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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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Key words:
- Insomnia /
- Sedative-hypnotic drugs /
- Abuse /
- Addictiveness /
- Safety /
- Appropriate use
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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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