By Mary L. Hardy, MD
Migraine, defined as an episodic headache disorder accompanied by neurological symptoms, is one of the most debilitating and under-diagnosed neurological conditions afflicting otherwise healthy people. Migraine headaches are most common in people aged 35-45 years and affect more than 11 million Americans (6-8% of men and 18% of women). As many as 5.5 million patients (3.4 million women and 1.1 million men) experience at least one migraine attack per month. Patients complain of increased sensory sensitivity, gastrointestinal disturbances, vasomotor symptoms, and pain, which can be disabling. Self-reports of pain intensity are high, rating an average of 7 on a 10-point scale.1-4
Although the direct costs of treating migraine headaches are significant, the indirect costs, including decline in quality of life, are much greater. If decreased productivity and absence from work are included in the determination of economic costs, 51% of women and 38% of men have experienced six or more lost work- day equivalents per year as calculated in a recent study.5 Further evaluation including these factors shows that combined direct medical and other indirect costs were 25% greater for all migraine patients compared to controls according to an economic analysis, but for more severely affected patients the costs were more than 50% greater.6 Thus, migraine is a common illness associated with significant costs for patients, the medical system, and the general economy. Management of the frequency, severity, and symptoms of attacks would be valuable.
Despite the marked symptoms and disability associated with migraines, 31% of American patients with frequent migraines (more than six per year) reported in a telephone survey never seeing a doctor for diagnosis or care.7,8 In fact, up to 57% of people who meet the criteria for migraines have not been diagnosed by a physician.9 It is therefore not surprising that the most popular therapy for these patients was over-the-counter (OTC) medications (49%), followed by prescription medication only (23%), and combinations of prescription and OTC medications (23%).10
Despite new choices for abortive and prophylactic therapy,11 compliance with prescribed medications for migraine is not high. Two-thirds of migraine sufferers reportedly delayed or avoided doses of prescribed medications due to concerns about side effects, even if needed to treat active attacks.12 Many patients do not find prophylactic therapy effective enough to continue. Realistic estimates of therapeutic gain for conventional prophylaxis is in the range of 30-40%.13 Finally, the majority of prophylaxis users quit or change therapy quickly, with the median duration of use equal to 2.8 months.14 Even the most popular prophylactic therapy in one study, valproic acid, only had a retention rate of 40% at one year. Therefore, a safe, effective, easily available alternative for prophylaxis would be of interest to most migraine patients.
CAM Therapies for Headache
As with many other chronic conditions for which conventional therapy has not been completely effective, headache sufferers commonly turn to complementary and alternative (CAM) therapies for relief. A survey of attendees at the headache clinic of a tertiary care medical center showed that 85% of the patients had used CAM therapies and rated them to be of benefit 60% of the time.15 Efficacy for alternative therapy was reported despite the fact that these patients were, in general, severely affected by their disease and had failed multiple attempts at conventional care. Migraine headaches were the most common type of headache experienced by this group, while massage therapy (42%), meditation (37%), and exercise (30%) were the most commonly used therapies. However, use of herbs (15%) and vitamins/nutritional supplements (14%) also were reported.15
Because of similar findings, some experts have recommended trying safe and possibly effective CAM therapies for selected patients.16 One review article cites positive evidence for magnesium, feverfew, and riboflavin and recommends their use in combination.17
Mechanism of Action for Magnesium and Riboflavin
A role for magnesium in the pathogenesis of migraines has been suggested by a variety of evidence.18 Low systemic magnesium (Mg) levels have been demonstrated in the serum, saliva, erythrocytes, monocytes, and/or central spinal fluid of migraineurs.19-26 However, it may be ionized Mg, not total Mg, that is most closely correlated with migraines.
In one series, serum Mg was observed to be normal while serum ionized Mg was low in 42% of migraine patients measured during an attack.26 A similar observation was made in subjects with menstrual migraine.27 Although there were no differences in total Mg levels between groups, the percentage of subjects with low ionized Mg was high (45%) during menstrual migraines and quite low during menstruation without migraines or between attacks (15%). In addition, the ratio of ionized calcium (Ca) to Mg was high, suggesting that while Mg levels were low, Ca levels were normal.
Further, the presence of a relative deficiency in Mg appears to be specific to migraine. The level of ionized Mg in red blood cells was significantly lower in migraine patients than in those suffering from tension headaches (85% vs. 9.5%).28
Finally, it was demonstrated that 20 migraine patients retained significantly more of an oral magnesium loading dose (3,000 mg of magnesium lactate in 24 hours) than healthy volunteers, again suggesting a greater retention of Mg in migraine patients (P < 0.0001).29 This evidence led investigators to postulate that migraine could be, at least in part, a Mg-deficiency disease and that Mg replacement could be an effective treatment.
