Headache Medicine, v.3, n.1, p.21-25, Jan./Feb./Mar. 2012 21

Magnesium ion serum profile in chronic migraine:

comparative study between treated and

non-treated patients

Perfil sérico do íon magnésio na migrânea crônica: um estudo comparativo

entre pacientes tratados e não tratados

ABSTRACTABSTRACT

ABSTRACT

Chronic migraine is recognized as a migraine complication

and is characterized by frequency of attacks up to 15 days/

month for more than three months, in absence of painkiller

abusive usage. Studies indicate that magnesium ion plays a

role in migraine pathophysiology but, until now, they have

never included only patients with chronic migraine as their

population.

Objective:Objective:

Objective: To compare serum magnesium levels

between treated and non-treated chronic migraineurs.

Methods:Methods:

Methods: Twenty-two patients with chronic migraine were

selected and divided in two groups (treated and non-treated),

matched by sex and age, and submitted to serum dosage of

magnesium ion for latter comparison.

Result:Result:

Result: The non-treated

chronic migraineurs presented serum magnesium ion level

within normal limits, but lower than those found in the treated

group with a statistically significant difference.

Conclusion:Conclusion:

Conclusion:

Similarly to other studies in the literature, this study stresses the

importance of magnesium ion in the migraine pathophysiology,

but studying only the chronic migraine patients.

ORIGINAL ARTICLEORIGINAL ARTICLE

ORIGINAL ARTICLE

Alan Chester Feitosa de Jesus

, Giselle Melo Fontes Silva

, Marcelo Oliveira Ribeiro Paixão

Felipe José Nascimento Barreto

, Luana Karla Braz Fonseca Dantas

, Philippe Joaquim Oliveira Menezes

Macedo

, Paulo Sérgio Faro Santos

, Larissy Lima Santos

, Marco Antônio Prado Nunes

Neurologist, Collaborating Professor, Department of Medicine,

Universidade Federal de Sergipe – UFS, Aracaju, SE, Brazil

Neurologist, Hospital Universitário Pedro Ernesto – UERJ, Rio de Janeiro, RJ, Brazil

Neurologist, Universidade Estadual Paulista “Júlio de Mesquita Flho” – UNESP, Botucatu, SP, Brazil

Medical Doctors, Universidade Federal de Sergipe – UFS, Aracaju, SE, Brazil

Medical Students, Universidade Federal de Sergipe – UFS, Aracaju, SE, Brazil

Head of the Department of Medicine, Assistant Professor of Surgical Clinic of the Department of Medicine,

Universidade Federal de Sergipe – UFS, Aracaju, SE, Brazil

Sergipe Headache Unit (LICESE), University Hospital, Universidade Federal de Sergipe – HU-UFS,

Aracaju, SE, Brazil

Jesus AC, Silva GM, Paixão MO, Barreto FJ, Dantas LK, Macedo PJ, et al.

Magnesium ion serum profile in chronic migraine: comparative study between treated and

non-treated patients. Headache Medicine. 2012;3(1):21-5

eywords: eywords:

eywords: Chronic migraine; Serum magnesium; Patho-

physiology

RESUMORESUMO

RESUMO

Migrânea crônica refere-se a uma complicação da migrânea

e é caracterizada por uma frequência de crises superior a 15

dias por mês durante mais de três meses, sem uso excessivo

de analgésicos. Pesquisas demonstram que o íon magnésio

está envolvido na fisiopatologia da migrânea, contudo nunca

incluíram, até o momento, pacientes com migrânea crônica

como população exclusiva.

Objetivo:Objetivo:

Objetivo: Comparar os níveis

de magnésio sérico entre migranosos crônicos tratados e não

tratados.

Métodos: Métodos:

Métodos: Vinte e dois pacientes com migrânea

crônica foram selecionados; divididos em dois grupos (tra-

tados e não tratados); pareados por sexo e idade e subme-

tidos à dosagem sérica do íon magnésio para comparação

posterior dos resultados obtidos.

