![]() The cyclic nature of melatonin's production by the pineal gland is controlled by neuronal output from the suprachiasmatic nucleus (SCN) of the hypothalamus. Since its discovery in 1958, melatonin has been shown to play a vital role in the regulation of circadian rhythms, including the sleep–wake cycle. Also, electroencephalographic (EEG) power spectral analyses revealed that there is a decrease in low-frequency (0.25–10.0 Hz) activity and increase in high-frequency activity in non-REM sleep. Newer non-benzodiazepine hypnotics, including zopiclone, zaleplon, and zolpidem, also have been shown to decrease REM sleep in the first half of the night, although the effects were milder than those of benzodiazepines such as triazolam and temazepam. Benzodiazepine receptor agonists reduce rapid eye movement (REM) sleep and increase stage 2 sleep. ![]() Furthermore, sleep produced by these agents is electrophysiologically different from that of naturally occurring physiological sleep. Benzodiazepine receptor agonists, including non-benzodiazepines, have abuse and dependence potential. However, at higher doses, non-benzodiazepine hypnotics also cause similar side effects as those caused by benzodiazepines, although the severity of side effects differs among specific drugs. It has been reported that there is no tolerance during treatment and no or limited rebound insomnia after therapy discontinuation in the long-term use of zaleplon, eszopiclone, and modified release formulation of zolpidem. Then benzodiazepine receptor agonists, the third generation of hypnotics with non-benzodiazepine chemical structures, such as zolpidem, zopiclone, and zaleplon, were developed to maintain sleep-inducing action and reduce side effects such as amnesia and motor dysfunction. However, these hypnotics produce several side effects including cognitive impairment, psychomotor impairment, dependence, tolerance, hangover, rebound insomnia, and so on. īenzodiazepines, the second generation of hypnotics, such as triazolam, lorazepam, and estazolam, have been used for treatment of insomnia, because benzodiazepines have a low potential for abuse and low danger of lethal overdose. However, barbiturates have a high abuse potential, and overdose can cause unconsciousness and even death due to respiratory suppression. The first-generation drugs for insomnia were barbiturates such as pentobarbital and phenobarbital, which were often used as sedative hypnotics/anxiolytics before benzodiazepines largely came to be used for these purposes. The incidence increases with age, and among older adults, insomnia affects women more often than men. Many people remain unaware of the behavioral and medical options available to treat insomnia. Although most of us know what insomnia is and how we feel and perform after one or more sleepless nights, few seek medical advice. An estimated one-third of the general population is affected by insomnia, and 10–15% have chronic insomnia. Most adults have experienced insomnia or sleeplessness at one time or another in their lives. Ramelteon has demonstrated sleep-promoting effects in clinical trials, and coupled with its favorable safety profile and lack of abuse potential or dependence, this chronohypnotic provides an important treatment option for insomnia. Unlike the sedative hypnotics that target GABA A receptor complexes, ramelteon is a chronohypnotic that acts on the melatonin MT 1 and MT 2 receptors, which are primarily located in the suprachiasmatic nucleus, the body's “master clock.” As such, ramelteon possesses the first new therapeutic mechanism of action for a prescription insomnia medication in over three decades. Ramelteon (Rozerem Takeda Pharmaceutical Company Limited, Osaka, Japan) is an orally active, highly selective melatonin MT 1/MT 2 receptor agonist. However, current treatment of insomnia with hypnotics, gamma-aminobutyric acid A (GABA A) receptor modulators, induces various side effects, including cognitive impairment, motor disturbance, dependence, tolerance, hangover, and rebound insomnia. ![]() An estimated one-third of the general population is affected by insomnia, and this number is increasing due to more stressful working conditions and the progressive aging of society.
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