antidepressants Doxepin Histamine antagonism of H1 receptor Insomnia: Phase Ⅱ clinical trial, 25 mg; Depression 25 mg National authorization policy 6 mg (3 mg in the elderly), for insomnia characterized by difficulties with sleep maintenance Not available 30-300 mg: Depression 75-300 mg: Depression 3-6 mg No None GABA: γ-aminobutyric acid; BZ: benzodiazepine; MT: melatonin; OX: orexin; H: histamine; NMPA: National Medical Products Administration; BNF: British National Formulary; FDA: Food and Drug Administration; EMA: European Medicines Agency; PMDA: Pharmaceuticals and Medical Devices Agency; TGA: Therapeutic Goods Administration. 1. 镇静催眠药的使用现状
失眠的发生率日益升高且逐渐年轻化,全世界多达三分之一的成年人患有失眠。《2022中国国民健康睡眠白皮书》显示,我国2021年超过3亿人存在睡眠障碍,成年人失眠发生率高达38.2%,此外,60岁以上老年人群和青少年的睡眠障碍的发生率分别约为35.9%和26%[4]。长期失眠对个体的正常生活和工作造成了严重影响,导致罹患各种疾病的风险升高、经济负担增加等。指南[1- 3]推荐失眠的主要治疗方法包括认知行为治疗及药物等。其中,认知行为疗法是失眠障碍的一线治疗方案,但由于其存在治疗周期长和起效时间慢等问题,因此镇静催眠药仍是我国大多数失眠患者治疗的选择方案。
近年来,全球的镇静催眠药使用量和生产量呈现上升趋势。根据国际麻醉品管制局2021年最新报告显示,苯二氮䓬类药物(benzodiazepines, BZDs)的主要使用国家为西班牙、比利时等欧洲国家,使用最多的BZDs依次为阿普唑仑、地西泮和劳拉西泮。由于新型冠状病毒感染(COVID-19)疫情加剧了失眠问题[5],各国的镇静催眠药处方量在疫情期间也呈上升趋势[6-7],其中美国女性非苯二氮䓬药物类药物的处方率从1.37%升至1.49%[6]。苯二氮䓬类受体激动剂的处方率所占比例整体上有所下降,而褪黑素受体激动剂、食欲素受体拮抗剂等新药存在上升的趋势。澳大利亚在2011–2018年BZDs处方率从56.6%下降至41.8%,其中阿普唑仑、硝西泮、替马西泮的处方率降低最为显著[8]。一项针对美国、加拿大和澳大利亚老年人群(≥65岁)的研究表明,2010–2016年,除澳大利亚外,美国及加拿大的老年人群BZDs的使用显著降低。一项2012–2018年的研究显示,瑞典、挪威和丹麦的青少年群体中褪黑素和抗组胺药使用率明显增高[9],其中褪黑素的使用量增加了近三倍。此外,丹麦一项针对青少年人群使用褪黑素类药物的调查研究显示,2012–2019年,24岁以下人群褪黑素类药物的使用率显著增高,特别是在14~24岁的女性中[10]。综上,虽然整体镇静催眠药的使用情况增加,但是苯二氮䓬类受体激动剂的使用比例下降,这可能与其长期使用的不良反应和其他药物的多选择性有关。
2. 镇静催眠药的依赖性
国际疾病分类第十一次修订本(Eleventh Revision of the International Classification of Diseases, ICD-11)更新关于“镇静催眠药或抗焦虑药依赖(6C44.2)”的诊断标准,包括耐受性、戒断症状、失控性使用等。药物依赖包括躯体依赖和精神依赖,躯体依赖是由反复用药造成的一种生理适应状态,主要表现为耐受性和戒断症状。精神依赖是使用人员对药品产生的强烈渴求感,需不断滥用来重复体验心理快感,是导致复吸的重要原因。
虽然苯二氮䓬类和Z类镇静催眠药起效快,但是这两类药物主要作为短期治疗,当长期或高剂量使用这两类药物,会导致人体对其产生依赖性,比如发生耐受性、停药后的反弹性失眠、滥用和依赖等风险增加[11]。长期使用(>6个月)BZDs的患者在突然停药后均会出现戒断症状,其中40%出现中度到重度的戒断症状[12]。而短期使用BZDs的患者中,有15%~44%的使用者会出现中到重度的稽延性戒断症状,包括突发的焦虑和抑郁症状[13]。2017年新英格兰医学杂志总结了BZDs戒断症状,包括惊厥、畏光、恶心头痛等躯体症状和焦虑、抑郁等精神症状[14]。动物研究表明,BZDs可以引起小鼠伏隔核内含有α1亚基的GABAA受体的表达升高,并使多巴胺神经元放电增加,这可能是BZDs成瘾的神经学基础[15]。此外,BZDs会对GABAA亚基组成、GABAA受体数量造成影响,并造成GABAA受体磷酸化等现象,但其耐受性的具体机制仍有待研究阐明[16-18]。值得注意的是,女性在Z类药物滥用、成瘾及戒断中表现出更多的不良反应,可能是因为体内性激素水平会影响CYP3A4代谢酶的活性,从而影响药物在体内的药代动力学及药效动力学[19]。