Resultado:Resultado:

Resultado: Os migranosos

crônicos não tratados apresentaram níveis de magnésio sérico

dentro dos limites da normalidade, embora menores que os

22 Headache Medicine, v.3, n.1, p.21-25, Jan./Feb./Mar. 2012

INTRODUCTION

As a common and disabling disorder, migraine is

the most studied primary headache nowadays.

(1)

Studies

reveal a prevalence of 11% of migraine in the general

population,

(1)

and 38% of headache patients admitted in

a tertiary center.

(2)

According to the World Health

Organization ranking, migraine holds the 19th position

among all the disabling diseases.

(1)

Chronic migraine is

considered by the International Classification of Headache

Disorders, 2

edition (ICHD-2), as a migraine

complication, whose main characteristics are: frequency

of migraine attacks up to 15 days/month for more than

three months, in absence of painkiller abusive usage.

(3)

Considering the pathophysiology of migraine,

magnesium ion is referred as a possible biomarker.

(4-7)

This ion has been already described as deficient at systemic

and brain levels in patients with migraine (with and without

aura) and in those with menstrual migraine.

(6,7)

Moreover,

studies show that in long-duration attacks the trigeminal

system is sensitized, what happens due to continuous and

repetitive stimulation of the primary afferent neuron through

long term glutamate release and Mg²

depletion from

NMDA receptors, followed by glutamate binding to these

receptors.

(6)

Thus, it leads to calcium influx in neurons of

the trigeminal nucleus caudalis, its sensitization and

increase of cortical excitability.

(4-6)

In addition to these

evidences, measures of magnesium ion obtained through

phosphorum-31 spectroscopy revealed low levels in the

brain posterior areas of people with familial hemiplegic

migraine.

(6,8)

The above-mentioned mechanism induces not only

epileptiform discharges and cortical spreading depression,

but also arterial vasospasm due to low serotonin (5-HT)

levels and other vasoactive substances.

(9)

More than that,

it increases thrombin-induced platelet aggregation,

leading to 5-HT release, reduction on prostacyclins action

over β-adrenergic-mediated relaxation of the blood vessel

walls. Consequently, low magnesium levels act as a pro-

inflammatory agent.

(9)

The entire amount of magnesium in an adult human

is about 24 g (1 mol) and it is equally distributed among

bones and soft tissues.

(10)

Less than 1% of total body

magnesium is contained in the blood and approximately

0.3%, presented in serum.

(10)

Serum magnesium

measurement has been largely used to estimate the amount

of this ion in the organism.

(10)

Therefore, researches have

already been made comparing magnesium levels

between patients with headache and healthy volunteers,

(11)

in accord to dosage of magnesium ion in migraneurs

with and without aura in the interictal period,

(12,13)

in patients

with menstrual migraine

(14)

and in others with hemodialysis

headache.

(15)

However, there are no citations of the serum levels of

magnesium in patients with chronic migraine. This study

tries to elucidate how magnesium ion acts in chronic

migraine, by comparing serum magnesium levels between

treated and non-treated chronic migraineurs, it also

analyzes clinical characteristics of these patients.

METHODS

The study was performed on patients of the

headache center of the Liga de Cefaleia de Sergipe,

located at the Teaching Hospital of the Universidade

Federal de Sergipe. A total of 22 patients, diagnosed

with chronic migraine by the same examiner according

to criteria of the ICHD-2, were divided in two groups.

The Group A was composed by eleven patients without

any kind of behavioral intervention or previous drug

therapy, at the moment of first admission; the 11

remaining patients, who were arranged into the Group

B, that had already been under treatment in that center

and achieved a reduction of their frequency of attacks

for less than 15 days per month, as assured by migraine-

daily chart. None of these patients were using any

medication containing magnesium for headache therapy

or any other purpose.

A dosage of serum magnesium ion was requested

for all the 22 patients at one laboratory in the city of

Aracaju, capital of Sergipe. This laboratory, whose serum

magnesium ion reference values range 1.6 to 2.3 mg/dL,

was not informed about the reason for requesting such

exam. Then, the results of each group were compared

through Student's t-test.

