Alternative Medicine in Migraine: Is It Ever a Good Alternative?

ABSTRACT: Although the data are relatively few, and sometimes weak, there is some evidence that so-called natural remedies may be effective at preventing or aborting migraine attacks. Magnesium supplementation is an effective prophylactic regimen in some patients, most often in those with aura or perimenstrual migraine. The main clinical problem associated with magnesium use is diarrhea. Two small randomized controlled trials (RCTs) have shown that riboflavin may reduce the frequency of migraine attacks in some patients; side effects may include diarrhea and polyuria. Although there have been only 2 very small studies of coenzyme Q10 for migraine prevention, both showed efficacy. Coenzyme Q10 appears to have a favorable side-effect profile, although it has been associated with a cutaneous reaction. The efficacy of feverfew for migraine prophylaxis has not been established, nor has its longterm safety. Two RCTs have demonstrated that Petadolex, an extract made from butterbur root by a German phytopharmaceutical company, is superior to placebo for migraine prevention. Because Petadolex is monitored by German regulatory authorities and has had significant postmarketing exposure and data collection, its safety is reasonably ensured. Key words: headache, migraine, alternative medicine ______________________________________________________________________________________________________ Patients who have frequent migraine attacks often ask about alternative or “natural” medications—or they may already be using such products. In this article, I provide concrete, evidence-based information that can help you advise patients about these alternative “medications.” In particular, I discuss the possible mechanism of action of 5 natural agents (minerals, vitamins, and herbs) that are commonly used without a prescription (or, often, without the physician’s knowledge) to prevent or abort migraine attacks, and I review the data on their efficacy—wherever possible, data from randomized controlled trials (RCTs). Bear in mind, however, that the sample numbers in all cited studies are quite small. Also, be sure to remind any patient who is considering use of an herbal medication that in the United States such products are classified as dietary supplements rather than drugs; thus, they are not regulated by the FDA in the same way that drugs are. This means that the contents of herbal medicines are not standardized, there is no guarantee of efficacy, and the standards for purity and safety are far lower than those for pharmaceuticals. MAGNESIUM Low levels of magnesium in the brain have been postulated as a cause of migraine.1  Magnesium binds to glutamate subreceptors to maintain calcium homeostasis. A low magnesium level opens calcium channels, increasing intracellular calcium; the increase in intracellular calcium results in excitatory glutamate release and increased platelet aggregation. This cascade initiates migraine aura—a slow neuronal discharge across the cortex that is followed by a postictal-like state referred to as cortical spreading depression. Thus, there is a link between low magnesium levels and aura genesis. In addition, the cascade described here is associated with increased serotonin levels and vascular instability.2 A number of studies have described low levels of magnesium in the brains of migraineurs.3-10  One RCT by Mauskop and colleagues11 suggested that magnesium deficiency plays a role in the precipitation of menstrual migraines. These reports have led to numerous trials of magnesium supplementation for migraine prophylaxis12-15  and of intravenous magnesium as an intervention for acute migraine. Results of these trials have been mixed. Those that found a favorable effect involved patients with aura and those with perimenstrual migraine. Two RCTs16,17  found intravenous magnesium to be beneficial in the termination of acute attacks; however, the larger of the 2 found the benefit only in patients who had migraine with aura. In another study, Mauskop and colleagues18  showed that 1 g of intravenous magnesium aborted severe migraine attacks in patients with low levels of ionized magnesium but not in patients with normal levels of ionized magnesium. The results of Mauskop’s study suggest that patients with migraine may have too-low levels of ionized magnesium rather than too-low levels of conventional  magnesium. Thus, the variation in the outcomes of magnesium supplementation studies may have resulted from the inclusion of patients with low levels of ionized magnesium and patients with normal ionized levels. Administration of intravenous magnesium, followed by a maintenance regimen of supplemental magnesium, is a tempting therapeutic approach in patients with migraine. However, normal levels of ionized magnesium can be difficult to maintain—even though they are fairly easy to establish with intravenous administration.19  Cady and colleagues20 randomized 41 migraineurs who responded poorly or not at all to sumatriptan to receive magnesium supplementation or placebo. They found that 83% of