Prophylaxis of migraine headaches with riboflavin: A systematic review

Migraine headache is a relatively common, debilitating condition that costs our healthcare system over 78 billion dollars per year. Riboflavin has been advocated as a safe, effective prophylactic therapy for the prevention of migraines. The purpose of this study was to provide a systematic review of the current role of riboflavin in the prophylaxis of migraine headache. A MEDLINE literature search inclusive of the dates 1966-2016 was performed using the search terms: riboflavin and migraine disorders. Excerpta Medica was searched from 1980 to 2016 using the search terms: riboflavin and migraine. Additionally, Web of Science was searched using the terms riboflavin and migraine inclusive of 1945-2016. Bibliographies of all relevant papers were reviewed for additional citations. We utilized the PRISMA guidelines to select English language, human, clinical trials of riboflavin as a single entity or in combination, review articles, and supporting pharmacokinetic and pharmacogenomic data assessing the efficacy and mechanism of riboflavin therapy in the prophylactic treatment of migraine headache. A total of 11 clinical trials reveal a mixed effect of riboflavin in the prophylaxis of migraine headache. Five clinical trials show a consistent positive therapeutic effect in adults; four clinical trials show a mixed effect in paediatric and adolescent patients, and two clinical trials of combination therapy have not shown benefit. Adverse reactions with riboflavin have generally been mild. Riboflavin is well tolerated, inexpensive and has demonstrated efficacy in the reduction of adult patient's migraine headache frequency. Additional data are needed, however, to resolve questions involving pharmacokinetic issues and pharmacogenomic implications of therapy. Migraine headache is a common, often disabling neurologic condition characterized by painful headaches associated with nausea, vomiting, and hypersensitivity to visual, auditory, and olfactory stimuli. The worldwide prevalence of migraine headache is about 10%; however, it is slightly higher in the United States at 12%.1, 2 Women experience migraine headache at a greater rate (15%-17%) as compared to men.1, 3 Epidemiologic data suggest that while 38% of patients with migraine headache need prophylactic therapy, only 3%-13% currently take prophylactic treatment.4 Prophylactic therapy should be considered in situations where the patient feels that the recurring migraine headaches interfere with their daily routines and responsibilities despite acute treatment.1-4 The goals of treatment for patients requiring prophylactic therapy are to decrease the frequency, duration and severity of attacks, reduce disability and allow acute treatment to work more effectively.5, 6 Migraine headache sufferers often experience substantial decreases in work productivity and function. This can result in a decreased quality of life for the patient and high financial burdens on individuals and employers. A conservative estimate of the cost of migraine-related costs in the United States is calculated to be $78 billion dollars per year.7-9 Obviously, effective prophylactic therapy for the prevention of migraine headaches could dramatically decrease the cost of health care for these patients and improve their quality of life. The pharmacotherapy of migraine headache prophylaxis begins with the goals of therapy in mind.10, 11 Drug therapy considerations include the evidence available supporting its efficacy, adverse event profile and the presence of comorbid conditions.12-14 Consideration should be given to medications with Level A ratings by the American Academy of Neurology (AAN).6, 15 These drugs include sodium valproate, topiramate, certain beta-blockers (metoprolol and propranolol), and frovatriptan. Level B medications include antidepressants (tricyclic and selective serotonin receptor inhibitors), additional beta-blockers (atenolol and nadolol), and additional triptans (naratriptan and zolmitriptan). Riboflavin is classified as a Level B medication according to the AAN evidence-based rating. Picking a specific drug therapy involves tailoring the agent to any comorbidity the patient may have present. For example, if a patient has concurrent epilepsy, sodium valproate or topiramate might be given greater consideration. If cardiovascular disease is present, a beta-blocker might be strongly considered. If weight loss would be advantageous, topiramate might be a preferred option or if the patient is underweight, a tricyclic antidepressant might be considered. If underlying depression is an issue, antidepressants should be considered and beta-blockers avoided. Additionally, the available triptan agents are used for the short-term prophylaxis of menstrually related migraine headache. Monotherapy is the preferred first step, starting with low doses and titrating upwards. An adequate trial should consist of a minimum of 3 months or longer depending on the specific therapy chosen.6, 10, 11, 15, 16 Brain energy metabolism has been found to be abnormal in migraine headache.17 Riboflavin catalyses the activity of flavoenzymes in the mitochondrial respiratory chain and improves the clinical and biochemical abnormalities