This research was approved by the Ethics Committee

of the Teaching Hospital of the Universidade Federal de

Sergipe and all participants included have signed a

permission term according to Helsinki Declaration rules.

JESUS AC, SILVA GM, PAIXÃO MO, BARRETO FJ, DANTAS LK, MACEDO PJ, ET AL.

encontrados no grupo tratado, com uma diferença estatisti-

camente significante.

Conclusão:Conclusão:

Conclusão: Em corroboração com a

literatura, este estudo enfatiza a importância do íon magnésio

na fisiopatologia da migrânea, apenas pacientes com

migrânea crônica.

alavrasalavras

alavras

chave: chave:

chave: Migrânea crônica; Magnésio sérico;

Fisiopatologia

Headache Medicine, v.3, n.1, p.21-25, Jan./Feb./Mar. 2012 23

RESULTS

In both groups, most members were women, being

nine for group A and ten for group B. The average age

in group A was 43 ± 14.9 years old, whereas in group

B, it was 41.0 ± 14.6 years old. Considering the age of

onset of migraine attacks, it varied from 6 to 48 years for

group A, and from 3 to 44 years for group B. The period

of chronification, 48 months, was similar in both groups.

The majority of subjects presented serum magnesium levels

within normal limits; except for one patient in group A whose

ion level was below 1.6 mg/dL, and another in group B

who showed magnesium level above 2.3 mg/dL (Table).

data, the sample of the present study was composed of

19 women, whose mean age was 46 years in the group

A and 41.8 in group B. Similarly, the average age for

men was compatible with the literature.

In this study, the age of onset of migraine varied from

3 to 48 years old, with mean age of 17.6 ± 12.5 years,

similar to the reviewed literature (mean age: 20.8 ± 11.2

years).

(19)

Considering time of chronification, our patients

presented, in mean, a period of 48 months, a result that

does not corroborate with some studies in the literature

which demonstrate a mean period of 12 months of

transformation from episodic to chronic migraine.

(16,17)

Several studies correlate changes on serum

magnesium levels with threshold and continuance of pain

attacks, reinforcing the importance of this ion in the

pathophysiology of various types of headache. Gallai et

al.,

(13)

when comparing magnesium levels in the blood

of patients suffering from migraine with aura, without aura

and controls, observed a lower concentration of

intracellular magnesium in migraneurs than in the control

group.

Mauskop et al.,

(14)

while studying the level of free

magnesium ion on 61 women with menstrual migraine

and patients without headache, found low magnesium

ion levels in 45% of women with menstrual migraine,

whereas only 14% of the menstruant women without

migraine had low free magnesium levels. All women had

normal total magnesium, and the researchers did not find

a correlation between the level of free magnesium and

the intensity of chronic headache.

Furthermore, Goksel et al.

(15)

studied serum levels of

magnesium before and after hemodialysis on patients with

dialysis headache compared to a control group of people

suffering from chronic kidney disease. There have been

found, on patients with dialysis headache, lower levels

than in the control group before and after hemodialysis,

but the absolute level of magnesium was normal in both

groups (reference levels: 1.6-3.0 mg/dL).

Once magnesium-deficient state has been

recognized, the supplementation of this ion was suggested

as a possible therapy for patients with headache, as much

for abortive, as for prophylactic treatment.

(9,20)

A study with

81 migraneurs in use of 600 mg of magnesium dicitrat in

the form of a soluble powder in water and placebo has

shown a 42% decrease in the frequency of crisis with such

medication, while those that received placebo presented

decreasing of headache attacks only on 16% after 12

weeks.

(9)

Another study conducted by Mauskop et al.

(20)

revealed that intravenous magnesium aborted migraine

MAGNESIUM ION SERUM PROFILE IN CHRONIC MIGRAINE: COMPARATIVE STUDY BETWEEN TREATED AND NON-TREATED PATIENTS

Even though results of the samples were normal in

20 of the 22 patients undergoing research, when Student's

t-test was applied in order to compare magnesium levels

of both groups, it was demonstrated that serum

magnesium levels of group A were lower than group B,

with a statistically significant difference (p=0.001).

