Dual Orexin Receptor Antagonists (DORAs) as an Adjunct Treatment for Smoking Cessation

Abstract

Smoking is recognized as the most avoidable cause for multiplicity of chronic diseases. However, smoking cessation rates remain low, in part due to the limited target engagement of the currently approved medications for smoking cessation. Sleep is a promising focus for increasing smoking cessation rates because smokers' sleep problems are exacerbated during the first week of smoking abstinence and are associated with poor smoking cessation outcomes. Furthermore, the currently approved smoking cessation pharmacological agents varenicline and nicotine replacement treatment exacerbate sleep problems beyond what would be observed as a consequence of natural nicotine withdrawal. Addressing sleep problems with dual orexin receptor antagonists (DORAs) is positioned to remedy the shortcoming of overlooking sleep as a viable smoking cessation intervention target. Based on previous animal literature, DORA agents suvorexant and lemborexant may accomplish this by diminishing withdrawal difficulty and reducing nicotine cravings. The pharmacologic focus is the orexin system, not only because orexin peptides mediate the sleep-wake cycle, but also because DORA agents have a milder adverse event profile over previous treatments for insomnia. A novel adjunct DORA treatment to a currently approved smoking cessation pharmacotherapy holds a potential to reduce morbidity and mortality caused by smoking.