与BZDs相比,唑吡坦和佐匹克隆等Z类药物的成瘾性较小,但对存在药物滥用史及精神病史的患者其成瘾风险增加[19]。2003–2017年,欧洲药品管理局(European Medicines Agency, EMA)报道,扎来普隆、佐匹克隆和唑吡坦的不良反应中,滥用、依赖和戒断相关的不良反应分别占总不良反应的12.58%、14.25%和11.35%。与扎来普隆相比,佐匹克隆表现出更高的依赖性和过量使用相关问题,但滥用和戒断反应略低。在Z类药物中,唑吡坦是欧洲药物管理局药物警戒中心(EudraVigilance, EV)数据库报道最多的药物,与静脉给药、高剂量使用和伴随使用娱乐性药物有关。与佐匹克隆和扎来普隆相比,唑吡坦更常发生非医疗使用、滥用和戒断反应[20]。系统综述发现,唑吡坦滥用会增加患者出现躁狂、妄想、抑郁或焦虑障碍以及其他药物依赖或滥用的风险[21]。
现有研究尚未发现褪黑素受体激动剂和食欲素受体拮抗剂具有依赖性[22]。褪黑素受体激动剂,包括雷美替胺、他司美琼和阿戈美拉汀,主要靶向丘脑下部视交叉上核的褪黑素受体1(MT1)和褪黑素受体2(MT2),调控睡眠-觉醒环路。MT1受体主要参与介导抑制“生物钟”促醒作用来诱导睡眠的起始;MT2受体则主要介导节律转换和昼夜节律调节。阿戈美拉汀是首个褪黑素受体激动剂,具有抗抑郁、抗焦虑及调整睡眠节律的作用,该药于2009年2月24日在欧盟获得批准上市。研究表明,阿戈美拉汀可以显著改善酒依赖患者戒断期间的失眠症状,由于该药物的不良反应及成瘾性较小,所以未来有望成为物质依赖患者的睡眠障碍治疗药物[23]。关于食欲素受体拮抗剂,目前只有苏沃雷生、莱博雷生和达利多雷生已经被美国食品药品监督管理局(Food and Drug Administration, FDA)批准用于治疗以入睡困难和/或睡眠维持困难为特征的成人失眠症,但在国内均未上市。苏沃雷生(suvorexant)是第一个被FDA批准用于治疗失眠的食欲素受体拮抗剂。一项纳入36名娱乐性多药滥用者的研究中,比较了苏沃雷生和唑吡坦滥用的潜在风险,结果发现,苏沃雷生整体滥用倾向略低于后者[24]。动物研究评估苏沃雷生的潜在滥用风险,结果也表明,在停止灌注苏沃雷生之后动物未出现明显的撤药或戒断反应;此外,在动物自身给药模型中,也未发苏沃雷生有明显的强化效应,提示苏沃雷生的滥用风险较小[25]。不过,FDA提出仍需警惕其导致的日间损害等多种不良风险。
3. 镇静催眠药的非医疗使用和滥用情况
药物的非医疗使用指的是在缺少处方的情况下获得药品或者和适应证不匹配。当出于非医疗目的,反复、大量地使用具有依赖特性或潜力的药物,即为药物滥用。目前苯二氮䓬类和Z类药物这两类是临床上最常用的镇静催眠药[26],也是最常报道被非医疗使用和滥用的药物。
目前,国内外医疗用药品滥用总体呈现增长趋势,其中阿普唑仑、依替唑仑等BZDs的滥用比例较高,同时存在多药滥用的现象。中国、美国和欧洲各国等多个国家的药品监督管理部门会定期在全国范围内进行药物使用和成瘾监测调查。我国最新国家药物滥用监测年度报告显示,近五年医疗用药品滥用/使用总体呈增长趋势,滥用/使用的医疗用第二类精神药品主要是地西泮和阿普唑仑;前五种主要滥用/使用的医疗用药品包括吗啡(含吗啡控/缓释片)、阿普唑仑、氯硝西泮、艾司唑仑和曲马多,其中三种是BZDs,分别为阿普唑仑、氯硝西泮和艾司唑仑。最新欧洲毒品滥用监测中心报告显示,在过去10年中,阿普唑仑等BZDs出现了非医疗性使用和滥用,2019年该类药物的缉获量占欧洲报告的所有新精神活性物质总量的13%。2021年美国全国药物使用与健康调查结果显示,在2.76亿人口中,21.4%的人在过去一年发生非法药品滥用,其中镇静催眠药的滥用约有6200万人,仅次于以阿片类药物为主的止痛药[27],且滥用情况在18~25岁人群中最高。此外,在美国成年人和青少年群体最常被滥用的非法或处方药物中,BZDs位居第三[28]。
针对于特殊人群中镇静催眠药的使用情况,各国研究者也展开进一步的探索。但由于滥用的定义、处方药物类别、调查人群和国家地区的不同,镇静催眠药的非医疗使用率和滥用率存在较大差异。瑞典针对20 000多名15至64岁人群的普查发现,镇静催眠药的总体滥用率为2.2%[29]。西班牙有2.81%~3.36% 的学生非医疗使用BZDs[12]。韩国全国调查显示,5%的失眠患者存在超剂量使用唑吡坦[30]。COVID-19疫情期间,法国卫生管理部门发现存在镇静催眠药过量使用的现象,但具体滥用率尚无明确数据[7]。除了单一药物的使用,也存在多种药物混合滥用的情况。KAPIL等[31]分析BZDs药物和Z类药物使用者的滥用模式,发现29.6%的人曾经滥用过这些药物,其中40.5%的人至少滥用了其中的两种药物。 NOVAK等[32]基于五个欧洲国家的研究发现,滥用镇静催眠药的人中有28%也合并使用了包括大麻在内的非法药物。
