**2.2 Melatonin in the treatment of insomnia**

Insomnia is a pathological condition caused by a variety of endogenous and exogenous factors. Insomnia is characterized primarily by the difficulty of initiating and maintaining sleep, which results in low-quality daily activity. People suffering from chronic insomnia are usually more prone to psychiatric disorders, primarily anxiety-depressive disorders, and cardiovascular diseases [29]. With age, the prevalence of insomnia increases; one of the reasons for this is an involutional decrease in the level of secretion of melatonin [30], a decrease in its concentration with SCN [6]. According to epidemiological studies, 6% of adults in industrialized countries

suffer from a chronic form of insomnia [30]. In addition to night manifestations, accompanied by an increase in sleep latency, a decrease in sleep time, low sleep efficiency, and an increase in wakefulness during sleep, daytime manifestations of this disease are also formed, namely, fatigue, decreased short-term memory, decreased mood, headaches, and gastrointestinal disturbances intestinal tract [31].

The architecture of sleep begins to change already in adulthood, while initially a decrease in the duration of slow sleep is observed. The main goals of treating insomnia are to improve the quality of sleep and its duration and also to improve daily activity. As polysomnographic markers used to objectify the effectiveness of therapy insomnia, wake time after sleep onset (WASO), sleep onset latency (SOL), the number of awakenings, and sleep effectiveness. Despite this, polysomnography is an optional research method. Its use is advisable in cases of suspected secondary genesis of insomnia, as well as to exclude other sleep disorders.

According to the questionnaire, patients with insomnia have higher values (more than 7 points) when questioning on the Insomnia Severity Index (ISI) scale. According to the Pittsburgh Sleep Quality Index (PSQI), there may be more than 5 points. The Beck Depression Questionnaire demonstrates at least the presence of minimal signs of a depressive state, reaching values of 10 or more points. To assess the long-term effects of therapy, keeping a sleep diary is one of the objective methods (recommendation level IIB, based on expert consensus).

According to the recommendations of the American Academy of Sleep Medicine (AASM) from 2008, the use of benzodiazepines and a melatonin receptor agonist (ramelteon) is recommended as a therapy for primary insomnia (psychophysiological, idiopathic, and paradoxical forms). At the same time, there are no clear recommendations regarding the order of initiation of therapy with one of the groups of these drugs. The simultaneous use of melatonin and benzodiazepines is acceptable, to reduce the severity of side effects of the latter. It has been shown that agonists of melatonin receptors have a positive effect on the subjective quality of night sleep and their positive therapeutic effect is objectively confirmed by a polysomnographic study. At the same time, the main criteria for the effectiveness of the treatment of insomnia are achieved, namely, a decrease in WASO and SOL by at least 30 minutes, a decrease in the frequency of awakenings, an increase in sleep duration of more than 6 hours, and an increase in sleep efficiency (ratio of sleep time to recording time) to 80% or more [32, 33]. However, given the short half-life of melatonin and melatonin receptor agonists (e.g., ramelteon), the main clinical effects of these drugs are aimed at the treatment of presomic disorders [33]. In this case, immediate-release melatonin has no other effects on the structure of night sleep, except as a decrease in sleep latency. At the same time, there are observations demonstrating, but not explaining, the reason for the increase in the efficiency of activation of MT1 receptors with SCN, which increases their sensitivity to melatonin, which may be the basis of the therapeutic effect in relation to presominal disorders [34].

One of the mechanisms for implementing the hypnotic effect of melatonin can be realized through hormonal stabilization of the limbic system, which is involved in adaptogenic behavior [7, 9].

