Aspectos regulatórios e evidências do uso de melatonina em distúrbio do sono e insônia: uma revisão integrativa

Ana Paula Rosinski BUENO1, Flávia Medeiros SAVI2, Izabel Almeida ALVES3, Vanessa Adelina Casali BANDEIRA1

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.

Keywords: Melatonin; Sleep Wake Disorders; Pineal Gland.

Antecedentes: Insônia é um distúrbio do sono caracterizado por dificuldade de iniciar e manter o sono, afetando diferentes faixas etárias. Atualmente, a melatonina é utilizada no tratamento de insônia em crianças, adultos e idosos. Objetivo: Avaliar a eficácia da melatonina nos distúrbios do sono, posologia e potenciais efeitos adversos, bem como a regulamentação vigente no Brasil. Métodos: Trata-se de uma revisão integrativa, os artigos foram identificados nas bases de dados Cochrane Library, Medline (Pubmed) e Science Direct, totalizando 25 artigos, e foram selecionados três materiais disponíveis no site da Sociedade Brasileira de Endocrinologia e Metabologia e Agência Nacional de Vigilância Sanitária, publicados entre 2015 e 2020. Resultados: Verificou-se na maioria dos artigos selecionados que a melatonina reduz a latência do sono. Quanto as dosagens de melatonina identificou-se variação em cada faixa etária, para crianças de 0,5 a 3mg; adolescentes de 3 a 5mg; adultos de 1 a 5mg e idosos 1 mg a 6 mg demostraram serem eficazes. Em doses habituais os efeitos colaterais são leves. No Brasil, não foi identificado medicamento registrado e regulamentação vigente sobre o uso e comercialização de melatonina. Conclusão: A utilização da melatonina é uma alternativa que pode ser utilizada em distúrbios do sono. De acordo com as evidências encontradas, não demonstrou toxicidade ou efeitos colaterais severos, nem dependência mesmo em doses elevadas, sendo, portanto, segura para tratamento de pacientes desde crianças a idosos que sofrem de distúrbios do sono.

Palavras-chave: Melatonina; Transtornos do Sono-Vigília; Glândula pineal.

Universidade Regional do Noroeste do Estado do Rio Grande do Sul, Departamento de Ciências da Vida, Ijuí RS, Brazil. 2Queensland University of Technology, Centre in Regenerative Medicine, Institute of Health and Biomedical Innovation, Kelvin Grove, Australia. 3Universidade Federal da Bahia, Faculdade de Farmácia, Departamento do Medicamento, Salvador BA, Brazil.

APRBhttps://orcid.org/0000-0002-3227-1492; FMShttps://orcid.org/0000-0003-0067-8308; IAAhttps://orcid.org/0000-0002-8935-6542; VACBhttps://orcid.org/0000-0002-6888-1532

Correspondence: Vanessa Adelina Casali Bandeira; Email: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contribution: APRB, IAA, VACB: contributed to the conception and design of the research project, data collection, data analysis and interpretation and writing of the article; FMS: contributed to the interpretation and editing of the article. Received on August 05, 2020; Received in its final form on December 20, 2020; Accepted on December 22, 2020.

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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 quality1. 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 routine2. 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 way3. In China, the prevalence of insomnia is 15%4, followed by Spain 21.1%5 and Brazil, reaching above 30% of the population6,7the 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 methods8,9. 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 officinalis3,8,9. 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 fractures3.

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 photoperiod10. 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 sleep11,12. Li et al.13Embase, 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 children14. 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 supplements15. 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 pharmacies16. 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-counter17. 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 effects18.

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.

This article is an integrative review in which the six methodological steps described by Mendes, Silveira and Galvão19 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.

Figure 1. Summary of the article selection process.

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® supplier16,17. 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.

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 system24.

Currently approved by the Food and Drug Administration (FDA) for the treatment of sleep disorders in elderly people35, 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 syndrome28. The synthetically produced melatonin can be administered exogenously and there are immediate and sustained release formulations available on the market.