Riboflavin (vitamin B2), first mentioned as a treatment for migraines in 1946, has been shown to work via a different mechanism than beta-blockers in the prophylaxis of migraine headaches.30 Mitochondrial dysfunction, resulting in impaired oxygen metabolism and deficient mitochondrial energy reserve, has been proposed to play a role in migraine pathogenesis.31-33 Riboflavin, a cofactor in the electron transport chain, is thought to have a key role in the oxidative phosphorylation of adenosine phosphate and therefore in intracellular energy production. In fact, a decrease in the phosphorylation potential of the brain has been demonstrated between attacks of both classic and common migraines, lending credence to this hypothesis.31,32
Magnesium. The strength of the association between low levels of Mg and migraine lends weight to the assumption that Mg replacement may be of benefit in treating or preventing migraine headaches. Mauskop and colleagues have reported on the efficacy of intravenous (IV) magnesium on the relief of a variety of headache types, including migraines.22,34 Forty consecutive patients suffering from migraine (n = 27) and other types of acute headaches were enrolled in a case comparison trial conducted at an outpatient headache clinic.34 After measurement of serum ionized Mg, an IV infusion of 1 g of magnesium sulfate was administered. Response was generally good; 80% of the subjects reported at least a 50% decrease in pain within 15 minutes of the infusion (complete relief was reported for 26 of these responders). For 56% of the responding patients, relief was durable and the pain did not worsen over the next 24 hours. For 18 of the patients, pain relief lasted longer than 24 hours. These 18 patients with the most durable response had lower average serum ionized Mg levels than partial or non-responders. For migraine headache sufferers, good relief of associated symptoms such as photophobia and nausea also was reported.
This same research group reported similar results for 40 migraine patients enrolled in another open trial using a similar protocol.22 Thirty-five patients reported 50% or greater reduction in pain within 15 minutes of receiving an IV infusion of 1 g of magnesium sulfate. Again, lower serum ionized Mg levels were statistically more likely to be found in subjects with the best response to therapy (P < 0.001). Although these results were promising, the non-randomized design and the possibility that some of the patients in the second study also were included in the first trial limited generalizability of these findings. The results were, however, replicated by another research group using a similar intervention (1 g IV MgSO4 infusion) for 30 patients in a randomized, double-blind placebo-controlled trial.35 All patients in the active group showed some response to treatment. More than 80% of patients in the active group reported greater than a 50% reduction in pain and all accompanying symptoms were completely ablated, even if the pain was not completely removed. Thirteen patients reported complete disappearance of pain. The placebo response rate was 7%. Mild side effects, such as burning sensation in face or flushing, were reported by most patients (86.6%), but none required cessation of therapy. Although the method of randomization was not adequate (patients were enrolled sequentially first in active treatment then placebo), the blinding was appropriate. The results of this trial demonstrate superiority of IV Mg over placebo for treatment of acute migraine attack.
A second, larger (n = 60) randomized, double-blind, placebo-controlled trial examined the efficacy of 1 g of IV MgSO4 in migraine patients with and without aura.36 This group reported a better analgesic response in migraine patients with aura than without (37% vs. 17% analgesic therapeutic gain at 1 hour). Response to photophobia was good, but treatment in this trial was less useful for control of nausea.
Mg has demonstrated a significant effect on acute migraine, but the IV method of administration would not be appropriate for use as a prophylactic medication. Three trials in adults and two in children have investigated a variety of regimens for efficacy in reducing severity and/or frequency of migraine attacks. A small study of 20 patients with menstrual migraines randomized patients after two menstrual cycles to either 360 mg/d of magnesium pyrrolidone carboxylic acid or placebo for two months.37 Two months of open-label treatment followed the blinded portion of the trial. Pain Total Index was significantly lower in treated patients than in placebo patients (P < 0.03), as was the number of days with headache. A favorable response of other menstrual symptoms also was reported in the treatment group.
A larger, randomized, double-blind, placebo-controlled multicenter trial was conducted of chronic migraine suffers (2-6 attacks/month for at least two years).38 Subjects were given 10 mmol of Mg twice daily or placebo for 12 weeks. A reduction of at least 50% in pain intensity or duration of migraine attacks was considered a positive response. Initial design called for the enrollment of 150 patients, but an interim analysis conducted after the first 60 patients completed the protocol showed no difference in response between the treatment and placebo groups, so the trial was stopped. Side effects in the active treatment group were mainly gastrointestinal (diarrhea and soft stools) and led to withdrawal of only one patient. The exact formulation of the magnesium salt was not described in the study, and some researchers have ascribed the disappointing results to poor bioavailability of the oral preparation.39
In another randomized, double-blind, placebo-controlled trial, 81 chronic migraine patients (average of 3.6 attacks/month) were given 600 mg/d of Mg (trimagnesium dicitrate equivalent to 24 mmol of magnesium).40 After 12 weeks of treatment, the attack rate was significantly reduced in the treatment vs. placebo group (42% vs. 16%, respectively, P < 0.05). Other parameters also improved, such as duration of attack, pain intensity, and medication usage. Again, mild gastrointestinal side effects (diarrhea mainly) were reported.
Migraine in children is less common than adults, but availability of a safe prophylactic medication is even more important in this group. A small, open trial of magnesium pidolate in doses ranging from 1.5 to 4.5 g/d was reported in children (average age: 10 years).41 Although the majority of the children enrolled had migraine (n = 25), children with other episodic spasmodic conditions also were included (n = 15). Results were not reported separately for migraine patients, but a good clinical response was reported in 73% of the cases at one month and partial response in 12.5%. Most of the response seen was achieved in the first month of treatment. Compliance with the therapy was high and no adverse events were reported.
