Regulatory aspects and evidences of melatonin use for sleep disorders and insomnia: an integrative review

ABSTRACT Background: Insomnia is a sleep disorder characterized by difficulty of falling asleep or maintaining sleep, which affects different age groups. Currently, melatonin is used as a therapeutic treatment in cases of insomnia in children, adults, and elderly people. Objective: To evaluate the effectiveness of melatonin in sleep disorders, its dosage, potential adverse effects, as well as labeling laws and regulations in Brazil. Methods: This integrative review was carried out using the Cochrane Library, Medline (Pubmed), and Science Direct databases. Twenty-five articles and three documents available on the Brazilian Society of Endocrinology and Metabology (SBEM) and National Health Surveillance Agency (ANVISA) websites published between 2015 and 2020 were selected to be evaluated in full. Results: It was found that in most of the selected articles the use of melatonin reduces sleep latency. The effective melatonin doses varied according to each age group, from 0.5 to 3 mg in children, 3 to 5 mg in adolescents, 1 to 5 mg in adults, and 1 to 6 mg in elderly people. Side effects are mild when taking usual doses. In Brazil, no registered drug and current regulation on the use and marketing of melatonin has been identified. Conclusion: The use of melatonin is an alternative therapy that can be used for sleeping disorders. According to the evidences found, it did not demonstrate toxicity or severe side effects, nor dependence even when administered at high doses, suggesting that it is a safe medication to treat patients of different ages suffering from sleeping disorders.


inTROdUCTiOn
Insomnia is a sleep disorder characterized by difficulty in falling asleep or maintaining sleep. It is defined as the persistent difficulty in falling and staying asleep, problems with sleep duration and maintenance and sleep quality 1 . Insomnia occurs in different age groups and can last for weeks, months, or longer periods. In these cases, it is considered as a chronic disease when it remains for three months or more and affects the individual's occupational performance and daily routine 2 . The prevalence of insomnia varies between 10 to 20% in the general population, and approximately 50% of these people live with this condition in a chronic way 3 . In China, the prevalence of insomnia is 15% 4 , followed by Spain 21.1% 5 and Brazil, reaching above 30% of the population 6,7 the gold standard for sleep assessment, this study aimed to describe the objective prevalence of insomnia in the São Paulo, Brazil, Epidemiologic Sleep Study cohort of 1,101 adults (20-80 years old. Non-pharmacological treatments can help the patient in improving symptoms, including sleep hygiene, stimulus control, relaxation techniques, among other methods 8,9 . Pharmacological treatments used to treat insomnia include selective agonists of the γ-aminobutyric acid type A (GABA-A) receptor, sedative antidepressants, melatonin and melatoninergic agonist, sedative antipsychotics, benzodiazepines, anticonvulsants, antihistamines, and herbal medicines such as Valeriana officinalis 3,8,9 . Widely used, the minor tranquilizers benzodiazepines can cause tolerance, dependence, and withdrawal syndrome, as well as being considered inappropriate for elderly people due to its high risk of accidents, including falls and concomitant fractures 3 .
Commonly known as melatonin, n-acetyl-5-methoxytryptamine is a neurohormone, a small lipophilic molecule produced by the pineal gland. Among its functions, the chronobiotic effect is associated with the regulation of the endogenous clock in relation to the photoperiod 10 . A physiological function of endogenous melatonin is to reinforce the behavior related to darkness. Its production increases about two hours before bed. In addition, during the night, melatonin is responsible for transmitting information to the brain and other organs of the central nervous system about the duration of sleep, reducing the watch signal, as well as promoting fatigue and inducing sleep 11,12 . Li et al. 13 Embase, Cochrane Library, ClinicalTrials.gov, and Web of Science reviewing exogenous melatonin as a treatment for secondary sleep disorders suggested that exogenous melatonin improves sleep quality, reduces onset latency, and increases total sleep time.
