Drug Insight: the use of melatonergic agonists for the treatment of insomnia—focus on ramelteon

Abstract

Melatonin, a chronobiotic that participates in the control of the circadian system, is known for its sleep-promoting effects, which include shortening of sleep latency and lengthening of sleep duration. As a result of its short half-life, melatonin does not exhibit undesirable side effects, and its broad applicability for a variety of sleep problems has been the focus of numerous scientific studies. Melatonin has not, however, received regulatory approval from the US FDA as a drug, because it can be sold freely as a food supplement. Consequently, there has been an active search for patentable melatonin receptor ligands in recent years. Ramelteon, an agonist that acts solely on melatonin MT(1) and MT(2) receptors, is of particular interest, and preliminary research indicates that it holds considerable promise for clinical applications. Ramelteon has been shown to induce sleep initiation and maintenance in various animal models and in clinical trials. In chronic insomnia, ramelteon decreases sleep latency and increases total sleep time and sleep efficiency, without causing hangover, addiction or withdrawal effects. Ramelteon is thought to promote sleep by influencing homeostatic sleep signaling mediated by the suprachiasmatic nucleus. Although ramelteon's metabolism and pharmacokinetics differ from those of melatonin, its safety seems to be sufficient for short-term application. Its long-term effects remain to be determined.

A Review of Melatonin, Its Receptors and Drugs

“…Melatonin reduces the sleep latency, even small doses such as 0.1-0.3 mg/day are sufficient for this purpose [39]. All synthetic melatonergic drugs can provide this effect.…”

Melatonergic Treatment: Focus on Metabolism and Chronobiology

“…Fast actions of immediate-release formulations are fully sufficient for substantially reducing sleep latency, and this can be achieved by all melatonergic agonists tested so-far [5,16,22,23,41]. In the case of melatonin, relatively low doses, such as 0.1 -0.3 mg/day, can already suffice [41], and no convincing necessity is obvious for using synthetic agonists at much higher recommended doses. The differences in efficiency between sleep maintenance and sleep onset can be explained on a chronobiological basis.…”

The Melatonin Receptor Agonist Is Effective for Free-Running Type Circadian Rhythm Sleep Disorder: Case Report on Two Sighted Patients

“…Melatonin binding at the MT1 receptor exerts a sleepinducing effect by suppressing the neural activity for maintaining wakefulness (Reppert et al 1994;Pandi-Perumal et al 2007), whereas binding at the MT2 receptor results in a phase-shift of the circadian rhythm (Reppert et al 1995). Ramelteon acts as a selective agonist for the MT1 and MT2 receptors; it has a time to maximum blood concentration of 0.75 h and a half-life of 1.14 ± 0.39 h. In Patient 1, the action at the MT2 receptor was thought to play a major role in the effectiveness of ramelteon, because possible hypnotic action mediated by the MT1 receptor did not appear even during the periods when the blood concentration was probably high.…”