首页
-
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.
-
Key words:
- Insomnia /
- Sedative-hypnotic drugs /
- Abuse /
- Addictiveness /
- Safety /
- Appropriate use
-
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. 
下载: 导出CSV
-
[1] De CRESCENZO F, D'ALÒ G L, OSTINELLI E G, et al. Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. Lancet,2022,400(10347): 170–184. doi: 10.1016/s0140-6736(22)00878-9 [2] PERLIS M L, POSNER D, RIEMANN D, et al. Insomnia. Lancet,2022,400(10357): 1047–1060. doi: 10.1016/S0140-6736(22)00879-0 [3] 中华医学会神经病学分会, 中华医学会神经病学分会睡眠障碍学组. 中国成人失眠诊断与治疗指南(2017版). 中华神经科杂志,2018,51(5): 324–335. doi: 10.3760/cma.j.issn.1006-7876.2018.05.002 [4] LIANG M, GUO L, HUO J, et al. Prevalence of sleep disturbances in Chinese adolescents: a systematic review and meta-analysis. PLoS One,2021,16(3): e0247333. doi: 10.1371/journal.pone.0247333 [5] SHI L, LU Z A, QUE J Y, et al. Prevalence of and risk factors associated with mental health symptoms among the general population in China during the coronavirus disease 2019 pandemic. JAMA Netw Open,2020,3(7): e2014053. doi: 10.1001/jamanetworkopen.2020.14053 [6] MILANI S A, RAJI M A, CHEN L, et al. Trends in the use of benzodiazepines, Z-hypnotics, and serotonergic drugs among us women and men before and during the COVID-19 pandemic. JAMA Netw Open,2021,4(10): e2131012. doi: 10.1001/jamanetworkopen.2021.31012 [7] LAPEYRE-MESTRE M, BOUCHER A, DAVELUY A, et al. Addictovigilance contribution during COVID-19 epidemic and lockdown in France. Therapie,2020,75(4): 343–354. doi: 10.1016/j.therap.2020.06.006 [8] BEGUM M, GONZALEZ-CHICA D, BERNARDO C, et al. Trends in the prescription of drugs used for insomnia: an open-cohort study in Australian general practice, 2011–2018. Br J Gen Pract,2021,71(712): e877–e886. doi: 10.3399/bjgp.2021.0054 [9] WESSELHOEFT R, RASMUSSEN L, JENSEN P B, et al. Use of hypnotic drugs among children, adolescents, and young adults in Scandinavia. Acta Psychiatr Scand,2021,144(2): 100–112. doi: 10.1111/acps.13329 [10] BLIDDAL M, KILDEGAARD H, RASMUSSEN L, et al. Melatonin use among children, adolescents, and young adults: a Danish nationwide drug utilization study. Eur Child Adolesc Psychiatry,2022. doi: 10.1007/s00787-022-02035-1 [11] LUGOBONI F, MIRIJELLO A, FACCINI M, et al. Quality of life in a cohort of high-dose benzodiazepine dependent patients. Drug Alcohol Depend,2014,142: 105–109. doi: 10.1016/j.drugalcdep.2014.06.020 [12] PETURSSON H, LADER M H. Psychological impairment and low-dose benzodiazepine treatment. Br Med J (Clin Res Ed),1982,285(6344): 815–816. doi: 10.1136/bmj.285.6344.815-d [13] ASHTON H. Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat,1991,8(1/2): 19–28. doi: 10.1016/0740-5472(91)90023-4 [14] SOYKA M. Treatment of benzodiazepine dependence. N Engl J Med,2017,376(12): 1147–1157. doi: 10.1056/NEJMra1611832 [15] TAN K R, BROWN M, LABOUÈBE G, et al. Neural bases for addictive properties of benzodiazepines. Nature,2010,463(7282): 769–774. doi: 10.1038/nature08758 [16] VINKERS C H, OLIVIER B. Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABA(A) receptor modulators? Adv Pharmacol Sci,2012,2012: 416864. doi: 10.1155/2012/416864 [17] UUSI-OUKARI M, KORPI E R. Regulation of GABA(A) receptor subunit expression by pharmacological agents. Pharmacol Rev,2010,62(1): 97–135. doi: 10.1124/pr.109.002063 [18] GRAVIELLE M C. Activation-induced regulation of GABAA receptors: is there a link with the molecular basis of benzodiazepine tolerance? Pharmacol Res,2016,109: 92–100. doi: 10.1016/j.phrs.2015.12.030 [19] HAJAK G, MÜLLER W E, WITTCHEN H U, et al. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction,2003,98(10): 1371–1378. doi: 10.1046/j.1360-0443.2003.00491.x [20] SCHIFANO F, CHIAPPINI S, CORKERY J M, et al. An insight into z-drug abuse and dependence: an examination of reports to the European medicines agency database of suspected adverse drug reactions. Int J Neuropsychopharmacol,2019,22(4): 270–277. doi: 10.1093/ijnp/pyz007 [21] SABE M, KASHEF H, GIRONI C, et al. Zolpidem stimulant effect: induced mania case report and systematic review of cases. Prog Neuropsychopharmacol Biol Psychiatry,2019,94: 109643. doi: 10.1016/j.pnpbp.2019.109643 [22] ATKIN T, COMAI S, GOBBI G. Drugs for insomnia beyond benzodiazepines: pharmacology, clinical applications, and discovery. Pharmacol Rev,2018,70(2): 197–245. doi: 10.1124/pr.117.014381 [23] GROSSHANS M, MUTSCHLER J, LUDERER M, et al. Agomelatine is effective in reducing insomnia in abstinent alcohol-dependent patients. Clin Neuropharmacol,2014,37(1): 6–8. doi: 10.1097/wnf.0000000000000007 [24] SCHOEDEL K A, SUN H, SELLERS E M, et al. Assessment of the abuse potential of the orexin receptor antagonist, suvorexant, compared with zolpidem in a randomized crossover study. J Clin Psychopharmacol,2016,36(4): 314–323. doi: 10.1097/jcp.0000000000000516 [25] BORN S, GAUVIN D V, MUKHERJEE S, et al. Preclinical assessment of the abuse potential of the orexin receptor antagonist, suvorexant. Regul Toxicol Pharmacol,2017,86: 181–192. doi: 10.1016/j.yrtph.2017.03.006 [26] 江海峰, 赵敏, 刘铁桥, 等. 镇静催眠药合理使用专家意见. 中国药物滥用防治杂志,2021,27(2): 103–106. doi: 10.15900/j.cnki.zylf1995.2021.02.034 [27] National Survey on Drug Use and Health (NSDUH). 2021. https://nsduhweb.rti.org/respweb/homepage.cfm. [28] VOTAW V R, GEYER R, RIESELBACH M M, et al. The epidemiology of benzodiazepine misuse: a systematic review. Drug Alcohol Depend,2019,200: 95–114. doi: 10.1016/j.drugalcdep.2019.02.033 [29] ABRAHAMSSON T, HAKANSSON A. Nonmedical prescription drug use (NMPDU) in the Swedish general population-correlates of analgesic and sedative use. Subst Use Misuse,2015,50(2): 148–155. doi: 10.3109/10826084.2014.962047 [30] KIM H, PARK S, KIM J, et al. Zolpidem overutilisation among Korean patients with insomnia. J Sleep Res,2020,29(4): e13071. doi: 10.1111/jsr.13071 [31] KAPIL V, GREEN J L, LE LAIT C, et al. Misuse of benzodiazepines and Z-drugs in the UK. Br J Psychiatry,2014,205(5): 407–408. doi: 10.1192/bjp.bp.114.149252 [32] NOVAK S P, HÅKANSSON A, MARTINEZ-RAGA J, et al. Nonmedical use of prescription drugs in the European Union. BMC Psychiatry,2016,16(1): 274. doi: 10.1186/s12888-016-0909-3 [33] SCHEPIS T S, TETER C J, SIMONI-WASTILA L, et al. Prescription tranquilizer/sedative misuse prevalence and correlates across age