Classified as a non-prescription supplement in the United States of America, melatonin is widely used as a natural product, among all age groups, including children 14 . Research conducted with 31 supplements in Guelph, Ontario, Canada has showed low quality of melatonin formulations, with high concentration variability between samples and batches and the presence of serotonin in 8 of the evaluated supplements 15 . In Brazil, the number of medical prescriptions for the use of melatonin to treat insomnia has increased, however their commercialization is available only in compounding pharmacies. Currently, only one supplier of pharmaceutical products is authorized to distribute melatonin in Brazil, and solely to compounding pharmacies 16 . Although the use of melatonin for the treatment of insomnia have expanded in recent years, information about its potential adverse effects and drug interactions are still limited. The National Health Surveillance Agency (ANVISA) newsletter (2019) 16 reports that marketed medications must have proof of safety, efficacy, and quality in Brazil, but due to an injunction that allows the sale of raw materials, melatonin is available overthe-counter 17 . Moreover, the Brazilian Sleep Society considers that the use of melatonin to treat circadian rhythm disorders is already established, but the results for insomnia are not consistent, despite some positive results in specific populations and a good tolerability and safety profile, with few side effects 18 .
These results demonstrate the need for greater control over the production and marketing of melatonin supplements. It is necessary to build and develop a more effective health care and identify the best practices for health professional bodies, especially prescribers and pharmacists who work directly in the prescription and provision of this medication to patients. In this perspective, this study aimed to evaluate the effectiveness of melatonin for sleep disorders and melatonin associated symptoms, dosage, potential adverse effects, as well as the law regulations of the drug in Brazil.

MeTHOdS
This article is an integrative review in which the six methodological steps described by Mendes, Silveira and Galvão 19 were followed: (i) identification of the theme and selection of the research question to carry out the integrative review; (ii) establishment of criteria for inclusion and exclusion of studies; (iii) definition of the information to be extracted from the selected studies; (iv) evaluation of studies included in the integrative review; (v) interpretation of results; and (vi) presentation of the review.
Data collection was performed using Cochrane Library, Medline (Pubmed), and Science Direct databases. To perform the searches, Health Sciences Descriptors (Decs) were used in Portuguese and English, and the articles were selected according to the objective of the project and including the following key words: melatonin, pineal gland, sleep disorders, and insomnia. In addition, for the regulatory aspects, the Brazilian Society of Endocrinology and Metabology (SBEM) and the ANVISA websites were accessed using the descriptor "melatonin". Fifty-six documents were found using the SBEM and two documents were selected to be evaluate in full. Thirty-four documents were identified using the ANVISA website and one document was selected to be assessed in full.
The article search using the databases was based on the following criteria: articles published between 2015 and 2020, in Portuguese or English. Articles that were not in the defined languages, did not have any descriptors of interest, or that were outside the defined publication period were excluded. Reviews, meta-analysis, cohort studies, and randomized clinical trials were selected.
For the selection of articles, an initial search based on title and abstract was carried out in the database. Then, a new selection was made with the reading of the articles in full, according to the Figure 1.  Total of selected articles = 25 1 st Phase: Guiding Question "What are the scientific evidences regarding the use of Melatonin for sleeping disorders?"

ReSULTS
The final selection consisted of 25 articles and three documents identified in the Brazilian websites. Table 1 summarizes the characteristics of the articles according to authors, year of publication, and database of publication.
No articles were identified reporting the current regulations of melatonin in Brazil. The only information found was that the commercialization of melatonin is authorized only for compounding pharmacies, and must be purchased from the Active Pharmaceutica ® supplier 16,17 . Similarly, no drug is registered with melatonin as the active ingredient. However, in Europe, a medicine registered under the trade name of Circadin ® is available in the market. Table 2 shows the characteristics of the selected articles according to the study design, population, dosage, intervention evaluation, therapeutic and adverse effects of melatonin. Of the 25 studies found, 22 showed positive results regarding the use of melatonin in insomnia disorders and three studies showed ineffective or inconclusive results.

diSCUSSiOn
The term circadian is derived from the Latin term circa diem, which means around one day. Circadian rhythms are endogenous oscillations that occur over a 24-hour period. In humans, this cycle lasts an average of 24.2 hours with individual variation of 23.7 to 25.3 hours. The waking and sleeping process is strongly influenced by the circadian system 24 .