A second trial was performed, correcting a number of the methodological problems with the previous study.42 The trial was double-blinded and placebo-controlled, only migraine patients were enrolled, the numbers were larger (n = 118), and Mg was dosed based on patient weight (9 mg/kg of magnesium oxide or placebo in three divided doses). A statistically significant decrease in headache was found in the treatment group compared to baseline (P = 0.0037), while the decrease in the placebo group was not significant (P < 0.086). Headache severity also was lower in the treatment vs. the placebo group (P < 0.003). Treatment was well tolerated.
Riboflavin. While the clinical evidence for effectiveness of riboflavin is not as robust as the data for magnesium, it is interesting. In a study designed to elucidate the mechanism of action of riboflavin vs. beta-blockers for migraine prophylaxis, data also were collected on efficacy.30 Twenty-six patients were given either metoprolol 200 mg/d or riboflavin 400 mg/d for 12 weeks. Headache frequency decreased significantly from baseline in each group (P < 0.05) and the proportion of patients reporting a decrease of at least 50% in attack rate (responders) was similar in both groups (beta-blocker 55% and riboflavin 53%).
Two open-label trials examined the effects of riboflavin alone. Forty-four migraineurs, enrolled for 3-5 months, received 400 mg of riboflavin daily.43 The first half of the patients also received 75 mg/d of aspirin. Eighty percent of the patients were responders (³ 50% reduction of monthly migraine days) and no significant added benefit was seen with aspirin. Migraine patients with and without aura responded well to treatment.
Another small open trial showed a similar degree of improvement.44 Twenty-three patients, recruited from a headache clinic, were given 400 mg of riboflavin per day for six months. A significant reduction in headache days, from four to two days per month was seen after three and six months (P < 0.05). Use of medication to abort attacks also significantly decreased (P < 0.05). Treatment was reportedly well tolerated.
The promising results seen in the open trials were confirmed in a three-month randomized trial.45 Fifty-five chronic migraine patients were randomized to receive either 400 mg of riboflavin or placebo (low-dose beta-carotene to color the urine). Results from the riboflavin group were superior to placebo for both frequency of attacks and number of headache days (P = 0.005 and P = 0.012, respectively). The number of responders in the treatment group (60%) was four times the placebo group response (P = 0.002) and the number to treat for effectiveness was low at 2.3. Drug consumption per migraine day was not different between the two groups, suggesting that the attacks that did occur, although reportedly less severe, were as responsive to treatment as those in the placebo group. Minimal side effects were reported in both groups.
Combinations. A single study reports on the efficacy of a combination product (400 mg riboflavin, 300 mg magnesium, and 100 mg of feverfew extract per day for 12 weeks) as an effective prophylactic for migraine.46 Forty-nine patients with chronic migraines were enrolled from a headache clinic. Patients were allowed to continue prophylactic medication as long as therapy had been stable for at least three months. At the end of the treatment period, there was no significant difference between placebo and treatment groups with respect to attack rate, migraine days, migraine index, or triptan use. However, both groups did show a significant improvement over baseline. This outcome was confounded by the enrollment of moderately to severely affected patients (many were already on more than one prophylactic drug) and on the use of a low, but possibly active, dose of riboflavin in the placebo.
Formulation and Dosage
Magnesium. Intravenous use of 1 g of magnesium sulfate infused over 15 minutes was effective in terminating acute migraine attacks. However, the route of administration limits utility. For prophylaxis, oral dosing is preferred, but no single oral preparation was tested in all of the clinical trials. Recommended doses range from 200 to 400 mg of elemental Mg per day. The preparation of Mg will affect tolerability and perhaps bioavailability. Limited data suggest that citrate salts are better absorbed; however, they are generally less available in the marketplace and are more expensive. A good portion of the research has been conducted with magnesium oxide, which is more commonly available, and benefit was usually seen. As always, caution should be used when giving any magnesium formulation to patients with renal insufficiency. Taking Mg with food may decrease the incidence of stool softening or diarrhea.47
Riboflavin. Oral doses of 400 mg per day have been consistently tested in clinical trials. Other than a bright yellow discoloration of the urine, no significant adverse effects have been reported.
Evidence for the use of magnesium and riboflavin in the treatment and prevention of migraine headaches is encouraging. Use of these supplements appears to offer a safe and well-tolerated therapeutic option that is likely to be acceptable to patients. Although the only trial to test these two agents in combination was negative, it is reasonable to administer them together. They work through different mechanisms of action and may provide additive benefits for patients dealing with a difficult and debilitating illness.
Based on the clinical evidence to date, physicians can safely recommend 400 mg/d of riboflavin and 200-400 mg/d of elemental magnesium to patients who suffer migraines often enough to make daily prophylaxis a reasonable choice.
Dr. Hardy is Associate Director, UCLA Center for Dietary Supplement Research: Botanicals; and Medical Director, Cedars-Sinai Integrative Medicine Program, Los Angeles, CA.
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