in patients with inborn errors of mitochondrial metabolism.18, 19 As mitochondrial deficits are suspected in some patients with migraine headache, riboflavin has been evaluated in clinical trials for prophylactic treatment. The purpose of this study was to provide a systematic review of the efficacy and adverse effects of riboflavin as a prophylactic agent in the treatment of migraine headaches. In addition, we have explored the pharmacogenomic and pharmacokinetic influences that might affect the therapeutic action or adverse drug event profile of riboflavin for this use. To provide systematic and transparent reporting, we incorporated the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.20 Our literature search consisted of MEDLINE (1966-2016) searching the Medical Subject Headings (MeSH) terms riboflavin and migraine disorders. Web of Science (WoS) (1945-2016) was also searched using the terms: riboflavin and migraine. Excerpta Medica (1980-2016) was searched using EMBASE with the EMTAG terms: riboflavin and migraine. Only English language articles were considered in our literature evaluation. Bibliographies of all relevant papers were reviewed for additional citations. See Figure 1 for inclusion and exclusion criteria. The mechanism of riboflavin absorption in humans is through active transport.21, 22 Therefore, the process is specific, saturable and competitive, that is structures similar to riboflavin can compete with its absorption. Riboflavin is mainly absorbed in the upper ileum of the human intestine.23 It has been reported that the absorption of riboflavin follows linear pharmacokinetics with up to 30 mg when given with food, and the absorption half-life was reported to be 1.1 hours.21 Zempleni and colleagues24 reported that a maximum of 27 mg of riboflavin per adult was absorbed after a single dose of riboflavin. The study was conducted using 20 mg, 40 mg and 60 mg doses of the vitamin, and there was no significant difference observed between maximal serum concentrations and area under the curve for the aforementioned doses. Factors, such as the aqueous solubility of the vitamin, the release kinetics of riboflavin from its source (such as food or dosage form), ingestion of vitamin with meal vs without meal, quantity of water consumed and saturable nature of active transport system can affect the bioavailability of the vitamin.22-26 Riboflavin is rapidly equilibrated between central and peripheral compartments. It first distributes into the central compartment and then enters into the peripheral compartment in the body.27 The elimination half-life of riboflavin is approximately one hour.24A delay in the tissue uptake of the vitamin occurs which is attributed to specific transport proteins required for the vitamin to penetrate through the cell membranes.25 Riboflavin is primarily excreted unchanged in urine. Other routes of excretion, such as secretion into the breast milk, may also contribute to the overall excretion of the vitamin.14, 18 Elimination of riboflavin in bile has been reported to be negligible (less than one per cent is eliminated through the bile in humans).21, 27 The exact cause of migraine headaches is not fully known at present. The pathophysiology of migraine headache is complex and involves many diverse dysfunctional areas in the brain ranging from a hyperexcitable frontal lobe to hypo-energetic mitochondria which can result in vascular dysfunction, cranial vasodilation and the release of a host of unbalanced neuromodulators including dopamine, norepinephrine and glutamine.19, 28 A genetic contribution to the aetiology of migraine headache has been suggested by studies which support an estimated 50% hereditability in identical twins.18 Further evidence comes from observations that at least 50% of patients suffering from migraine headache has a parent who reported similar symptoms29 and that the risk is higher in people who have relatives affected by it than the general population.30, 31 One of the major genetic disorders that has been linked to migraine headaches is dysfunctional mitochondria.32 Wang and co-workers proved a link between migraine headaches and cyclic vomiting with variations in gene sequence of mitochondrial DNA (mtDNA).33 Mitochondria, also known as the power house of the cell, and the nucleus are the only two human cell organelles that possess a distinct DNA called mtDNA and nuclear DNA, respectively. Because of the lack of chromatin protection and a reduced DNA repair system in the mitochondria, the chances of mtDNA mutation are 10-20 times higher than nuclear DNA. As most of the cellular oxygen is utilized by mitochondria (almost 90%), dysfunctional mitochondria can result in the generation of reactive oxygen species which results in oxidative stress to the organelle.32, 34 The production of free radicals in the mitochondria increases the probability of mtDNA mutation, which can lead to cell death.35 Di Lorenzo et al.36 have investigated the relationship between the therapeutic responses of patients with migraine headache to riboflavin with its association with specific mtDNA haplogroups. It is known, for example, that non-H haplotype mtDNA is less metabolically active than H haplotype mtDNA. The authors postulated that riboflavin might