Riboflavin for migraine prophylaxis?

 A systematic review and meta-analysis found that riboflavin (vitamin B2) has significant benefit in migraine prophylaxis, including decreases in the number of migraine days, duration and frequency (see migraine riboflavin prophy NutrNeurosci2022 in dropbox, or doi.org/10.1080/1028415X.2021.1904542)

 

Details:

 -- nine articles were included in this systematic review and meta-analysis: eight randomized controlled trials and one controlled clinical trial were analyzed, with an overall total of 678 individuals

    -- the overall sample sizes ranged from 26-130 adult subjects with varying doses of riboflavin

    -- the intervention groups were on 400 mg of vitamin B2 daily in eight studies, 100 mg in one

-- four of the studies compared vitamin B2 to other migraine prophylactics (propranolol 80 mg, valproate 500 mg, metoprolol 200 mg or bisoprolol 10 mg, and aspirin 75 mg)

-- overall these studies were felt to have low risk of bias

 

Results:

 -- review of their studies:

    -- open-label study of riboflavin 400 mg but no comparison (n=23): decreased frequency and decreased use of abortive drugs with riboflavin

    -- riboflavin 400 mg versus placebo (n=55): decreased frequency and days of migraine

    -- riboflavin 400 mg plus magnesium 600 mg plus coenzyme Q10 50 mg versus placebo (n=130): decreased pain intensity and pain score, provided migraine prophylaxis

    -- riboflavin 100 mg versus propranolol 80 mg (n=100): both found reduction of migraine frequency, duration, and severity of headache; no significant difference between riboflavin and propranolol; adverse effects were significantly less with riboflavin

    -- riboflavin 400 mg combined with magnesium 300 mg and the herb feverfew 100 mg versus riboflavin 25 mg (this low dose riboflavin was used as placebo, to mimic the bright yellow color of the urine as found with a higher doses of riboflavin),  (n=120): no significant difference was found, with similar efficacy of this combo to the riboflavin 25 mg for prophylaxis

    -- riboflavin 400 mg a day versus valproate 500 mg (n=90): no significant difference in effect, riboflavin had fewer side effects. riboflavin did provide prophylaxis

    -- riboflavin 400 mg per day versus placebo (n=80): significant reduction in the frequency, days, and pain score of migraine; no difference in placebo group. few adverse effects.

    -- riboflavin 400 mg per day versus metoprolol 200 mg and bisoprolol 10 mg (n=26): beta blockers were significantly better than riboflavin

    -- riboflavin 400 mg a day versus aspirin 75 mg per day (n=54): no significant difference between the groups; riboflavin did provide migraine prophylaxis

  

-- Summary evaluation (this is a rough calculation based on quite different results in the quite different studies):

    -- riboflavin 400 mg might decrease the number of migraine days by 2-3 days per month

    -- riboflavin might also decrease migraine duration by 0.4 to 10 hours

    -- riboflavin also seems to decrease migraine frequency by about 2 attacks per month

    -- riboflavin was associated with significant decrease in migraine severity by 68.2%

 

Commentary:

 -- migraine headaches are remarkably common, with the World Health Organization in their Global Burden of Disease Study ranking severe migraine in the “highest disability class”: https://jamanetwork.com/journals/jamaneurology/fullarticle/776117 , and a 2019 study finding an estimated global prevalence of migraine increasing from 721.9 million in 1992 to 1.1 billion in 2019, indicating a global prevalence on the order of 14 to 15%, with 45.1 million YLDs (years of life lived with disability): https://pubmed.ncbi.nlm.nih.gov/30353868/

-- migraine also is relatively undertreated: A 2007 study based on questionnaires of 262,576 individuals found a prevalence of migraine of 11.7%. only 13% of patients were currently taking preventive medications and 43% had never used any preventive treatment, though per recommendations 26% should have been on prophylaxis: https://pubmed.ncbi.nlm.nih.gov/17261680/

 

-- the mechanism by which riboflavin works is a bit unclear; it does improve energy generation in the mitochondria and can potentially ameliorate the mitochondrial dysfunction that seems to be associated with the development of migraine

 

-- just to provide a bit more granularity to the above studies, i did review the second study noted above:

    -- A three-month Belgian study (DOI: 10.1212/WNL.50.2.466 ) of 55 patients who had a history of migraines for at least a year and between 2 to 8 attacks per month were randomized to three months of riboflavin 400 mg versus placebo, finding that riboflavin was superior in reducing attack frequency by 2 attacks/month (p=0 .005) and headache days (p=0.012); the proportion of patients who improved at least 50% of those on riboflavin was 59% versus 15% for placebo (p=0.002) and a number needed to treat for effectiveness was 2.3

