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Article Type: Original Article
Pediatric Off-Label Use of Melatonin – A Register Linkage Study between the Norwegian Prescription Database and Patient Register
Ingeborg Hartz1, Marte Handal2, Aage Tverdal2 and Svetlana Skurtveit2,3
1
Faculty of Public Health, Hedmark University College, Elverum, Norway
2
Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
3
Norwegian Centre for Addiction Research, University of Oslo, Oslo, Norway
Author for correspondence: Ingeborg Hartz, Faculty of Public Health, Hedmark University College, P.b. 400, 2418 Elverum, Norway (email: [email protected]).
Abstract: The aims were, for the entire Norwegian population aged 4–17 years, to study prevalence of melatonin use during 2004–2012, recurrent use in incident users and psychiatric and neurological morbidity in recurrent users. Data on dispensed melatonin were retrieved from the Norwegian Prescription Database and linked to diagnostic data from the Norwegian Patient Register. Outcome measures were: 1-year prevalence of use, proportion of recurrent use (use over three consecutive 365-day periods among incident users in 2009) and annual number of milligrams and number of prescriptions dispensed in recurrent users. The prevalence of registered ICD-10 diagnoses during the period of 2008-2012 was given for the recurrent users. Prevalence of melatonin use increased annually in both genders during 2004–2012 (boys: 3.4–11.0 per 1000; girls: 1.5–7.7 per 1000). 29% of boys and 23% of girls were recurrent melatonin user, and the prevalence was highest among the youngest (aged 4–8 years; boys: 47%, girls: 42%). In the third year, the median annual amount of melatonin dispensed was 1080 (IQR 586-1800) milligrams in boys and 900 (IQR 402-1620) milligrams in girls. Among recurrent users, 91% had a diagnosis of either psychiatric (84%) or neurological (32%) disorder. Off-label recurrent use of melatonin seems to have acquired a role mainly in treating secondary sleep problems in children and adolescent with psychiatric and neurological disorders.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcpt.12411 This article is protected by copyright. All rights reserved.
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Once melatonin has been started, a large proportion of patients continue for at least 3 years, in doses corresponding to daily use in the majority. Sleep difficulties has been reported to increase and are estimated to affect up to 20–30% of all children and adolescents [1, 2]. At the same time, a few studies have documented a trend towards increasing use of hypnotic drugs by young people in several European countries [3-9]. Most of the studies published on hypnotic drug use among children and adolescents do not provide any detailed or up-to-date information on patterns of hypnotic drug use over time, including information on the underlying morbidity in the patient group who uses such drugs.
Two studies have called attention to the observed increase in hypnotic drug use, and off-label use of melatonin in children and adolescents over the period of 2004–2011 [5, 8]. During this period, there was an increase of more than 30% in hypnotic drug use by children and adolescents and melatonin became the most frequently used hypnotic drug by this patient group.
In EU, melatonin is indicated for use among individuals aged >55 years, and it is not recommended for use for those aged 55 years [10, 14]. Melatonin is not a reimbursed drug in Norway and indication for use is therefore not included on the prescription.
The Norwegian Patient Register (NPR) The Norwegian Patient Register (NPR) contains individual-level specialist health care data from 2008 and onwards[13, 15]. NPR receives administrative data on diagnostic codes for the conditions (ICD codes) relevant for the treatment that has been provided to the patient. Recurrent melatonin users were described according to diagnostic ICD-10 codes of mental and behavioural disorders (F00-F99) and diseases of the nervous system (G00-G99) as registered in the NPR from 2008 to 2012. The distribution of diagnostic codes with prevalence greater than 4% was given for the recurrent users.
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Register linkage Incident melatonin users in 2009 were identified from NorPD and were linked at an individual level to information on diagnostic codes from the NPR in the period of 2008-2012 by using the unique person identity number assigned to all individuals in Norway.
Analyses and statistics 1.
Prevalence of melatonin use in the period of 2004–2012
Period (1-year) prevalence of melatonin use, according to age and gender, was estimated as the number of 4–17-year-olds who had at least one prescription of melatonin dispensed each year from 2004 to 2012, per 1000 inhabitants in the same age range. Further, 1-year prevalence in 2012 according age subgroups was estimated. The denominator was based on the total number of inhabitants aged 4–17 years in Norway at 1 July for the actual year, as registered in Statistics Norway. Information on prescriber characteristics (speciality) was retrieved for all melatonin prescriptions.
