Addiction is a chronic relapsing disorder which presents a significant global 
health burden and unmet medical need. The orexin/hypocretin system is an 
attractive potential therapeutic target as demonstrated by the successful 
clinical trials of antagonist medications like Suvorexant for insomnia. It is 
composed of two neuropeptides, orexin-A and orexin-B and two excitatory and 
promiscuous G-protein coupled receptors, OX1 and OX2. Orexins are known to have 
a variety of functions, most notably in regulating arousal, appetite and reward. 
The orexins have been shown to have a role in mediating the effects of several 
drugs of abuse, such as cocaine, morphine and alcohol via projections to key 
brain regions such as the ventral tegmental area, nucleus accumbens and 
prefrontal cortex. However, it has not yet been demonstrated whether the dual 
orexin receptor antagonists (DORAs) under development for insomnia are ideal 
drugs for the treatment of addiction. The question of whether to use a DORA or 
single orexin receptor antagonist (SORA) for the treatment of addiction is a key 
question that will need to be answered in order to maximize the clinical utility 
of orexin receptor antagonists. This review will examine the role of the 
orexin/hypocretin system in addiction, orexin-based pharmacotherapies under 
development and factors affecting the selection of one or both orexin receptors 
as drug targets for the treatment of addiction.