4. 镇静催眠药滥用的高危因素
识别镇静催眠药非医疗使用和滥用的高危因素和易感人群,有助于对人群的个体化管理。现有证据显示青年期、高龄、合并其他药物滥用、存在焦虑抑郁等心理健康问题与镇静催眠药滥用密切相关。
在包括学生在内的青年人中,存在镇静催眠药和非法药物的滥用,尤其是BZDs。由于青少年时期的好奇心和易受同伴影响,镇静催眠药的滥用和危害可能没有得到足够的重视,从而娱乐化使用镇静催眠药。2016年美国全国药物使用与健康调查显示,镇静催眠药非医疗使用和滥用率最高的年龄阶段是18至25岁,比例分别为42.8%和5.8%[33]。在我国,一项针对北京和澳门两地大学生的研究显示,两地分别有33.4%(北京)和21.8%(澳门)的大学生表示在调查前3个月内曾存在处方药的非医疗使用情况,使用比例较高的药物包括镇痛药〔 62.9%(北京),35.5%(澳门)〕,镇静催眠药〔 4.0% (北京),0.9% (澳门)〕,抗焦虑药〔 2.7%(北京),0.6%(澳门)〕[34]。一项包括31个欧洲国家青少年学生的调查发现,非医疗使用镇静催眠药的患病率为5.6%[35]。不良的生活方式会影响药物的滥用,吸烟、饮酒的青少年中非医疗使用BZDs的风险较高[36-37]。
随着人口的老龄化和寿命的延长,老年群体人数增加,而与之伴随的是老年人在镇静催眠药等药物使用和依赖的危险性和易感性增加。联合国数据显示,2019年全世界65岁或以上人口有7.03亿。从全球来看,65岁及以上人口的比例从1990年的6%上升到2019年的9%。国际麻醉品管制局(International Narcotics Control Board, INCB)报告中显示,近年来,老年人滥用精神活性物质和因使用具有精神活性的药品而导致死亡和接受治疗的人数均有所增加,这种增长主要发生在高收入国家。这一现象也出现在镇静催眠药的非医疗使用和滥用中,而且老年人长期不合理使用BZDs等镇静催眠药和抗焦虑药时易发生药物依赖的风险[16]。在日本,医生会给睡眠障碍和/或焦虑障碍患者开具高剂量的抗焦虑药和安眠药处方,尤其在老年患者中比例过高[38]。我国的一项针对精神专科医院住院患者的调查研究发现,近十年来该院老年患者使用镇静催眠药的比例由7.68%增加至12.57%[39]。在美国,65岁及以上的人占总人口的10%以上,该年龄组使用BZDs的比例高于总人口,为10.7%;从2005–2006年到2013–2014年,50岁以上人群镇静催眠药滥用的比例迅速增加,从7.9%上升到16.5%[40]。2018年的调查也发现65~80岁的人群BZDs的使用增幅最大[41]。2006–2015年,德国约164万人使用过镇静催眠药,50%以上使用者年龄大于60岁[42],中国台湾的研究也发现在65岁以上群体中,处方率与年龄呈正相关[43]。
合并烟草、酒精和其他药物滥用也是镇静催眠药非医疗使用的高危因素[36-37,44]。美国全国药物使用及健康调查(National Survey on Drug Use and Health, NSDUH)数据的分析发现,2008–2014年物质使用障碍患者滥用BZDs药物的比例是普通人群的3.5到24倍,阿片类物质使用障碍患者使用镇静催眠药的比例约为一般人群的20倍,其中43%报告在过去一年中存在非医疗使用[45]。英国一项抽样调查显示,2019–2020年BZDs和Z类药物非医疗性使用占比1.2%,其中Z类药物与海洛因合并使用比例最高,为5.4%;BZDs主要与可卡因、苯丙胺和亚甲二氧基甲基苯丙胺(MDMA)合并使用,比例分别为5.9%、5.6%和5.2%[46],其原因包括增强阿片类物质等毒品的使用效果和缓解戒断后的症状,如睡眠障碍和情绪障碍[47]。物质使用障碍患者的睡眠问题较为严重,这可能是其非医疗使用镇静催眠药和滥用的潜在动机。我国的一项研究发现,约有68.5%的物质使用障碍患者存在睡眠障碍,远远高于正常人群(26.4%),在海洛因、甲基苯丙胺及氯胺酮成瘾者中睡眠障碍的发生率分别为80.24%、54.16%及81.98%,提示药物成瘾者具有滥用镇静催眠药的潜在风险[48]。
焦虑抑郁等心理健康问题与镇静催眠药非医疗使用及滥用密切相关,是潜在的预测因子。针对五个欧洲国家的调查显示,有精神疾病史的人群其BZDs非医疗使用的风险明显升高[49]。韩国全国调查显示,患有精神疾病(抑郁症、双相障碍、精神分裂症和焦虑症)以及其他疾病(高血压、糖尿病和关节炎)等可能是唑吡坦过度使用的预测因子[30]。美国大学生群体的研究显示,凯斯勒心理困扰量表评分与镇静催眠药非医疗使用显著相关,评分每增加1分,镇静催眠药非医疗使用的概率增加9%[50]。性别在镇静催眠药滥用和心理健康问题存在差异,研究显示女性比男性更有可能滥用BZDs来应对消极情绪和不良生活事件[44]。另有研究显示,女性滥用BZDs的主要原因是焦虑,而男性主要是增强酒精等成瘾性物质使用的快感[51]。此外,加拿大的一项队列研究发现,自杀未遂后的8~19岁女性青年在15年的随访期间中镇静催眠药的滥用发生率显著升高[52]。