2.
Duration of treatment among incident users in 2009 (recurrent melatonin use)
Incident melatonin users in 2009 were defined as individuals with no recorded fillings of melatonin prescriptions back to 2004. Among incident users, recurrent users were defined as individuals who were dispensed melatonin at least once during each of the three consecutive 365-day periods (at least one prescription in the first, second and third years) after the date of the first melatonin prescription in 2009. Even though adolescents became older than 17 years during the three years of follow-up (2010-2012), we were able to follow them and to define them as recurrent users or not. Eg., a 17-year-old incident user in 2009 was followed for three years until he/she was 20 years old.
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Among incident melatonin users in 2009, the proportions of recurrent users, according to age groups and gender were presented. Statistical differences in proportion of recurrent use, between gender and between age groups within each gender, were tested with chi-square test.
To study aspects of sporadic versus regular use in recurrent melatonin users, the annual amounts (milligrams) of melatonin and number of prescriptions filled were presented as medians with interquartile ranges (IQR).
3.
Morbidity among recurrent users
Analysis of recorded ICD-codes in NPR during 2008 to 2012 among recurrent users was performed. Presence of diagnoses was presented as proportions with 95% confidence interval. All analyses were done using SPSS 22.0 for Windows.
Ethical considerations The register linkage was approved by the Regional Committee for Medical Research Ethics and by the Norwegian Data Protection Authority.
Results One-year prevalence of melatonin use among 4–17-year-olds during 2004–2012 The prevalence of melatonin use among 4–17-year-olds increased during the period of 2004–2012: threefold among boys (from 3.4 [n = 1489] to 11.0 [n = 4913] per 1000 inhabitants) and fivefold
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among girls (1.5 [n = 612] to 7.7 [n = 3281] per 1000 inhabitants) (fig. 1). The overall increase in this period resulted from increased use in those aged ≥6 years, and most among older adolescents (data not shown). Patterns of melatonin drug use differed between boys and girls by age (fig. 1) and these gender patterns were stable during the study period (data not shown). Among the boys, there was an increase in use from age six, reaching a peak at 10 and then levelling until 17.
Among the girls, an annual increased use from age six onwards was also observed (fig. 1). However, the pattern differed from that in boys: there was a gradual increase in use with age, peaking at age 17.
Prescriber’s speciality Overall, 186,235 melatonin prescriptions were filled during 2004-2012 to children and adolescents aged 55 years of age [17-20]. The absolute benefit of melatonin compared with placebo seems smaller than other pharmacological treatments in adults [21]. The pharmacokinetic profile of Circadin seem to be similar in children and adults; including a peak in concentration around 2 hr after administration, a prolonged release profile, and total melatonin exposure derived from area under the curve (AUC) data corresponding to a linear relationship between dose and concentration in saliva [22]. In contrast to other hypnotic drugs, there appears to be no evidence of tolerance and dependence with melatonin, as compared to the more traditional hypnotics such as benzodiazepines and benzodiazepine-related drugs (e.g. zolpidem, zopiclone) [19]. Too few studies have been conducted in children to conclude on a beneficial effect for primary insomnia in children and adolescents [21].
However, randomized, controlled trials reveal that melatonin may be useful for treatment for certain secondary sleep problems in children and adolescents [23, 24], such as in chronic sleep onset insomnia [25-27], ADHD [28-30], autistic spectrum disorder (ASD) [31, 32], epilepsy [33] and neurodevelopmental disabilities [34, 35]. In this context, the observed increasing use of melatonin may be associated with the increase in stimulant use, and thus treatment for ADHD, in children and
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adolescents observed over time [12]. There are, however, limitations in the very few studies carried out to date that support melatonin use for the treatment of these conditions [23, 24]. The trials include a small number of participants, and last for a short period of time; this limits the power of evidence in favour of melatonin treatment in general and the long-term effects in particular.