cohorts in the US. Addict Behav,2018,87: 24–32. doi: 10.1016/j.addbeh.2018.06.013 [34] TAM C C, BENOTSCH E G, WANG X, et al. Non-medical use of prescription drugs and cultural orientation among college students in China. Drug Alcohol Depend,2018,192: 271–276. doi: 10.1016/j.drugalcdep.2018.08.012 [35] KOKKEVI A, FOTIOU A, ARAPAKI A, et al. Prevalence, patterns, and correlates of tranquilizer and sedative use among European adolescents. J Adolesc Health,2008,43(6): 584–592. doi: 10.1016/j.jadohealth.2008.05.001 [36] CARRASCO-GARRIDO P, JIMÉNEZ-TRUJILLO I, HERNÁNDEZ-BARRERA V, et al. Trends in the misuse of tranquilizers, sedatives, and sleeping pills by adolescents in Spain, 2004–2014. J Adolesc Health,2018,63(6): 709–716. doi: 10.1016/j.jadohealth.2018.04.003 [37] CARRASCO-GARRIDO P, DÍAZ RODRÍGUEZ D R, JIMÉNEZ-TRUJILLO I, et al. Nonmedical use of benzodiazepines among immigrant and native-born adolescents in Spain: national trends and related factors. Int J Environ Res Public Health,2021,18(3): 1171. doi: 10.3390/ijerph18031171 [38] HIROOKA T. Excessive prescribing of hypnotic and anxiolytic drugs in Japan. Nihon Rinsho,2015,73(6): 1049–1056. [39] 潘雯, 邓佳慧, 倪照军,等. 2009–2018年某三甲医院住院患者镇静催眠药使用变化趋势分析. 中国药物依赖性杂志,2022,31(3): 212–217. doi: 10.13936/j.cnki.cjdd1992.2022.03.011 [40] PALAMAR J J, HAN B H, MARTINS S S. Shifting characteristics of nonmedical prescription tranquilizer users in the United States, 2005–2014. Drug Alcohol Depend,2019,195: 1–5. doi: 10.1016/j.drugalcdep.2018.11.015 [41] OLFSON M, KING M, SCHOENBAUM M. Benzodiazepine use in the United States. JAMA Psychiatry,2015,72(2): 136–142. doi: 10.1001/jamapsychiatry.2014.1763 [42] VERTHEIN U, BUTH S, HOLZBACH R, et al. Benzodiazepines and Z-drugs-analyses of ambulatory prescriptions from 2006 to 2015. Psychiatr Prax,2019,46(7): 399–405. doi: 10.1055/a-0961-2371 [43] TSENG H Y, YU S H, LEE C Y, et al. Sedative-hypnotic drug use among community-dwelling elderly in Taiwan. Int Psychogeriatr,2018,30(7): 957–965. doi: 10.1017/s1041610217002940 [44] MCHUGH R K, GEYER R, KARAKULA S, et al. Nonmedical benzodiazepine use in adults with alcohol use disorder: the role of anxiety sensitivity and polysubstance use. Am J Addict,2018,27(6): 485–490. doi: 10.1111/ajad.12765 [45] VOTAW V R, WITKIEWITZ K, VALERI L, et al. Nonmedical prescription sedative/tranquilizer use in alcohol and opioid use disorders. Addict Behav,2019,88: 48–55. doi: 10.1016/j.addbeh.2018.08.010 [46] HOCKENHULL J, BLACK J C, HAYNES C M, et al. Nonmedical use of benzodiazepines and Z-drugs in the UK. Br J Clin Pharmacol,2021,87(4): 1676–1683. doi: 10.1111/bcp.14397 [47] JONES J D, MOGALI S, COMER S D. Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug Alcohol Depend,2012,125(1/2): 8–18. doi: 10.1016/j.drugalcdep.2012.07.004 [48] TANG J, LIAO Y, HE H, et al. Sleeping problems in Chinese illicit drug dependent subjects. BMC Psychiatry,2015,15: 28. doi: 10.1186/s12888-015-0409-x [49] HOCKENHULL J, AMIOKA E, BLACK J C, et al. Non-medical use of benzodiazepines and GABA analogues in Europe. Br J Clin Pharmacol,2021,87(4): 1684–1694. doi: 10.1111/bcp.14537 [50] KLARE D L, MCCABE S E, FORD J A, et