5. 镇静催眠药的安全性
镇静催眠药的长期使用和滥用会对患者的身体健康造成多方面的危害,包括跌倒[53]、抑郁焦虑、认知障碍[54-55]和死亡风险[56-57]等。欧洲药品管理局的数据显示,2003–2017年,在扎来普隆、佐匹克隆、唑吡坦三种Z类药物报告发生的不良反应事件中,因药物滥用所占的比例分别为12.58%、14.25%、11.35%[20]。在认知方面,BZDs的戒断者其工作记忆、信息处理速度、视觉结构、注意力等均存在缺陷[54]。而服用长效BZDs以及超过3年的长期使用会显著增加老年人罹患痴呆的风险[55]。动物研究表明,地西泮会改变小胶质细胞的形态,以及突触物质的吞噬作用,损害树突棘的结构可塑性,从而导致小鼠的认知功能受损[58]。
值得关注的是,镇静催眠药的使用会增加死亡率和自杀风险[56-57]。英国一项纳入12 118名阿片类物质使用障碍患者的回顾性研究发现,在1998–2014年间,合并使用BZDs者的药物相关中毒(drug-related poisoning, DRP)类型的死亡风险显著增加,此外,合并使用Z类药物也可以显著升高死亡风险[57]。根据美国疾病控制与预防中心的数据显示,使用或过量使用BDZs的死亡人数均呈上升趋势[59],过量致死率从2000年的每10万人中0.46人到2019年的2.96人,其中83.5%的死亡原因与阿片类药物共同使用相关[60]。这种死亡风险可能与呼吸抑制有关,案例报告6名青少年在非法使用阿普唑仑后产生言语不清、意识模糊和呼吸抑制等症状[61]。2020年9月23日,FDA更新BZDs的黑框警告、修订用药指南,以反映与这些药物相关的滥用、成瘾、身体依赖和戒断反应的严重风险,提高使用安全。
6. 镇静催眠药滥用的防控
在国际上,为保证麻醉药品和精神药品的合法、安全、合理使用,联合国等国际组织签订了三大公约,分别为《1961年麻醉药品单一公约》、《1971年精神药品公约》和1988年《联合国禁止非法贩运麻醉药品和精神药品公约》来规范使用和管制,中国于1985年先后加入。针对镇静催眠药,国际麻醉品管制局2021年更新的精神活性物质中,将氟硝西泮列为Ⅲ类管制药品,而阿普唑仑、地西泮、氟西泮、苯巴比妥、唑吡坦等其他镇静催眠药大多列为Ⅳ类管制药品[62]。美国司法部的缉毒局(Drug Enforcement Administration, DEA)将麻精药品定义为管制物质,根据其医疗用途、滥用潜力及成瘾性分为Ⅰ~Ⅴ级,其中阿普唑仑、氯硝西泮等被列为表Ⅳ。而英国根据1971年颁发的《药品滥用法案》,及其成瘾性、对个人和社会的危害性,将其分为A、B、C类,地西泮、氟硝西泮、阿普唑仑等镇静催眠药归为C类,监管力度较弱。
我国也采取了一系列有效措施来管控镇静催眠药等医疗用药品,国务院在2005年颁布了《麻醉药品和精神药品管理条例》,并经过2013年和2016年两次修订,旨在加强麻精药品的管理,保证麻精药品的合法、安全、合理使用[63]。精神药品分为第一类精神药品(68种)和第二类精神药品(82种),其中三唑仑被列为第一类精神药品管理,地西泮、阿普唑仑、 唑吡坦、苯巴比妥等镇静催眠药作为第二类精神药品管理。
7. 对于镇静催眠药合理使用的思考
国内外指南均推荐镇静催眠药作为短期失眠的有效治疗药物,但考虑该类药物可能出现的耐受性、依赖性和突然停药的戒断反应,建议避免长期使用。临床诊疗中应密切关注BZDs使用的时长和剂量,同时甄别滥用风险高、依从性差的人群。《中国成人失眠诊断与治疗指南(2017版)》指出,长期应用BZDs的慢性失眠患者至少每4周进行1次临床评估,慢性失眠患者应在医师指导下采用间歇治疗或按需治疗方式服药[3]。BZDs的治疗只能用于短期(即4至12周,包括停药期),然而长期使用的现象仍然存在。日本队列研究显示9%的门诊患者持续使用BZDs的时间≥8个月[64]。我国有些地区的调查显示,BZDs药物长期使用者(≥6个月)的平均使用年限为8.13年,其中阿普唑仑、氯硝西泮是长期使用频率最高的药物[65]。长期使用BZDs仍然存在的原因可能是多重的,比如患者担心停药后症状复发、停药动机不足、缺乏风险意识和没有其他的有效药物替代。因此,医生和患者应给予重视,关注并及时调整失眠药物的剂量和使用时间。另外,针对高龄、有精神疾病史、情绪障碍和合并有其他药物滥用等特殊人群,应警惕催眠药物滥用的潜在风险。建议临床医师诊疗过程中加强全面和个体化评估,密切监测高风险人群对药物的使用和滥用情况。
