Plasma concentrations of glutamate in patients suffering from chronic migraine overusing acute medication, before and after withdrawal treatment

A dysfunction of the glutamatergic system would have an essential role in the pathogenetic mechanism of the migraine. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, and central sensitization [1]. Higher glutamate levels than those of healthy controls have been reported in migraine patients’ plasma and platelets [2] and in chronic migraine patients’ cerebrospinal fluid [3].
Our aim was verifying if there were differences in the plasma levels of glutamate between patients with chronic migraine overusing acute medications and control subjects, and if plasma levels of glutamate in chronic migraine patients modified after withdrawal from the overused medication.
Methods. We studied 12 patients (F=10, M=2; mean age 50.3±9.8 years) with diagnosis of chronic migraine, according to ICHD-II criteria, overusing acute medications, and 15 healthy subjects as controls (F=2, M=3; mean age 48.2±7.3 years). Patients were studied twice, before and after 15 days of standardized inpatient withdrawal treatment. Venous blood samples for the assay of glutamate concentrations were taken in the morning, after overnight fasting. Glutamate concentrations were measured by means of a fluorimetric detector high pressure liquid chromatographic (HPLC/FD) method.
Results. Plasma concentrations of glutamate were significantly higher in chronic migraine patients either before (62.5±5.1 µmol/L) or after treatment (27.7±11.3 µmol/L) than in control subjects (7.3±2.9 µmol/L) (P<0.05, ANOVA followed by Student-Newman-Keuls’ test). However, after 15 days of inpatient withdrawal treatment, once overuse was interrupted, and the frequency of headache reduced, plasma glutamate concentrations were significantly lower in the same patient with respect to the prior level (P<0.0001, Student’s t-test for paired data), without any differences depending on the kind of medication overused.
Conclusions. Elevated plasma levels of glutamate in chronic migraine sufferers could support the role of this excitatory aminoacid in the process of central sensitization. The decline in glutamate plasma concentrations is associated with medication-overuse discontinuation and reduced headache frequency; thus, plasma glutamate levels monitoring in chronic migraine might serve as a biomarker of clinical improvement.

[1] Ramadan NM. The link between glutamate and migraine. CNS Spectr 2003; 8(6):446-9
[2] Alam Z, Coombes N, Waring RH, Williams AC, Steventon GB. Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache. J Neurol Sci 1998; 156(1):102-6
[3] Peres MF, Zukerman E, Senne Soares CA, Alonso EO, Santos BF, Faulhaber MH. Cerebrospinal fluid glutamate levels in chronic migraine. Cephalalgia 2004; 24(9):735-9