2011
Lisa A. Yablon and Alexander Mauskop.

 

Abstract

Magnesium's role in migraine pathogenesis is well-described, with deficiencies known to promote cortical spreading depression, alter nociceptive processing and neurotransmitter release, and encourage the hyperaggregation of platelets, all major elements of migraine development. Research on magnesium has found it to be a potentially well-tolerated, safe and inexpensive option for migraine prevention, while it may also be effective as an acute treatment option for headaches including migraines, tension- type headaches and cluster headaches, particularly in certain patient subsets.

This chapter will review the various aspects of migraine in which magnesium plays a part, as well as numerous studies on the use of magnesium in both headache prophylaxis and in the acute treatment of headaches, offering recommendations in its use in clinical practice.

 

Magnesium in the Body

Magnesium (Mg), the second most abundant intracellular divalent cation, is a cofactor of many enzymes and is involved in a plethora of cellular functions. It plays a central role in both glucose metabolism and in ATP function. Over 300 enzymes require the presence of magnesium ions for their catalytic action, including all enzymes utilizing or synthesizing ATP, or those that use other nucleotides to synthesize DNA and RNA. ATP exists in cells as a chelate of ATP and a magnesium ion. Because of the important interaction between phosphate and magnesium ions, magnesium ions are essential to the basic nucleic acid chemistry of life, and thus are essential to all cells of all known living organisms.

Magnesium is involved in the formation of phospholipids and the insertion of proteins into the phospholipid membrane, and is therefore critical to membrane stabilization (Durlach et al., 1987). It also contributes to contraction of the cytoskeleton at the myoneural junction, playing a vital role in the function of both skeletal, cardiac and other smooth muscles.

Magnesium is absorbed in the gastrointestinal tract, via intestinal epithelial channels in the ileum as well as by the renal system’s thick ascending limb, distal tubule, and loop of Henle of the nephron (Wagner, 2007). It facilitates calcium absorption via the thick ascending limb, and the absorption of both ions is regulated by the parathyroid hormone (PTH) secreting cells of the parathyroid gland (Bapty et al., 1998). The calcium/magnesium sensing receptor within the parathyroid gland regulates absorption of both ions by detecting their levels in ionized form, and then controlling PTH secretion, thereby maintain- ing calcium homeostasis (Brown et al., 1993). Dietarily, absorption is affected by protein intake as well as phosphate, phytate and fat. Absorbed dietary magnesium is largely excreted through the urine, although most iatrogenically admin- istered oral magnesium is excreted through the faeces.

Adult human bodies contain approximately 24 grams of magnesium, with 67% located in the skeleton, 31% intracellularly (20% in skeletal muscle), and only 1-2% extracellularly. Of this amount, one half is ionized, and 25-30% is protein bound. As a result, levels found on routine serum testing, which only reflects that magnesium found in the extracellular space, is not represent- ative of true total body magnesium stores (Moe, 2008).

Serum levels are typically 0.7–1.0 mmol/L or 1.8– 2.4 mEq/L. Serum magnesium levels may appear normal even in cases of underlying intracellular deficiency, and true hypomagnesemia is common, possibly due to decreased intake or absorption, increased loss via the urine or diarrhea, or genetic factors (Henrotte, 1982).

 

Primary and Secondary Hypomagnesemia

Familial hypomagnesemia with secondary hypo- calcemia has been studied in various kindreds, and heredity has been found to be X linked in some families, and autosomal recessive in others (Walder et al., 1997). There are currently more than 30 known mutations in the TRPM6 gene that are associated with familial hypomagnesemia and hypocalcemia. Another hereditary form of hypo- magnesemia, tubular hypomagnesemia/hypo- kalemia with hypocalciuria (Gitelman's synd- rome), is hypothesized to be due to two different types of genetic transmission, one autosomal recessive and one autosomal dominant with high phenotype variability (Bettinelli et al., 1995).