There is a lack of certainty about melatonin dosage in young people [24]. A daily dose at around 3 mg or more throughout the year in half of the recurrent users seems, however, to be within the range of what is recommended in recent clinical recommendations for melatonin use in children and adolescents [11, 24]. As a comparison, the licensed and recommended daily dose of Circadin for short-term therapy of primary insomnia in adults is 2 mg. The recommendations for use in young people conclude on a maximum dose at 3 mg in children and 5 mg in adolescents when used as a chronobiotic in sleep-wake disorders, and a starting dose at 1-3 mg when used as a sleep inductor [24]. BNF for Children recommends a maximum daily dose at 10 mg [11]. The recommendations emphasize, however, that long-term effects are unknown.
The melatonin receptors MT1 and MT2 are present in many human tissues [16, 36]. Melatonin is a hormone with diverse physiological functions; in addition to the regulation of circadian rhythms and seasonal behaviour, it has great functional versatility related to sexual development and reproductive functions, retinal physiology and tumour inhibition, and as an antioxidant with immune-modulatory and anti-ageing properties [16, 36-41]. There is concern that melatonin levels from external uptake may postpone onset of puberty [38, 41]. To our knowledge, only one observational study of long-term (three years) effects of exogenous melatonin on pubertal development has been published, which revealed no effects on pubertal development [42]. However, this study was small, which raises questions about its power to detect true deviations in pubertal development. Information on melatonin’s long-term effects still seems unexplored.
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In EU, melatonin is not licenced or recommended for use below the age of 18 because of insufficient data on safety and efficacy. Still, the risk of side-effects after the increasing off-label use of melatonin, for long-term use, in children and adolescents may need to be discussed in relation to the fact that this seems to be a population with severe and chronical diagnosis, in whom a potential beneficial effect of melatonin may outweigh potential side-effects. A three-fold higher level of recurrent use at around 40% in younger people, as compared to those aged 14-17 years when started on melatonin is interesting in view of the lack of knowledge of long-term effects of melatonin as a hormone with diverse actions in the human body.
Increasing paediatric off-label use of melatonin does not seem to be a Norwegian phenomenon only. Information retrieved from the Danish and Swedish prescription databases reveals a parallel trend in increasing melatonin use in the age group 5–19 years [43, 44]. From 2007 to 2013, the prevalence of melatonin use in this age group increased from 0.06/1000 to 6.9/1000 in Denmark and from 1.6/1000 to 9.1/1000 in Sweden. Parallel to our observations, it is reported in Denmark that the increasing use in young people is caused by use in populations with high degree of co-morbidity in Denmark [45].
One of this study’s strengths is the use of national registers, which eliminates recall bias and underreporting by the respondents. All melatonin use is captured, because over-the-counter melatonin is not available in Norway. However, compliance is always an issue when using prescription data in studies of drug use. We do not have information on the extent to which dispensed drugs were actually taken.
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Summary
More than 8000 4-17-year-olds were dispensed melatonin at least once in 2012 in Norway. Among recurrent users, melatonin was almost entirely used to treat secondary sleep problems in children and adolescents with psychiatric and neurological disorders. There are concerns about long-term melatonin use in children and adolescents because the safety of recurrent melatonin use still is uncertain. Still, 4 out of 10 of those aged 4-13 years when initiated on melatonin continue to use melatonin over at least three years. The risk benefit evaluation of melatonin use should, however, reflect use for secondary sleep problems in children and adolescents with psychiatric and neurological disorders.
