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

Melatonin and Sleep Regulation

Melatonin secretion not only correlates with the timing of sleep, but also participates in sleep regulation through actions exerted on the SCN.[19] Neurons in the SCN express MT1 and MT2 melatonin receptors, which have different functional roles.[20] Melatonin causes acute inhibition of electrical activity in SCN neurons via MT1 receptors, as shown in transgenic mice not expressing these receptors; the phase-shifting effect of melatonin was found to persist in animals in which expression of MT2 receptors was normal.[21] From this and other studies, it has become clear that whereas SCN MT1 receptors mediate the inhibitory effects of melatonin, MT2-expressing neurons are essential for melatonin's rhythm-regulatory effect.[21,22]

A reduction in sleep onset latency is the most consistently reported effect of melatonin administration.[23,24,25,26] There is evidence that exogenous melatonin treatment of sleep disorders is most effective in cases in which physiological melatonin production is deficient.[6] Considerable improvements in sleep maintenance and duration have been obtained by using slow-release tablets of melatonin, a treatment that has also been found to reduce sleep latency.[27] Serum melatonin has a very short half-life (~20 min), and slow-release preparations can extend the period of elevated serum levels to 5-7 hours.[27]

A recent meta-analysis of the effects of melatonin in sleep disturbances, which included all age-groups (and presumably individuals with normal melatonin levels), failed to document clinically meaningful effects of exogenous melatonin on sleep quality, efficiency or latency.[15] The studies reviewed had a significant heterogeneity index and a low-quality size-effect estimation (indicated by the wide 95% confidence intervals reported). Additionally, the reviewed papers showed notable variations in the route of administration of melatonin, the dose administered and the way in which outcomes were measured, and consequently the findings were difficult to interpret.[15]

By contrast, another meta-analysis that comprised 17 studies involving a total of 284 subjects, most of whom were older, concluded that melatonin was effective in increasing sleep efficiency and reducing sleep onset time.[28] The authors of this meta-analysis proposed the utility of exogenous melatonin treatment for insomnia, particularly in aged individuals with nocturnal melatonin deficiency.


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