The current study compared the efficacy of sodium valproate (group A), sodium valproate plus magnesium oxide (group B), and magnesium oxide (group C) in the migraine prophylaxis of patients within the age range of 18-65 years. Besides, MIDAS and HIT6 scores were compared between three treatment groups. The obtained results showed that the combination of magnesium and sodium valproate had an appropriate efficacy in migraine prophylaxis, as headache severity, duration of headache, and amount of utilized painkillers were significantly lower in group B, compared to those reported in group A. Moreover, the MIDAS score reduced more in B group than A and HIT score changes were not significantly different between A and B. Furthermore, by the addition of magnesium to valproate (group B), the sodium valproate dose reduced significantly, compared to group A.
Sodium valproate belongs to an antiepileptic drug class with an important role in the treatment of migraine. Increasing GABA activity and inhibiting NMDA-evoked neuroexcitatory signals are two main mechanisms of valproate in blocking cortical spreading depression during a migraine attack. It can inhibit GABA-degrading enzymes (i.e., aminotransferase and succinic semialdehyde) and increase the neuro-inhibitory activity of GABA. In addition, the active metabolites of valproate can activate the GABA-synthesizing enzyme (i.e., glutamic acid decarboxylase) and increase GABA activity more over time. Furthermore, valproate decreases neurogenic inflammation by debilitating plasma extravasation of vasoactive neuropeptides, such as substance P, CGRP, and neurokinin A (Parikh and Silberstein 2019, Waldrop and Kolb 2019).
There is much evidence that valproate is effective in the prevention of migraine attacks; however, different response rates were reported in various studies (Mathew, Saper et al. 1995, Shaygannejad, Janghorbani et al. 2006). Ichikawa et al. demonstrated that different factors, such as the history of hyperlipidemia, allergy, and psychiatric disorders, are involved in the clinical responses to valproate (Ichikawa, Katoh et al. 2016). Sodium valproate has been used in doses within the range of 500 to 1,000 mg/day in migraine prevention trials (Parikh and Silberstein 2019). Nevertheless, in the current study, a lower dose of 200 mg was prescribed twice a day for patients with an acceptable response. Other studies in Iranian population also revealed that the therapeutic effect is achieved using 200 to 500 mg sodium valproate daily in migraine prophylaxis (Bostani, Rajabi et al. 2013, Homam, Farajpour et al. 2016, Hesami, Shams et al. 2018).
The effectiveness of magnesium in migraine prophylaxis was firstly investigated by Facchinetti et al. in 1991 (Facchinetti, Sances et al. 1991). Other trials also reported different results of magnesium efficacy in migraine patients (Taubert 1994, Köseoglu, Talaslıoglu et al. 2008). Therefore, further clinical trials were suggested in studies to clarify the exact efficacy of magnesium in the prevention of migraine. It is proposed that magnesium is linked to migraine pathogenesis by counteracting both vascular and neurogenic mechanisms of migraine (Von Luckner, Riederer et al. 2018). Magnesium may be effective in migraine through the regulation of neuronal excitability because magnesium not only acts as a physiologic calcium-antagonist but also inhibits NMDA receptors and glutamate-dependent excitatory pathways (Dalla Volta 2017, Hoffmann and Charles 2018). In addition, magnesium can regulate neurotransmitter release and substance P release and reduce free radical accumulation within the cell and vasoconstriction (Altura and Altura 1980, Facchinetti, Sances et al. 1991, Weglicki, Phillips et al. 1992). Magnesium through modulating mitochondrial oxidative phosphorylation, 5-HT neurotransmission, and the NO system, regulating the uptake of glutamate into astrocytes, and blocking of NMDA receptor can be effective in migraine-preventive therapy (Sprenger, Viana et al. 2018).
Magnesium has numerous effects on the nervous system, and other mechanisms, including the inhibition of voltage-gated calcium channels, connexin channels, and other ion channels, can be involved in the prevention of migraine (Hoffmann and Charles 2018). Based on the evidence, magnesium was strongly recommended by the Canadian Headache Society in migraine prophylaxis. The Swiss Headache Society also suggests magnesium to children and pregnant women with migraine (Pringsheim, Davenport et al. 2012).
In a crossover study conducted by Karimi et al., the comparison of efficacy between magnesium oxide and sodium valproate was carried out for migraine prophylaxis. The results showed that 500 mg/day magnesium has comparable efficacy to 400 mg/day valproate in migraine prophylaxis (Karimi, Razian et al. 2019). However, the obtained results of the present study showed that valproate was significantly more effective than magnesium in the reduction of migraine frequency and severity, duration of attacks, pain killer number as well as the MIDAS and HIT scores.
According to the literature, it was shown that the addition of magnesium to valproic acid in magnesium valproate can reduce calcium ion conductance efficiently, activate the Na+/K+ ion pump, and modulate the NMDA receptors of the neuronal membrane, compared to valproate alone in epilepsy (Canger and Guidolin 2000). Animal studies also demonstrated that magnesium enhances the anticonvulsant potential of a subprotective dose of valproic acid in pentylenetetrazol-treated rats by the improvement of redox balance and modulation of some brain excitatory amino acids, such as aspartate, asparagine, and glycine (Safar, Abdallah et al. 2010).
It should be noted that epilepsy and migraine have some similar pathophysiological mechanisms, including the imbalance between GABA-mediated inhibition, excitatory glutamate-mediated transmission, as well as the abnormal function of voltage-gated sodium and calcium channels (Shahien and Beiruti 2012). The results of in vitro studies demonstrated that magnesium improves valproic acid efficacy against 4-aminopyridine-induced ictal activity (Fueta, Siniscalchi et al. 1995). The findings of the present clinical study also confirmed this idea and indicated that a combination of magnesium and low-dose valproate (200 mg) have appropriate efficacy in migraine prophylaxis without any reported exacerbation of side effects.
Some participants in this study did not contribute to blood sampling. Lack of complete data about serum magnesium level limits our analysis about studying the correlation between serum levels of magnesium and the efficacy of treatment in three groups. Furthermore, adverse effects assessment during the study was not carried out completely due to faulty reports so the precise analysis was impossible.