Malow and collaborators42 report that melatonin is effective for sleep disorders in children and adolescents

Table 1. Distribution of references included in the study, according to the authors, year of publication, database and journal.

Authors Year Data base Periodic Hajak & Zisapel20 2015 PUBMED International clinical psychopharmacology Culpepper & Wingertzahn21 2015 PUBMED Prim Care Companion CNS Disord Wright et al.22 2015 SCIENCE DIRECT Drugs & Aging Foley & Steel23 2015 SCIENCE DIRECT Complementary Therapies in Medicine Williams et al.24 2016 PUBMED Pharmacotherapy Mccleery & Sharpley25 2016 COCHRANE LIBRARY Cochrane Database of Systematic Reviews Cardinali et al.26 2016 SCIENCE DIRECT Pharmacological Research Chang et al.27 2016 PUBMED JAMA pediatrics. Hohl et al.28 2016 SITE SBEM SITE SBEM Sociedade Brasileira de Endocrinologia e Metabologia29

2016 SITE SBEM SITE SBEM

Auld et al.11 2017 PUBMED Sleep Medicine Reviews Madsen et al.30 2017 PUBMED Trials journal Riemann et al.9 2017 PUBMED European Sleep Research Society Abdelgadir et al.31 2018 PUBMED Archives of Disease Childhood Maras et al.32 2018 PUBMED Journal Of Child And Adolescent Psychopharmacology Quera-Salva & Claustrat33 2018 PUBMED Encephale Zwart et al.34 2018 PUBMED Healthcare Myers et al.35 2018 PUBMED Journal of clinical sleep medicine Sletten et al.36 2018 PUBMED Public Library of Science Lewis et al.37 2018 COCHRANE LIBRARY Cochrane Database of Systematic Reviews Anvisa16 2019 SITE ANVISA SITE ANVISA Besag et al.38 2019 PUDMED CNS Drugs Schroder et al.39 2019 PUDMED Journal of autism and developmental disorders Lemoine; Bablon & Silva40 2019 PUBMED Complementary therapies in medicine Seiden & Shah41 2019 PUBMED Prim Care Companion CNS Disord Li et al.13 2019 PUBMED Frontiers in neuroendocrinology

Journal of the American Academy of Child & Adolescent Psychiatry

Malow et al.42 2020 SCIENCE DIRECT

Low, Choo & Tan43 2020 SCIENCE DIRECT Journal of Psychiatric Research

(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

Table 2.Effects of melatonin in insomnia.

AuthorsStudy typePopulationAimsPosologyEvaluation of the interventionEffects of melatonin in insomnia

regular to good or very good. No serious adverse

and morning alertness had improved to at least

75% of patients reported that sleep quality

effects have been reported.

change (decrease) of at least one point from

good, 2 = good, 3 = regular, 4 = poor and 5 =

very poor. Morning alertness was classified

Improvement or worsening of sleep quality

as 1 = fully alert, 2 = alert, 3 = regular, 4 =

Sleep quality was classified as 1 = very

or morning alertness was defined as a

tired and 5 = very tired.

the baseline.

2 hours before sleep

3 weeks

.rebound from Circadin® 2 mg

for

interruption, withdrawal and

women) To investigate the effects of

(210 men and 387

cohort study 597 patients

Zisapel20 Prospective

Hajak &

favorable tolerability profile, but the effects may

be limited to individuals over 55 years old with

associated with onset of sleep and shows a

It appears to be effective for symptoms

insomnia.

Primary: sleep latency actigraphy, sleep

Secondary: sleep diary, awakenings,

time, awakenings, sleep efficiency

alertness.

5 mg daily for 8

2 mg daily for 3

weeks

weeks

years old To investigate the level of evidence

counter agents: diphenhydramine,

that supports the use of over-the-

valerian for occasional sleep

doxylamine, melatonin and

disorders or insomnia.

review 1344 patients aged 55

Wingertzahn21 Systematic

Culpepper &

4 -18 weeks Pittsburgh sleep quality score.The effect of melatonin on sleep quality was

inconsistent.

