Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning. Currently, treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed arousal, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

Although not discernible at first glance, sleep is a highly active and regulated brain state. Although we spend practically one third of our lifetimes in this stage, its importance is often taken for granted. Sleep loss can lead to disease, error and economic loss. Our understanding of how sleep is achieved has greatly advanced in recent years, and with that, the management of sleep disorders has improved. There is still room for improvement and recently many new compounds have reached clinical trials with a few being approved for commercial use. Areas covered: In this review, the authors make the case of sleep disorders as a matter of public health. The mechanisms of sleep transition are discussed emphasizing the wake and sleep promoting interaction of different brain regions. Finally, advances in pharmacotherapy are examined in the context of chronic insomnia and narcolepsy. Expert opinion: The orexinergic system is an example of a breakthrough in sleep medicine that has catalyzed drug development. Nevertheless, sleep is a topic still with many unanswered questions. That being said, the melanin-concentrating hormone system is becoming increasingly relevant and we speculate it will be the next target of sleep medication.

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Insomnia is a common clinical condition portrayed by difficulty in initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning, such as irritability or fatigue during wakefulness. This ailment is one of the most rampant health concerns; however, it represents an everyday struggle to clinicians because of its many potential causes, unfamiliarity with behavioral treatments, and concerns about pharmacologic treatments. The etiology and pathophysiology of insomnia involve genetic, environmental, behavioral, and physiological factors culminating in hyperarousal.Current pharmacological treatment for insomnia exists in the form of benzodiazepine receptor agonist drugs (GABA-A receptor). Nonetheless, the use of these hypnotic medications must be carefully monitored for adverse effects and concerns persist regarding their safety and limited efficacy.The recent advances made in elucidating the processes of sleep/wake regulation have altered the way that insomnia is approached. Current studies have highlighted new targets for drug discovery. One of the most promising ones is the orexin (hypocretin) system. Orexin neuropeptides regulate transitions between wakefulness and sleep by promoting arousal through activation of cholinergic/monoaminergic neural pathways. This has led to a swift development of a novel class of drugs that antagonize the physiological effects of orexin. These pharmacological agents may lead to new therapies for insomnia without the side effect profile of benzodiazepines (e.g., impaired cognition, disturbed arousal, and motor balance difficulties); however, antagonizing the orexin system may produce an entirely new plethora of side effects.Despite the impending side effect profile of orexin antagonists, these drugs will inevitably supplement or replace conventional BZD receptor agonists for treating insomnia.

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