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Tables and Figures Table 1. Morbidity among recurrent melatonin users (ICD-10 diagnosis > 4% period prevalence 200812)
Recurrent users
Diagno sis
Boys
Girls
(N= 362)
(N= 227)
n (%, 95% CI)
n (%, 95% CI)
Mental and behavioural disorders (F00F99) F30F39
Affective disorders
20 (5.5, 7.6-13.8)
26 (11.5, 7.315.6)
F40F48
Neurotic, stress-related and somatoform disorders
45 (12.4, 9.0-15.8)
51 (22.5, 17.027.9)
F70F79
Mental retardation
28 (7.7, 5.0-10.5)
F80F89
Disorders of psychological development
125 (34.5, 29.639.4)
54 (23.8, 18.329.3)
F90
Hyperkinetic disorders
221 (61.0, 56.066.1)
104 (45.8, 39.352.3)
F91F98
Other behavioural and emotional disorders
105 (29.0, 24.3-33.7)
64 (28.2, 22.334.1)
12 (5.3, 2.48.2)
(- hyperkinetic disorders) Diseases of the nervous system (G00G99) G43G44
Migraine and other Headache Syndromes
12 (3.3, 1.5-5.2)
11 (4.8, 2.1-7.6)
G40G41
Epilepsy and Status Epilepticus
42 (11.6, 8.3-14.9 )
21 (9.3. 5.5-13.0)
G47
Sleep disorders
28 (7.7, 5.0-10.5)
18 (7.9, 4.4-11.4)
66 (18.2, 14.322.2)
36 (15.9, 11.120.6)
G90-99 Other disorders of the nervous system
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Table 2. Morbidity among recurrent melatonin users, according to age and gender (ICD-10 diagnosis > 10% period prevalence 2008-12)
Boys Age (year-interval)
Girls
4-8
9-13
14-17
4-8
9-13
14-17
N=121
N=171
N=70
N=52
N=98
N=77
n (%, 95% CI)
n (%, 95% CI)
n (%, 95% CI)
n (%, 95% CI)
n (%, 95% CI)
n (%, 95% CI)
0 (0)
9 (5.3, 1.98.6)
11 (15.7, 7.2-24.2)
2 (3.8, 0.714.3)
6 (6.1, 1.410.9)
18 (23.4, 13.9-32.8)
3 (2.5, 0.67.6)
25 (14.6, 9.3-19.9)
17 (24.3, 14.2-34.3)
3 (5.8, 1.516.9)
23 (23.5, 15.1-31.9)
25 (32.5, 22.0-42.9)
F80- Disorders of F89 psychological development
40 (33.1, 24.7-41.4)
63 (36.8, 29.6-44.1)
22 (31.4, 20.6-42.3)
17 (32.7, 19.9-45.4)
26 (26.5, 17.8-35.3)
11 (14.3, 6.5-22.1)
F90
Hyperkinetic disorders
84 (69.4, 61.2-77.6)
114 (66.7, 59.6-73.7)
23 (32.9, 21.9-43.9)
30 (57.7, 44.3-71.1)
45 (45.9, 36.1-55.8)
29 (37.7, 26.8-48.5)
F91- Other behavioural and F98 emotional disorders (hyperkinetic disorders)
24 (22.3, 12.7-26.9)
64 (37.4, 30.2-44.7)
14 (20.0, 10.6-29.4)
13 (25.0, 13.2-36.8)
31 (31.6, 22.4-40.8)
20 (26.0, 16.2-35.8)
20 (16.5, 9.9-23.2)
16 (9.4, 5.013.7)
6 (8.6, 2.015.1)
9 (17.3, 7.027.6)
9 (9.2, 3.514.9)
3 (3.9, 1.011.7)
Sleep disorders
8 (6.6, 2.211.0)
13 (7.6, 3.611.6)
7 (10.0, 2.017.3)
4 (7.7, 4.55 (5.1, 0.8- 9 (11.7, 4.514.9) 9.5) 18.9)
G90- Other disorders of the 99 nervous system
23 (19.0, 12.0-26.0)
28 (16.4, 10.8-31.0)
15 (21.4, 11.9-31.0)
8 (15.4, 5.6- 12 (12.2, 5.825.2) 18.7)
Mental and behavioural disorders (F00-F99) F30- Affective disorders F39
F40- Neurotic, stressF48 related and somatoform disorders
Diseases of the nervous system (G00-G99) G40- Epilepsy and Status 41 Epilepticus G47
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16 (20.8, 11.7-29.8)
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Figure 1. One-year prevalence of melatonin use in 4–17-year-olds in the period of 2004– 2012, according to age and gender.