2 to 5 mg once a day

before bed

melatonin on sleep quality in this

placebo on discontinuation of

benzodiazepines, in addition

to determining the effect of

old To determine the effect of

melatonin compared to

population.

mean age of 64 years

meta-analysis 322 patients with a

SystematicWright et al.22

review and

Supplementation appears to be relatively safe.

Adverse events are generally minor.

Simulated driving task, sedation scale and

Hematology, electrolytes, urinalysis,

Selection of cognitive, psychomotor,

dexterity and memory recall tasks.

old Questionnaire applied weekly.

Holter monitoring 24 hours by

physical examination.

radioimmunoassay.

electrocardiogram.

Period: 3 to 5 years

of melatonin. 2 to 10 mg

evidence on the safety of oral use

To explore the available clinical

years old; 50 to 85 years

chronic sleep problems,

3 to 16 years old with

old with Alzheimer’s,

16-25 years old with

review Patients from 1 to 8

autism and sleep

disorders

Foley & SteelSystematic23

bioavailability 15%, T 1/2, average 3.5-4.0 hours,

and duration of naps. Adverse reactions: headache, nasopharyngitis,

back pain, arthralgia, and potential for hepatic

T max, interval, hours 0.75–3.0. In vitro protein

binding: ~ 60%, mainly for albumin,1- acidα

glycoprotein and high-density lipoprotein.

metabolism interaction with other drugs

Pharmacokinetic parameters: Absolute

for up to 13 weeks Sleep latency, sleep onset time, number

2 mg day, 1 - 2 hours

before bed

disorders in patients with moderate to severe

sleep to night sleep. There is no evidence that it helped with sleep

dementia due to Alzheimer’s disease.

8 to 10 weeks Total night sleep time, proportion of day

Up to 10 mg

and pharmacodynamic properties

release melatonin and ramelteon,

years old To compare the pharmacokinetic

pharmacological properties on

of agomelatine, prolonged

to examine the impact of

clinical efficacy.

et al.24 ReviewPatients older than 55

Williams

effects, compared to placebo for

sleep disorders in people with

review 222 patientsTo evaluate common adverse

dementia.

Sharpley25 Systematic

Mccleery &

Table 2.Cont.

some studies, has been administered to patients

polysomnography. It has a very safe profile, is well tolerated and, in

in very large doses and for long periods, without

treated with benzodiazepines discontinue use

dependence on benzodiazepine medications.

any potential for drug abuse. Several studies

may become the therapy of choice to reduce

have found that more than 50% of patients

AuthorsStudy typePopulationAimsPosologyEvaluation of the interventionEffects of melatonin in insomnia

after treatment with melatonin. Melatonin

wakefulness filled in by patients, and

1 day - 18 months Daily records of sleep and quality of

1 mg, 2 mg, 3 mg, 5

mg, 10 mg

benzodiazepine drugs in patients

years old To discuss the available data on

the effectiveness of melatonin

to reduce chronic use of

with insomnia.

et al.26 ReviewPatients aged 20 to 90

Cardinali

effective way to improve sleep onset latency

and disease severity in children with Atopic

Melatonin supplementation is a safe and

Dermatitis.

and dermatitis, sleep variables measured

levels of 6-sulfatoxymelatonin and serum

by polysomnography, nocturnal urinary

for 4 weeks Actigraphy, subjective change in sleep

immunoglobulin levels.

3 mg or placebo daily

disease severity in children with

to improve sleep disorders and

of melatonin supplementation

To evaluate the effectiveness

Atopic Dermatitis.

years old with attention

adolescents of 1 to 18

73 children and

deficit.

double-blind,

et al.27 Randomized,

clinical trial.

controlled

placebo-

Chang

patients with primary insomnia. Treating delayed

Reduction in the time to fall asleep between the

improvement in sleep onset latency compared

effect on sleep onset latency for melatonin in

demonstrated an overall significant

sleep phase syndrome

with placebo.

delayed sleep phase syndrome, non 24

patients and REM-behaviour disorder

weeks Sleep parameters: primary insomnia,

hours sleep wake syndrome in blind

0.1 a 10mg for five

well as its proven anxiolytic and hypnotic effects.

measured by visual scales. It may have advantages due to its low toxicity, as

12 weeks. Actigraphy, Pittsburgh sleep diary, pain,

anxiety, fatigue and general well-being

25 mg for

clinical point of view. It has been regarded as a

quality. However, the effects were small from a

Reduces sleep onset latency, improves sleep

safe medicine.

