Magnesium (Mg), often called “the master mineral”, found abundantly in the body, is a cofactor in more than 300 enzyme systems regulating biochemical reactions, including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation [1-2].
An adult body contains about 25 g Mg, (50% to 60% in the bones, rest mostly in soft tissues and less than 1% of total Mg in blood serum). Mg homeostasis is controlled by kidneys with about 120 mg excreted into urine each day. Normal serum Mg is 0.75 to 0.95 mmol/L (millimoles) [1]. Hypomagnesemia is serum Mg level less than 0.75 mmol/L [2].
Mg plays is important in prevention of central sensitization and attenuation of established pain hypersensitivity. The main mode of action is its voltage-gated antagonist action at N-methyl-D-aspartate (NMDA) receptors. Parenteral administration of Mg (via intravenous, intrathecal, or epidural routes), may reduce pain, as well as the anesthetic and analgesic requirements during the intra- and post-operative periods.
Neuropathic Pain The effect of Mg has been shown in neuropathic pain cases, such as in malignancy-related symptoms, postherpetic neuralgia, diabetic neuropathy, and chemotherapy-induced peripheral neuropathy. Mg therapy is found to alleviate dysmenorrhea, headaches, and acute migraine attacks. When magnesium sulphate was given to patients with neuropathic pain due to cancer infiltration, pain intensity and pain relief scores improved (Crosby et al., 2000). Magnesium chloride reduced protracted pain and regions of allodynia in patient’s peripheral neuropathic pain (Felsby et al., 1996). Brill et al. 2002 showed IV Magnesium Sulphate relieved hyperalgesia and allodynia in patients with Post Herpetic Neuralgia.
Headache Mg deficiency is linked to cortical spreading depression (CSD), associated with aura in migraines[3], and imbalanced neurotransmitter release [4]. Substance P is released during Mg deficiency, possibly acting on sensory fibers, producing headache. [5]. Mg has also been shown to decrease the level of CGRP, involved in migraine pathogenesis through its ability to dilate intracranial blood vessels and produce nociceptive stimuli [3,6]. External Mg, is involved in the control of NMDA glutamate receptors, [7], regulation of cerebral blood flow [8], as well as CSD initiation and spread. It has been shown that ionized Mg can block CSD by regulating glutamatergic neurotransmission, closing the NMDA receptor calcium channel and modulating the cyclic adenosine monophosphate (cAMP) response element-binding protein signaling [9,10]. The modulation of the cerebral blood flow by circulating nitric oxide involved in headaches, has been shown to be influenced by Mg intake [3,11]. Magnesium can increase vasodilation directly through blocking calcium-sensitive potassium channels on smooth muscle cells [12]. There is some evidence that Mg is most beneficial in migraines with aura [13,14].
The therapeutic efficacy of Mg supplementation (360 mg of magnesium pyrrolidone carboxylic acid) in headache patients has been shown in two double-blind, placebo-controlled randomized trials [15,16]. A larger double-blind, placebo-controlled randomized study of 81 adult patients with migraines, according to the IHS criteria, also showed improvements in patients on therapy of 600 mg of trimagnesium dicitrate [16]. A further randomized controlled trial of 118 children 3–17 years of age receiving 9 mg/kg daily oral magnesium oxide or placebo showed that treatment led to a significant reduction in headache days [17]. A recent systematic review of five randomized, double-blind, placebo-controlled trials in adult migraine patients showed possible evidence for the prevention of migraines with 600 mg magnesium dicitrate daily, and that it is a well-tolerated and cost efficient strategy in clinical use [18]. In view of the results of these studies, several national and international guidelines added the recommendation of oral magnesium for headache patients [19,20,21]. Mg is a better alternative treatment due to relative lack of side effects, particularly in children, pregnant women and elderly.
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10. Hou H., Wang L., Fu T., Papasergi M., Yule D.I., Xia H. Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons. Mol. Neurobiol. 2020 doi: 10.1007/s12035-020-01871-z.
11. Chiarello D.I., Marin R., Proverbio F., Coronado P., Toledo F., Salsoso R., Gutierrez J., Sobrevia L. Mechanisms of the effect of magnesium salts in preeclampsia. Placenta. 2018;69:134–139. doi: 10.1016/j.placenta.2018.04.011.
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14. Choi H., Parmar N. The use of intravenous magnesium sulphate for acute migraine: Meta-analysis of randomized controlled trials. Eur. J. Emerg. Med. 2014;21:2–9. doi: 10.1097/MEJ.0b013e3283646e1b.