DISCUSSION

It is reckoned that chronic migraine is a complication

of episodic migraine.

(3)

Some risk factors are believed to

be related to the transformation, such as caffeine, painkiller

abusive consumption, obesity, psychiatric comorbidities,

Caucasian race, sleep disturbances, lower socioeconomic

status, among others.

(16-18)

Also, female gender is

considered a risk factor for chronification of migraine.

(16,17)

Twenty-two patients took part in this study; among them,

there has been observed female predominance (n=19),

oppositely to male gender (n=3). Chronic migraine is

more prevalent during childbearing age (15-49 years)

(16)

in the female gender and during adulthood among the

male group (25-49 years).

(18)

Corroborating with these

24 Headache Medicine, v.3, n.1, p.21-25, Jan./Feb./Mar. 2012

JESUS AC, SILVA GM, PAIXÃO MO, BARRETO FJ, DANTAS LK, MACEDO PJ, ET AL.

attacks of high intensity on patients with low magnesium

serum levels, but not on patients with normal ones.

CONCLUSIONS

Until now, there is no study in the literature which

correlates exclusively chronic migraine and serum

magnesium ion levels. In this research, non-treated patients

with chronic migraine presented normal serum magnesium

levels, but significantly lower when compared to patients

that, under treatment, would be then classified as episodic

migraineurs. This study was carried out with a reduced

number of patients, which limits a more precise conclusion.

However, like other studies, it points magnesium ion as a

possible biomarker of pathophysiological mechanisms of

migraine.

REFERENCES

1. Stovner LJ, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, et

al. The global burden of headache: a documentation of headache

prevalence and disability worldwide. Cephalalgia. 2007;

27(3):193-210.

2. Felício AC, Bichuetti DB, Santos WA, Godeiro Junior Cde O,

Marin LF, Carvalho Dde S. Epidemiology of primary and

secondary headaches in a Brazilian tertiary-care center. Arq

Neuropsiq. 2006;64(1):41-4.

3. Headache Classification Subcommittee of the International

Headache Society. The International Classification of Headache

Disorders, 2a. ed. Cephalalgia. 2004;24(Suppl1):S1-160.

4. Boska MD, Welch KMA, Barker PB, Nelson JA, Schultz L.

Contrasts in cortical magnesium, phospholipid and energy

metabolism between migraine syndromes. Neurology. 2002;

58(8):1227-33.

5. Burstein R, Collins B, Bajwa Z, Jakubowski M . Triptan therapy

can abort migraine attacks if given before the establishment or

in the absence of cutaneous allodynia and central sensitization:

clinical and preclinical evidence (abstract). Headache. 2002;

42:390.

6. Sun-Eldestein C, Mauskop A. Role of magnesium in the

pathogenesis and treatment of migraine. Expert Rev Neurother.

2009;9(3): 369-79.

7. Loder E, Harrington MG, Cutrer M, Sandor P, De Vries B. Selected

confirmed, probable, and exploratory migraine biomarkers.

Headache. 2006;46(7):1108-27.

8. Welch, KM. Brain Hyperexcitability: the basis for antiepileptic

drugs in migraine prevention. Headache. 2005;45(Suppl 1):

S25-32.

9. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine

with oral magnesium: results from a prospective, multi-center,

placebo-controlled and double-blind randomized study.

Cephalalgia. 1996;16(4):257-63.

10. Trauninger A, Pfund Z, Koszegi T, Czopf J. Oral Magnesium load

test in patients with migraine. Headache 2002;42(2):114-9.

11. Ramadan NM, Halvorson H, Vande-Linde A, Levine SR, Helpern

JA, Welch KM. Low brain magnesium in migraine.Headache.

1989;29(7):416-9. Comment in Headache. 1990;30(3):168.

12. Soriani S, Arnaldi C, De Carlo L, Arcudi D, Mazzotta D, Battistella

PA et al. Serum and Red Blood Cell Magnesium Levels in Juvenile

Migraine Patients. Headache 1995;35(1):14-6.

