Although the GABAergic benzodiazepines (BZDs) and Z-drugs (zolpidem, zopiclone, and zaleplon) are FDA-approved for insomnia disorders with a strong evidence base, they have many side effects, including cognitive impairment, tolerance, rebound insomnia upon discontinuation, car accidents/falls, abuse, and dependence liability. Consequently, the clinical use of off-label drugs and novel drugs that do not target the GABAergic system is increasing. The purpose of this review is to analyze the neurobiological and clinical evidence of pharmacological treatments of insomnia, excluding the BZDs and Z-drugs. We analyzed the melatonergic agonist drugs, agomelatine, prolonged-release melatonin, ramelteon, and tasimelteon; the dual orexin receptor antagonist suvorexant; the modulators of the α₂δ subunit of voltage-sensitive calcium channels, gabapentin and pregabalin; the H₁ antagonist, low-dose doxepin; and the histamine and serotonin receptor antagonists, amitriptyline, mirtazapine, trazodone, olanzapine, and quetiapine. The pharmacology and mechanism of action of these treatments and the evidence-base for the use of these drugs in clinical practice is outlined along with novel pipelines. There is evidence to recommend suvorexant and low-dose doxepin for sleep maintenance insomnia; there is also sufficient evidence to recommend ramelteon for sleep onset insomnia. Although there is limited evidence for the use of the quetiapine, trazodone, mirtazapine, amitriptyline, pregabalin, gabapentin, agomelatine, and olanzapine as treatments for insomnia disorder, these drugs may improve sleep while successfully treating comorbid disorders, with a different side effect profile than the BZDs and Z-drugs. The unique mechanism of action of each drug allows for a more personalized and targeted medical management of insomnia.

中文翻译：

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苯二氮卓类药物以外的失眠药物：药理学，临床应用和发现

尽管GABA能级苯二氮卓类（BZDs）和Z类药物（zolpidem，zopiclone和zaleplon）已获FDA批准用于失眠症，并具有强大的证据基础，但它们具有许多副作用，包括认知障碍，耐受性，停药后反弹性失眠，汽车事故/坠落，虐待和抚养责任。因此，不针对GABA能系统的非标签药物和新药的临床应用正在增加。这篇综述的目的是分析失眠的药物治疗的神经生物学和临床证据，不包括BZD和Z药物。我们分析了褪黑激素激动剂药物，阿戈美拉汀，褪黑素缓释剂，雷美替尼和他西美汀。双食欲素受体拮抗剂suvorexant；所述的调节剂α ₂ δ电压敏感钙通道的亚基，加巴喷丁和普瑞巴林；H ₁拮抗剂，低剂量多塞平；以及组胺和5-羟色胺受体拮抗剂，阿米替林，米氮平，曲唑酮，奥氮平和喹硫平。这些疗法的药理作用和作用机理，以及在临床实践中使用这些药物的证据基础，以及新颖的方法都得到了概述。有证据建议使用舒马替尼和小剂量多塞平治疗维持睡眠失眠。也有足够的证据推荐雷米替尼用于睡眠发作性失眠。尽管使用喹硫平，曲唑酮，米氮平，阿米替林，普瑞巴林，加巴喷丁，阿戈美拉汀和奥氮平治疗失眠症的证据有限，但这些药物可改善睡眠，同时成功治疗合并症，其副作用不同于BZD和Z药物。