Currently approved by the Food and Drug Administration (FDA) for the treatment of sleep disorders in elderly people 35 , melatonin has been used for delayed insomnia, sleepwake cycle with periods shorter than 24 hours, sleep correction in the elderly, as an adjuvant in the treatment of autism spectrum disorder, attention deficit hyperactivity syndrome, migraine, anesthesia, metabolic diseases, and polycystic ovary syndrome 28 . The synthetically produced melatonin can be administered exogenously and there are immediate and sustained release formulations available on the market.
Malow and collaborators 42 report that melatonin is effective for sleep disorders in children and adolescents (2-17.5 years) with autism spectrum disorder and insomnia. According to the authors, there was an improvement in sleep quality with no changes in weight, height, body mass index, and pubertal status, and no evidence of developmental delays. Nunes et al. 7 recommend doses of 0.5 to 3 mg for children and 3 to 5 mg for adolescents. Chang et al. 27 suggest that melatonin supplementation is a relatively safe and effective way to improve sleep-onset in addition to decreasing the severity of symptoms of atopic dermatitis in children, due to melatonin immunomodulatory, anti-inflammatory, and antioxidant effects, thus improving the skin and helping to maintain the epidermal barrier.
The review demonstrated that the use of melatonin is effective to treat primary and secondary insomnia at different stages of life, from children and teenagers to adults and the elderly. There was also a great diversity in the variables investigated, especially regarding the dose, time of use, and sleep outcomes. Despite of some biases, most studies demonstrated that the use of melatonin for sleep disorders is efficient and safe. Table 3 shows the dosages of melatonin indicated for each age group according to the publications found.
As for the use in elderly people, Culpepper et al. 21 report that prolonged-release melatonin formulations are effective in symptoms associated with sleep-onset, however the effects may be limited to individuals over 55 years old who suffer from insomnia. Quera-Salva et al. 33 evaluated a dose of 2 mg of melatonin administered once a day for three months.
The authors found that Circadin ® is well tolerated, has no rebound, withdrawal or hangover effects, in addition to not causing drug interactions with antihypertensive, antidiabetic, hypolipidemic or anti-inflammatory drugs, which are the drugs most used by elderly people.
No evidence was found that the use of melatonin (up to 10 mg) assists in sleep disorders in patients with moderate to severe dementia due to Alzheimer's disease. The doses There is no evidence that it helped with sleep disorders in patients with moderate to severe dementia due to Alzheimer's disease. To assess whether melatonin improves physical and psychological results.
3 and 10 mg. Orally or enterally for a minimum of two days or until discharge from the ICU. Sleep quantity and quality, measured by polysomnography, actigraphy, bispectral index or electroencephalogram.
Insufficient evidence was found to determine whether administration would improve the quality and quantity of sleep in ICU patients. Sparse data and differences were found in the study methodology, in the ICU sedation protocols, and in the methods used to measure and report sleep. There was a statistically significant improvement in latency and total sleep time, with a lack of consensus on whether these are clinically significant. of melatonin used in these studies were equal to or higher than the doses indicated for healthy elderly people, however, the doses were lower compared to those used or studied in populations without dementia. Several different mechanisms are likely to cause sleep disorders in patients suffering from dementia, some of which may be related to circadian misalignment. Achieving full melatonin's chronobiotic effect in these circumstances can take several months. Therefore, it is possible that some patients respond after longer periods of treatment with melatonin 25 .
Overall, no significant adverse effects were reported in most studies; however, Besag et al. 38 reported that daytime drowsiness and headache are among the most frequent related side effects. Similarly, Maras et al. 32 stated that after 52 weeks of use of melatonin the most frequent treatmentrelated adverse events observed were fatigue and mood swings. Additionally, Myers et al. 35 in a randomized clinical study, reported that a patient had an increased serum level (within the toxic range) of valproate while using melatonin concomitantly. According to the authors, clinicians must ponder possible interactions of melatonin with antiepileptic drugs. Since melatonin is also metabolized by cytochrome P450 enzymes (CYP1A2, CYP1A1, and CYP2C19), the concomitant use of melatonin with antiepileptic and antidepressant drugs can potentially cause drug interaction. Consequently, the metabolism may be reduced leading to longer drug action time, which can cause severe sedation 35 .