A population study in Germany found the prevalence of serum hypomagnesemia to be 14.5%, with even higher frequencies in females (Schimatschek and Rempis, 2001). Additionally, chronic disease is associated with hypo- magnesemia, including diabetes, asthma, cardio- vascular disease, sickle cell anaemia, pre- eclampsia and eclampsia (Laires et al., 2004). 10- 20% of hospitalized patients are deficient in magnesium, and up to 65% of patients in intensive care units are hypomagnesemic. Alcoholism is also associated with inadequate magnesium levels, in part due to poor nutrition (Bohmer and Mathiesen, 1982). It has also been implicated in patients with end-stage renal disease suffering from hemodialysis headache (Goksel et al., 2006), and is often seen in conjunction with electrolyte abnormalities including hypokalemia, hyponatremia, hypo- calcemia and hypophosphatemia (Whang et al., 1985). A number of medications such as diuretics, aminoglycosides and digoxin are associated with hypomagnesemia, and patients with refractory hypocalcemia and hypokalemia should be evaluated for hypomagnesemia (Innerarity, 2000)

 

Magnesium Imbalances

Clinical symptoms of hypomagnesemia include hallucinations, depression, delirium, lethargy, weakness, paresthesias, tremors, premenstrual syndrome, cold extremities, leg or foot cramps, seizures, ventricular arrhythmias and congestive heart failure (Douban et al., 1996). However, since total body stores are not accurately represented by serum levels, routine blood testing and even erythrocyte Mg concentrations may reveal normal levels, particularly in patients with low free (ionized) magnesium levels. Urinary fractional excretion or the oral magnesium load test can estimate the total body magnesium status. Intravenous magnesium loading tests are likely the most accurate and practical assessment, whereby total excretion of urinary magnesium is calculated over a 24 hour period, following administration of a loading dose; a retention of 20% or more indicates deficiency (Arnaud, 2008).

Hypermagnesemia, on the other hand, is a rare condition due to the nephron’s rapid response to increased levels. It usually develops only in people with kidney failure who are given magnesium salts or who take drugs that contain magnesium such as laxatives or antacids. Clinical symptoms include nausea, muscle weakness, lethargy, confusion, hypotension and arrhythmias. In mild cases, withdrawing magnesium supple- mentation is often sufficient. In more severe cases, intravenous calcium gluconate and diuretics or dialysis may be required.

 

Magnesium Levels in Migraineurs

For many decades, it was postulated that magnesium deficiency played a role in migraine pathogenesis. However, the lack of simple and reliable measures of magnesium levels prevented further research to prove this theory. While low serum, cerebrospinal fluid and cerebral tissue levels of magnesium have been found to be low in patients with migraine (Jain et al., 1985; Ramadan et al., 1989; Schoenen et al., 1991), these results have been inconsistent, with both normal and low levels detected in the same tissues of some patients. The variability of results may be due to the need to measure ionized magnesium as a true reflection of magnesium metabolism, and the development of an ion selective electrode for ionized magnesium in whole blood, serum, plasma and aqueous samples has made an accurate and rapid measurement of ionized magnesium levels possible (Altura et al., 1992).

A study measuring ionized magnesium levels in 40 patients during an acute migraine attack found that 50% had levels below 0.54 mmol/l (normal adult range 0.54-0.65 mmol/l) (Mauskop et al., 1995), with all subjects having total serum magnesium levels within normal limits. Intravenous administration of 1g of magnesium sulfate was most effective in those with low ionized magnesium, with 86% of patients reporting sustained pain relief over 24 hours in those found to have low serum ionized magnesium, while this was the case in only 16% of patients with normal levels. This finding was extended to patients with various headache types, including migraine without aura, cluster head-ache, chronic migraine and chronic tension type headache (Mauskop et al., 1996), with most patients demonstrating low ionized magnesium levels. In addition, high serum ionized calcium to magnesium ratios were found in all headache types except for in those patients with chronic tension-type headaches. Based on these findings, it has been suggested that tension type headache may possibly be discriminated from chronic migraine based on serum ionized magnesium levels (Mauskop et al., 1994).

 

Conclusion

Magnesium is central to numerous physiological functions, and the role it plays in the various aspects of migraine pathogenesis is well described. Although some studies have shown an association between migraines and magnesium deficiency, it is difficult to assess this with routine blood testing and serum magnesium levels are a poor reflection of body stores of the cation. Therefore, treatment should be based on clinical suspicion, with both oral and intravenous magnesium available as simple, safe, inexpensive and well-tolerated options for the management of migraines. In patients with symptoms suggestive of hypomagnesemia such as pre- menstrual syndrome, cold extremities and foot or leg cramps, we suggest daily magnesium supplementation with 400mg of chelated magnesium, magnesium oxide or slow-release magnesium. While some patients may require doses of up to 1000mg, diarrhea and abdominal pain may be limiting factors. Intravenous magnesium may be used in patients who are unable to tolerate or absorb oral magnesium or who are non-compliant with daily dosing. It may also be used for the treatment of acute migraines, or as a monthly prophylactic infusion, often administered premenstrually.