12 weeks Sleep parameters: objective and subjective,

number of awakenings, sleep efficiency;

sleep onset latency; total sleep time,

awakenings after sleep onset.

0.3 - 40 mg

exogenous melatonin in treating

for the therapeutic effects of

80 years old To assess the evidence base

primary sleep disorders

meta-analysis 1500 patients of 18 and

et al.11 Systematic

review and

Auld

melatonin has a preventive effect

circadian disorders after Acute

on depression, depressive and

anxiety symptoms, sleep and

prophylactic treatment with

240 patientsTo investigate whether

Coronary Syndrome.

double-blind,

et al.30 Randomized,

clinical trial.

controlled

placebo-

Madsen

management of adult patients

recommendations for the

4099 patients To provide clinical

with insomnia.

Guideline Different populations

with insomnia.

et al.9 Clinical

Riemann

disorders, with few adverse events related

and sleep onset latency in children with

Melatonin improves total sleep time

neurodevelopmental

1. 0.1 – 12mg
2. 1 a 13 weeks Sleep parameters: total sleep time, sleep

awakening, adverse events and child´s

onset latency, frequency of nocturnal

behaviour

neurodevelopmental disorders

melatonin as therapy for sleep

To determine the efficacy and

problems in children with

safety of

neurodevelopmental

meta-analysis 682 children aged

<18 years with

disorders

et al.31 Systematic

review and

Abdelgadir

1. Table 2.Cont.

most frequent treatment-related adverse events

randomized group. The drug was generally safe;

asleep 48.6 minutes faster (p <0.001), had 89.1

quality compared with baseline and placebo-

minutes longer uninterrupted sleep episodes

AuthorsStudy typePopulationAimsPosologyEvaluation of the interventionEffects of melatonin in insomnia

e less nightly awakenings and better sleep

subjects slept 62.08 minutes longer, fell

After 52 weeks of continuous treatment

were fatigue and mood swings.

caregiver’s Pittsburgh Sleep Quality Index,

and 52 weeks Sleep parameters: Sleep and Nap Diary,

Composite Sleep Disturbance Index,

Scale, and quality of life

Epworth Sleepiness

2.5 a 10mg for 13, 39

pediatric-appropriate prolonged-

optimal daily dose and impact of

long-term efficacy and safety of

sleepiness, and quality of life.

caregivers’ sleep, daytime

release melatonin at the

the treatment on

To describe

years old with Autism

Spectrum Disorder.

between 2 to 17.5

95 patients aged

et al.32 A prospective

double-blind

randomized

controlled

placebo-

Maras

antidiabetic, lipid-lowering or anti-inflammatory

in concomitant therapy with antihypertensive,

hangover effect, and without safety concerns

Benefits: improvement in sleep quality and

latency, alertness the next day, and quality

of life. Absence of rebound, abstinence or

drugs.

score upon awakening and improvement in

the falling asleep score, performance the

2 mg for 3 monthsSleep quality, sleep latency assessed by

next morning assessed by the behavior

quality of life.

physiological and pharmacological

effects of melatonin related to

55 years old or older. To provide data on the

sleep.

& Claustra33 ReviewInsomnia patients aged

Quera-Salva

an average of 7.1 years of treatment. The results

of children with chronic insomnia in early sleep

treated with melatonin will have normal sleep

of this study indicate that approximately 75%

Long-term therapy appeared to be safe after

quality without medication ten years later.

medications and daytime dysfunction. Each

efficiency, sleep disorders, use of sleeping

treatment 7.1 years. Pittsburgh Sleep Quality Index, subjective

sleep quality, sleep duration, usual sleep

item is weighted on a scale of 0 to 3.