a. 1- year prevalence of melatonin use in 4-17-year-olds in 2004-2012, according to gender
b. 1-year prevalence of melatonin use in 2012 according to age and gender
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Figure 2. Proportion (%) of recurrent melatonin use over a 3-year period (1095 days) among incident melatonin users in 2009
Variation among age groups: p < 0.001 in both genders
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Article Type: Original Article
Pediatric Off-Label Use of Melatonin – A Register Linkage Study between the Norwegian Prescription Database and Patient Register
Ingeborg Hartz1, Marte Handal2, Aage Tverdal2 and Svetlana Skurtveit2,3
1
Faculty of Public Health, Hedmark University College, Elverum, Norway
2
Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
3
Norwegian Centre for Addiction Research, University of Oslo, Oslo, Norway
Author for correspondence: Ingeborg Hartz, Faculty of Public Health, Hedmark University College, P.b. 400, 2418 Elverum, Norway (email: [email protected]).
Abstract: The aims were, for the entire Norwegian population aged 4–17 years, to study prevalence of melatonin use during 2004–2012, recurrent use in incident users and psychiatric and neurological morbidity in recurrent users. Data on dispensed melatonin were retrieved from the Norwegian Prescription Database and linked to diagnostic data from the Norwegian Patient Register. Outcome measures were: 1-year prevalence of use, proportion of recurrent use (use over three consecutive 365-day periods among incident users in 2009) and annual number of milligrams and number of prescriptions dispensed in recurrent users. The prevalence of registered ICD-10 diagnoses during the period of 2008-2012 was given for the recurrent users. Prevalence of melatonin use increased annually in both genders during 2004–2012 (boys: 3.4–11.0 per 1000; girls: 1.5–7.7 per 1000). 29% of boys and 23% of girls were recurrent melatonin user, and the prevalence was highest among the youngest (aged 4–8 years; boys: 47%, girls: 42%). In the third year, the median annual amount of melatonin dispensed was 1080 (IQR 586-1800) milligrams in boys and 900 (IQR 402-1620) milligrams in girls. Among recurrent users, 91% had a diagnosis of either psychiatric (84%) or neurological (32%) disorder. Off-label recurrent use of melatonin seems to have acquired a role mainly in treating secondary sleep problems in children and adolescent with psychiatric and neurological disorders.
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Once melatonin has been started, a large proportion of patients continue for at least 3 years, in doses corresponding to daily use in the majority. Sleep difficulties has been reported to increase and are estimated to affect up to 20–30% of all children and adolescents [1, 2]. At the same time, a few studies have documented a trend towards increasing use of hypnotic drugs by young people in several European countries [3-9]. Most of the studies published on hypnotic drug use among children and adolescents do not provide any detailed or up-to-date information on patterns of hypnotic drug use over time, including information on the underlying morbidity in the patient group who uses such drugs.
Two studies have called attention to the observed increase in hypnotic drug use, and off-label use of melatonin in children and adolescents over the period of 2004–2011 [5, 8]. During this period, there was an increase of more than 30% in hypnotic drug use by children and adolescents and melatonin became the most frequently used hypnotic drug by this patient group.
In EU, melatonin is indicated for use among individuals aged >55 years, and it is not recommended for use for those aged 55 years [10, 14]. Melatonin is not a reimbursed drug in Norway and indication for use is therefore not included on the prescription.
The Norwegian Patient Register (NPR) The Norwegian Patient Register (NPR) contains individual-level specialist health care data from 2008 and onwards[13, 15]. NPR receives administrative data on diagnostic codes for the conditions (ICD codes) relevant for the treatment that has been provided to the patient. Recurrent melatonin users were described according to diagnostic ICD-10 codes of mental and behavioural disorders (F00-F99) and diseases of the nervous system (G00-G99) as registered in the NPR from 2008 to 2012. The distribution of diagnostic codes with prevalence greater than 4% was given for the recurrent users.
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Register linkage Incident melatonin users in 2009 were identified from NorPD and were linked at an individual level to information on diagnostic codes from the NPR in the period of 2008-2012 by using the unique person identity number assigned to all individuals in Norway.
Analyses and statistics 1.
Prevalence of melatonin use in the period of 2004–2012
Period (1-year) prevalence of melatonin use, according to age and gender, was estimated as the number of 4–17-year-olds who had at least one prescription of melatonin dispensed each year from 2004 to 2012, per 1000 inhabitants in the same age range. Further, 1-year prevalence in 2012 according age subgroups was estimated. The denominator was based on the total number of inhabitants aged 4–17 years in Norway at 1 July for the actual year, as registered in Statistics Norway. Information on prescriber characteristics (speciality) was retrieved for all melatonin prescriptions.
