New approaches in the management of insomnia: weighing the advantages of prolonged-release melatonin and synthetic melatoninergic agonists

Abstract

Hypnotic effects of melatonin and melatoninergic drugs are mediated via MT(1) and MT(2) receptors, especially those in the circadian pacemaker, the suprachiasmatic nucleus, which acts on the hypothalamic sleep switch. Therefore, they differ fundamentally from GABAergic hypnotics. Melatoninergic agonists primarily favor sleep initiation and reset the circadian clock to phases allowing persistent sleep, as required in circadian rhythm sleep disorders. A major obstacle for the use of melatonin to support sleep maintenance in primary insomnia results from its short half-life in the circulation. Solutions to this problem have been sought by developing prolonged-release formulations of the natural hormone, or melatoninergic drugs of longer half-life, such as ramelteon, tasimelteon and agomelatine. With all these drugs, improvements of sleep are statistically demonstrable, but remain limited, especially in primary chronic insomnia, so that GABAergic drugs may be indicated. Melatoninergic agonists do not cause next-day hangover and withdrawal effects, or dependence. They do not induce behavioral changes, as sometimes observed with z-drugs. Despite otherwise good tolerability, the use of melatoninergic drugs in children, adolescents, and during pregnancy has been a matter of concern, and should be avoided in autoimmune diseases and Parkinsonism. Problems and limits of melatoninergic hypnotics are compared.

Keywords: agomelatine; hypnotics; melatonin; prolonged-release; ramelteon; tasimelteon.

Figure 1

Chemical structures and main metabolic routes of melatonin and synthetic melatoninergic hypnotics. Flashes = sites of metabolic reactions. Abbreviations: AFMK, N¹-acetyl-N²-formyl-5-methoxykynuramine; Me, methyl; mel, melatonin; 5-MT, 5-methoxytryptamine; NAS, N-acetylserotonin. For other details see current text.