13. Gallai V, Sarchielli P, Coata G, Firenze C, Morucci P, Abbritti G.

Serum and Salivary Magnesium Levels in Migraine. Results in a

Group of Juvenile Patients. Headache. 1992;32(3):132-5

14. Mauskop A, Altura BT, Altura BM. Serum ionized magnesium

levels and serum ionized calcium/ ionized magnesium ratios

in women with menstrual migraine. Headache. 2002;42(4):

242-8.

15. Goksel BK, Torun D, Karaca S, Karatas M, Tan M, Sezgin N et al.

Is low blood magnesium level associated with hemodialysis

headache? Headache. 2006;46(1):40-5.

16. Vargas BB, Dodick DW. The face of chronic migraine:

epidemiology, demographics, and treatment strategies. Neurol

Clin. 2009;27(2):467-79.

17. Silberstein S, Diener HC, Lipton R, Goadsby P, Dodick D,

Bussone G, et al. Epidemiology, risk factors, and treatment of

chronic migraine: a focus on topiramate. Headache. 2008;

48(7):1087-95.

18. Midgette LA, Scher AI. The epidemiology of chronic daily

headache. Curr Pain Headache Rep. 2009;13(1):59-63.

19. Oliveira MF, Speciali JG. Cefaléia crônica diária: conceitos e

tratamentos. Medicina, Ribeirão Preto 2002;35:455-63.

20. Mauskop A, Altura, BT, Cracco, RQ, Altura, BM. Intravenous

Magnesium Sulfate Rapidly Alleviates Headaches of Various

Types. Headache. 1996;36(3):154-60.

COMMENTS

aimundo Paimundo P

aimundo P

ereira Silva-Nétoereira Silva-Néto

ereira Silva-Néto

Neurologist and member of the Brazilian Headache Society

Editorial board member of Headache Medicine

Neurology and Headache Center of Piauí – Teresina, PI, Brazil

Jesus and colleagues show, concisely, in article

“Magnesium ion serum profile in chronic migraine:

comparative study between treated and non-treated

patients” that magnesium ion plays a role in patho-

physiology of migraine. According to these authors, serum

magnesium levels are reduced in patients with migraine.

This change would make it a migraine biomarker. This

information can also be seen in research Talebi et al.

As result of magnesium deficiency, Jesus and

colleagues cite the supplementation of this ion in both

abortive and prophylactic treatment of migraine. However,

in a recent review on the acute treatment of migraine,

Headache Medicine, v.3, n.1, p.21-25, Jan./Feb./Mar. 2012 25

Kelley et al.

found that magnesium seems to have only

limited effectiveness in treating photophobia and

phonophobia.

As demonstrated, current research on the role of

magnesium in pathophysiology and treatment of migraine

have been performed only in episodic migraine. This

article is certainly the first on the magnesium ion in patients

with chronic migraine.

Finally, the findings of lower serum magnesium levels

in patients with untreated chronic migraine corroborate

the fact that repeated attacks of headache causes

continuous stimulation of primary afferent neuron, with

consequent depletion of magnesium.

REFERENCES

1. Talebi M, Savadi-Oskouei D, Farhoudi M, Mohammadzade S,

Ghaemmaghamihezaveh S, Hasani A, Hamdi A. Relation between

serum magnesium level and migraine attacks. Neurosciences.

2011;16(4):320-3.

2. Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 1:

triptans, dihydroergotamine, and magnesium. Headache

2012;52(1):114-28.

Correspondence

Alan Chester Feitosa de JesusAlan Chester Feitosa de Jesus

Alan Chester Feitosa de Jesus

Rua Percílio da Costa Andrade 175/1401

49200-600 – Aracaju, SE, Brasil

E-mail: alanchester@uol.com.br

MAGNESIUM ION SERUM PROFILE IN CHRONIC MIGRAINE: COMPARATIVE STUDY BETWEEN TREATED AND NON-TREATED PATIENTS

Received: 12/5/2011

Accepted: 2/2/2012