According to the recommendations of the European Sleep Research Society (ESRS) from 2017, based on a meta-analysis of 109 studies with a total number of patients 13,969 for the period from 2005 to 2016, melatonin and melatonin receptor agonists have shown unequivocal efficacy in the treatment of insomnia (weak recommendation – low-quality evidence). According to the results of individual studies, polysomnographic criteria for the effectiveness of insomnia therapy were achieved, namely, a decrease in sleep latency and an increase in the total sleep time and sleep efficiency [35, 36]. In a number of studies, even a decrease in the number

**25**

*Clinical Use of Melatonin in the Treatment of Sleep Disorders*

of nocturnal awakenings was noted, which demonstrated effectiveness in relation to intrasomnic disorders. According to these studies, no dependence of the clinical effect on the dose of melatonin used was revealed. A common opinion formed as a

Melatonin is approved in Europe for the treatment of primary insomnia in adults

Studies are demonstrating the effectiveness and perspective use of new forms of melatonin delivery [38]. Modified release tablet formulations with melatonin (MLT) are clinically more useful in initiating and maintaining sleep in elderly insomniacs than those designed for immediate release. The release of MLT from formulation F(nf)2 (nanofiber mats incorporated into 3-layered tablets containing lactose monohydrate both in the upper and lower layers) was found to be in closer

Among healthy children, sleep problems are observed in 20–40% [40] and, among children with impaired development of the nervous system, up to 80% [41, 42]. In pediatric practice, sleep disturbance is most often found among children with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), as well as in anxiety or depressive states [43]. Numerous clinical studies have shown the effectiveness of melatonin in the treatment of falling asleep in patients of various age groups, including children with ASD [44] or adolescents suffering from depression [45]. The physiological concentration of melatonin is crucial for the development of cognitive and behavioral functions [46]. A number of studies have demonstrated a causal relationship between a decrease in melatonin levels and the onset of ASD. Forty percent of children with ASD experienced an increase in serotonin while a decrease in melatonin. An increase in the intermediate metabolite of N-acetylserotonin (NAS) was also observed in 47% of patients [47]. One of the reasons for a decrease in the level of melatonin and an increase in the concentration of its precursor may be due to a violation of the activity of hydroxy-

Despite the lack of clinical recommendations, the use of delayed-release melatonin is recommended for children with difficulty maintaining sleep, while immediate-release melatonin is recommended for children with difficulty falling asleep [41, 48]. According to individual recommendations (level of evidence C), melatonin should be used as a sleep inducer at a dose of 1–3 mg 30 minutes before bedtime. To obtain chronobiological effects, a melatonin drug should be taken with immediate release 3–4 hours before bedtime at a dose of 0.2–0.5 mg; the maximum

Despite the fact that in a number of studies melatonin has been shown to be effective in treating insomnia in patients with attention ADHD, its effect on cognitive function and behavior in this population of children has not been found [50]. Melatonin has also been shown to be effective in patients with secondary iatrogenic insomnia receiving beta blockers for hypertension [51] as well as in children with attention deficit hyperactivity disorder (level of IA recommendations based on

The use of melatonin in pediatric practice is associated with a minimal number of side effects. However, there are reports of undesirable phenomena of mild severity, namely, an increase in the clinical manifestations of nocturnal enuresis, morn-

Thus, according to the main clinical recommendations in the treatment of insomnia, melatonin has a positive effect both on the subjective quality of night sleep and on its objective characteristics. The drug has a high level of evidence of its effectiveness in the long-term therapy of insomnia in patients older than

the results of randomized, placebo-controlled clinical trials) [52, 53].

result of the analysis of research data is a high safety profile for melatonin.

results of several randomized, placebo-controlled trials) [37].

alignment with these effects than the other delivery systems [39].

over the age of 55, with a level of evidence of 1B (level of evidence based on the

*DOI: http://dx.doi.org/10.5772/intechopen.92656*

indole-O-methyltransferase [46].

dose for children is 3 mg and for adolescents 5 mg [49].

ing drowsiness, and extremely rare insomnia [54].

#### *Clinical Use of Melatonin in the Treatment of Sleep Disorders DOI: http://dx.doi.org/10.5772/intechopen.92656*

*Melatonin - The Hormone of Darkness and Its Therapeutic Potential and Perspectives*

mood, headaches, and gastrointestinal disturbances intestinal tract [31].

genesis of insomnia, as well as to exclude other sleep disorders.

methods (recommendation level IIB, based on expert consensus).

suffer from a chronic form of insomnia [30]. In addition to night manifestations, accompanied by an increase in sleep latency, a decrease in sleep time, low sleep efficiency, and an increase in wakefulness during sleep, daytime manifestations of this disease are also formed, namely, fatigue, decreased short-term memory, decreased

