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Three Part Question

In[children and adolescents with migraine] does [riboflavin prophylaxis] reduce [frequency, duration or severity of migraine attacks]

Clinical Scenario

A 13 year old adolescent presents to emergency department with one day history of unilateral headache associated with phonophobia and photophobia which gets better on lying down in a dark room after taking NSAIDs. There is a past history of recurrent headaches of similar nature and frequency has increased over past two months (4-5 episodes/month) and response to NSAIDS has also reduced. This affects his quality of life in terms of missed school days. After complete history and examination, a diagnosis of migraine is made. I wonder if migraine prophylaxis should be considered and if riboflavin is effective prophylactic medicine in reducing the frequency, duration or severity of migraine attacks.

Search Strategy

PUBMED - Most recent evidence
COCHRANE library – May 2020
Riboflavin prophylaxis in children with migraine.

Search Outcome

17 papers were identified on PubMed of which four were full text articles and relevant. Two systemic reviews were identified on Cochrane library of which one was relevant. Two more articles were found from references of systemic review.Systemic review was excluded to avoid duplication.
Relevant papers are as follows
1) Riboflavin prophylaxis in pediatric and adolescent migraine.(Condo et al)
2) Prophylactic effect of riboflavin on paediatric migraine: A randomized, double –blind, placebo controlled trial. (Telbian et al.)
3) Medium dose riboflavin as a prophylactic agent in children with migraine:A preliminary placebo controlled,randomised,double blind,cross over trial.(Brujin et al)
4) Riboflavin as migraine prophylaxis in adolescents.(Athaillah et al)
5) High dose riboflavin for migraine prophylaxis in children:a double blind, randomised, placebo controlled trial.(MacLennan et al.)

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
MacLennon et al 2008 Australia	48 children with HIS criteria(International headache society) criteria migraine headaches, 5-15 year old	Double blind,placebo controlled randomised study	Reduction in frequency of migraine headaches after 3 months riboflavin prophylaxis.	No significant reduction in frequency of migraine headaches between riboflavin and placebo group. 14/21(66.6%) in placebo and 12/27(44.4%) in riboflavin group had 50% reduction in number of migraine attacks.(p=0.125)	Abstract only.
Condo et al 01/08/2009 Italy	41 children and adolescents 8-18 year old, who were treated with riboflavin for headaches at a specialised children neurology centre	Retrospective study	Reduction in migraine frequency and intensity, increase of responsiveness to systemic therapy	Significant reduction of mean attack frequency: 21.7+/- 13.7 vs 13.2 +/- 11.8 in phase 2(p value <0.01) 23.4+/- 12.2 vs 8.9+/- 9.4 in phase 2a(p value <0.01) 19.3+/- 13.4 vs 11.4+/- 9.6 in phase 2b(p value>0.05 Mean headache intensity: Significant reduction in intensity, effect continued atfollow up after stopping riboflavin propylaxis. Phase 2:Decreased from 2+/-0.5 to 1.6+/-0.8 (p value ,0.01), Phase 3: Decreased from 2+/-0.5 to 1.4+/- 0.9 (p value <0.01) Response to systemic medications: 5 patients(12.5%): no use of systemic drugs in phase 2 and 3- complete remission/mild and infrequent occurrence. 27/35(77%): report systemic drugs to be more effective.	Retrospective study design Study sample taken from Specialised neurology centre No placebo control
Telbian et al 02/01/2018 Iran	90 children 5-13 year old with migraine	Randomised, double blind placebo controlled tri	Significant reduction in frequency and duration of migraine in high dose versus placebo group.	4/30(13.3%) in placebo, 6/30(20%) in low dose and 24/30(80%) in high dose riboflavin group had 50% or more decrease in frequency of migraine attacks(p value 0.000). Mean duration of headache attacks last month of prophylaxis between placebo and low dose riboflavin(0.30+/- 1.12 vs 0.30+/-1.12, p value 0.69. Mean duration of headache attacks among high dose versus placebo group(4+/- 3.49 vs 0.30+/- 1.12)(p value 0.000)	Comparatively lesser duration of riboflavin prophylaxis(3 vs recommender 4 months). Cross over design not performed.
Brujin et al 26/03/2010 Netherlands	42 children, 6-13 year old with HIS criteria migraine headaches and tension headaches	Double blind, placebo controlled, randomised, crossover trial design.	Reduction of frequency of migraine headaches and tension headache after 16 weeks of riboflavin and 16 weeks of placebo therapy separated by a 4 week washout period..	No significant reduction in frequency of migraine headaches between riboflavin and placebo therapy. Frequency reduced during riboflavin therapy ( 3.60/month at baseline to 2.05/month) vs placebo therapy(3.05/month at baseline to 1.4/month)(p value= 0.44) Significant reduction in tension headache frequency by riboflavin compared to placebo. (p= 0.04)	Relatively low dose of riboflavin used as compared to other studies in children
Athaillah et al December 2010 Indonesia	98 adolescents 12-19 year old	Randomized double blind placebo controlled trial	Significant reduction in frequency and duration of migraine headaches in riboflavin vs placebo group.	Duration and frequency of headache were significantly less in 2nd and 3rd month of study for riboflavin versus placebo.(p value 0.012 and 0.001 in 2nd and 3rd month respectively) Functional disability significantly reduced in riboflavin group.(p value 0.001)	Baseline characteristics of groups and any statistically significant differences not stated clearly.

Comment(s)

Migraine is a common neurological disorder which has a prevalence of 3% in early childhood and 23% in adolescence. Increased intensity and frequency of migraine can cause a relevant impaired quality of life in terms of missed school days, less leisure and family time. In such cases with increased severity, an effective prophylactic treatment can help to reduce the severity of migraine and improving the quality of life. Riboflavin is a safe, well tolerated and inexpensive medication that is thought to prevent the migraines by improving the brain mitochondrial functions. Riboflavin has demonstrated efficacy in reduction of frequency in adult patients migraines. There is mixed data on riboflavin efficacy in reducing the frequency, intensity and duration of migraines in children.

Clinical Bottom Line

Riboflavin shows a mixed effect in reducing the migraine severity by reducing the intensity, frequency or duration of migraine attacks in children. However, adequately powered RCTs are required to demonstrate the efficacy. Currently, there is insufficient evidence to support the routine riboflavin prophylaxis in children.

References

1. MacLennan SC, Wade FM, Forrest KML, Ratanayake PD, Fagan E, Anthony J. High dose riboflavin for migraine prophylaxis in children:a double blind, randomised, placebo controlled trial.(
2. Condo M, Posar A, Arbizzani A, Parmeggiani A Riboflavin prophylaxis in pediatric and adolescent migraine.
3. Telbian et al Prophylactic effect of riboflavin on paediatric migraine: A randomized, double –blind, placebo controlled trial.
4. Brujin et al Medium dose riboflavin as a prophylactic agent in children with migraine:A preliminary placebo controlled,randomised,double blind,cross over trial.(
5. Athaillah et al Riboflavin as migraine prophylaxis in adolescents.