Khani S, Hejazi SA, Yaghoubi M, Sharifipour E. Comparative study of magnesium, sodium valproate, and concurrent magnesium-sodium valproate therapy in the prevention of migraine headaches: a randomized controlled double-blind trial. J Headache Pain. 2021;22(1):21.
To examine the effectiveness of using both magnesium and sodium valproate concurrently vs either magnesium or sodium valproate as single-agent therapy in prevention of migraines
Randomized, double-blind, placebo-controlled clinical trial at a single center
Researchers recruited a total of 260 participants, and 222 patients (including 125 females and 97 males) completed the study. The participants were migraine patients, aged 18 to 65 years, with at least 4 monthly attacks. They were randomly assigned to a sodium valproate only–group (V; plus a placebo tablet; n=82), a magnesium oxide–plus–sodium valproate group (V+MAG; n=70), and a magnesium oxide–only group (MAG; plus a placebo tablet; n=70). The dose of the sodium valproate was 200 mg twice daily for 12 weeks, and the dose of the magnesium oxide was 250 mg twice daily for 12 weeks.
Study Parameters Assessed
The study participants underwent a 1-month baseline without preventative therapy and then received 12 weeks of study treatment. At each visit, researchers recorded the baseline characteristics of each migraine, including frequency, severity, duration of the attacks, and the number of painkillers taken per month. They also recorded the Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) scores at the baseline and after 12 weeks of treatment in each group. There was no significant difference in demographics, migraine type, and headache history at baseline for the 3 participant groups.
Primary Outcome Measures
The primary outcome measures were the efficacy of intervention on migraine frequency in the 3 groups at 4 timepoints: baseline, 4 weeks, 8 weeks, and 12 weeks. Secondary measures included severity, duration, and use of painkillers in each of the intervention groups.
All 3 groups showed a significant reduction in the study parameters assessed after 12 weeks of treatment, as compared to baseline (P<0.001). However, a significant reduction in migraine duration did not occur in the first month of the study for the MAG group. There was no statistically significant difference in migraine frequency between the V and the V+MAG groups in the first and third months; however, the combination group showed a significant reduction of migraine frequency in the second month, as compared to the V group. The MAG group showed a significant difference in migraine frequency vs the other 2 groups over 3 months (P<0.001).
There was no difference in migraine severity over the first month among the 3 groups; however, a reduction in migraine severity was significant in the V+MAG group, as compared to the V group (P=0.01 and P=0.002) and the MAG group (P<0.001) over the second and third months. Both groups with sodium valproate used significantly lower amounts of painkillers than the MAG group in the second and third months (P<0.001).
In the United States 18% of women, 6% of men, and 10% of children experience migraines.
The MIDAS and HIT-6 scores were significantly lower in all of the treatment groups in comparison to those measured at baseline (P<0.001). The V and V+MAG groups had significantly greater changes in MIDAS and HIT-6 scores than the MAG group (P<0.001). However, no significant difference was observed between the 2 groups in HIT-score change (P=0.999). The changes in MIDAS scores were significantly different between the 2 groups (V vs V+MAG; P=0.023).
Migraines have classically been categorized as a pain disorder, focusing on headache as the most defining characteristic. Migraines, however, also consist of a complex array of premonitory and postdromal symptoms that occur in the hours before and after the actual headache.1 The pathophysiology of migraines is incredibly complex and is largely accepted to be an inherited tendency of the brain to lose control of its inputs, influenced both by genetics and the environment.2 Migraines affect nearly 1 billion people worldwide. In the United States 18% of women, 6% of men, and 10% of children experience migraines.3 Migraines are ranked sixth by the World Health Organization for years lost to disability,4 thus affecting both an individual’s productivity and quality of life. Migraines cause more than 1.2 million visits to emergency departments in the United States annually.5
The aim of effective migraine management is not only to effectively treat the acute onset of migraine headaches, but to prevent them from occurring in the first place. This study compared the use of both magnesium and sodium valproate concurrently vs either magnesium or sodium valproate as single agents in the prevention of migraines. While valproate is widely used for migraine prophylaxis, it is not effective in all patients.6 Of interest to integrative practitioners, this study showed that magnesium can both enhance the effectiveness of sodium valproate in migraine prophylaxis, and also enable a lower dose of valproate to be used.7 This has clinical relevance, as sodium valproate has a number of serious adverse effects, including hepatotoxicity, pancreatitis, and birth defects.8
To provide background, sodium valproate is the sodium salt of valproic acid. Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, naturally found in Valeriana officinalis,9 and came into medical use in 1962.10 It is on the World Health Organization’s List of Essential Medicines11 as a pharmaceutical to treat epilepsy, bipolar disorder, and neuropathic pain from diabetes and to prevent migraine headaches. Sodium valproate is available in the United Kingdom, and valproate is marketed in the United States under the brand name Depakote.