The architecture of sleep begins to change already in adulthood, while initially a decrease in the duration of slow sleep is observed. The main goals of treating insomnia are to improve the quality of sleep and its duration and also to improve daily activity. As polysomnographic markers used to objectify the effectiveness of therapy insomnia, wake time after sleep onset (WASO), sleep onset latency (SOL), the number of awakenings, and sleep effectiveness. Despite this, polysomnography is an optional research method. Its use is advisable in cases of suspected secondary

According to the questionnaire, patients with insomnia have higher values (more than 7 points) when questioning on the Insomnia Severity Index (ISI) scale. According to the Pittsburgh Sleep Quality Index (PSQI), there may be more than 5 points. The Beck Depression Questionnaire demonstrates at least the presence of minimal signs of a depressive state, reaching values of 10 or more points. To assess the long-term effects of therapy, keeping a sleep diary is one of the objective

According to the recommendations of the American Academy of Sleep Medicine (AASM) from 2008, the use of benzodiazepines and a melatonin receptor agonist (ramelteon) is recommended as a therapy for primary insomnia (psychophysiological, idiopathic, and paradoxical forms). At the same time, there are no clear recommendations regarding the order of initiation of therapy with one of the groups of these drugs. The simultaneous use of melatonin and benzodiazepines is acceptable, to reduce the severity of side effects of the latter. It has been shown that agonists of melatonin receptors have a positive effect on the subjective quality of night sleep and their positive therapeutic effect is objectively confirmed by a polysomnographic study. At the same time, the main criteria for the effectiveness of the treatment of insomnia are achieved, namely, a decrease in WASO and SOL by at least 30 minutes, a decrease in the frequency of awakenings, an increase in sleep duration of more than 6 hours, and an increase in sleep efficiency (ratio of sleep time to recording time) to 80% or more [32, 33]. However, given the short half-life of melatonin and melatonin receptor agonists (e.g., ramelteon), the main clinical effects of these drugs are aimed at the treatment of presomic disorders [33]. In this case, immediate-release melatonin has no other effects on the structure of night sleep, except as a decrease in sleep latency. At the same time, there are observations demonstrating, but not explaining, the reason for the increase in the efficiency of activation of MT1 receptors with SCN, which increases their sensitivity to melatonin, which may be the basis of the therapeutic effect in relation to presominal

One of the mechanisms for implementing the hypnotic effect of melatonin can be realized through hormonal stabilization of the limbic system, which is involved

According to the recommendations of the European Sleep Research Society (ESRS) from 2017, based on a meta-analysis of 109 studies with a total number of patients 13,969 for the period from 2005 to 2016, melatonin and melatonin receptor agonists have shown unequivocal efficacy in the treatment of insomnia (weak recommendation – low-quality evidence). According to the results of individual studies, polysomnographic criteria for the effectiveness of insomnia therapy were achieved, namely, a decrease in sleep latency and an increase in the total sleep time and sleep efficiency [35, 36]. In a number of studies, even a decrease in the number

**24**

disorders [34].

in adaptogenic behavior [7, 9].

of nocturnal awakenings was noted, which demonstrated effectiveness in relation to intrasomnic disorders. According to these studies, no dependence of the clinical effect on the dose of melatonin used was revealed. A common opinion formed as a result of the analysis of research data is a high safety profile for melatonin.

Melatonin is approved in Europe for the treatment of primary insomnia in adults over the age of 55, with a level of evidence of 1B (level of evidence based on the results of several randomized, placebo-controlled trials) [37].

Studies are demonstrating the effectiveness and perspective use of new forms of melatonin delivery [38]. Modified release tablet formulations with melatonin (MLT) are clinically more useful in initiating and maintaining sleep in elderly insomniacs than those designed for immediate release. The release of MLT from formulation F(nf)2 (nanofiber mats incorporated into 3-layered tablets containing lactose monohydrate both in the upper and lower layers) was found to be in closer alignment with these effects than the other delivery systems [39].

