Orexin pathway drug development has focused on the relative binding affinities of two key peptides, orexin A and orexin B, to their two key receptors. Blocking receptors damps down wakefulness/alertness signals to the brain, as compared to direct sedating/hypnotic effects of GABA agonists.

The US Food & Drug Administration has approved orexin antagonists for use in insomnia with suvorexant (Belsomra) being licensed in 2014 and lemborexant (Dayvigo) in December 2019. Daridorexant (previously known as nemoraxant) is in phase 3 trials in the EU and USA, while seltorexant has completed phase 2 trials. Side effects stopped the development of another orexin receptor antagonist, almorexant, after phase 3 trials in 2011.26,27,28,29,30

Esmirtazapine, the S-enantiomer of the alpha-2-adrenoreceptor antagonist mirtazapine, has H1 histamine receptor specificity. It was originally investigated for insomnia over a decade ago, but was dropped in 2010. However, clinicians have taken up clinical trials again and in 2020 reported favourable outcomes in a phase 3 trial with esmirtazapine used for 6 months in chronic insomnia.4,31,32