Drug Insight: The Use of Melatonergic Agonists for the Treatment of Insomnia -- Focus on Ramelteon

Seithikurippu R Pandi-Perumal; Venkataramanujan Srinivasan; Burkhard Poeggeler; Rüdiger Hardeland; Daniel P Cardinali


Nat Clin Pract Neurol. 2007;3(4):221-228. 

In This Article

Summary and Introduction

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 MT1 and MT2 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.

The natural compound melatonin promotes sleep by aiding its initiation and maintenance. Additionally, among numerous other actions, melatonin makes an important contribution to the regulation of the body's circadian rhythms.[1,2] In its role as a hormone of the pineal gland (it is also produced in other organs), melatonin is released into the circulation and is distributed throughout the body. It is also released directly into the cerebrospinal fluid, via the pineal recess, where it attains concentrations that are considerably higher than those reached in serum.[3]

Physiologically, melatonin has important chronobiological effects, including sleep-promoting actions, which are mediated through specific receptors located in the major circadian pacemaker, the suprachiasmatic nucleus (SCN).[4] These effects are distinct from those that result from the introduction of supraphysiological amounts of melatonin from exogenous sources, some of which are not receptor-mediated and involve metabolism, either in terms of formation of new bioactive compounds or interactions with free radicals.[1,2]

Melatonin has been used successfully in the treatment of insomnia in older individuals,[5,6,7] in circadian rhythm sleep disorders -- in particular, delayed sleep phase syndrome[8,9,10] -- and in sleep disorders in children with various neurologic diseases.[11,12,13] Studies of the effects of melatonin on decreasing sleep latency and on total sleep have not always produced consistent results, however, with some investigators reporting an absence of effects.[14,15] This lack of effect has been attributed mainly to the short half-life of melatonin. In addition, melatonin has not received approval from the US FDA because of regulations allowing it to be sold freely as a food supplement, and its status as a nonpatentable agent means that it has been of limited interest to the pharmaceutical industry.

In view of the fact that melatonin promotes and synchronizes sleep by acting on SCN melatonin MT1 and MT2 receptors, respectively, it has been suggested that synthesized melatonin receptor agonists with a longer duration of action might have significant clinical value for the treatment of patients with insomnia. Consequently, several melatonin receptor agonists have now been developed and tested in humans,[16,17,18] including the nonselective MT1/MT2 agonist ramelteon, which was recently approved by the FDA for use as a hypnotic.

This Review summarizes the pharmacology and metabolism of ramelteon, with reference to current knowledge regarding the role of melatonin in sleep regulation. We discuss the actions of ramelteon in animal models, the clinical studies that support its efficacy in patients with insomnia, and the possible mechanism of action, safety, and adverse effects of this new drug.


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