Nature and Science of Sleep (Jan 2023)
Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations
Abstract
Maria P Mogavero,1,2,* Alessandro Silvani,3,* Giuseppe Lanza,4,5 Lourdes M DelRosso,6 Luigi Ferini-Strambi,1,2 Raffaele Ferri4 1Vita-Salute San Raffaele University, Milan, Italy; 2Sleep Disorders Center, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy; 3PRISM Lab, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 4Sleep Research Centre, Oasi Research Institute - IRCCS, Troina, Italy; 5Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy; 6Pulmonary and Sleep Medicine, University of California San Francisco-Fresno, Fresno, CA, USA*These authors contributed equally to this workCorrespondence: Raffaele Ferri, Sleep Research Centre, Oasi Research Institute – IRCCS, Troina, 94018, Italy, Tel +39 0935 936111, Fax +39 0935 936231, Email [email protected]: After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions.Keywords: insomnia, orexin, hypocretin, orexin receptor antagonist, dual orexin receptor antagonists, selective orexin receptor antagonists
