Insomnia melatonin

Patients older than 65 years of age tend to suffer from sleep maintenance insomnia melatonin serum levels have been reported to be low in these patients. Elderly patients with sleep maintenance insomnia who received immediate-release and sustained-release melatonin had improved sleep onset time. They did not, however, experience an improvement in sleep maintenance or total sleep time. 

Evening primrose oil Chaste tree or chasteberry Vitamin E Insomnia Melatonin Valerian... 

Clinicians should ask patients if they take any herbs and supplements, as they may not volunteer this information. The most common herbs and supplements that patients ask about are vitamins, melatonin, valerian, and coenzyme Q10. There is very little support for using creatinine, gingko, ginseng, green tea, ginger, yohimbine, and St lohn s wort in patients with PD. Patients should be cautioned that supplements and herbs are not well controlled by the FDA and may not contain the amounts indicated on the label. Melatonin and valerian may improve insomnia, but they are not commonly used because there is insufficient information in PD patients.39... 

Antihistamines such as diphenhydramine are known for their sedating properties and are frequently used over-the-counter medications (usual doses 25-50 mg) for difficulty sleeping. Diphenhydramine is approved by the FDA for the treatment of insomnia and can be effective at reducing sleep latency and increasing sleep time.43 However, diphenhydramine produces undesirable anticholinergic effects and carryover sedation that limit its use. As with TCAs and BZDRAs, diphenhydramine should be used with caution in the elderly. Valerian root is an herbal sleep remedy that has inconsistent effects on sleep but may reduce sleep latency and efficiency at commonly used doses of 400 to 900 mg valerian extract. Ramelteon, a new melatonin receptor agonist, is indicated for insomnia characterized by difficulty with sleep onset. The recommended dose is 8 mg at bedtime. Ramelteon is not a controlled substance and thus may be a viable option for patients with a history of substance abuse. 

Melatonin secretion is synchronized to the light/dark (LD) cycle, with a nocturnal maximum (in young humans, about 200 pg/ml plasma) and low diurnal baseline levels (about 10 pg/ml plasma). Studies have supported the value of the exogenous administration of melatonin in circadian rhythm sleep disorders, insomnia, cancer, neurodegenerative diseases, disorders of the immune function, and oxidative damage (Karasek et al. 2002 Pandi-Perumal et al. 2005, 2006 Srinivasan et al. 2005a,b, 2006 Hardeland et al. 2006). 

In contrast, another meta-analysis undertaken by Brzezinski et al., using 17 different studies involving 284 subjects, most of whom were older, concluded that melatonin is effective in increasing sleep efficiency and reducing sleep onset time (Brzezinski et al. 2005). Based on this meta-analysis the use of melatonin in the treatment of insomnia, particularly in aged individuals with nocturnal melatonin deficiency, was proposed. 

LY 156735 is a [1-substituted analog of melatonin that has greater bioavailability than melatonin (Nickelsen et al. 2002). It is in an earlier stage of clinical trials in initial trials, it reduced the sleep onset time in patients with moderate sleep-onset insomnia. Several other specific melatonin receptor agonists and antagonists are in development (Rivara et al. 2005 Zlotos 2005) and presumably will be clinically tested over the next few years. 

Olde Rikkert, M. G. Rigaud, A. S. (2001). Melatonin in elderly patients with insomnia. A systematic review. Z. Gerontol. Geriatr. 34, 491-7. 

To mimic melatonin action and increase the half-life is the goal of melatonin receptor agonists, which are the more recent addition to the insomnia therapeutic armamentarium. These compounds, in addition to use for insomnia, may have potential application in the synchronization of disturbed circadian rhythms, sleep disturbances in the elderly, seasonal depression and jet lag, to name a few. Furthermore, studies have shown that melatonin receptor agonists do not induce any of the hypothermic, hypotensive or bradycardic effects caused by melatonin in humans [27,28]. 

Takeda s melatonin (MT1/MT2) receptor agonist ramelteon (11) was approved and launched in 2005 in the U.S., indicated for the treatment of primary insomnia characterized by difficulty with sleep onset. It is the first prescription medication for insomnia with a novel mechanism of action to reach the US market in 35 years. It is also the first and only prescription sleep medication that has not exhibited potential for abuse and dependence, and as such is not designated as a scheduled substance by the DEA. Moreover, ramelteon was also filed in late March 2007 in E.U. for primary insomnia. 

Ramelteon (Rozerem). Recently approved by the FDA for treatment of insomnia in the US, ramelteon acts via a completely novel mechanism of action, that is, stimulating so-called melatonin Ti and T2 receptors in the brain s suprachiasmatic nucleus (SCN). The SCN is regarded as the body s master clock that regulates the sleep-wake cycle and other circadian rhythms. The effects of ramelteon in some respects mimic those of melatonin. Ramelteon, in clinical trials, administered at bedtime doses of 8 mg, outperformed placebo with respect to several indices of sleep disturbance (see Table 9.4). 

