There are mixed results for the use of exogenous melatonin in primary insomnia. Definite trends toward the efficacy of melatonin were seen in one meta-analysis.6 Results from another study reported as negative actually demonstrated a statistically significant positive result of a decrease in sleep latency by an average of 7.2 minutes for melatonin.7 For reasons that are unclear, this result was considered clinically insignificant, although such improvement in sleep latency is well within the range of other marketed pharmaceutical hypnotic agents.8
Study findings from large groups of middle-aged and elderly patients indicate a clear improvement in primary insomnia with the use of 2 mg of extended-release melatonin. In the largest study of more than 500 patients, positive results were primarily seen in patients aged 55 and older and efficacy was seen over a 6-month period.9 The preferential result of exogenous melatonin in an older population may be linked to an age-related decrease in melatonin levels. Some possible causes of this include less effective light input, a decrease of activity of the SCN, or calcification of the pineal gland. Support for this mechanism comes from a study of patients of all ages with relatively low melatonin levels who showed preferential response to the sleep effects of exogenous melatonin.10
Extended-release melatonin has also been found to be safe and well tolerated.9 No significant withdrawal, cognitive adverse effects, or rebound insomnia were seen. These are universally consistent findings in all of the studies of exogenous melatonin in insomnia.6,8,9,11 As a result of the findings from the studies mentioned above, extended-release melatonin has been indicated by the European Medicines Agency and a number of regulatory agencies in other countries as a monotherapy for the short-term treatment of insomnia in patients aged 55 and older. Given the low risk of adverse effects with short-term use and the excellent safety profile, a recent consensus statement from the British Association for Psychopharmacology went a step further and concluded that “a controlled-release formulation of melatonin is the first-choice treatment when a hypnotic is indicated in patients over 55.”12
Ramelteon, a newer MT1/MT2 melatonin receptor agonist approved by the FDA in 2005 for the treatment of insomnia, has addressed some of the intrinsic biological problems linked to the inconsistent findings of melatonin on sleep. It has a much longer half-life than exogenous melatonin and has a 3- to 16-fold greater affinity for the MT1 and MT2 receptors.13 It has greater lipophilic properties than melatonin, with increased tissue absorption and an active metabolite that contributes to its action. Most of the action of ramelteon is specifically on the SCN, and it has no affinity for benzodiazepine, opioid, dopamine, or serotonin receptor subtypes.14 It is also MT1 receptor- selective, which suggests that it targets sleep onset more than melato-nin itself.15
Ramelteon is clearly effective for treating primary insomnia at a wide dose range (4 to 32 mg) on multiple variables of sleep in patients aged 18 and older, including patients older than 65. Effects occurred as quickly as 1 week and efficacy was seen over 6 months, without significant next morning residual effects, rebound insomnia, cognitive adverse effects, and withdrawal.16-18 A number of studies also indicate a dose-independent effect of ramelteon, which suggests a more regulatory than sedative mechanism of improving sleep.19
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