慢性失眠患者的确存在长期用药的需求,在药物的选择方面,可以考虑选择成瘾性低和无滥用潜力的药物。2017年美国睡眠医学会指南和《中国成人失眠诊断与治疗指南(2017版)》指出慢性失眠患者的长期治疗可使用右佐匹克隆、唑吡坦等Z类药,但需要临床专业医师的指导和针对患者的定期评估。除了BZDs和Z类药物,靶向不同位点的新药也在上市和开发,比如褪黑素受体激动剂和食欲素受体拮抗剂,这些药物的成瘾性比较低,为失眠治疗提供更多的选择(表1)。流行病学数据显示,国际上BZDs受体激动剂的处方率所占比例整体上有所下降,而食欲素受体拮抗剂、褪黑素受体激动剂等新药存在上升的趋势, 提示其具有潜在的优势。2022年Lancet杂志发表的网状荟萃分析研究,系统评估了药物干预对成人失眠的短期和长期疗效。发现从短期疗效看,BZDs、苏沃雷生和曲唑酮等可有效治疗急性期失眠,但由于药物的不良反应,不推荐长期使用。而从长期疗效看,右佐匹克隆和莱博雷生具有良好的疗效,但右佐匹克隆导致的不良反应较多,报道莱博雷生的不良反应相对较少[1]。以上用药趋势和最近研究进展提示临床对于失眠治疗药物的选择可以更加多样。
社会公众需积极应对失眠和相关的心理健康问题,减少药物依赖、精神疾病的污名化和病耻感。除了失眠外,在抑郁、焦虑障碍等精神疾病的临床治疗中,指南推荐使用镇静催眠药对症治疗。英国精神药理学会等指南指出在抑郁症治疗的初期,联合使用镇静催眠药,有助于改善症状、缓解抗抑郁药的不良反应和提高患者依从性。失眠问题常常是抑郁焦虑等精神疾病的伴发症状,然而很多人由于病耻感,没有及时就医,采取自我用药的方式,从而引发镇静催眠药的不合理使用,甚至滥用。医疗性合理使用BZDs导致成瘾的案例很少,临床规范的用药能够规避该风险。此外,BZDs或Z类药长期使用后会导致耐受性增加,突然停药和剂量减少会出现焦虑抑郁等戒断症状,当出现药物依赖和戒断症状,鼓励其积极就医,寻求治疗。
最后,目前中国关于镇静催眠药的非医疗使用和滥用的科学证据有限,针对镇静催眠药的人群特征研究和相关纵向研究仍需进一步开展,比如探究镇静催眠药非医疗使用和滥用的动机、易感因素,以及如何在临床诊疗中识别镇静催眠成瘾等。这些研究将有助于开发筛选相关工具,以探索非医疗使用和滥用的易感因子和高危因素,并确定可能成为预防和治疗滥用的潜在靶点,从而帮助医师在临床实践中能客观、科学地评估患者长期使用镇静催眠药潜在的成瘾问题和不良反应,给出针对性的医学建议。
综上,越来越多的人出现了失眠问题,尤其在疫情期间。镇静催眠药在临床应用广泛,但也存在着非医疗性使用和滥用的情况,我们在充分、及时地解决失眠患者的诊疗问题的同时,也应该客观、科学地评估患者用药的潜在滥用风险和长期安全性,从而促进镇静催眠药的合理科学使用。
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利益冲突 所有作者均声明不存在利益冲突
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Drug Mechanism of action The availability and indications Dose range for insomnia treatment Level of potential addiction Control policies China (NMPA) European Union (EMA) The United States (FDA) Japan (PMDA) Australia (TGA) The United Kingdom (BNF) Benzodiazepines (BZDs) Diazepam Indirect GABA agonism of BZ1 and BZ2 receptors Anxiety disorders, difficulty in sleep initiation National authorization policy Anxiety disorders, symptoms of anxiety, and convulsive disorders Anxiety, depressed mood, muscle cramps Anxiety disorders, muscle cramps and Panic attacks Insomnia associated with anxiety 5-15 mg ++ China: Diazepam, alprazolam, and temazepam are classified as second-class psychotropic drugs. America: Diazepam, alprazolam, and clonazepam are classified as List Ⅳ. England: Diazepam, alprazolam, and flunitrazepam are classified as Class C. Clonazepam Difficulty maintaining sleep National