be more effective in non-H haplotype mtDNA migraine headache sufferers than those with H haplotype mtDNA. Their results found that patients with non-H mtDNA haplotypes responded significantly better to riboflavin treatment (77%) than with H mtDNA haplotypes (44.8%) (P<.01). In addition, they found a significant reduction in mean monthly attack frequency between baseline and the fourth month of riboflavin monotherapy in the total population of patients treated (P<.001). These data suggest that riboflavin may be more effective in patients with certain genetic features and less effective in others. While very preliminary, these results suggest the possibility of tailoring riboflavin therapy to patients with specific genetic profiles in the future.36 The American Academy of Neurology (AAN) has established an evidenced rating system for clinical trial data to evaluate therapies for the treatment of episodic migraine headache prevention. This system involves the rating of clinical trials as Class I, II, III or IV depending on the rigour of the study's methodology.6, 37 These classifications of clinical trials are then used to provide evidence-based guidelines for various pharmacologic treatments for migraine headache prevention. Level A recommendations require ≥2 Class I trials; Level B requires one Class I or two Class II studies; Level C requires one Class II study and Level U represents inadequate or conflicting data. These classifications are used throughout the study to provide insight into the relative quality of the data analysed. In addition, the Canadian Headache Society38 study quality parameters and European Federation of Neurological Sciences39 rating systems are mentioned to provide a broader picture of the relative efficacy of riboflavin in migraine headache prevention. (See Tables 1, 2 and 3). American Headache Society/American( ) Academy of Neurology6 (2012) Level A: established as effective (≥2 Class I trials Level B: probably effective (1 Class I trial or 2 Class II studies) Level C: possibly effective 1 Class II trials Level U: (Inadequate or conflicting data) B Canadian Headache Society39 (2012) The overall recommendation is graded as strong or weak based on assessment of the balance of benefits and harm. Each drug is also assigned an evidence quality recommendation from high, moderate, low or very low Strong recommendation, Low-quality evidence European Federation of Neurological Societies38 (2009) Level A: drugs of first choice Level B: drugs of second choice; evidence of efficacy less effective or more effects than Level A Level C: drugs of choice; probably effective C et et et (2009) et et Class Class Class Class Class Class Class Class Class In and conducted a Class I study riboflavin vs in a patients Headache for migraine headache with and without were assigned to riboflavin or mg of and mg of The study was 3 months in duration with the of in attack frequency from the to the month of treatment. were the of migraine severity in the patient's duration of headache and with and an significant were found in attack frequency and of One patient in the riboflavin and one one patient in the Five not the was by in this study was were not and a longer study could the with riboflavin and a Class II study in riboflavin compared to sodium valproate in the prophylaxis of migraine headache. This was a study in migraine headache were to of riboflavin or of sodium valproate over a for not include patients who migraine headaches with and without for at least 6 months the with or underlying such as disease or with or patients were were frequency and severity of migraine headache at and month as by the patient after with the of a Adverse effects were also as of the were in the two from the riboflavin and from the sodium valproate treatments in in the frequency, duration and severity of migraine headaches not significantly from Riboflavin decreased the of from to while sodium valproate reduced the frequency from to patients adverse effects the study with a higher in the sodium valproate The observed adverse effects weight and Further on adverse were not While this study demonstrated the of riboflavin to sodium valproate, it also demonstrated a significantly risk of adverse effects with riboflavin. of the study were the lack of for migraine of baseline between and associated and the nature of the and evaluated riboflavin in an Class III study with patients migraine headache criteria. of riboflavin over a of were the frequency of which was reduced from to 2 The of drugs also decreased from to Headache and headache not patients and and in an study in evaluated patients with migraine headache with and without patients at least two no prophylactic therapy for the 3 In this Class III patients were treated with of riboflavin over a The first patients also mg of the authors not the patients would to a vitamin was by a as the mean between a disease severity by the patient on a and the of as by review of the was with of the patients a 50% or greater reduction of monthly migraine headache significant were found between the riboflavin and the riboflavin One patient from the study of additional adverse drug were In a Class IV et compared of to of riboflavin. 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