ABSTRACT
Medications used for the treatment of insomnia during the past century have largely employed two basic mechanisms for sleep promotion. Prescription sleeping pills such as barbiturates, benzodiazepines (BZDs), and other BZD receptor agonistic modulators (BzRAs) act at the GABAA receptor complex to enhance GABA inhibitory activity and promote sleep. Over-the-counter sleep medications have been and continue to be formulations of nonselective histamine antagonists such as diphenhydramine or doxylamine. Advances in the understanding of neurochemical control of sleep-wake, coupled with identification of previously unknown transmitters, such as hypocretin/orexin, have created new horizons in the pharmacotherapy of insomnia. While some pipeline development continues to target activation of sleep-promoting GABAergic mechanisms, many of the current pharmaceutical efforts are directed at the identification of safe and efficacious medications that antagonize wake-active transmitter systems such as orexin, 5-HT2A, and histamine. Other agents are targeted at the melatonin system, potentially expanding the choice of such agents beyond ramelteon. Certain pipeline drugs offer multiple potential mechanisms of sleep-promoting action.