Among healthy children, sleep problems are observed in 20–40% [40] and, among children with impaired development of the nervous system, up to 80% [41, 42]. In pediatric practice, sleep disturbance is most often found among children with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), as well as in anxiety or depressive states [43]. Numerous clinical studies have shown the effectiveness of melatonin in the treatment of falling asleep in patients of various age groups, including children with ASD [44] or adolescents suffering from depression [45]. The physiological concentration of melatonin is crucial for the development of cognitive and behavioral functions [46]. A number of studies have demonstrated a causal relationship between a decrease in melatonin levels and the onset of ASD. Forty percent of children with ASD experienced an increase in serotonin while a decrease in melatonin. An increase in the intermediate metabolite of N-acetylserotonin (NAS) was also observed in 47% of patients [47]. One of the reasons for a decrease in the level of melatonin and an increase in the concentration of its precursor may be due to a violation of the activity of hydroxyindole-O-methyltransferase [46].

Despite the lack of clinical recommendations, the use of delayed-release melatonin is recommended for children with difficulty maintaining sleep, while immediate-release melatonin is recommended for children with difficulty falling asleep [41, 48]. According to individual recommendations (level of evidence C), melatonin should be used as a sleep inducer at a dose of 1–3 mg 30 minutes before bedtime. To obtain chronobiological effects, a melatonin drug should be taken with immediate release 3–4 hours before bedtime at a dose of 0.2–0.5 mg; the maximum dose for children is 3 mg and for adolescents 5 mg [49].

Despite the fact that in a number of studies melatonin has been shown to be effective in treating insomnia in patients with attention ADHD, its effect on cognitive function and behavior in this population of children has not been found [50].

Melatonin has also been shown to be effective in patients with secondary iatrogenic insomnia receiving beta blockers for hypertension [51] as well as in children with attention deficit hyperactivity disorder (level of IA recommendations based on the results of randomized, placebo-controlled clinical trials) [52, 53].

The use of melatonin in pediatric practice is associated with a minimal number of side effects. However, there are reports of undesirable phenomena of mild severity, namely, an increase in the clinical manifestations of nocturnal enuresis, morning drowsiness, and extremely rare insomnia [54].

Thus, according to the main clinical recommendations in the treatment of insomnia, melatonin has a positive effect both on the subjective quality of night sleep and on its objective characteristics. The drug has a high level of evidence of its effectiveness in the long-term therapy of insomnia in patients older than

55 years, associated mainly with the difficulty of falling asleep and the poor quality of night sleep. Ensuring physiological control of the sleep-wake cycle in children with pathology of the development of the nervous system and patients older than 55 years with insomnia is the goal of replacement therapy with melatonin, since in both groups there is a decrease in the secretion of endogenous melatonin during the night [55, 56].

## **2.3 Melatonin and parasomnia**

Parasomnias are undesirable physical or psychological phenomena that usually form at certain stages of sleep, causing a number of clinical manifestations, including the formation of secondary insomnia. Quite often, parasomnia, especially accompanied by motor manifestations, can lead to injuries of varying severity and the formation of psychological problems or social maladaptation [21, 57]. The most striking in its clinical manifestation is REM behavior disorder (RBD). In the treatment of this form of parasomnia, clonazepam is most successfully used. But, the use of this drug is associated with numerous side effects typical of benzodiazepines, especially if the elderly patient has sleep-related breathing disorders (SRBD). An alternative pharmacological method is the use of melatonin. Melatonin also causes a decrease in the frequency and severity of motor activity during an RBD episode, which leads to a decrease in the frequency and severity of injuries. According to the results of a few studies, the use of melatonin at a dose of 3–15 mg led to a significant reduction in paradoxical sleep without atony, as well as the severity of motor manifestations of behavior disorder in the REM phase [58]. One of the options for therapeutic treatment may be taking the drug melatonin for 5–7 days at a minimum dose of 3 mg, followed by an increase in the dose of the drug every 5–7 days to a maximum of 12 mg at night [59, 60]. Little information is available regarding the efficacy of prolonged forms of melatonin or agonists in patients with RBD. There were also no comparisons of the clinical efficacy of clonazepam and melatonin.

