The Effect of Flunarizine Prophylactic Treatment on Headache Frequency and Plasma Glutamate Levels in Chronic Tension-type Headache Patients


  • Khairul Putra Surbakti Department of Neurology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
  • Hasan Sjahrir Department of Neurology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia



Flunarizine, Plasma Glutamate, Chronic Tension-type headache


Background: Previous research has shown that flunarizine may be used for the prophylactic treatment of migraine and that plasma glutamate level monitoring in patients with migraine can serve as a biomarker of response to treatment. Our aim was to assess the efficacy of flunarizine and the correlation of glutamate levels in Chronic Tension-type Headache (CTTH) with response to medication.

Methods: We studied 19 patients with diagnosis of CTTH according to International Classification of Headache Disorder, 2nd edition criteria. The level of plasma glutamate was measured before and after 8-weeks prophylactic treatments. Subjects were randomized into three interventional groups (flunarizine 5 mg, flunarizine 10 mg and placebo). Glutamate levels were measured by means of Glutamate ELISA Kit KA1909 Abnova.       

Results: Flunarizine 5 mg group had lower mean plasma glutamate levels significantly compared to placebo (p < 0.00; 95% CI: 0.40-1.07). Flunarizine 10 mg group had lower mean of plasma glutamate levels significantly compared to placebo (p< 0.00; 95% CI: 0.53-1.27). However, there were no significant differences of mean plasma glutamate levels between flunarizine 5 mg group and flunarizine 10 mg group (p < 0.37; 95% CI: -(0.54) - 0.21). There were no significant differences in headache frequency reduction among the three interventional groups.

Conclusions: The usage of flunarizine as prophylactic treatment can reduce plasma glutamate levels significantly in CTTH patients. Either flunarizine or placebo showed no significant difference in reducing headache frequency in CTTH patients.


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Zebenholzer K, Andree C, Lechner A, Brossner G, Lampl C, Luthringshausen G, et al. Prevalence, management and burden of episodic and chronic headaches a cross sectional multicentre study in eight Austrian headache centres. J Headache Pain. 2015;16:531. PMid:25990699 DOI:

Stovner LJ, Hagen K, Jensen R, Katsarava Z, Lipton RB, Scher A, et al. The global burden of headache: A documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3):193-210. PMid:17381554 DOI:

Sjahrir H. Nyeri Kepala 1. Medan: USU Press; 2004.

Mengistu G, Alemayehu S. Prevalence and burden of primary headache disorders among a local community in Addis Ababa, Ethiopia. J Headache Pain. 2013;14:30. DOI:

Bendtsen L. Central sensitization in tension-type headache possible pathophysiological mechanisms. Cephalalgia. 2000;20(5):486-508. PMid:11037746 DOI:

Chen Y. Advances in the pathophysiology of tension-type headache: From stress to central sensitization. Curr Pain Headache Rep. 2009;13(6):484-94. PMid:19889292 DOI:

Sacco S, Ricci S, Carolei A. Tension-type headache and systemic medical disorders. Curr Pain Headache Rep. 2011;15:438-43. DOI:

Verhagen AP, Damen L, Berger MY, Passchier J, Koes BW. Lack of benefit for prophylactic drugs of tension-type headache in adults: A systematic review. Family Pract. 2010;27:151-65. DOI:

Huang L, Bocek M, Jordan JK, Sheehan AH. Memantine for the prevention of primary headache disorders. Ann Pharmacother 2014;48(11):1507-11. PMid:25159002 DOI:

Ferrari A, Spaccapelo L, Pinetti D, Tacchi R, Bertolini A. Effective prophylactic treatments of migraine lower plasma glutamate levels. Cephalalgia. 2008;29(4):423-9. PMid:19170689 DOI:

Gasparini CF, Smith RA, Griffiths LR. Biochemical studies of the neurotransmitter glutamate: A key player in migraine. Austin J Clin Neurol. 2015;2(9):1079.

Clauhan S, Devi P, Nidhi. Pharmacological profile of flunarizine: A calcium channel blocker. Int J Innov Pharm Sci Res. 2014;2(6):1260-9.

Mohammed BP, Goadsby PJ, Prabhakar P. Safety and efficacy of flunarizine in childhood migraine: 11-year experience with emphasis on its hemiplegic migraine. Dev Med Child Neurol. 2012;54(3):274-7. PMid:22268377 DOI:

Cousin MD, Nicholls DG, Pocock JM. Flunarizine inhibits both calcium-dependent and -independent release of glutamate from synaptosomes and cultured neurones. Brain Res. 1993;606:227-36. DOI:

International Headache Society. The international classification of headache disorders, 2nd edition. Cephalalgia. 2004;24(Suppl 1):1-160. PMid:14979299

Kataki MS, Kumar KT, Rajkumari A. Neuropsychopharmacological profiling of flunarizine: A calcium channel blocker. Int J PharmTech Res. 2010;2(3):1703-13.

McGale EH, Pye IF, Stonier C, Hutchinson EC, Aber GM. Studies of the inter-relationship between cerebrospinal fluid and plasma amino acid concentrations in normal individuals. J Neurochem. 1977;29(2):291-7. PMid:886334 DOI:

Alfredsson G, Wiesel FA, Tylec A. Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers. Biol Psychiatry. 1988;23(7):689-97. PMid:2453224 DOI:

Martinez M, Frank A, Diez-Tejedar E, Hernanz A. Amino acids concentration in cerebrospinal fluid and serum in Alzheimer disease and vascular dementia. J Neural Transm Park Dis Dement Sect. 1993;6(1):1-9. PMid:8216758 DOI:

Rainesalo S, Keränen T, Palmio J, Peltola J, Oja SS, Saransaari P. Plasma and cerebrospinal fluid amino acids in epileptic patients. Neurochem Res. 2004;29(1):319-24. PMid:14992292 DOI:

Ilzecka J, Stelmasiak Z, Solski J, Wawrzycki S, Szpetnar M. Plasma amino acids concentration in amyotrophic lateral sclerosis patients. Amino Acids. 2003;25(1):69-73. PMid:12836061 DOI:




How to Cite

Surbakti KP, Sjahrir H. The Effect of Flunarizine Prophylactic Treatment on Headache Frequency and Plasma Glutamate Levels in Chronic Tension-type Headache Patients. Open Access Maced J Med Sci [Internet]. 2021 Jun. 21 [cited 2024 Jun. 15];9(T3):223-7. Available from:

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