Traumatic brain injury (TBI) is one of the most common causes of neurological morbidity and it is more common in childhood and adolescence than at any other time of life [1–4]. Mild traumatic brain injury (mTBI) is the acute neurophysiological effect of blunt impact or other mechanical energy applied to the head, such as from sudden acceleration, deceleration or rotational forces [5, 6]. It accounts for 90% of all TBIs . Epidemiological studies suggest that one in five children will experience a mTBI by the age of 10, [1, 8] and 799 out of 100,000 children under 14 years visit the emergency department (ED) with a mTBI in the United States  and Canada . Falls (51%) and sports-related activities (25%) are the commonest causes [2, 10, 11].
One in seven school children sustaining an mTBI will suffer post-concussion syndrome (PCS) symptoms for three months or longer . PCS is a combination of clinical symptoms including physical (such as headaches), cognitive (such as learning and/or memory dysfunction), and behavioral (such as mood) disturbances [7, 10, 12]. It is associated with significant disability in the child and his/her family [5, 12–17]. It has been shown that 2% of mTBI children continue to have PCS symptoms one year later . Using these figures, we estimate that annually over a 1000 children in Canada have PCS for over a year due to a ‘mild’ TBI and yet there are no evidence-based medical treatments available . This suggests an urgent need to develop novel treatment options to improve outcomes for children suffering from PCS . Furthermore, our neurobiological understanding of PCS is lacking [6, 18], and routine clinical tests are not informative and so are not helpful in guiding treatment.
The complex pathophysiology of mTBI is well described [19–26], but the explanations for prolonged PCS are unclear [21, 27]. The mechanisms leading to neuronal dysfunction, cell death and altered connectivity include: oxidative stress, metabolic dysfunction, neuroinflammation, axonal damage and alterations in cerebral blood flow [19, 21, 28]. Most animal studies demonstrate recovery from mTBI within 7 to 15 days [22, 29, 30], similar to the clinical experience of the majority of humans [6, 10, 12]. However, the pathophysiological explanations for prolonged PCS, seen in 11% of children with mTBI, have been elusive [10, 27]. Recent animal and human research suggest that the explanations for the persistent PCS symptoms may be due to alterations in neuronal circuitry and neurotransmission [29–36].
Treatment of post-concussion syndrome
There are few evidence-based treatments for PCS and these studies usually do not include children, and so pediatricians have to rely on consensus guidelines for adults [37–44]. Avoidance of repeat injury is the mainstay in any treatment regimen for TBI as is rest until symptoms resolve [18, 45]. As PCS symptoms resolve quickly in the majority of people, clinicians do not use pharmacological treatments (except for analgesics) in the first few weeks after injury [38, 46–50]. There are few evidence-based treatments for PCS that persists for one month or more [37, 40, 43, 44, 51–53], providing the clinician with little guidance for the management of significantly debilitated patients . Treatments are used without conclusive evidence  and are chosen to target the most problematic symptom [49, 54–60]. A frequently recommended treatment for sleep dysfunction after mTBI is melatonin .
Melatonin as a potential treatment for PCS
Melatonin, naturally produced in the body by the pineal gland, has neuroprotective, analgesic, and anxiolytic properties and is a promising agent in TBI [62–67]. Melatonin’s role in the chronological regulation of major physiological processes (such as the sleep/wake cycle) [68–70] is well accepted. More recently, its therapeutic potential is being explored in other neurobehavioral conditions (for example chronic pain, headaches and anxiety) and TBI [67, 71, 72]. The many separate biological activities of melatonin are both receptor-mediated (at physiological levels) and non-receptor mediated (especially at supraphysiological levels) [63, 72]. It is lipophilic, can cross cell membranes easily [73, 74] and its neuroprotective mechanisms include i) reducing oxidative stress (for example decreasing oxidative and nitrosative abuse, lipid peroxidation, and increasing antioxidant enzymes) [75–81], ii) improving mitochondrial function [62, 73, 74, 82, 83], iii) inhibiting apoptosis (cell death) [84–86], iv) decreasing the neuroinflammation [64, 87, 88], and v) decreasing glutamate toxicity via GABA receptors [89–91].
The inherent biochemical and physiological characteristics of the brain, including high polyunsaturated fatty acids and energy requirements, make it particularly susceptible to free radicals mediated insult. Melatonin has been shown to decrease oxidative stress induced by exercise in young athletes [92, 93] and in patients with renal failure . It protects against focal and global brain injury in adult and juvenile TBI [87, 95–97], ischemic brain injury [98, 99], cerebral edema [67, 100], spinal cord injury [101, 102] and radiation injury .
Further, melatonin improves many of the symptoms seen in PCS such as headaches, pain, and anxiety  probably via the gamma Aminobuteric acid (GABA)-ergic system and opiate receptors [66, 105–107]. It is used to aid sleep in children with disabilities and visual impairment . Melatonin has analgesic properties and has been shown to be useful in adult and pediatric migraine [109, 110] and disorders of chronic pain (such as fibromyalgia and irritable bowel syndrome) [111, 112]. It is also effective in treating anxiety. In a systematic review, premedication with melatonin significantly decreased preoperative anxiety .
The dose of melatonin in clinical pediatric practice ranges between 1 and 10 mg. Receptor-mediated effects occur at physiological doses (for example in children with chronic insomnia effects are achieved at 0.05 to 0.15 mg/kg) . Lower doses do not achieve the same analgesic and anxiolytic effects [109, 111, 115–118]. In order to saturate melatonin receptors and achieve non-receptor mediated effects, supra-physiological doses are required [114, 119, 120]. A dose of 10 mg melatonin is likely to achieve this and yet stay within clinically-accepted parameters .
Pilot data using melatonin in PCS
We found that children with prolonged PCS and headaches had a significant response to melatonin treatment [61, 121]. Post-traumatic headaches (PTH) are thought to be particularly resistant to treatment [55, 122, 123]. Few studies have specifically analyzed how patients respond to treatment [124, 125], and none of these were in children. Our study aimed to: 1) describe the headache characteristics of PCS in children and 2) their response to pharmacological treatments . A retrospective chart review of 48 children treated for PTH since 2007 was performed. The mean age was 14.1 years (SD 3.1) and 66% were female. The time since injury was 10.6 (SD 8.1) months. Melatonin was used as a first-line treatment where sleep dysfunction was a comorbidity. A total of 15 out of 18 children responded to melatonin treatment. Seven children were treated with 3 to 5 mg of sublingual melatonin; 11 children were treated with 6 to 10 mg. Significantly more children responded to treatment with melatonin (83%) when compared with the other treatments used (P <0.05) and no serious side effects were reported. As these children were on average 10.2 months post-injury, it is very unlikely that this response was due to time alone.
In summary, melatonin has potential as a safe therapeutic candidate for the treatment of PCS in children. It has efficacy in many of symptoms commonly encountered in PCS. In preliminary work, we found that children with prolonged PCS and headaches had a significant response to sublingual melatonin treatment . Melatonin’s therapeutic potentials in mTBI include: 1) as a free radical scavenger and broad-spectrum antioxidant [75, 76, 82, 88, 126] and 2) symptomatically via the GABAergic system and opiate receptors [66, 95, 105, 106, 127]. The aim of this trial is to determine if treatment with melatonin improves PCS following mTBI in youths.