Q&A 428.1
Can riboflavin reduce the incidence of migraines in children?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at
Date prepared:18th November 2013
Background
Riboflavin (vitamin B2) is an essential vitamin required for tissue respiration which may be found in foods such as milk, meat, eggs, nuts, and vegetables.[1]
For adults and young people aged 12 years and over, UK guidelines for the management of headaches advise that riboflavin at a dose of 400mg daily may be effective in reducing migraine frequency and intensity for some patients. This recommendation refers to self-purchase only as there is no licensed riboflavin product available in the UK, or any cost effectiveness data to justify its use on NHS prescription.Initiation of preventative treatment for children should generally be managed by a specialist.[2],[3]
Information on the use of riboflavin in prevention of migraines in adults can be found in Q&A 424: Can riboflavin reduce the incidence of migraines in adults?
Answer
Mechanism of action
Riboflavin is converted into a co-enzyme called riboflavin-5-phosphate, which is in turn converted to flavin adenine dinucleotide. These co-enzymes act as hydrogen carriers for a number of enzymes involved in oxidation-reduction reactions in the mitochondrial chain.1
Although the molecular causes of migraine are not well understood, it would appear that a reduction in mitochondrial oxidative metabolism may be involved. It would therefore follow that riboflavin supplementation may reduce migraine frequency or severity.[4]
One study has suggested that patients with a mitochondrial DNA haplogroup H are significantly less likely to respond to riboflavin treatment than other haplotypes.[5]
Evidence
There are no good quality meta-analyses or systematic reviews looking at the effect of riboflavin on migraine.
The potential efficacy of riboflavin was first studied in children by MacLennan et al in 2008. They performed a double blind, randomised, placebo-controlled trial in children aged 5-15 years who had migraine with or without aura for at least 3 months.6 Unfortunately, though this trial is well-designed, it was not adequately powered to detect a significant difference. In addition, though steps were taken to ensure the placebo looked identical to the riboflavin, the possibility of discoloured urine causing unblinding does not appear to have been taken into account in the placebo design. Blinding was assessed at the end of the trial, but discoloured urine appears to have been a factor in only one patient correctly guessing their treatment. Following 12 weeks of treatment with 200mg riboflavin daily, no significant difference in the primary outcome (number of patients achieving a 50% or greater reduction in number of attacks) was found. There was also no significant difference in migraine severity. Where duration was recorded, there was again no significant difference in the riboflavin group compared to placebo.[6]
Another randomised double-blind controlled trial used a 40-week crossover design to assess the effects of riboflavin 50mg daily for 16 weeks in patients between 6-13 years of age. Carotene was used as a placebo in this study, as it is known to produce a similar discolouration of the urine as riboflavin. Again, no significant difference was found between number of attacks when taking riboflavin compared to placebo, nor was there any significant change in intensity or duration of the attacks. Interestingly, 20 of the children included in the study also suffered from tension-type headaches, and a significant reduction (p=0.04) in the frequency of these type of headaches was found where riboflavin was taken. However, this group is likely too small to draw any conclusions from.[7] An accompanying commentary piece on this paper cites reasons such as the relatively low dose of riboflavin, possibly reduced absorption if it is not taken with food, and high placebo responder rate as reasons for the lack of significant difference.[8]
A retrospective examination of 41 patients aged 8-18 did find a significant reduction in migraine frequency (21.7 attacks ± 13.7 vs 13.2 ± 11.8, p<0.01). Headache intensity was also found to significantly decrease (2 ± 0.5 vs 1.4 ± 0.9, p<0.001). Doses used in this study were either 200 or 400mg, with no statistical significance in response rate between the doses. This trial is limited by the lack of placebo control group, which the authors believe would be unethical due to the migraine severity of the children included in the study.The retrospective nature of the study, lack of control group and unconventional study design may be insufficient to rule out a placebo response, regression to the mean, or investigator bias.[9]
Safety
Riboflavin appears to be well-tolerated. It may cause a discolouration of the urine. Diarrhoea and polyuria have been reported in patients using doses 400mg per day.1One child taking riboflavin reported new onset of tension headache during the Maclennan trial, though causality has not been established.6
Despite the authors’ claim that riboflavin is “devoid of adverse effects”, in the retrospective trial described above one child experienced vomiting which necessitated discontinuation of treatment. One child in this study also experienced an increased appetite which was not associated with weight gain.9
Summary
Two randomized, placebo controlled trials, though limited in size, did not find any significant effect of riboflavin on migraine duration, intensity, or frequency. One poorly designed retrospective study found conflicting results.
There is currently no compelling evidence to suggest that riboflavin is effective in preventing migraines in children or adolescents.
Riboflavin appears to be well tolerated. Adverse effects in children may include vomiting and discolouration of the urine.
UK Guidelines advise that riboflavin may be useful in preventing migraines in adults. Guidelines do not recommend the use of riboflavin in children or adolescents of less than 12 years for this purpose.
Limitations
This Q&A looks only at the use of riboflavin in children and adolescents up to 18 years and over. It does not include data for riboflavin used in combination with other agents.
Quality Assurance
Prepared by
Hayley Johnson, Regional Drug & Therapeutics Centre, Newcastle
Date Prepared
18th November 2013
Checked by
Nancy Kane, Regional Drug & Therapeutics Centre, Newcastle
Date of check
20th December 2013
Search strategy
Embase:
*Riboflavin AND *Migraine [limit to: (Human Age Groups Adult 18 to 64 years or 65+ years
Medline
*Riboflavin AND *Migraine disorders [limit to: Humans and (Age Group All Adult 19 plus years)]
In-house resources
Micromedex
Medicines Complete
References
1
Available throughNICE Evidence Search at
[1] Therapeutic Research Facility: Riboflavin monograph. Natural Medicines Comprehensive Database. Accessed via on 6th November 2013
[2] National Institute of Health and Care Excellence and the National Clinical Guideline Centre. Clinical Guidance CG150: Headaches. September 2012. Accessed via on 6th November 2013
[3] Migraine. Clinical Knowledge Summaries, Last revised August 2013. Accessed via on 7th November 2013
[4] Sparaco M, Feleppa M, Lipton R et al. Mitochondrial dysfunction and migraine: evidence and hypotheses. Cephalagia 2006; 26: 361-372
[5] Di Lorenzo C, Pierelli F, Coppola G et al. Mitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs. Neurology 2009; 72(18):1588-1594
[6] Maclennan S, Wade F, Forrest K et al. High Dose Riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial. J Child Neurol 2008; 23:1300-1304
[7] Bruijn J, Duivenvoorden H, Passchier J et al. Medum-dose riboflavin as a prophylactic agent in children with migraine: a preliminary placebo –controlled, randomised, double-blind, cross-over trial. Cephalagia 2010; 30(12): 1426-1434.
[8] O’Brien H and Hershey A. Vitamins and paediatric migraine: riboflavin as a preventative medication. Cephalagia 2010; 30(12): 1417-1418
[9] Condo M, Posar Am Arbizzani A et al. Riboflavin prophylaxis in pediatric and adolescent migraine. J Headache Pain 2009; 10: 361-365.