2.
Duration of treatment among incident users in 2009 (recurrent melatonin use)
Incident melatonin users in 2009 were defined as individuals with no recorded fillings of melatonin prescriptions back to 2004. Among incident users, recurrent users were defined as individuals who were dispensed melatonin at least once during each of the three consecutive 365-day periods (at least one prescription in the first, second and third years) after the date of the first melatonin prescription in 2009. Even though adolescents became older than 17 years during the three years of follow-up (2010-2012), we were able to follow them and to define them as recurrent users or not. Eg., a 17-year-old incident user in 2009 was followed for three years until he/she was 20 years old.
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Among incident melatonin users in 2009, the proportions of recurrent users, according to age groups and gender were presented. Statistical differences in proportion of recurrent use, between gender and between age groups within each gender, were tested with chi-square test.
To study aspects of sporadic versus regular use in recurrent melatonin users, the annual amounts (milligrams) of melatonin and number of prescriptions filled were presented as medians with interquartile ranges (IQR).
3.
Morbidity among recurrent users
Analysis of recorded ICD-codes in NPR during 2008 to 2012 among recurrent users was performed. Presence of diagnoses was presented as proportions with 95% confidence interval. All analyses were done using SPSS 22.0 for Windows.
Ethical considerations The register linkage was approved by the Regional Committee for Medical Research Ethics and by the Norwegian Data Protection Authority.
Results One-year prevalence of melatonin use among 4–17-year-olds during 2004–2012 The prevalence of melatonin use among 4–17-year-olds increased during the period of 2004–2012: threefold among boys (from 3.4 [n = 1489] to 11.0 [n = 4913] per 1000 inhabitants) and fivefold
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among girls (1.5 [n = 612] to 7.7 [n = 3281] per 1000 inhabitants) (fig. 1). The overall increase in this period resulted from increased use in those aged ≥6 years, and most among older adolescents (data not shown). Patterns of melatonin drug use differed between boys and girls by age (fig. 1) and these gender patterns were stable during the study period (data not shown). Among the boys, there was an increase in use from age six, reaching a peak at 10 and then levelling until 17.
Among the girls, an annual increased use from age six onwards was also observed (fig. 1). However, the pattern differed from that in boys: there was a gradual increase in use with age, peaking at age 17.
Prescriber’s speciality Overall, 186,235 melatonin prescriptions were filled during 2004-2012 to children and adolescents aged 55 years of age [17-20]. The absolute benefit of melatonin compared with placebo seems smaller than other pharmacological treatments in adults [21]. The pharmacokinetic profile of Circadin seem to be similar in children and adults; including a peak in concentration around 2 hr after administration, a prolonged release profile, and total melatonin exposure derived from area under the curve (AUC) data corresponding to a linear relationship between dose and concentration in saliva [22]. In contrast to other hypnotic drugs, there appears to be no evidence of tolerance and dependence with melatonin, as compared to the more traditional hypnotics such as benzodiazepines and benzodiazepine-related drugs (e.g. zolpidem, zopiclone) [19]. Too few studies have been conducted in children to conclude on a beneficial effect for primary insomnia in children and adolescents [21].
However, randomized, controlled trials reveal that melatonin may be useful for treatment for certain secondary sleep problems in children and adolescents [23, 24], such as in chronic sleep onset insomnia [25-27], ADHD [28-30], autistic spectrum disorder (ASD) [31, 32], epilepsy [33] and neurodevelopmental disabilities [34, 35]. In this context, the observed increasing use of melatonin may be associated with the increase in stimulant use, and thus treatment for ADHD, in children and
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adolescents observed over time [12]. There are, however, limitations in the very few studies carried out to date that support melatonin use for the treatment of these conditions [23, 24]. The trials include a small number of participants, and last for a short period of time; this limits the power of evidence in favour of melatonin treatment in general and the long-term effects in particular.