authorization policy Not approved Insomnia Severe insomnia Not available 0.5-2 mg ++ Estazolam Difficulty initiating sleep, difficulty maintaining sleep National authorization policy Short-term management of insomnia Insomnia and anaesthetic premedication Not available Not available 0.5-4 mg + Temazepam Not available National authorization policy Short-term treatment of insomnia Not available Short-term treatment of insomnia Short-term treatment of insomnia 7.5-40 mg ++ Lorazepam Difficulty maintaining sleep, anxiety disorders National authorization policy Insomnia and anxiety Somatic symptoms in psychosomatic diseases Insomnia due to anxiety, anxiety, and anaesthetic premedication Short-term treatment of insomnia associated with anxiety 1-4 mg + Triazolam Difficulty initiating sleep, difficulty maintaining sleep or early morning awakening National authorization policy Short-term treatment of insomnia Insomnia Not available Not available 0.125-0.5 mg ++ Z-drugs Zopiclone Indirect GABA agonism of BZ1 receptor Difficulty maintaining sleep National authorization policy Not approved Insomnia and anaesthetic premedication Short-term treatment of insomnia Short-term treatment of insomnia 3.75-10 mg + China: Zopiclone and zolpidem are classified as second-class psychotropic drugs. Eszopiclone Difficulty maintaining sleep, difficulty maintaining sleep or early morning awakening Not available Insomnia Insomnia Not available Not available 1-3 mg + Zaleplon Difficulty maintaining sleep Insomnia characterized by difficulty in sleep initiation Short-term treatment of insomnia Not available Not available Not available 5-10 mg + Zolpidem Difficulty maintaining sleep Insomnia Short-term treatment of insomnia characterized by difficulties with sleep initiation Insomnia (except for insomnia associated with schizophrenia or manic depressive) Short-term treatment of insomnia Short-term treatment of insomnia 5-10 mg (6.125-12.5 mg extended release) + Melatonin and melatonin agonists Melatonin Melatonin agonism of MT1, MT2, and MT3 receptors Not approved 2 mg modified release for short-term treatment of primary