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Keywords: Sleep disorder is common in children and adolescents, particularly in those with attention deficit hyperactivity
Children and adolescents disorder (ADHD) or autism spectrum disorder (ASD). While non-pharmacological treatment is first line, occa
Drug utilization sionally an add-on of an oral drug is needed. The endogenous hormone melatonin is increasingly used for sleep
Melatonin
disorders in children and adolescents. In this registry-based cohort study we follow dispensation of melatonin in
Sleep disorder
young individuals, 0–25 years of age, in Stockholm, Sweden during 2016–2019.
In all 9980 individuals, were dispensed melatonin in 2016 and followed for 3 years. Child psychiatrist was the
most common prescribing specialty, 55% of all prescriptions. Only 20% had a recorded diagnosis of sleep dis
order. The majority, 65% had a neuro psychiatric diagnose. Half of the individuals had at least 4 prescribed drugs
dispensed during the follow-up. Almost half of our cohort were dispensed melatonin during the entire study
period and doses and volumes of drug dispensed increased by 50 and 100%, respectively. Continuous medication
was most common among children 6–12 years, where 7 out of 10 individuals were still adherent after three years.
As long-term safety data is lacking, we find this concerning, and this illustrates the need of long-term follow-up of
melatonin use in children and young individuals.
* Corresponding author. Department of Clinical Science and Education, Södersjukhuset S1 KI SÖS Pediatrik Kull, 118 83, Stockholm, Sweden.
E-mail address: elin.dahlen@ki.se (E. Dahlén).
https://doi.org/10.1016/j.ejpn.2022.05.007
Received 23 December 2021; Received in revised form 8 March 2022; Accepted 22 May 2022
Available online 25 May 2022
1090-3798/© 2022 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
K. Tedroff et al. European Journal of Paediatric Neurology 39 (2022) 30–34
Nevertheless, in Sweden, UK, and other high-income countries, the 3.1. Statistical analysis
use of melatonin has seen an explosive increase in pediatric use during
the last years [12–14]. Descriptive statistics including frequencies and proportions was used
Between 2014 and 2017 in Stockholm, Sweden, our preliminary to describe the study population. A t-test was used to calculate differ
investigation identified a steep increase in numbers of children having ences between groups and a significance level of 0.05 was applied. The
melatonin dispensed and in the dispensed doses. This is concerning, as median number of DDDs per individual was calculated as well as the min
evidence for treating sleep problems in children with melatonin is and max of DDDs dispensed.
limited and long-term safety data is lacking. Adherence to melatonin was measured as a refill of a prescription
within 12 months i.e., melatonin dispensed at least two times within 12
2. Aim months for the same individual.
The overall aim was to assess the drug utilization of melatonin in 4. Results
children and young adults including adherence to medication, comor
bidity and the prescribing specialists in Stockholm, Sweden during In total, 9980 individuals 0–25 years were dispensed at least one
2016–2019. prescription of melatonin in 2016 i.e., the study population (Fig. 1).
Among them, 5454 were males and 4526 were females.
3. Materials and methods The prevalence of dispensed melatonin in 2016 was 1.4%, 1.5%
among males and 1.3% among females (Table 1). Across the different
This is a registry-based cohort study of all children and young adults age categories, the prevalence was 0.2% in preschoolers 0–5 years, 1.4%
in Region Stockholm (an urban area with a population of 2 267 970 in school children 6–12 years, 3.4% among adolescents 13–17 years, and
individuals in 2016). All individuals 0–25 years of age with at least one 1.2% among young adults 18–25 years.
prescription of melatonin (ATC-code N05CH01) dispensed in 2016 were Polypharmacy (i.e., ≥4 different ATC-codes) was identified in 4567
included. These individuals were followed for three years until individuals (46%) and was more common among females than males
December 31, 2019, thus the total study period reach from 2016 to (56% vs. 37%; p-value <0.01). Among the 9980 individuals with
2019. The individuals were divided into four different age categories at melatonin, 27% (n = 2648) were dispensed at least one other medica
the index year 2016: 0–6 years, 7–12 years, 13–17 years, and 18–25 tion for sleep disorder in 2016. Females had more often additional
years. medications, compared to males (41% vs. 23%; p-value <0.01). The
Data source: We used individual-level patient data from the Stock number of individuals with a recorded diagnosis of sleep disorder was
holm regional health care data warehouse (VAL). The data base contains 1953 (20%). In total, 8374 individuals (84%) were having at least one
encrypted, anonymized data on diagnoses, hospitalizations, and con recorded diagnosis of a comorbidity during 2013–2016.