A formulation containing melatonin, vitamin B6, California poppy extract, passion fruit extract, and lemon balm extract was tested on patients of both genders between 20 and 75 years old who had moderate insomnia. There was a statistically significant improvement in sleep quality during the two-week treatment period with no serious adverse events being reported, suggesting that this combination of assets is beneficial for mild to moderate insomnia 40 .
As for the doses, 0.1 to 0.5 mg is recommended for sleeprelated rhythmic movement disorder, 1 to 5 mg for sleep disorders, and 3 to 10 mg for neurological diseases. These recommended doses should be taken daily, in a single dose at night, one hour before the usual bedtime. However, there is no established minimum or maximum effective dose for each use 29 . Among the advantages of melatonin described in the included studies are its favorable safety profile, good toleration, and no addiction potential when administered for long periods 26 . The adverse reactions commonly found in the reviewed studies included headache, nasopharyngitis, back pain, arthralgia, nausea, dizziness, and restlessness 20,24 . Additionally, melatonin may have advantages attributed to its anxiolytic and hypnotic effects, and low toxicity levels, as reported by Madsen et al. 30 while investigating the melatonin toxicity in patients with depressive, anxiety, and sleep disorder symptoms.
In Europe, the drug Circadin ® , which has a prolonged release formulation containing 2 mg of melatonin, has been marketed since 2008 as an innovative treatment for primary insomnia in patients aged 55 years and older who have sleep disorders characterized by poor quality of sleep 20 . As a food supplement, it has not been evaluated or approved by the United States FDA to prevent or treat any diseases 24 .
In Brazil, there is no registration of drugs with melatonin as the active ingredient, therefore, its sale is prohibited in drugstores and national websites. Although melatonin is used in some countries as an ingredient in food supplements, this substance is not authorized for use in food supplements in Brazil. Additionally, according to the rules of Ordinance SVS / MS nº 344/1998, melatonin is not an asset subject to special control, however, its commercialization is restricted to compounding pharmacists which must acquire the product from the company Active Pharmaceutica, have operation authorization granted by the ANVISA, and follow the current guidelines of Good Handling Practices. Additionally, prescription from a legally qualified professional is required, and the prescription must contain the composition, the pharmaceutical form, the dosage, and directions for use.
In this context, it is up to health professional bodies, especially doctors and pharmacists, to provide counseling to ensure the maintenance of therapy, symptom relief, functional changes, and assessment of potential adverse effects and drug interactions. These professionals must act in a multidisciplinary way, taking into account the benefit of reducing the use of benzodiazepine drugs, which can cause dependence, abuse, and contribute to higher costs of public resources resulting from the irrational use of medicines. Doctors and pharmacists can work together and offer the patient nonpharmacological and pharmacological treatments with the use of alternative, safe, and effective drugs such as melatonin.
In conclusion, it is evident from the identified studies that melatonin can be used in specific dosages according to age for sleep disorders, jet lag, insomnia in children with neurological disorders. Exogenous melatonin has emerged as an alternative therapy that can be used in sleep disorders. According to the evidence found, melatonin has not demonstrated toxicity or severe adverse effects, nor dependence even at high doses, demonstrating that its use is safe for treating young and elderly patients. However, despite the findings discussed, further investigations are needed in order to assess the dosages required for each age group, as well as dosages' safety profile.
Currently, no melatonin drug has been approved for use by regulatory bodies or legislation in Brazil, and the available information only determines the pharmaceutical form, excipient substance, and general guidelines for melatonin handling. Guidelines addressing the accurate use of melatonin to support clinicians and pharmacists in the treatment decision-making for sleep disorders is required. In addition, as melatonin is a relatively new drug, pharmacovigilance is essential, as it is up to health professionals to report any adverse events to the authorities.