There is a lack of certainty about melatonin dosage in young people [24]. A daily dose at around 3 mg or more throughout the year in half of the recurrent users seems, however, to be within the range of what is recommended in recent clinical recommendations for melatonin use in children and adolescents [11, 24]. As a comparison, the licensed and recommended daily dose of Circadin for short-term therapy of primary insomnia in adults is 2 mg. The recommendations for use in young people conclude on a maximum dose at 3 mg in children and 5 mg in adolescents when used as a chronobiotic in sleep-wake disorders, and a starting dose at 1-3 mg when used as a sleep inductor [24]. BNF for Children recommends a maximum daily dose at 10 mg [11]. The recommendations emphasize, however, that long-term effects are unknown.
The melatonin receptors MT1 and MT2 are present in many human tissues [16, 36]. Melatonin is a hormone with diverse physiological functions; in addition to the regulation of circadian rhythms and seasonal behaviour, it has great functional versatility related to sexual development and reproductive functions, retinal physiology and tumour inhibition, and as an antioxidant with immune-modulatory and anti-ageing properties [16, 36-41]. There is concern that melatonin levels from external uptake may postpone onset of puberty [38, 41]. To our knowledge, only one observational study of long-term (three years) effects of exogenous melatonin on pubertal development has been published, which revealed no effects on pubertal development [42]. However, this study was small, which raises questions about its power to detect true deviations in pubertal development. Information on melatonin’s long-term effects still seems unexplored.
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In EU, melatonin is not licenced or recommended for use below the age of 18 because of insufficient data on safety and efficacy. Still, the risk of side-effects after the increasing off-label use of melatonin, for long-term use, in children and adolescents may need to be discussed in relation to the fact that this seems to be a population with severe and chronical diagnosis, in whom a potential beneficial effect of melatonin may outweigh potential side-effects. A three-fold higher level of recurrent use at around 40% in younger people, as compared to those aged 14-17 years when started on melatonin is interesting in view of the lack of knowledge of long-term effects of melatonin as a hormone with diverse actions in the human body.
Increasing paediatric off-label use of melatonin does not seem to be a Norwegian phenomenon only. Information retrieved from the Danish and Swedish prescription databases reveals a parallel trend in increasing melatonin use in the age group 5–19 years [43, 44]. From 2007 to 2013, the prevalence of melatonin use in this age group increased from 0.06/1000 to 6.9/1000 in Denmark and from 1.6/1000 to 9.1/1000 in Sweden. Parallel to our observations, it is reported in Denmark that the increasing use in young people is caused by use in populations with high degree of co-morbidity in Denmark [45].
One of this study’s strengths is the use of national registers, which eliminates recall bias and underreporting by the respondents. All melatonin use is captured, because over-the-counter melatonin is not available in Norway. However, compliance is always an issue when using prescription data in studies of drug use. We do not have information on the extent to which dispensed drugs were actually taken.
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Summary
More than 8000 4-17-year-olds were dispensed melatonin at least once in 2012 in Norway. Among recurrent users, melatonin was almost entirely used to treat secondary sleep problems in children and adolescents with psychiatric and neurological disorders. There are concerns about long-term melatonin use in children and adolescents because the safety of recurrent melatonin use still is uncertain. Still, 4 out of 10 of those aged 4-13 years when initiated on melatonin continue to use melatonin over at least three years. The risk benefit evaluation of melatonin use should, however, reflect use for secondary sleep problems in children and adolescents with psychiatric and neurological disorders.