sultations in hospital-based specialist care, consultations in primary In total, 32 147 prescriptions of melatonin were dispensed in 2016.
care, and prescription claims for all individuals in the region. The most common prescribing specialties were child psychiatrist (55%),
Measurements: Number of individuals, number of prescriptions, pediatrician (25%), and general psychiatrist (13%) (Table 2).
number of defined daily doses (DDDs). DDD is a volume measure defined The most common strength of dispensed Melatonin was 2 mg tablets/
as the assumed average maintenance dose per day for a drug used for its capsules (67% of all prescriptions), followed by 3 mg tablets/capsules
main indication in adults. The DDDs are assigned to drugs by the WHO (13%) and an oral solution of 1 mg/ml (10%) (Fig. 2). The mean overall
Collaborating Centre in Oslo. The DDD for melatonin is 2 mg [15]. dose was 2.26 mg melatonin, 2.37 mg when prescribed by a general
Sleeping medication other than melatonin was defined with ATC- psychiatrist, and 2.11 mg by a general practitioner. The mean dose
codes as: N05BB01 hydroxyzine, R06AD01 alimemazine, R06AD02 melatonin increased from 2.17 among children 6–12 years old, to 2.33
promethazine, N05CD benzodiazepine derivatives, N05CF benzodiaze among young adults aged 18–25 years. Among children 0–5 years of age,
pine related drugs, N05CM other hypnotics and sedatives. 76% of all the prescriptions were the oral solution of 1 mg/ml.
In this study polypharmacy was denoted if an individual was
dispensed four or more different types of medications (different ATC-
codes) during 2016 including melatonin.
For the diagnosis of a sleep disorder an ICD 10 code registered in
2015–2016 were required. The following codes were included: G470
Insomnia unspecified, G472 Circadian rhythm sleep disorders, G478
Other sleep disorders, G479 sleep disorder, unspecified, F510 Nonor
ganic insomnia, F512 Nonorganic disorder of the sleep-wake state, F518
Other sleep disorders, or F519 Sleep disorder not due to a substance or
known physiological condition, unspecified.
Co morbidities from the following ICD 10 groups were included:
cognitive developmental disorder (F70-79), psychiatric disorder
(F20–29, F30–39, F41, F42) neuropsychiatric disorder (F84, F90-98),
visual impairment (H54.0, H54.1, H54.2), or epilepsy (G40, G41). For
the identification of a comorbidity a diagnosis between 2013 and 2016
was required.
The prescribing specialty was identified through the prescribing
physician’s workplace, i.e., a secondary care pediatric clinic or child
psychiatry clinic. The prescribing specialty was divided into five groups:
child psychiatrist, pediatrician, general psychiatrist, general practi
tioner, and other specialty.
Ethical approval was obtained from the Swedish Ethical Review
Authority, (no 2020–03473).
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K. Tedroff et al. European Journal of Paediatric Neurology 39 (2022) 30–34
Table 1 Table 3
Number of individuals with dispensed melatonin in 2016 by age category (n = The median number of prescriptions and DDDs of melatonin dispensed annually
9980). per individual 2016–2019 by sex and age category.
