Mid-Atlantic Permanente Medical Group, Fairfax, Virginia 22033, USA.
Curr Pharm Des. 2011;17(15):1471-5. doi: 10.2174/138161211796197052.
Insomnia is a highly prevalent condition, and due to ongoing demand from patients suffering with this condition, new pharmacological treatments are actively being sought. As our neurophysiological understanding of insomnia grows, so too do the available treatment options. A significant advance in the treatment of insomnia came with the development of the nonbenzodiazepine hypnotic medications, zolpidem, zaleplon and eszopiclone. These medications have shorter durations of action than many traditional benzodiazepines and may be associated with less risk of tolerance and abuse. They have also been demonstrated to be helpful in cases in which insomnia is comorbid with depression or anxiety, leading to beneficial effects not only with sleep but also with mood and anxiety symptoms. Melatonin, a naturally-occurring substance intimately involved in the regulation of the circadian rhythm, has also been explored as a hypnotic. Little data to date support its use; however, there is evidence that ramelteon, a melatonin agonist, may be helpful for sleep initiation difficulties. Tri-cyclic antidepressants have long been used for insomnia, but use has been limited by unwanted anticholinergic side effects. Low-dose doxepin, at doses of 3 and 6mg, has been demonstrated to have the unique property among its class of being free of anticholinergic effects at those doses. In addition, it seems to have particular efficacy for sleep maintenance insomnia, exhibiting the most robust effects in the latter third of the night. The hypocretin/orexin system has been identified as a possible target. Almorexant, a hypocretin/orexin antagonist displayed evidence of efficacy during Phase III clinical trials but these trials were recently discontinued due to its side effect profile. Another hypocretin/orexin antagonist with a different mechanism of action, MK-4035, is presently in clinical trials. Serotonin antagonists and inverse agonists have been investigated; however, a recent trial with APD125 was discontinued due to lack of efficacy. Sodium oxybate has been used off-label for insomnia by some providers, although data supporting its use are limited. While the sleep-promoting effects of GABA(A) (nonbenzodiazepines and benzodiazepines) enhancement is well-established, newer research examining other mechanisms of action suggest that agents which modulate the histaminergic, serotonergic, melontonergic, and hypocretin/orexin and perhaps GABA-B systems show promise.
失眠是一种高发疾病，由于患者对治疗的需求持续存在，新的药物治疗方案正在积极研发。随着我们对失眠的神经生理学认识不断深入，治疗方法也在不断增多。非苯二氮䓬类催眠药物（唑吡坦、扎来普隆和右佐匹克隆）的出现是失眠治疗的重大进展。与许多传统苯二氮䓬类药物相比，这些药物的作用时间更短，可能产生耐受性和滥用的风险更小。此外，它们在失眠合并抑郁或焦虑的情况下也有帮助，不仅能改善睡眠，还能改善情绪和焦虑症状。褪黑素是一种在调节昼夜节律中起重要作用的天然物质，也被探索作为催眠药。目前，支持其使用的数据很少；然而，有证据表明，褪黑素激动剂雷美尔酮可能有助于改善入睡困难。三环类抗抑郁药长期以来一直用于治疗失眠，但由于其抗胆碱能副作用而受到限制。小剂量多塞平（3 毫克和 6 毫克）已被证明在其同类药物中具有独特的特性，即在这些剂量下没有抗胆碱能作用。此外，它似乎对维持睡眠的失眠特别有效，在夜间后三分之一表现出最显著的效果。下丘脑分泌素/食欲素系统已被确定为可能的靶点。下丘脑分泌素/食欲素拮抗剂阿莫雷克斯坦在 III 期临床试验中显示出疗效，但由于其副作用，这些试验最近被停止。另一种具有不同作用机制的下丘脑分泌素/食欲素拮抗剂 MK-4035 目前正在临床试验中。已对 5-羟色胺拮抗剂和反向激动剂进行了研究；然而，由于缺乏疗效，最近对 APD125 的试验被停止。一些提供者在标签外使用γ-羟基丁酸（GHB）治疗失眠，尽管支持其使用的数据有限。虽然 GABA(A)（非苯二氮䓬类和苯二氮䓬类）增强的促睡眠作用已得到充分证实，但新的研究表明，调节组胺能、5-羟色胺能、褪黑素能、下丘脑分泌素/食欲素和 GABA-B 系统的药物可能有希望。
