Orexin/hypocretin antagonists in insomnia: From bench to clinic

Abstract

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.