Insomnia persistently affects the quality and quantity of sleep. Currently 
approved treatments for insomnia primarily target γ-aminobutyric acid-A (GABA-A) 
receptor signalling and include benzodiazepines and GABA-A receptor modulators. 
These drugs are used to address this sleep disorder, but have the potential for 
side effects such as tolerance and dependence, making them less attractive as 
maintenance therapy. Forward and reverse genetic approaches in animals have 
implicated orexin signalling (also referred to as hypocretin signalling) in the 
control of vigilance and sleep/wake states. Screening for orexin receptor 
antagonists using in vitro and in vivo methods in animals has identified 
compounds that block one or other of the orexin receptors (single or dual orexin 
receptor antagonists [SORAs and DORAs], respectively) in animals and humans. 
SORAs have primarily been used as probes to further elucidate the roles of the 
individual orexin receptors, while a number of DORAs have progressed to clinical 
development as pharmaceutical candidates for insomnia. The DORA almorexant 
demonstrated significant improvements in a number of clinically relevant sleep 
parameters in animal models and in patients with insomnia but its development 
was halted. SB-649868 and suvorexant have demonstrated efficacy and tolerability 
in Phase II and III trials respectively. Furthermore, suvorexant is currently 
under review by the Food and Drug Administration for the treatment of insomnia. 
Based on the publication of recent non-clinical and clinical data, orexin 
receptor antagonists potentially represent a targeted, effective and 
well-tolerated new class of medications for insomnia.