Circadin is the proprietary preparation of melatonin, which is used for the short-term management of insomnia. 

Garfinkel et al. (168) conducted an investigation of melatonin s effects on sleep quality in 12 elderly subjects with insomnia [seven men, five women mean age, 76 years (range, 68 to 93 years standard deviation (SD), 8 years)]. These authors used a randomized, double-blind, crossover design with 2 mg controlled-release melatonin or a placebo taken 2 hours before desired bedtime every night for 3 weeks. After a 1-week washout, the subjects then received 3 weeks treatment with the other preparation. Compared with placebo, the controlled-release melatonin improved the sleep quality of these elderly subjects and was well tolerated. Further, 2 months treatment with 2 mg of controlled-release melatonin in these relatively healthy elderly subjects was much more effective than 1 week of treatment ( 168). 

Andrade et al. (169a) conducted a placebo-controlled, double-blind study, which found that a mean stable dose of 5.4 mg of melatonin was helpful for initial insomnia in medically-ill patients for whom standard sedative-hypnotics may be problematic. 

Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep-maintenance insomnia assessment in a clinical trial of melatonin replacement. Sleep 1998 21 52-68. 

Melatonin is promoted commercially as a sleep aid by the food supplement industry (see Chapter 64). Ramelteon is a selective MTi and MT2 agonist that is approved for the medical treatment of insomnia. This drug has no addiction liability (it is not a controlled substance), and it appears to be distinctly more efficacious than melatonin (but less efficacious than benzodiazepines) as a hypnotic. It is metabolized by P450 enzymes and should not be used in individuals taking CYP1A2 inhibitors. It has a half-life of... 

Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syndrome. It has been reported to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect. Melatonin has also been shown to increase rapid-eye-movement (REM) sleep. These observations have been applied to the development of ramel-teon, a prescription hypnotic, which is an agonist at melatonin receptors (see Chapter 22). 

So how is insomnia treated Most commonly, people self-medicate their insomnia with over-the-counter medications such as Tylenol PM , Sominex , Unisom , or other drugs such as antihistamines (discussed in Chapter 3). Other people try natural remedies such as melatonin (see Chapter 4). When such medications don t work, people often ask their doctor for a prescription sleep aid, which is usually a type of medication called a benzodiazepine such as Halcion or a related type of drug such as Ambien or Sonata (see Chapter 6 for more on these types of drugs). 

In recent years, there has been a lot of hype in the media about melatonin and its use as an aid to treat temporary insomnia or jet lag. There has also been some controversy and debate among scientists and physicians as to whether or not melatonin actually helps people sleep. Regardless, melatonin is sold as an over-the-counter supplement in most pharmacies and nutrition and health food stores (Figure 4.1). However, since it is sold as a dietary supplement, the amount of melatonin in each pill as well as the makeup of other ingredients that these melatonin pills might contain, are not regulated by the U.S. Food and Drug Administration. 

In recent years, natural products such as melatonin and herbs such as valerian have become popular over-the-counter remedies for insomnia. There are no comprehensive evaluations of safety and efficacy of these products. Beyond questions of safety and efficacy, there is no consensus on what their doses should be. Nevertheless, these products continue to be used widely by some patients. 

Involuntary movements of the lip and tongue, restlessness, and insomnia developed twice when chronic melatonin therapy was abruptly withdrawn in a young woman with cerebral palsy these symptoms resolved when melatonin was restarted, but did not recur with gradual withdrawal over 2 months (13). This again suggests that endogenous melatonin secretion is suppressed after chronic use. 

Melatonin is an endogenous neurohormone that is produced primarily by the pineal gland. In humans, melatonin is normally released at night, with plasma levels tending to peak between 2 and 4 AM.47 Melatonin is associated with the ability to regulate sleep-wake cycles, and perhaps other circadian rhythms.3,31 Because of this effect, synthetic melatonin supplements have been used primarily to treat insomnia, especially in individuals with disturbed sleep cycles or persons who are blind and cannot regulate melatonin release because they are unable to respond visually to normal light-dark cycles.3... 

Researchers used to think that older adults produced very little melatonin. Since the elderly tend to have more problems with insomnia and other sleeping disorders, scientists hypothesized that these lower levels of melatonin were the cause of sleeping problems in this population. 

In spite of this lack of information, several popular books came out during the 1990s advocating the supposed usefulness of melatonin as a treatment for everything from insomnia to jet lag to aging. Consumer interest in melatonin increased dramatically. It is estimated that millions of Americans take melatonin supplements as a natural remedy. 

---