Age category Age group (years) Median (min- 2017 2018 2019
max) 2016
0–5 N 6–12 13–17 18–25 0–25
(5%) N (%) N (%) N (%) N (%) Number of prescriptions/individual
Sex
Total 368 2809 4175 2628 9980
Males 2 (1–31) 4 (1–47) 4 (1–43) 4 (1–45)
(100) (100) (100) (100) (100)
Females 2 (1–34) 3 (1–37) 3 (1–44) 3 (1–45)
Males 235 1935 2069 1215 5451
Age categories
(64) (69) (50) (46) (55)
0–5 years 2 (1–20) 5 (1–19) 5 (1–20) 6 (1–25)
Females 133 874 2106 1413 4526
6–12 3 (1–34) 4 (1–47) 4 (1–44) 4 (1–45)
(36) (31) (50) (54) (45)
years
Number of prescriptions 1227 11 336 12 706 6878 32 147
13–17 2 (1–31) 3 (1–34) 3 (1–37) 3 (1–27)
Number of individuals with: 169 961 1840 1597 4567
years
Polypharmacy (at least 4 (46) (34) (44) (61) (46)
18–25 years 2 (1–25) 3 (1–24) 3 (1–19) 3 (1–35)
ATC-codes)
Number of DDDs/individual
Sleeping medication other 96 391 1194 967 2648
Sex
than melatonin (26) (14) (29) (37) (27)
Males 100 (0–1000) 100 120 (0–750) 150
Recorded diagnosis for sleep 167 520 808 458 1953
(0–1000) (14–1000)
disorder (45) (19) (19) (17) (20)
Females 100 (0–750) 100 150 150
Recorded diagnosis of 206 2405 3554 2209 8374
(0–800) (14–1500) (14–1500)
comorbidity (any) (56) (86) (85) (84) (84)
Age categories
Cognitive developmental 17 140 109 86
0–5 years 50 (0–500) 50 100 (0–400) 100
disorder
(25–400) (25–500)
Psychiatric disorder <10 288 1752 1497
6–12 100 (0–600) 100 100 (0–750) 150
Neuropsychiatric disorder 161 2246 2620 1447
years (25–600) (14–750)
Visual impairment <10 <10 <10 <10
13–17 100 (25–1000) 100 150 (0–600) 150
Epilepsy 43 101 78 58
years (0–750) (14–750)
18–25 90 (0–750) 100 150 (0–750) 150
years (0–1000) (14–1500)
Table 2
Number of melatonin prescriptions dispensed in 2016 by prescribing specialty.
The proportion of individuals adherent (refill of a melatonin pre
Prescribing Age group (years) scription within 12 months) to melatonin was higher among males
specialty
0–5 N 6–12 N 13–17 N 18–25 N 0–25 N compared to females (77% and 73% respectively after one year; p-value
(5) (%) (%) (%) (%) <0.01; Fig. 3a).
Child 327 (27) 7305 (65) 8822 (69) 1317 17 771 The proportion of individuals who were adherent was highest among
psychiatrist (19) (55) children 6–12 years. After one year, the adherence to melatonin was
Pediatrician 855 (70) 3764 (33) 3012 (24) 407 (6) 8038 (25) 87% among children 6–12 years, 76% among those 0–5 years, 75%
General <10 (0) 47 (0) 212 (2) 3810 4071 (13)
among those 13–17 years and 62% among those 18–25 years (Fig. 3b).
psychiatrist (55)
General 19 (1.5) 126 (1) 243 (2) 720 (11) 1108 (3)
practitioner 5. Discussion
Other 24 (1.5) 94 (1) 417 (3) 624 (9) 1159 (4)
Total 1227 11 336 12 706 6878 32 147 This study shows that a substantial number of children in the
(100) (100) (100) (100) (100)
Stockholm Region use melatonin continuously, in adolescents 3.4%. Of
the 1.4% of all children and young individuals who were dispensed
melatonin in 2016, 50% of males and 40% of females continued to use
melatonin throughout the 3 years follow up. During this period, the
median DDDs/individual increased by on average 50% and the amounts
of dispensed drugs increased by 100%. Additionally, we found that only
1/5 had a recorded sleep disorder diagnosis. Many had comorbid di
agnoses and polypharmacy was common.
In a study based on national Swedish data, 2% of the boys and 1.5%
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K. Tedroff et al. European Journal of Paediatric Neurology 39 (2022) 30–34
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K. Tedroff et al. European Journal of Paediatric Neurology 39 (2022) 30–34
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