Abstract
Migraine is a common condition among adults and has become increasingly more recognised as a common condition among children and adolescents. When headaches are frequent or disabling, preventative treatments are indicated. Few studies have addressed the effectiveness of preventative treatments in children and adolescents in a controlled manner. Due to a concern of potential adverse risks, parents are often reluctant to start prophylactic medications and inquire about the use of alternative treatments including vitamin supplementation. Vitamins, in general, are viewed as more ‘natural’ and may be involved in the biological pathways underlying migraine. The use of nutraceutical treatment for migraine is a favourable option because they are essentially well tolerated with minimal side effects. Several nutraceuticals have been studied in the literature with some showing positive results in adult patients with migraine (1); however, studies in children and adolescents are scarce with none showing favourable outcomes. As children and adolescents are increasingly diagnosed with migraine, the need for prophylactic or preventative treatment is warranted. Therefore, it is important that headache clinicians and researchers treating paediatric migraine explore therapies that are safe, effective and affordable.
Riboflavin, or vitamin B2, is a co-factor used in mitochondrial function and has been shown to be effective in children with mitochondrial disorders with mild side effects (2). In order to achieve this, high doses were required to overcome the mitochondrial impairment. In the pathogenesis of migraine, riboflavin is believed to be a major co-factor in oxidative metabolism as it acts as a precursor to flavin compounds involved in electron transport and generation of energy in the mitochondria (3,4). Thus, in theory, low riboflavin levels may be associated with mitochondrial dysfunction linked to migraine. Several studies have shown efficacy and tolerability of riboflavin in migraine prevention in adults (5,6); however. MacLennan et al. (7) were the first to study the efficacy of high-dose riboflavin (at least 200 mg/day) in migraine prevention in children. The results did not show any difference in those who received treatment with riboflavin compared to placebo – although the placebo rate was high. A subsequent, open-label, retrospective study examining high-dose riboflavin in children and adolescents with migraine who failed pharmacological preventative therapy suggested that riboflavin may be effective in migraine, with a more favourable response in boys (8). This sample population was notable for more individuals with severe migraine. A randomised, placebo-controlled study of a combination of high-dose riboflavin, magnesium and feverfew using low-dose riboflavin (25 mg), found no difference between high-dose and low-dose riboflavin with equivalent responses (9).
The study by Bruijn et al. (10) presented the results of a randomised, double-blind, placebo-controlled, cross-over designed trial that addressed the effectiveness of a medium dose of riboflavin (50 mg/day) in the prevention of childhood migraine. Subjects were 6–13 years old that met ICHD II criteria for migraine with or without aura and a frequency of at least two headache attacks per month recruited from two hospitals. The study showed no difference in migraine frequency, severity or duration between riboflavin and placebo in each phase. However, there was a reduction in frequency of the tension-type headaches in these children.
The reason for this ineffectiveness in contrast to the positive results in adults is likely multifactorial. First, the dose of riboflavin used may not be sufficient to alter mitochondrial metabolism or be clinically relevant. The pharmacokinetics of riboflavin suggested that the maximal amount of riboflavin the human body can absorb from a single dose is 27 mg with saturation of absorption reached at doses 30–50 mg decreasing the absorption at higher doses (11,12). Furthermore, the half-life of riboflavin is between 1–2 h. This observation of limited absorption with a short half-life suggests that riboflavin therapy may require multiple daily dosing to attain a positive effect. This may explain why the single daily high dose of riboflavin was comparable to the low-dose arm in one adult study (9).
The absorption of riboflavin is also diminished when riboflavin is administered on an empty stomach. It is uncertain whether the instruction to take with food was given for any of the migraine studies and the subsequent impact this would have on the results. One way to assess this would be to obtain serum levels during a treatment study to evaluate the pharmacokinetics, the effective serum level and adherence to the study to see if changes in serum riboflavin levels correspond to improvement of migraine.
Finally, addressing the issue of a high-placebo rate is often challenging in studies involving children and adolescents. The inclusion criteria may have been too restrictive as the age range may have been too limited and the headache frequency too low to be able to show much difference compared to controls.
Studying the effect of nutraceuticals to the same level that pharmaceuticals are important in the treatment of migraine, as it attempts to fill the void that exists in studies of preventative treatment for migraine in the paediatric population. Challenges exist in determining the correct dosage and dose timing as the dose used for mitochondrial disorders may not be adequate for migraine. The authors are to be commended in their efforts at tackling the challenge of studying nutraceuticals. Though inconsistencies remain in regard to the efficacy of riboflavin in treating paediatric migraine, hopefully this study will spark continued interest in investigating this supplement.