Indeed, a number of studies demonstrate a more effective therapeutic effect with the combination of clonazepam and melatonin [61]. The potentiation of the effects of melatonin and clonazepam in the context of RBD therapy has no definitive explanation. It is believed that clonazepam reduces the phase activity inherent in paradoxical sleep, but at the same time, motor activity and minimal disturbance of behavior may remain, according to a polysomnographic survey [62]. The effect of melatonin in combination with clonazepam is due to the modulating effect of the structure of paradoxical sleep, reducing the number of transitions to other stages [59]. An alternative hypothesis explaining the effectiveness of melatonin in RBD may be its effect on increasing the effect of GABA on the GABA receptors of motor neurons of the anterior horns of the spinal cord, which leads to more intense muscle atony. Efficiency may also be related to the fact that melatonin helps to reduce the concentration of calmodulin, which affects the structure of the cytoskeleton and nicotinic acetylcholine receptors of skeletal muscles, which also leads to a progressive decrease in muscle tone [61]. The presence of a favorable safety profile makes the use of melatonin more attractive relative to clonazepam, especially in the elderly [61]. Therefore, in some few clinical trials, melatonin is used as a first-line therapy for RBD, especially in the presence of cognitive impairment, Parkinsonism, or SRBD. In the presence of minimal effectiveness of melatonin or a decrease in its effectiveness during therapy, clonazepam should be additionally prescribed. According to AASM recommendations, melatonin has a "B" level of evidence regarding its effectiveness. Doses of the drug in the studies on the basis of which these recommendations were made ranged from 8 to 12 mg; therefore, there are no clear recommendations regarding the dose of administration [63].

**27**

*Clinical Use of Melatonin in the Treatment of Sleep Disorders*

There is also another class of parasomnia in the treatment of which the effectiveness of melatonin was studied. These are parasomnia associated with slow eye movement, which is defined as undesirable motor and psychophysiological manifestations that occur at the time of awakening from a slow-wave sleep. Parasomnia associated with slow eye movement is defined as undesirable motor and psychophysiological manifestations that occur at the time of awakening from a slow-wave sleep [64]. In cases of severe clinical manifestations of these forms of parasomnia, benzodiazepines (clonazepam) or antidepressants (imipramine or clomipramine) may be used. When walking in a dream, the drugs of choice are benzodiazepines or selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and imipramine [64]. The use of melatonin did not reveal a reliable therapeutic effect on the clinical manifestations of these forms of parasomnia. There are only a few studies on the use of melatonin as a first-line therapy for nightly fears in children; the first-line drug is melatonin or L-5-hydroxytryptophan [65]. The absence of a significant clinical effect is associated with the absence of a homeostatic effect on sleep in

**2.4 Melatonin in the treatment of complications of sleep-dependent** 

Sleep-dependent respiratory disorders are represented by several types of pathological conditions: Obstructive sleep apnea (OSA), central sleep apnea, sleep-related hypoventilation, and sleep-related hypoxemia disorder. Most studies are devoted to the study of melatonin metabolism in OSA. A number of studies have demonstrated impaired melatonin secretion in OSA. At the same time, it is believed that the decrease in secretion is secondary. There is also data on the relationship between the concentration of melatonin at night and the duration of night sleep, as well as body weight [66–68]. Some studies have shown a relationship between the severity of OSA and the degree of decrease in melatonin [69]. Approximately 25% of patients with OSA have an altered circadian rhythm of melatonin secretion. In patients with OSA with a maintained rhythm of secretion, peak melatonin levels at night are significantly lower than in healthy people. The 3-month treatment period with continuous positive airway pressure (CPAP) can help restore the physiological rhythm of melatonin in patients with OSA with an impaired secretion profile [70]. One of the uses of melatonin is its use as a drug that reduces the complications associated with respiratory failure during sleep. Numerous studies on biological models demonstrate the positive effect of melatonin on the unfolding pathophysiological cascade of changes in the body in the presence of sleep-dependent respiratory disorders. For example, melatonin inhibits an increase in glucose, the concentration of which increases during periods of apnea [71]. Melatonin modulation of the activity of adenosine monophosphate-activated protein kinase reduces the progression of cardiac muscle hypertrophy. Melatonin also inhibits the expression of inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-6, and cyclooxygenase-2 [72]. It also helps to reduce the severity of Ca2+ caused by impaired myocardial contractile function, thus reducing the manifestations of endothelial dysfunction. The use of melatonin as a prophylactic helps to prevent cardiac remodeling due to hypoxia arising from obstructive apnea [73]. Effects on the cardiovascular system are also realized due to the ability of melatonin and melatonin receptor agonists to inhibit bradykinin B2 receptors, as well as dimerization of angiotensin-converting enzyme I, improving therapeutic control of blood pressure [74]. Another way of realizing the effects of melatonin is the stabilizing effect on angiotensin II receptors and ACE-B2R dimers, which increases the production of nitric oxide by endothelial cells, increasing tissue perfusion. The activation of the MT1 receptor promotes