Average duration of

0.5 - 5 mg

discontinuing the use of melatonin.

adverse events and the reasons for

and the real quality of sleep. To

et al.34 Cohort study69 childrenTo assess the discontinuity of

investigate the occurrence of

melatonin therapy, the time

atZw

No significant adverse events were reported by

was that melatonin is very beneficial in some

significant difference in total sleep time, the

overall impression from the parents’ report

Although the double-blind study found no

caregivers.

patients.

weeks. Actigraphy, average sleep latency, average

caregiver’s impression of clinical change

sleep efficiency, frequency of seizures,

and adverse events.

6 mg 30 minutes

before bed for 2

subjective quality of sleep, daytime function, and

DSWPD with confirmed circadian misalignment,

effective and safe treatment for patients with

0.5 mg for 4 weeks.Sleep onset time, sleep efficiency.Short-term and casual administration is an

resulting in improvements in objective and

severity of clinical symptoms.

patients with Dravet’s Syndrome.

treatment of sleep disorders in

and safety of melatonin in the

old. To investigate the efficacy

between 2 to 50 years

13 patients aged

melatonin in patients with Delayed

Sleep-Wake Phase Disorder

old of both genders. To test the effectiveness of

(DSWPD)

average age of 29 years

116 patients with an

double-blind,

et al.35 Randomized,

clinical trial.

controlled

placebo-

Myers

double-blind,

et al.36 Randomized,

clinical trial.

controlled

placebo-

Sletten

protocols, and in the methods used to measure

index or electroencephalogram. Insufficient evidence was found to determine

quality and quantity of sleep in ICU patients.

the study methodology, in the ICU sedation

whether administration would improve the

Sparse data and differences were found in

and report sleep.

polysomnography, actigraphy, bispectral

Sleep quantity and quality, measured by

discharge from the

Orally or enterally

for a minimum of

two days or until

3 and 10 mg.

ICU.

To assess whether the quantity

melatonin to adults in the ICU.

To assess whether melatonin

and quality of sleep can be

improved by administering

improves physical and

psychological results.

16 admitted to the

intensive care unit

review 151 patients, with

(ICU).

et al.37 Systematic

Lewis

Table 2.Cont.

were daytime sleepiness and headache. There is

short term, the most frequent adverse effects

associated with the use of melatonin in the

AuthorsStudy typePopulationAimsPosologyEvaluation of the interventionEffects of melatonin in insomnia

short and long term. There were no serious adverse effects

scarcity of data with long-term use.

effects with the use of melatonin in the

1. 0.15 - 12 mg/day for
2. 1 to 29 weeks To evaluate the occurrence of adverse

old To assess the evidence for adverse

events associated with short-term

and longer-term treatment for

sleep disorders

between 1 and 93 years

review 1625 participants

et al.38 Systematic

Besag

children and adolescents. The prolonged-release

Epworth Sleepiness Scale. The treatment improved externalizing behaviors

formulation was effective in improving sleep

initiation and maintenance, as well as being

(hyperactivity-inattention and conduct) in

safe.

3-5 mg for 13 weeks.World Health Organization Welfare Index,

Pittsburgh Sleep Quality Index and the

mini-pills in improving the duration

To evaluate the efficacy and safety

with Autism Spectrum Disorder or

of prolonged release melatonin

and onset of sleep in patients

Smith-Magenis syndrome.

with Autism Spectrum

125 individuals aged

Magenis syndrome.

Disorder or Smith-

2 to 17.5 years old

et al.39 Double-blind

clinical trial.

controlled

placebo-

Schroder

daytime parameters related to sleep. No serious

latency of sleep onset, total sleep duration and

There was an improvement in sleep quality,

adverse events have been reported.

number of daytime naps and their duration,

Total sleep duration, sleep onset latency,

assessed by participants in their sleep

daytime fatigue was also subjectively

number of nightmares per night and

diary.

consideration as a therapy for sleeping disorder.

