Magnesium Sulfate Helpful in Treatment of Acute Migraines
Migraine headache, one of the most complex pain disorders known in medicine, is fairly common, affecting approximately 16.2% of the US population.1 According to the most recent American Migraine Prevalence and Prevention study, the burden of headache was highest in women between the ages of 18 to 44, in whom the 3-month prevalence of migraine or severe headache was 26.1%.1 The burden of migraine is considered to be substantial even in the least affected subpopulation, men ages 75 and older, who demonstrate a 3-month prevalence of 4.6%.1 Given the widespread nature of this affliction, its associated psychiatric comorbidities, and its tendency toward disability, migraine headache constitutes an important public health issue that warrants a search for effective treatment.
Various acute abortive agents, including non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, dihydroergotamine injections, and the triptan family of drugs, are used to treat migraine headache. Recently, the role of magnesium sulfate in the treatment of migraine headache has been gaining scientific attention.2 This review will discuss the biological effects of magnesium in the body, the history of its use in medicine and other health practices, and its use in the setting of migraine. Finally, this review will critically examine the available literature exploring the efficacy of magnesium sulfate as treatment for acute migraine, refractory migraine, and status migrainosus.
Discovery of an Essential Mineral
The term “magnesium” has its roots in the Greek word, magnesia, originally named for the district in Thessaly where it was discovered, along with manganese and magnetite.3 Centuries later in 1618, magnesium was separately discovered by an English farmer who tried to provide water to his cows from a well in the town of Epsom. It was observed at this time that the mineral, dissolved as a salt in the water, was capable of healing scratches and rashes. Thus, the substance was referred to as “Epsom salt” and, ultimately, was found to be chemically equivalent to hydrated magnesium sulphate.3
In 1808, Sir Humphrey Davy was the first to produce the metal through electrolysis of a mixture of mercuric oxide and magnesia.3 Its elemental form was finally prepared stably in 1831 by Antoine Bussy. Although initially referred to as “magnium” by Davy, the name of the mineral was later changed to magnesium. Magnesium has been since discovered in nature in the following forms: magnesite (magnesium carbonate), an insoluble rock salt, magnesium chloride in the ocean, and as the central element in chlorophyll.3
Biological Role of Magnesium
Inside human cells, magnesium is the second-most abundant element, and it is involved in a wide variety of physiologic functions. An estimated 300 separate biochemical reactions are regulated by magnesium ions in their role as enzyme cofactors. Magnesium is a key regulator of multiple enzymes, including those involved in glycolysis and the creatine kinase enzyme, involved in energy metabolism.4 Additionally, the chelation of DNA and RNA adenine nucleotides by magnesium ions controls the synthesis of these crucial glycolytic enzymes: pyruvate kinase, phosphoglycerate kinase, aldolase, phosphofructokinase, and hexokinase.4,5
Multiple enzymes in the Kreb’s cycle (also known as the citric acid cycle) also are regulated by the magnesium ion. Studies utilizing a variety of mammalian cell types have revealed the presence of magnesium ions in mitochondria, whereas magnesium deficiency leads to the swelling of these organelles with a concomitant decrease in mitochondria count per cell.6 Mitochondrial synthesis also depends on enzymes requiring magnesium as a co-factor. 6-10
Magnesium is partly responsible for the maintenance of DNA and RNA stability, evidenced by impaired nucleic acid synthesis in patient with magnesium deficiency.11 Additionally, magnesium also influences vital DNA repair processes, without which mutagenic damage would accumulate and might become clinically significant.12 Magnesium is involved in the homeostasis of crucial minerals such as potassium, sodium, and calcium. An absence of magnesium causes malfunctioning of the sodium-potassium pump, which may contribute to the arrhythmias associated with magnesium deficiency.13 Effective correction of magnesium deficiency is, thereby, necessary to resolve a potassium deficiency. Magnesium also modulates calcium levels by competing with calcium for entry into the cell.14 Through these roles, magnesium status impacts muscle contraction dynamics, nerve impulse generation and conduction, cardiac automaticity, and cardiac rhythmicity.13,14
Other intercellular signaling cascades are greatly influenced by magnesium. Magnesium affects the ability of blood vessels to remain appropriately dilated through its regulation of serotonin release.15 In the bloodstream itself, magnesium antagonizes excessive activation of blood clotting factors by calcium.15 Magnesium is a central player in certain neurological processes, and it has been implicated in memory formation and storage via inhibition of hippocampal N-methyl-D-aspartate receptors.16 Magnesium ions also might modulate the release of leukotrienes, prostaglandins, and the neuropeptide substance P, thereby influencing pain sensitivity.2 It is not yet known as to which of these functions are responsible in treating migraines in the acute and chronic setting, and it is likely a combination of effects.
Structurally, magnesium is a critical component of bones; approximately 67% of the body’s total magnesium resides in the skeleton. About 1% to 2% of the body’s magnesium can be found in the blood, with the remainder located intracellularly (31%) and responsible for the intracellular functions mentioned above.15
Magnesium in Migraine Prevention
Multiple studies have demonstrated drastically reduced levels of magnesium in migraine patients compared to controls, though only a few of these have been able to demonstrate reduced levels in the brain or in spinal fluid specifically.2,16 One large case-control study, which included 140 migraine patients and 140 individuals without migraine, found that migraine patients had significantly lower serum magnesium levels (26.14 ± 4.3) than non-migraine patients (31.09 ± 4.32).17 Additionally, magnesium deficiency is a prevalent finding in patients who experience menstrual migraine18 and in childhood migraine syndromes.19 These findings, paired with the knowledge that adequate magnesium is necessary for proper nerve function and the prevention of vasospasm and platelet aggregation, implicate a relationship between magnesium deficiency and migraine occurrence, which has recently been supported by various clinical trials.15-20