*DOI: http://dx.doi.org/10.5772/intechopen.92656*

melatonin.

**respiratory disorders**

*Clinical Use of Melatonin in the Treatment of Sleep Disorders DOI: http://dx.doi.org/10.5772/intechopen.92656*

*Melatonin - The Hormone of Darkness and Its Therapeutic Potential and Perspectives*

night [55, 56].

**2.3 Melatonin and parasomnia**

55 years, associated mainly with the difficulty of falling asleep and the poor quality of night sleep. Ensuring physiological control of the sleep-wake cycle in children with pathology of the development of the nervous system and patients older than 55 years with insomnia is the goal of replacement therapy with melatonin, since in both groups there is a decrease in the secretion of endogenous melatonin during the

Parasomnias are undesirable physical or psychological phenomena that usually form at certain stages of sleep, causing a number of clinical manifestations, including the formation of secondary insomnia. Quite often, parasomnia, especially accompanied by motor manifestations, can lead to injuries of varying severity and the formation of psychological problems or social maladaptation [21, 57]. The most striking in its clinical manifestation is REM behavior disorder (RBD). In the treatment of this form of parasomnia, clonazepam is most successfully used. But, the use of this drug is associated with numerous side effects typical of benzodiazepines, especially if the elderly patient has sleep-related breathing disorders (SRBD). An alternative pharmacological method is the use of melatonin. Melatonin also causes a decrease in the frequency and severity of motor activity during an RBD episode, which leads to a decrease in the frequency and severity of injuries. According to the results of a few studies, the use of melatonin at a dose of 3–15 mg led to a significant reduction in paradoxical sleep without atony, as well as the severity of motor manifestations of behavior disorder in the REM phase [58]. One of the options for therapeutic treatment may be taking the drug melatonin for 5–7 days at a minimum dose of 3 mg, followed by an increase in the dose of the drug every 5–7 days to a maximum of 12 mg at night [59, 60]. Little information is available regarding the efficacy of prolonged forms of melatonin or agonists in patients with RBD. There were also no comparisons of the clinical efficacy of clonazepam and melatonin. Indeed, a number of studies demonstrate a more effective therapeutic effect with the combination of clonazepam and melatonin [61]. The potentiation of the effects of melatonin and clonazepam in the context of RBD therapy has no definitive explanation. It is believed that clonazepam reduces the phase activity inherent in paradoxical sleep, but at the same time, motor activity and minimal disturbance of behavior may remain, according to a polysomnographic survey [62]. The effect of melatonin in combination with clonazepam is due to the modulating effect of the structure of paradoxical sleep, reducing the number of transitions to other stages [59]. An alternative hypothesis explaining the effectiveness of melatonin in RBD may be its effect on increasing the effect of GABA on the GABA receptors of motor neurons of the anterior horns of the spinal cord, which leads to more intense muscle atony. Efficiency may also be related to the fact that melatonin helps to reduce the concentration of calmodulin, which affects the structure of the cytoskeleton and nicotinic acetylcholine receptors of skeletal muscles, which also leads to a progressive decrease in muscle tone [61]. The presence of a favorable safety profile makes the use of melatonin more attractive relative to clonazepam, especially in the elderly [61]. Therefore, in some few clinical trials, melatonin is used as a first-line therapy for RBD, especially in the presence of cognitive impairment, Parkinsonism, or SRBD. In the presence of minimal effectiveness of melatonin or a decrease in its effectiveness during therapy, clonazepam should be additionally prescribed. According to AASM recommendations, melatonin has a "B" level of evidence regarding its effectiveness. Doses of the drug in the studies on the basis of which these recommendations were made ranged from 8 to 12 mg; therefore, there are no

clear recommendations regarding the dose of administration [63].