    -- adverse effects were minor (two had diarrhea and polyuria in the riboflavin group) and one had abdominal cramps in the placebo group

 

-- the American Academy of Neurology and the American Headache Society published guidelines in 2012 that were reaffirmed in 2022 (https://www.neurology.org/doi/10.1212/wnl.0b013e3182535d20): they listed an array of medications with different levels of recommendations, but did not include riboflavin in this guideline

 

-- This current study found a few things:

    -- riboflavin (vitamin B2) taken daily for three continuous months had a significant effect in decreasing migraine days, migraine duration, and migraine frequency (however there are very few studies on pain score, so no statistically significant effect was determined)

    -- the study had limited information on the appropriate riboflavin dose (almost all were on 400 mg per day):

       -- the one study with 100 mg, and another using 25 mg as a placebo, had similar results to the 400 mg dose

       -- the recommended daily allowance (RDA) for riboflavin is 1.3 mg per day for men and 1.1 mg a day for women

       -- but, is there a danger and taking too much riboflavin? Milk and dairy products are rich in riboflavin. Riboflavin is a water-soluble vitamin, and gut absorption is limited with the excess quickly excreted in the urine:  https://www.ncbi.nlm.nih.gov/books/NBK525977/. So, it seems that riboflavin is reasonably safe in these high amounts, though patients should be advised that the urine might turn a bright yellow color

            -- though, is there a danger in having an imbalance in B vitamins? These B vitamins do seem to work together in the body. And most people who eat well have an appropriate combination of B vitamins. Is giving a large quantity of a specific one (vitamin B2) appropriate? Is it reductionist to assume that a single B vitamin in high quantity is healthy? especially for the long-term? Many women in the childbearing age seem to have a high risk of migraine. Is a high dose of vitamin B2, especially disproportionally high compared to other vitamins, going to affect a fetus? On the other hand, vitamin B2 might well be a lot safer than the standard migraine prophylactic medications…

 

-- It should be noted that the benefits of riboflavin supplementation on migraine frequency could take three months or so

-- all the studies that compared riboflavin to the more standard medical therapies (beta blockers, valproate) found relatively equivalent effects between riboflavin and these meds

  

Limitations:

-- this systematic review and meta-analysis is the single worst-edited journal article I have personally ever read: large numbers of typos, the whole section evaluating pain score with riboflavin actually is just a copy of the section on migraine frequency with no mention of pain score, and there are blatantly contradictory statements (as only one example, the abstract states that there were 673 subjects overall but there actually were 678) . And this is in a peer-reviewed journal!!!! I have checked out several of their articles included in the analysis, and I am reasonably confident that the results and conclusions noted above are accurate. But, the quality of this article (which was not retracted or amended) does raise pretty big issues of what “peer review” actually means.

-- This meta-analysis involves combining very different studies with different interventions and different measurements and having pretty different results. The above summary numbers reflect the synthesis of these disparate studies into average effects. the large diversity of the studies, and their different biases, might be mitigated by a large well-conducted randomized controlled trial (which should not be hard to do, given the very large number of patients with moderate to severe migraines)

    -- and these studies did have pretty small numbers of people involved, likely a factor in the outcome differences

-- from the study, we do not have a clear understanding of what the dose of riboflavin should be: most studies were done at 400 mg, one study was at 100 mg (the one comparing riboflavin 100 mg to propranolol 80 mg and finding no difference in results), and one study using the 25 mg dose in the placebo (as a means to mask riboflavin-induced urinary color change between the intervention and control groups), finding no difference between the 25 mg and 400 mg in migraine prophylaxis.

-- The studies cited above were somewhat limited, most involved females (up to 90%) and most involved people 35 to 47 years old. In addition, most patients had migraine without aura or complex migraine. These limitations may make generalizability of the results difficult

so, pretty intriguing:

-- the aggregate data in this constellation of small studies does suggest that riboflavin might well work for migraine prophylaxis, decreasing the important quality-of-life issues of the number of migraine days, duration and frequency

-- the dose of riboflavin needed is pretty unclear, though most studies did employ the 400mg dose

-- riboflavin in these small studies did seem as good as our typical medications, with  fewer adverse effects (but beware of the bright yellow urine!!!)

-- we really do need a large, well-conducted (and well-written) RCT to formally determine the role of riboflavin in migraine prophylaxis

-- but, in the meantime, many patients may be interested in a more natural medication for migraine prophylaxis. and it does seem that even now (without better studies) we should discuss riboflavin as an option with patients...

geoff

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