al. Prescription drug misuse, other substance use, and sexual identity: the significance of educational status and psychological distress in US young adults. Subst Abus,2021,42(3): 377–387. doi: 10.1080/08897077.2020.1784358 [51] MCHUGH R K, GEYER R B, CHASE A R, et al. Sex differences in benzodiazepine misuse among adults with substance use disorders. Addict Behav,2021,112: 106608. doi: 10.1016/j.addbeh.2020.106608 [52] AUGER N, CHADI N, AYOUB A, et al. Suicide attempt and risk of substance use disorders among female youths. JAMA Psychiatry,2022,79(7): 710–717. doi: 10.1001/jamapsychiatry.2022.1025 [53] POLY T N, ISLAM M M, YANG H C, et al. Association between benzodiazepines use and risk of hip fracture in the elderly people: a meta-analysis of observational studies. Joint Bone Spine,2020,87(3): 241–249. doi: 10.1016/j.jbspin.2019.11.003 [54] CROWE S F, STRANKS E K. The residual medium and long-term cognitive effects of benzodiazepine use: an updated meta-analysis. Arch Clin Neuropsychol,2018,33(7): 901–911. doi: 10.1093/arclin/acx120 [55] HE Q, CHEN X, WU T, et al. Risk of dementia in long-term benzodiazepine users: evidence from a meta-analysis of observational studies. J Clin Neurol,2019,15(1): 9–19. doi: 10.3988/jcn.2019.15.1.9 [56] MURPHY Y, WILSON E, GOLDNER E M, et al. Benzodiazepine use, misuse, and harm at the population level in Canada: a comprehensive narrative review of data and developments since 1995. Clin Drug Investig,2016,36(7): 519–530. doi: 10.1007/s40261-016-0397-8 [57] MACLEOD J, STEER C, TILLING K, et al. Prescription of benzodiazepines, Z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records. PLoS Med,2019,16(11): e1002965. doi: 10.1371/journal.pmed.1002965 [58] SHI Y, CUI M, OCHS K, et al. Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO). Nat Neurosci,2022,25(3): 317–329. doi: 10.1038/s41593-022-01013-9 [59] BACHHUBER M A, HENNESSY S, CUNNINGHAM C O, et al. Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996–2013. Am J Public Health,2016,106(4): 686–688. doi: 10.2105/ajph.2016.303061 [60] KLEINMAN R A, WEISS R D. Benzodiazepine-involved overdose deaths in the USA: 2000–2019. J Gen Intern Med,2022,37(8): 2103–2109. doi: 10.1007/s11606-021-07035-6 [61] BLUMENBERG A, HUGHES A, RECKERS A, et al. Flualprazolam: report of an outbreak of a new psychoactive substance in adolescents. Pediatrics,2020,146(1): e20192953. doi: 10.1542/peds.2019-2953 [62] Board INC. Green list-list of psychotropic substances under international control. 33st ed. [2022-12-30]. https://www.incb.org/incb/en/psychotropics/green-list.html. [63] 中华人民共和国国务院 . 麻醉药品和精神药品管理条例 . (2016-02-06)[2022-12-15]. https://gkml.samr.gov.cn/nsjg/bgt/202106/t20210611_330612.html. [64] TAKANO A, ONO S, YAMANA H, et al. Factors associated with long-term prescription of benzodiazepine: a retrospective cohort study using a health insurance database in Japan. BMJ Open,2019,9(7): e029641. doi: 10.1136/bmjopen-2019-029641 [65] 杨哓哲. 某精神病院长期使用苯二氮䓬类药物的门诊患者用药模式及成瘾性研究. 济宁: 济宁医学院, 2022. https://doi.org/10.27856/d.cnki.gjnyx.2022.000039. -
下载: 
版权所有©《四川大学学报(医学版)》编辑部 2023
点击查看大图
表(1)
计量
- 文章访问数: 2156
- HTML全文浏览量: 161
- PDF下载量: 104
- 被引次数: 0