Improves the quality of sleep of secondary sleep

delivery and therefore an important potential

The formulation demonstrated rapid release

and then continuous release and absorption

significant advance in the pharmacokinetic

of melatonin for up to 7 hours, making it a

release profile of exogenous melatonin

disorders.

For each individual, the melatonin plasma

maximum time and threshold (time above

calculate the following pharmacokinetic

parameters: maximum concentration,

concentration time data was used to

the target threshold concentration).

of lemon balm for 14

fruit extract; 240 mg

1 mg of melatonin;

150 mg of passion

0.42mg of vitamin

California Poppy;

B6; 8.4 mg of

days.

the clinic, included

5 mg. The subjects

standard ambient

were confined to

and exposure to

blood collection

daytime dosing,

light, to prevent

production of

endogenous

melatonin.

significant

combination of melatonin, vitamin

patients with mild to moderate

years old. To investigate the effect of a

B6 and medicinal plants in

sleep disorders.

between 20 and 75

Study 40 participants

& Silva40 Prospective

Lemoine;

Bablon

and absorption (CRA-melatonin) in

immediate release (IR-melatonin).

comparison with the melatonin of

18 and 40 years old. To evaluate the pharmacokinetic

melatonin of continuous release

and safety profile of a new

women aged between

clinical trial 10 patients, 4 men, 6

& Shah41 Randomized

Seiden

sleep efficiency. Improves the quality of sleep of secondary sleep

disorders.

days. Sleep onset latency, total sleep time and

treatment of sleep disorders. 3 - 6 mg for 3 to 9

29 and 41 years old. To determine the effectiveness of

melatonin versus placebo in the

meta-analysis. 205 patients between

et al.13 Systematic

review and

Li

It is safe and effective for long-term treatment

spectrum disorder and insomnia. There were

no detrimental effects on children’s pubertal

growth and development and no abstinence

in children and adolescents with autism

or safety problems related to the use or

discontinuation of the medication.

induction, waking up at night, resettlement,

during the one-year study period using the

month (six habits: sitting at bedtime, sleep

participant’s sleep habits in the previous

scores the frequency and duration of the

Compound Sleep Disorders Index, which

Infant sleep was assessed at each visit

time of wake up, and early sleep.

intake for up to 104

withdrawal effects.

weeks, followed by

a 2-week placebo

period to assess

2, 5, 10 mg daily

with a lack of consensus on whether these are

improvement in latency and total sleep time,

awakenings, day to night sleep ratio. There was a statistically significant

clinically significant.

3 days to 6 months Actigraphy, waking time during sleep,

0.3 - 75 mg,

treatment appropriate for children

on sleep, growth, body mass index

of prolonged-release melatonin

To report the long-term effects

and pubertal development.

between 2 – 17.5 years

adolescents aged

80 children and

old.

et al.42 Double-blind

clinical trial.

controlled

placebo-

Malow

effectiveness of melatonin and

systematic reviews and meta-

melatonin agonists in primary

analyzes that investigate the

18 - 65 years old. To summarize all available

insomnia disorders.

review Patients aged

& Tan43 Systematic

Low, Choo

CRA-melatonin: melatonin of continuous release and absorption; DSWPD: Delayed Sleep-Wake Phase Disorder; ICU: Intensive Care Unit; IR-melatonin: melatonin of immediate release

1. Table 3. Melatonin dosages according to selected articles. Population Daily dose Children 0.1mg – 3mg Teenagers 3mg – 12mg Adults 1mg – 25 mg Elderly 1mg – 6mg

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 melatonin25.

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 sedation35.

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 insomnia40.

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 use29. 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 periods26. The adverse reactions commonly found in the reviewed studies included headache, nasopharyngitis, back

pain, arthralgia, nausea, dizziness, and restlessness20,24. 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 sleep20. As a food supplement, it has not been evaluated or approved by the United States FDA to prevent or treat any diseases24.

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.

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