**26**

There is also another class of parasomnia in the treatment of which the effectiveness of melatonin was studied. These are parasomnia associated with slow eye movement, which is defined as undesirable motor and psychophysiological manifestations that occur at the time of awakening from a slow-wave sleep. Parasomnia associated with slow eye movement is defined as undesirable motor and psychophysiological manifestations that occur at the time of awakening from a slow-wave sleep [64]. In cases of severe clinical manifestations of these forms of parasomnia, benzodiazepines (clonazepam) or antidepressants (imipramine or clomipramine) may be used. When walking in a dream, the drugs of choice are benzodiazepines or selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and imipramine [64]. The use of melatonin did not reveal a reliable therapeutic effect on the clinical manifestations of these forms of parasomnia. There are only a few studies on the use of melatonin as a first-line therapy for nightly fears in children; the first-line drug is melatonin or L-5-hydroxytryptophan [65]. The absence of a significant clinical effect is associated with the absence of a homeostatic effect on sleep in melatonin.

### **2.4 Melatonin in the treatment of complications of sleep-dependent respiratory disorders**

Sleep-dependent respiratory disorders are represented by several types of pathological conditions: Obstructive sleep apnea (OSA), central sleep apnea, sleep-related hypoventilation, and sleep-related hypoxemia disorder. Most studies are devoted to the study of melatonin metabolism in OSA. A number of studies have demonstrated impaired melatonin secretion in OSA. At the same time, it is believed that the decrease in secretion is secondary. There is also data on the relationship between the concentration of melatonin at night and the duration of night sleep, as well as body weight [66–68]. Some studies have shown a relationship between the severity of OSA and the degree of decrease in melatonin [69]. Approximately 25% of patients with OSA have an altered circadian rhythm of melatonin secretion. In patients with OSA with a maintained rhythm of secretion, peak melatonin levels at night are significantly lower than in healthy people. The 3-month treatment period with continuous positive airway pressure (CPAP) can help restore the physiological rhythm of melatonin in patients with OSA with an impaired secretion profile [70]. One of the uses of melatonin is its use as a drug that reduces the complications associated with respiratory failure during sleep. Numerous studies on biological models demonstrate the positive effect of melatonin on the unfolding pathophysiological cascade of changes in the body in the presence of sleep-dependent respiratory disorders. For example, melatonin inhibits an increase in glucose, the concentration of which increases during periods of apnea [71]. Melatonin modulation of the activity of adenosine monophosphate-activated protein kinase reduces the progression of cardiac muscle hypertrophy. Melatonin also inhibits the expression of inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-6, and cyclooxygenase-2 [72]. It also helps to reduce the severity of Ca2+ caused by impaired myocardial contractile function, thus reducing the manifestations of endothelial dysfunction.

The use of melatonin as a prophylactic helps to prevent cardiac remodeling due to hypoxia arising from obstructive apnea [73]. Effects on the cardiovascular system are also realized due to the ability of melatonin and melatonin receptor agonists to inhibit bradykinin B2 receptors, as well as dimerization of angiotensin-converting enzyme I, improving therapeutic control of blood pressure [74]. Another way of realizing the effects of melatonin is the stabilizing effect on angiotensin II receptors and ACE-B2R dimers, which increases the production of nitric oxide by endothelial cells, increasing tissue perfusion. The activation of the MT1 receptor promotes

vasoconstriction and MT2 receptor vasodilation. Thus, melatonin can act as a therapeutic agent in the treatment of cardiovascular diseases and hypertension resulting from comorbid diseases in sleep-dependent respiratory disorders. These effects of melatonin in carotid-dependent respiratory disorders were found as a result of a few studies; therefore, they do not have a sufficient recommended level.

