Table 6.

Melatonin Studies in Children in the European Union (Countries Include Netherlands) (cont.)

Study	N (age range, yr)	Melatonin Dosage	Duration	Summary/Comments
Insomnia
Van Maanen68	84 (7–12)	3 mg (IR) of melatonin at 1900 Melatonin was provided by Pharma Nord.	3–4 wk	A randomized controlled study of the effects of melatonin (n = 26), DLMO (n = 30), and placebo (n = 27) in children with CSOI. Some in the melatonin group had underlying disorders (ADHD [5] and ASD [2]). Similar values were noted in the other 2 groups. Other participants were generally healthy children experiencing insomnia. DLMO melatonin levels were measured from saliva. Outcomes were measured via actigraphy, sleep diaries completed daily via the internet by parents, and sleep reduction questionnaires taken prior to and following the study. Sleep latency improved with melatonin compared with placebo (β = −0.33, p < 0.01). Sleep onset time advanced for both the melatonin (β = −0.65, p < 0.01) and DLMO (β = −0.23, p = 0.02). Melatonin provided the best results in total sleep time. Although there was an increase in sleep onset, the reduction of about 15 min on sleep latency ensured an overall improved sleep outcome. One child left the melatonin group due to various complaints (joint pain, headache). No other SEs were reported.
Van Geijlswijk21	59 (6–12)	0.3–10 mg	≥6 mo	A follow-up study evaluating sleep and safety of long-term melatonin in children with idiopathic CSOI. Duration of melatonin use was 3.1 yr with an average dose of 2.7 mg. Multiple SEs were noted (e.g., nausea [n= 1], apathy with weight gain [n = 1], and headaches). Twenty-one (38%) reported experiencing headaches regularly, 11 (20%) once a month, and 23 (42%) reported never experiencing headaches. There was no change in puberty onset. Limitation: Subjective data.
Van Geijlswijk69	120 (6–12)	0.05, 0.1, and 0.15 mg/kg given between 1730 and 1930	1 wk	In order to determine if there is a dose-response of melatonin for reducing sleep onset latency and advancing DLMO, patients were randomly assigned into a group with different weight-based dose of melatonin or placebo. Melatonin/advance sleep onset by approximately 1 hr (p < 0.001) and decrease sleep onset latency by about 35 min (p = 0.007 for 0.05 mg/kg, p = 0.001 for 0.1 mg/kg, and p < 0.001 for 0.15 mg/kg). DLMO was advanced by 50–90 min in the melatonin groups, which was statistically different from placebo (p < 0.001) in the 0.1 and 0.15 mg/kg groups. It did not achieve statistical significance in the 0.5 mg/kg group. Authors propose only 1 wk of data are difficult to ascertain dose-response. Common SEs were red cheeks (n = 15), red eyes (n = 15), yawning (n = 15), pale complexion (n = 8), dizziness (n = 8), feeling cold (n = 8), headache (n = 2), nausea and stomach pain (n = 1), and dizziness and nausea (n = 1).
Van Der Heijden70	110 (6–12)	5 mg given at 1800 or 1900	4 wk	The purpose of this study was to determine if DLMO could predict the time of treatment for melatonin. Results were measured via saliva hourly from 1900 to 2300 and via actigraphy. Melatonin advanced DLMO with positive 1:12 hr (p < 0.001), sleep onset with positive 0:42 hr (p = 0.004), and sleep latency decreased by approximately 25 min (p = 0.019). Total sleep duration was not statistical different from placebo.

ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; CBT, cognitive-behavioral therapy; CR, controlled release; CSOI, chronic sleep onset insomnia; DLMO, dim light melatonin onset; FR, fast release; IR, immediate release; PR, prolonged release; SE, side effect; tx, treatment