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Tables and Figures Table 1. Morbidity among recurrent melatonin users (ICD-10 diagnosis > 4% period prevalence 200812)
Recurrent users
Diagno sis
Boys
Girls
(N= 362)
(N= 227)
n (%, 95% CI)
n (%, 95% CI)
Mental and behavioural disorders (F00F99) F30F39
Affective disorders
20 (5.5, 7.6-13.8)
26 (11.5, 7.315.6)
F40F48
Neurotic, stress-related and somatoform disorders
45 (12.4, 9.0-15.8)
51 (22.5, 17.027.9)
F70F79
Mental retardation
28 (7.7, 5.0-10.5)
F80F89
Disorders of psychological development
125 (34.5, 29.639.4)
54 (23.8, 18.329.3)
F90
Hyperkinetic disorders
221 (61.0, 56.066.1)
104 (45.8, 39.352.3)
F91F98
Other behavioural and emotional disorders
105 (29.0, 24.3-33.7)
64 (28.2, 22.334.1)
12 (5.3, 2.48.2)
(- hyperkinetic disorders) Diseases of the nervous system (G00G99) G43G44
Migraine and other Headache Syndromes
12 (3.3, 1.5-5.2)
11 (4.8, 2.1-7.6)
G40G41
Epilepsy and Status Epilepticus
42 (11.6, 8.3-14.9 )
21 (9.3. 5.5-13.0)
G47
Sleep disorders
28 (7.7, 5.0-10.5)
18 (7.9, 4.4-11.4)
66 (18.2, 14.322.2)
36 (15.9, 11.120.6)
G90-99 Other disorders of the nervous system
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Table 2. Morbidity among recurrent melatonin users, according to age and gender (ICD-10 diagnosis > 10% period prevalence 2008-12)
Boys Age (year-interval)
Girls
4-8
9-13
14-17
4-8
9-13
14-17
N=121
N=171
N=70
N=52
N=98
N=77
n (%, 95% CI)
n (%, 95% CI)
n (%, 95% CI)
n (%, 95% CI)
n (%, 95% CI)
n (%, 95% CI)
0 (0)
9 (5.3, 1.98.6)
11 (15.7, 7.2-24.2)
2 (3.8, 0.714.3)
6 (6.1, 1.410.9)
18 (23.4, 13.9-32.8)
3 (2.5, 0.67.6)
25 (14.6, 9.3-19.9)
17 (24.3, 14.2-34.3)
3 (5.8, 1.516.9)
23 (23.5, 15.1-31.9)
25 (32.5, 22.0-42.9)
F80- Disorders of F89 psychological development
40 (33.1, 24.7-41.4)
63 (36.8, 29.6-44.1)
22 (31.4, 20.6-42.3)
17 (32.7, 19.9-45.4)
26 (26.5, 17.8-35.3)
11 (14.3, 6.5-22.1)
F90
Hyperkinetic disorders
84 (69.4, 61.2-77.6)
114 (66.7, 59.6-73.7)
23 (32.9, 21.9-43.9)
30 (57.7, 44.3-71.1)
45 (45.9, 36.1-55.8)
29 (37.7, 26.8-48.5)
F91- Other behavioural and F98 emotional disorders (hyperkinetic disorders)
24 (22.3, 12.7-26.9)
64 (37.4, 30.2-44.7)
14 (20.0, 10.6-29.4)
13 (25.0, 13.2-36.8)
31 (31.6, 22.4-40.8)
20 (26.0, 16.2-35.8)
20 (16.5, 9.9-23.2)
16 (9.4, 5.013.7)
6 (8.6, 2.015.1)
9 (17.3, 7.027.6)
9 (9.2, 3.514.9)
3 (3.9, 1.011.7)
Sleep disorders
8 (6.6, 2.211.0)
13 (7.6, 3.611.6)
7 (10.0, 2.017.3)
4 (7.7, 4.55 (5.1, 0.8- 9 (11.7, 4.514.9) 9.5) 18.9)
G90- Other disorders of the 99 nervous system
23 (19.0, 12.0-26.0)
28 (16.4, 10.8-31.0)
15 (21.4, 11.9-31.0)
8 (15.4, 5.6- 12 (12.2, 5.825.2) 18.7)
Mental and behavioural disorders (F00-F99) F30- Affective disorders F39
F40- Neurotic, stressF48 related and somatoform disorders
Diseases of the nervous system (G00-G99) G40- Epilepsy and Status 41 Epilepticus G47
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16 (20.8, 11.7-29.8)
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Figure 1. One-year prevalence of melatonin use in 4–17-year-olds in the period of 2004– 2012, according to age and gender.
a. 1- year prevalence of melatonin use in 4-17-year-olds in 2004-2012, according to gender
b. 1-year prevalence of melatonin use in 2012 according to age and gender
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Figure 2. Proportion (%) of recurrent melatonin use over a 3-year period (1095 days) among incident melatonin users in 2009
Variation among age groups: p < 0.001 in both genders
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