study participants were deficient in ionized magnesium at baseline. New responsiveness to sumatriptan was associated with normalization of ionized magnesium levels. However, even after normalization through intravenous treatment, a daily dose of 250 mg of oral magnesium taurate for 5 1/2 months was not adequate to maintain normal levels of ionized magnesium. These findings suggest that Mauskop is correct to recommend that a daily dose of 600 mg of chelated or slow-release oral magnesium be used for supplementation.21  These findings also suggest that high-dose magnesium supplementation may be a reasonable approach in patients who have episodic migraine and who do not respond to triptans. However, the development of diarrhea may prevent adequate oral magnesium supplementation. RIBOFLAVIN (VITAMIN B2) Some patients with migraine do not produce adenosine triphosphate (ATP) in sufficient quantity because of mitochondrial dysfunction.1,22,23  Riboflavin is a precursor of the flavin mononucleotides that play an integral role in the electron transport chain—a key part of the process by which ATP is synthesized in the mitochondrial membrane from the by-products of glycolysis. Schoenen wondered whether the mitochondrial dysfunction seen in migraineurs could be corrected by the administration of high-dose riboflavin. In both an open-label trial24 and a subsequent small (N = 55) double- blind, placebo-controlled study,25 he found that riboflavin, 400 mg/d for 3 months, significantly reduced migraine frequency and the number of headache days. Of patients in the RCT who received riboflavin, 59% had at least a 50% reduction in migraine attacks, compared with 15% of those who received placebo.25  Two patients in the RCT experienced diarrhea and polyuria.25 Maizels and colleagues26  published a second RCT of riboflavin in migraineurs. In this study, 24 patients were given a daily combination tablet that contained riboflavin, 400 mg; magnesium, 300 mg; and feverfew, 100 mg. Twenty-five were given “placebo” (a 25-mg dose of riboflavin— to turn their urine as bright yellow as the combination pill would have). After 3 months, there was no difference between the active and placebo groups for any end point. However, the number of migraine attacks, the number of migraine days, and the migraine index were lower in both groups compared with baseline. Also, there was at least a 50% reduction in the number of migraine attacks in 42% of those who received riboflavin, 25 mg/d, and in 44% of those who received the combination tablet. These results suggest that a riboflavin dosage of 25 mg/d may be active; they also indicate a need for additional, larger RCTs that involve a range of dosages. COENZYME Q10 Coenzyme Q10, like riboflavin derivatives, plays a role in the electron transport chain in mitochondria. Coenzyme Q10 is used to treat neurologic mitochondrial encephalomyopathies, such as Kearns-Sayre syndrome.27,28 When used for these disorders, coenzyme Q10 has an established, favorable side-effect profile, even at very high dosages. In a small open-label study by Rozen and colleagues,29 32 patients with episodic migraine received 150 mg/d of coenzyme Q10. There was a statistically significant reduction in migraine frequency after 3 months of therapy, and no side effects were noted. The results of the Rozen study led Sandor and colleagues30 to conduct a controlled trial of 42 patients, half of whom were randomly assigned to receive 100 mg tid of a new water-soluble, non–commercially available form of coenzyme Q10 for 3 months, and the rest of whom received placebo. Coenzyme Q10 significantly reduced attack frequency, headache days, and days with nausea. Attack frequency was reduced by 50% or more in 48% of participants who received coenzyme Q10. Adverse events associated with coenzyme Q10 are generally minimal. GI disturbances (nausea, anorexia, dyspepsia, and diarrhea) occur in fewer than 1% of users.29 One patient in the Sandor study withdrew because of “cutaneous allergy.”30 FEVERFEW Feverfew (Tanacetum parthenium) is an herb whose leaves are dried and used as medicine. If feverfew is effective for the prevention of migraine, it may be because of the sesquiterpene lactone parthenolides that are found in varying concentrations in the leaves. It has been postulated that parthenolides may inhibit serotonin release31 and platelet aggregation.32 Feverfew may also have an anti-inflammatory effect because of its inhibition of prostaglandin synthesis and phospholipase A.33,34 However, it appears that the likelihood of benefit is greater when whole feverfew leaves, rather than the parthenolides alone, are used (see below). Thus, other components of the leaves have been suggested as active ingredients. One in particular, chrysanthenyl acetate, may have an analgesic effect because of its inhibition of prostaglandin synthesis.35,36 Murch and colleagues36 have noted the presence of melatonin in feverfew. Melatonin and serotonin have structural similarities, and the soporific effects of the former may be useful in the treatment of migraine. Vogler and colleagues37 published a systematic review