insomnia characterized by poor quality of sleep in patients aged 55 or over Not approved Not available The improvement of sleep quality and morning alertness in patients over 55 with poor quality of sleep The short-term treatment of insomnia in adults 55 years and over and jetlag 2 mg No None Tasimelteon Melatonin agonism of MT1 and MT2 receptors Not approved Not available Non-24-hour sleep-wake rhythm disorder and jetlag Not available Not available Not available Not available No Ramelteon Not approved Not approved Insomnia characterized by difficulty with sleep initiation Insomnia characterized by difficulty with sleep initiation Not available Not available 8 mg No Orexin receptor antagonists Suvorexant Orexin antagonism of OX1 and OX2 receptors Not yet approved (ongoing application) Not approved Insomnia characterized by difficulties with sleep initiation and/or sleep maintenance Insomnia Insomnia Not available 5-20 mg Low None Lemborexant Not approved (Phase Ⅲ clinical trial) Not approved Insomnia characterized by difficulties with sleep initiation and/or sleep maintenance Insomnia, dose increase should be determined carefully Insomnia characterized by difficulties with sleep onset and/or sleep maintenance Not available 5-10 mg No Daridorexant Not approved Not available Insomnia characterized by difficulties with sleep initiation and/or sleep maintenance Not available Not available Not available 25-50 mg No Antidepressants Doxepin Histamine antagonism of H1 receptor Insomnia: Phase Ⅱ clinical trial, 25 mg; Depression 25 mg National authorization policy 6 mg (3 mg in the elderly), for insomnia characterized by difficulties with sleep maintenance Not available 30-300 mg: Depression 75-300 mg: Depression 3-6 mg No None GABA: γ-aminobutyric acid; BZ: benzodiazepine; MT: melatonin; OX: orexin; H: histamine; NMPA: National Medical Products Administration; BNF: British National Formulary; FDA: Food and Drug Administration; EMA: European Medicines Agency; PMDA: Pharmaceuticals and Medical Devices Agency; TGA: Therapeutic Goods Administration. -
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