#### **2.5 Melatonin in the treatment of hypersomnia**

Hypersomnia, such as type I and type II narcolepsy, and idiopathic hypersomnia, are diseases of which the main clinical syndrome is excessive daytime sleepiness. At the same time, drowsiness, being one of the obligate syndromes of diseases, can be modulated by sleep disturbances, observed in these patients, associated with disturbances in sleep structure, and the stability of being in a slow-wave sleep. Currently, drugs approved by FDA, for example, include methylphenidate, modafinil, oxybate, and pitolisant. Methylphenidate, being an analogue of amphetamine, blocks the transport of dopamine and norepinephrine, increasing their concentration. This drug has a fairly large number of side effects. Modaphenyl is better tolerated but may cause psychological dependence on administration [75]. Oxybate and pitolisant are well tolerated. Pitolisant is currently undergoing an expansion of indications up to 6 years of age in the treatment of types 1 and 2 narcolepsy.

Melatonin can affect the severity of hypersomnia in these patients indirectly due to the effect on the architecture of night sleep. A positive impact on the architecture of night sleep is realized by increasing the representation of paradoxical sleep. The positive effects of melatonin administration in patients with hypersomnia in Parkinson's disease have been described, slowing down the decrease in the loss of dopamine-producing neurons and contributing to the suppression of dopamine transport [76]. Presumably, one of the causes of excessive daytime sleepiness in Parkinson's disease is the decrease in the concentration of melatonin [77]. The use of melatonin in patients with neurodegenerative diseases is promising, since a number of interesting effects of melatonin exposure were obtained on biological models. For example, melatonin, freely penetrating the blood-brain barrier, activates brain-derived neurotrophic factor and cyclooxygenase-10, suppressing plasma tumor necrosis factor (TNF-alpha) and IL-10 levels. In experiments, a decrease in the number of apoptotic cells induced by phenylhydrazine was demonstrated. These studies confirm the role of melatonin in neuroprotection and protection against apoptosis in oxidative damage to neurons [78]. According to domestic guidelines for the treatment of nonmotor manifestations of Parkinson's disease, melatonin is recommended for use as a therapy for excessive daytime sleepiness [79].

### **3. Conclusion**

A decrease in the secretion of melatonin is often observed with aging and diseases of various etiologies. Inadequate sleep hygiene, namely, excessive night illumination or night work, are the most common causes of suppression of pineal melatonin production, which has a chronobiological effect on the body. A decrease in the production of melatonin in some cases can be caused by neurodegeneration, accompanied by a change in the functioning of SCN, disrupting the operation of the circadic oscillator. The most common manifestations of epiphyseal deficiency of this hormone are various functional psychopathological disorders in the form of insomnia, anxiety, or depressive disorders. The role of melatonin is currently being actively discussed in the treatment of insomnia and the sleep-wake cycle disorder. A few clinical studies demonstrate the effects in the treatment of the main

**29**

**Author details**

Samara, Russia

Alexander Zakharov\* and Elena Khivintseva

provided the original work is properly cited.

\*Address all correspondence to: zakharov1977@mail.ru

Department Neurology and Neurosurgery, Samara State Medical University,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Clinical Use of Melatonin in the Treatment of Sleep Disorders*

The authors declare no conflict of interest.

Alexander) for the opportunity to conduct scientific work.

**Notes/thanks/other declarations**

manifestations of such forms of sleep disorders as hypersomnia and parasomnia. A positive effect is noted in the correction of the pathophysiological cascade arising as a result of hypoxia against the background of sleep-dependent respiratory disorders. Thus, the numerous clinical effects of melatonin demonstrate its universal modulating effect on physiological processes in the body and some common features of the pathogenesis of pathological conditions such as insomnia and circadian

We thank Pytin Vasiliy and Poverennova Irina (Samara Medical University).

We thank the management and rector Samara Medical University (Kolsanov

*DOI: http://dx.doi.org/10.5772/intechopen.92656*

rhythm disturbances.

**Acknowledgements**

**Conflict of interest**

*Clinical Use of Melatonin in the Treatment of Sleep Disorders DOI: http://dx.doi.org/10.5772/intechopen.92656*

manifestations of such forms of sleep disorders as hypersomnia and parasomnia. A positive effect is noted in the correction of the pathophysiological cascade arising as a result of hypoxia against the background of sleep-dependent respiratory disorders. Thus, the numerous clinical effects of melatonin demonstrate its universal modulating effect on physiological processes in the body and some common features of the pathogenesis of pathological conditions such as insomnia and circadian rhythm disturbances.