of RCTs of feverfew for migraine prophylaxis that were conducted before 1998. The investigators measured methodologic quality with a technique called Jadad scoring.38 Only 5 studies qualified for inclusion; only 216 patients were involved.37,39-42 The researchers concluded: “In view of the popularity of feverfew, perhaps the most striking finding was the paucity and low average quality of the existing RCTs on the subject.”37 Three of the five qualified studies—which included two thirds of the patients in the combined qualified studies—showed greater benefit with feverfew than with placebo. Of the 3 largest studies (not considering quality), 2 showed a benefit with feverfew and 1 showed no benefit. Significantly, the better the standardization of the active feverfew parthenolides used in a study, the less likely the study was to show benefit. In fact, Vogler and colleagues37 noted that one trial35  that used an extract of feverfew with a standardized and constant concentration of parthenolides showed no beneficial effect. A more recent RCT of a new stable extract of feverfew, MIG-99, followed the same pattern: the results were not significant for the primary end point and did not show a dose response.43 Adverse events reported in the RCTs of feverfew include GI disturbances and mouth ulcers. A “postfeverfew syndrome” of joint aches has also been described.39  Long-term toxicity has not been systematically evaluated. Because the potency of preparations varies, adverse effects may vary as well. BUTTERBUR ROOT Petasites hybridus (butterbur) is a perennial shrub whose stem and leaves are carcinogenic, hepatotoxic, and capable of causing coagulopathies and pulmonary damage. Its root was used in the Middle Ages to treat plague. P hybridus is used to treat allergies, and it inhibits leukotriene synthesis. Because leukotrienes have been implicated in migraine neurogenic inflammation, an anti-inflammatory mechanism is proposed as the basis for use of this herb as a migraine prophylactic.44-48  (Interestingly, another species in the same genus, Petasites formosanus, inhibits calcium channels49-51 ; as noted in the discussion of magnesium, open calcium channels play a role in the genesis of migraine aura.) In 1988, a German company, Weber & Weber GmbH & Co, patented a rhizome root extraction technique that keeps toxic alkaloids below detectable levels.52,53  Since 1992, the company has sold Petasites  root extract under the brand name Petadolex, with the supervision and approval of the German government’s Health Authority regulatory agency; it is available in the United States as well as in Europe. The potential for hepatotoxicity with other preparations of Petasites  has apparently not been completely eliminated.47  More than 500,000 patients have used Petadolex since it became available; the average duration of use is estimated at 3 months. This German preparation affords a standardized, governmentally regulated medication for use in clinical studies—something that is not often available to researchers conducting studies of herbal medications. Petadolex has been studied in 2 RCTs. In the first, Grossmann and Schmidramsl54  randomly assigned 60 patients to receive either placebo or 50 mg of Petadolex bid for 12 weeks. They concluded: “The frequency of migraine attacks decreased by a maximum of 60% compared to the baseline. . . and was significant (P  .05) compared to placebo.”54 In a larger study by Lipton and colleagues,52  245 patients were randomly assigned to 3 groups: one that received 75 mg of Petadolex bid, another that received 50 mg of Petadolex bid, and a third that received placebo. The trial lasted 4 months. Migraine attack frequency was reduced by 48% in patients who received 75 mg of Petadolex bid, compared with a 26% reduction in those who received placebo; however, the 50-mg bid dosage was not statistically superior to placebo (36% reduction in migraine attack frequency). Of patients who received 75 mg of Petadolex bid, 68% had a reduction in migraine frequency of at least 50%, compared with 49% of those who received placebo. The onset of effect was detectable at 1 month. The only significant adverse event was increased burping in patients who received either dosage of Petadolex compared with those who received placebo. Dr Tepper is assistant clinical professor of neurology at Yale University School of Medicine in New Haven, Conn, and director of the New England Center for Headache in Stamford, Conn. REFERENCES: 1. Welch KM, Ramadan NM. Mitochondria, magnesium and migraine. J Neurol Sci. 1995;134:9-14. 2. Tepper SJ, Rapoport AM, Sheftell F. The pathophysiology of migraine. Neurologist. 2001;7:279-286. 3. Jain AC, Sethi NC, Babbar PK. A clinical electroencephalographic and trace element study with special reference to zinc, copper and magnesium in serum and cerebrospinal fluid (CSF) in cases of migraine. J Neurol. 1985;232(suppl):161. Abstract. 4. Schoenen J, Sianard-Gainko J, Lenaerts M. Blood magnesium levels in migraine. Cephalalgia. 1991;11: 97-99. 5. Sarchielli P, Coata G, Firenze C, et al. 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