Original articleAn efficacy, safety, and dose–response study of Ramelteon in patients with chronic primary insomnia
Introduction
Insomnia is a common condition characterized by difficulty falling asleep, increased nighttime wakefulness, or waking too early. The inability to have restful sleep can result in daytime complaints, including impaired concentration and disturbed quality of social interactions [1], [2].
Management of insomnia includes sleep hygiene education, cognitive behavioral therapy, and pharmacological therapy. Available pharmacological agents indicated for insomnia include zolpidem, zaleplon, and eszopiclone; these sedative-hypnotics act via gamma-aminobutyric acid (GABA-A)—benzodiazepine receptor complexes and have been associated with cognitive impairment and the potential for abuse [3], [4], [5], [6], [7], [8], [9], [10]. Although not approved for insomnia by the Food and Drug Administration (FDA), sedating antidepressants and antipsychotics are commonly prescribed in clinical practice; their use has also been associated with undesirable side effects due to their non-specific binding at various binding sites in the central nervous system [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15].
Ramelteon is a novel agent with high selectivity for the melatonin receptors MT1 and MT2. These receptors are located in the suprachiasmatic nucleus (SCN) and have been implicated in the regulation of sleepiness and the sleep–wake cycle [16], [17]. Nonclinical in vitro binding studies show the affinities of ramelteon for these receptors to be 3–16 times higher than those of melatonin [18]. Although there may be overlap in function [19], it is thought that MT1 receptors mediate the suppressive effect of melatonin on the SCN [20] and MT2 receptors mediate phase shifting effects [21]. Because of the activity of ramelteon at both of these receptors, it may be referred to as a chronohypnotic or chronosomnotic agent. Ramelteon has higher affinity for the MT1 than MT2 receptor. Ramelteon has negligible affinity for a third melatonin binding site, MT3, which is a melatonin-sensitive form of quinone reductase 2 [22] and is unlikely to be involved in sleep. Ramelteon also possesses negligible affinity for a wide range of other binding sites in the central nervous system (including GABA, benzodiazepine, opioid, muscarinic, histamine, serotonin, and dopamine receptors) [18] known to affect cognitive function and underlie abuse potential.
Ramelteon has a relatively short half-life (1.2 h) [23] and is metabolized in humans to four main metabolites: M-I, M-II, M-III, and M-IV. Pharmacokinetic studies indicate that M-II is the major metabolite formed, followed by M-IV, M-I, and M-III, respectively [24]. M-II shows selectivity for the MT1/MT2 receptors [25] similar to the parent compound but with only 10% of the potency of the parent compound. The other metabolites, M-I, M-III, and M-IV, are pharmacologically inactive.
Ramelteon has been studied in various animal models. It has been shown to decrease wakefulness in freely moving cats [26] and to reduce sleep latency and increase sleep duration in freely moving monkeys [27]. In rodent studies, ramelteon had no effect on learning, memory, or motor coordination and did not exhibit rewarding properties [26].
In a clinical model of transient insomnia, healthy adults experienced statistically significant reductions in latency to persistent sleep (LPS) and increases in total sleep time (TST) following ramelteon administration (16 and 64 mg), with no evidence of residual sedation, as measured by digit symbol substitution test (DSST) [28].
The current study assessed the efficacy, safety, and dose–response of ramelteon in patients with chronic primary insomnia. Because cognitive performance and alertness are important safety considerations for a sleep-promoting agent, this study also assessed the effects of ramelteon in the patient groups by using visual analog scales (VAS) for mood and feeling, the DSST, and the word-list memory tests.
Section snippets
Patients
Men and non-pregnant, non-lactating women between the ages of 18 and 64 years who had chronic insomnia were recruited for this 13-center, placebo-controlled, double-blind, randomized, five-period crossover study. Patients were recruited from existing clinical patient populations and in response to advertisements. An evaluation process that included an initial screening and two consecutive nights of single-blind placebo and polysomnographic (PSG) recording assured that all patients met the
Study population
One hundred and seven patients were enrolled in this study and 103 patients completed the study. Reasons for withdrawal from the study were lack of compliance with the PSG schedule, withdrawal of consent, or errors in medication dosing. At screening, the mean LPS for all patients was 75.2 min, mean TST was 347.9 min, and mean WASO was 63.0 min.
Sleep induction and maintenance
Compared with placebo, all doses of ramelteon resulted in statistically significant reductions in LPS (P<0.001) and increases in TST (P<0.05) (Table 1).
Discussion
In this study of chronic primary insomnia, all doses of ramelteon (4, 8, 16, and 32 mg) resulted in statistically significant reductions in LPS and increases in sleep duration, as measured with PSG. When compared to placebo, ramelteon reduced LPS by 13–15 min, well within the range seen with commonly prescribed sedative hypnotics (e.g. zaleplon and zolpidem) of 8–17 min reduction in LPS compared to placebo [30], [31].
The study was not powered to detect a difference in subjective effects, and
Acknowledgements
The authors would like to thank Thomas Roth for his assistance in scoring PSG results, and the following investigators for their assistance with data collection: Richard Bogan, Bruce Corser, John Gillin, Max Hirshkowitz, Andrew Jamieson, Dennis Riff, Russell Rosenberg, Martin Scharf, Jonathan Schwartz, Renata Shafor, and David Winslow. Preparation of this manuscript was supported by Takeda Global Research and Development Center, Inc.
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