Current issues of ACP Journal Club are published in Annals of Internal Medicine


High-dose riboflavin reduced the frequency of migraine headaches

ACP J Club. 1998 Sep-Oct;129:33. doi:10.7326/ACPJC-1998-129-2-033

Source Citation

Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology. 1998 Feb;50:466-70.



Can high-dose riboflavin prevent migraine headaches?


Randomized, double-blind, placebo-controlled trial with 3-month follow-up after a 1-month baseline period.


6 study centers in Belgium and the Grand Duchy of Luxembourg.


55 patients who were 18 to 65 years of age (mean age 36 y, 78% women) who met the International Headache Society criteria for migraine with or without aura; had a history of migraine for ≥ 1 year, 2 to 8 migraine headaches/mo, ≤ 5 days of interval headaches/mo, no analgesic or ergotamine overconsumption, and no serious organic or psychiatric disease; and used adequate contraception (women only).


All patients received placebo for a 1-month baseline period. If they had ≥ 1 migraine during that time, they were allocated to oral riboflavin (Riboflavinum D 2914A, Federa, Brussels), 400 mg/d (n = 28), or to placebo (Avicel RC 581®, 850 mg, and β-carotene, 0.473 mg) (n = 27). Study medications were randomized in 10 blocks of 10 packages; each block comprised 5 riboflavin and 5 placebo treatments.

Main outcome measures

Proportion of patients with ≥ 50% improvement in headache frequency (change in frequency of headaches in month 4 compared with baseline month 1), headache days, and migraine index (headache days and mean severity). Data on headaches (severity, nausea and vomiting, medication taken, and duration of headache) were recorded in patient diaries.

Main results

Analysis was by intention to treat (although 1 patient was excluded from the analysis because of protocol violation). Proportion of patients who had ≥ 50% improvement was higher for the riboflavin group than for the placebo group for headache frequency (P = 0.01), headache days (P = 0.002), and migraine index (P = 0.01) (Table). The groups did not differ for the number of patients who had adverse effects (2 patients vs 1 patient).


Patients who received high-dose oral riboflavin had greater improvement in the frequency of migraine headaches, the number of headache days, and a migraine index reflecting headache days and severity than did patients who received placebo.

Source of funding: Belgian Migraine Society.

For correspondence: Dr. J. Schoenen, Department of Neurology, University of Liège, CHR Citadelle, Bld. du 12ème de Ligne, 4000 Liège, Belgium. FAX 32-4-2256451.

Table. Proportion of patients with ≥ 50% improvement in outcomes for riboflavin vs placebo at 3 months*

Outcomes Riboflavin Placebo RBI (95% CI) NNT (CI)
Frequency of headaches 54% 19% 179% (262 to 566) 3 (2 to 11)
Headache days 57% 15% 271% (56 to 870) 3 (2 to 6)
Migraine index 39% 8% 411% (46 to 1850) 4 (2 to 10)

*Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data provided by author.


Over the past decade, the introduction of sumatriptan and other 5HT 1B/1D agonists has focused attention on the role of serotonin in migraine treatment. Increased understanding of the complex cascade of events that culminates in the clinical expression of migraine, however, suggests that there must be more than one way to stop a migraine.

Evidence implicates aberrations in brain energy metabolism in the pathogenesis of migraine (1). The occurrence of migraine-like headaches in the MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome has also been noted (2). Encouraging results from the use of high-dose riboflavin (a precursor of the flavoenzymes involved in brain energy production) in the MELAS syndrome led Schoenen and colleagues to test its use in migraine, and the results were impressive.

This 4-month trial, done in accordance with established International Headache Society guidelines, showed that riboflavin had a marked effect on headache frequency but less effect on severity. This is similar to effects seen with other prophylactic agents and suggests that these drugs act by raising the threshold necessary to induce a headache, but do less to interfere with subsequent factors that affect headache severity once the headache has begun. The benefits of riboflavin became significant only at 4 months, underscoring the need for patience and careful headache diaries if these results are to be applied to clinical practice.

The favorable risk-benefit ratio of riboflavin (number needed to treat = 3) and excellent tolerance suggests that current use may be appropriate in patients who need prophylaxis (patients with > 2 headaches/wk). Additional studies will help to confirm the benefits, more clearly define the optimal dose, and clarify the subgroup of patients most likely to benefit from treatment.

Elizabeth Loder, MD
Spaulding Rehabilitation HospitalBoston, Massachusetts, USA


1. Samuels MA, ed. Office Practice of Neurology. New York: Churchill Livingstone; 1996:1142.

2. Welch KM, Levine SR, D'Andrea G, Schultz LR, Helpern JA. Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy. Neurology. 1989;39: 538-41.