Valproate is structurally similar to γ-aminobutyric acid (GABA) and, thus, has strong GABA-like effects.12 Valproate also inhibits N-methyl-D-aspartate (NMDA)–evoked neuroexcitatory signals and can inhibit GABA-degrading enzymes and increase the neuroinhibitory activities of GABA.13 Migraines occur during an alteration in the electrical activity of the brain, which is described as a wave of brain signaling, or cortical-spreading depression, which produces the visual and sensory changes that are the common forms of aura. One of the proposed mechanisms by which valproic acid may prevent migraines is by preventing the cortical-spreading depression, possibly by its effect on GABA.14
Magnesium is an essential mineral that has a well-described role in the prophylaxis of migraines, with deficiencies of magnesium known to promote cortical-spreading depression, alter nociceptive processing and neurotransmitter release, and encourage the hyperaggregation of platelets, all major elements in the development of migraines.15 Research on magnesium has found it to be a potentially well-tolerated, safe, and inexpensive option for migraine prevention.16
Magnesium is the second most abundant intracellular divalent cation.17 More than 300 enzymes require the presence of magnesium for their activity, including all enzymes utilizing or synthesizing adenosine triphosphate (ATP).18 Serum levels may appear normal, even in the cases of underlying intracellular deficiency, and true hypomagnesemia is common.19 It is estimated that approximately 50% of Americans consume less than the Estimated Average Requirement (EAR) for magnesium, and some age groups consume substantially less.20 A large body of literature suggests a relationship between magnesium deficiency and mild and moderate tension-type headaches and migraines.21 A recent systematic review of 5 randomized, double-blind, placebo-controlled trials in adult migraine patients showed possible evidence for the prevention of migraines with 600 mg magnesium dicitrate daily; the review also found that it is a well-tolerated and cost-efficient strategy in clinical use.22
Of note, there are a variety of different forms of magnesium that have differing bioavailability. It is outside of the scope of this review to delve too deeply into the literature on forms of magnesium and absorbability; however, a possible weakness of this study is that it used magnesium oxide, which may not be as bioavailable as other forms of magnesium.23
From an integrative medicine perspective, there are some interesting natural-product studies on migraines, which include the use of magnesium. A recent prospective, observational study evaluated the combination of coenzyme Q10, feverfew, and magnesium for migraine prevention and found that supplementation significantly reduced the number of days with migraine headache during the third month of supplementation, as compared to baseline, and researchers observed an improvement in quality of life.24
Likewise, an open-label, prospective study investigating the efficacy and safety of supplementation with a combination of magnesium, vitamin B2, feverfew, Andrographis paniculata, and coenzyme Q10 showed a reduction in migraine frequency, intensity, and use of acute headache medications per month.25
While the above is of interest, particularly as a nutrient (magnesium) successfully potentiated the effectiveness of a pharmaceutical (sodium valproate) and allowed lower doses of the pharmaceutical to be used, from an integrative practitioner standpoint, it is important to consider the study in the larger context of migraine prevention. Ideally, practitioners are evaluating and treating patients for the underlying causes of their migraines and assessing common triggers such as stress, environmental allergens, food allergens/sensitivities, inflammation, comorbidities, methylation defects, etc. Approaching patients from a dietary, lifestyle, and appropriate-supplementation perspective may prevent a patient from needing to consider pharmaceutical approaches. However, it is worth being aware of pharmaceutical prevention of migraines for patients who need additional support and helpful knowing that the synergistic effects of supplemental magnesium may allow them to be on lower doses.