A New Class of Hypnotic Compounds for the Treatment of Insomnia: The Dual Orexin Receptor Antagonists

Insomnia is a widespread, debilitating disorder responsible for enormous individual and societal costs. Currently available pharmacologic treatments for insomnia, including allosteric modulators of the gamma-aminobutyric acid type A receptor (GABAA), such as zolpidem (Ambien®) and eszopiclone (Lunesta®), have undesirable effects that limit their tolerability and utility. The dual orexin receptor antagonists (DORAs), possessing novel mechanisms of action, have demonstrated efficacy in improving sleep latency and quantity in several preclinical species, healthy human volunteers, and patients with insomnia. Importantly, accumulating data suggest that DORAs may be better tolerated than allosteric modulators of the GABAA receptor with respect to cognitive impairment and motor side effects. A greater understanding of the differences between these drug classes is warranted. This chapter attempts to explain some of their key differences in mechanisms of action as well as describe areas where greater experimentation is warranted.