Effect of Flunarizine on Serum Glutamate Levels and its Correlation with Headache Intensity in Chronic Tension-Type Headache Patients

  • Khairul Putra Surbakti Department of Neurology, Faculty of Medicine, Universitas Sumatera Utara, Medan
  • Hasan Sjahrir Department of Neurology, Faculty of Medicine, Universitas Sumatera Utara, Medan
  • Rosita Juwita-Sembiring Faculty of Medicine, Universitas Sumatera Utara, Medan
  • Erna Mutiara Department of Biostatistics and Health Information, Faculty of Public Health, Universitas Sumatera Utara, Medan
Keywords: flunarizine, glutamate, headache intensity, chronic tension-type headache


BACKGROUND: Some of the excitatory neurotransmitters including glutamate have been suggested to be involved in headache pathophysiology. To our knowledge, there is a lack of publication about flunarizine efficacy in chronic tension-type headache (CTTH) treatments and the roles of glutamate in CTTH pathophysiology.

AIM: This study aimed to investigate the flunarizine effect on serum levels of glutamate and its correlation with headache intensity based on the Numeric Rating Scale for pain (NRS) scores in CTTH patients.

METHOD: In a prospective randomised, double-blind study with pre and post-test design, seventy-three CTTH patients were randomly allocated with flunarizine 5 mg, flunarizine 10 mg and amitriptyline 12.5 mg groups. The serum levels of glutamate and NRS scores were measured before and after 15-day treatment.

RESULTS: Flunarizine 5 mg was more effective than flunarizine 10 mg and amitriptyline 12.5 mg in reducing serum glutamate levels, whereas amitriptyline 12.5 mg was the most effective in reducing headache intensity. There was found nonsignificant, but very weak negative correlation between headache intensity and serum glutamate levels after flunarizine 5 mg administration (r = -0.062; P = 0.385), nonsignificant very weak negative correlation after flunarizine 10 mg administration (r = -0.007; P = 0.488) and there was found a significant moderate positive correlation (r = 0.508; P = 0.007) between headache intensity and serum glutamate levels after amitriptyline 12.5 mg administration.

CONCLUSION: Since there was no significant correlation found between serum glutamate and headache intensity after treatment with flunarizine, it is suggested that decreasing of headache intensity after flunarizine treatment occurred not through glutamate pathways in CTTH patients.


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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: 193-210. https://doi.org/10.1111/j.1468-2982.2007.01288.x PMid:17381554

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

Sacco S, Ricci S, Carolei A. Tension-type Headache and Systemic Medical Disorders. Curr Pain Headache Rep. 2011; 15: 438-443. https://doi.org/10.1007/s11916-011-0222-2 PMid:21861098

Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders: 3rd edition. Cephalalgia. 2013; 33(9):629-808.

Bendtsen, L. Central sensitization in tension-type headache - possible pathophysiological mechanisms. Cephalalgia. 2000; 20:486–508. https://doi.org/10.1046/j.1468-2982.2000.00070.x PMid:11037746

Chen, Y. Advances in the Pathophysiology of Tension-type Headache: From Stress to Central Sensitization. Current Pain & Headache Reports. 2009; 13:484-494. https://doi.org/10.1007/s11916-009-0078-x

Gasparini CF, Smith RA and Griffiths LR. Biochemical Studies of the Neurotransmitter Glutamate: A Key Player in Migraine. Austin J Clin Neurol. 2015; 2(9):1079.

Huang L, Bocek M, Jordan JK, Sheehan AH. Memantine for the Prevention of Primary Headache Disorders. Annals of Pharmacotherapy. 2014;1-5. https://doi.org/10.1177/1060028014548872

Ferrari A, Spaccapelo, L, Pinetti, D, Tacchi, R, Bertolini, A. Effective prophylactic treatments of migraine lower plasma glutamate levels. Cephalalgia. 2008; 29:423-429. https://doi.org/10.1111/j.1468-2982.2008.01749.x PMid:19170689

Clauhan S, Devi P & Nidhi. Pharmacological profile of flunarizine: A calcium channel blocker. International Journal of Innovative Pharmaceutical Sciences and Research. 2014; 2(6):1260-1269.

Mohammed BP, Goadsby PJ, Prabhakar P. Safety and efficacy of flunarizine in childhood migraine: 11-year experience with emphasis on its hemiplegic migraine. 2011. Available from: http://dx.doi.org/10.1111/J.1469- 8749.2011.04152.x

Headache Classification Subcommittee of the International Headache Society. The International Classification of headache Disorders. Cephalalgia. 2004; 24(Suppl. 1): 1–160.

Cousin MD, Nicholls DG, Pocock JM. Flunarizine inhibits both calcium- dependent and -independent release of glutamate from synaptosomes and cultured neurones. Brain Research. 1993; 606:227-236. https://doi.org/10.1016/0006-8993(93)90989-Z

Kataki, MS, Kumar, KTMS, Rajkumari, A. Neuropsycho-pharmacological Profiling of Flunarizine: A Calcium Channel Blocker. Int.J. PharmTech Res. 2010; 2(3):1703-11713.

Su M, Liang L and Yu S. Amitriptyline Therapy in Chronic Pain. Int Arch Clin Pharmacol. 2015;1(1):1-5. https://doi.org/10.23937/2572-3987.1510001

Tomkins GE, Jackson JL, O'Malley PG, Balden E, Santoro JE. Treatment of Chronic Headache with Antidepressants: A Meta-analysis. Am J Med. 2001; 111:54-63. https://doi.org/10.1016/S0002-9343(01)00762-8

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: 291–297. https://doi.org/10.1111/j.1471-4159.1977.tb09621.x PMid:886334

Alfredsson G, Wiesel FA, Tylec A. Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers. Biol Psychiatry. 1988; 23: 689–697. https://doi.org/10.1016/0006-3223(88)90052-2

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 [P-D Sect]. 1993; 6: 1-9. https://doi.org/10.1007/BF02252617

Rainesalo S, Keränen T, Palmio J, Peltola J, Oja SS, Saransaari P. Plasma and Cerebrospinal Fluid Amino Acids in Epileptic Patients. Neurochemical Research. 2004 ;29(1): 319–324. https://doi.org/10.1023/B:NERE.0000010461.34920.0c PMid:14992292

Ilzecka J, Stelmasiak Z, Solski J, Wawrzycki S, Szpetnar M. Plasma amino acids concentration in amyotrophic lateral sclerosis patients. Amino Acids. 2003; 25: 69–73. https://doi.org/10.1007/s00726-002-0352-2 PMid:12836061

How to Cite
Surbakti KP, Sjahrir H, Juwita-Sembiring R, Mutiara E. Effect of Flunarizine on Serum Glutamate Levels and its Correlation with Headache Intensity in Chronic Tension-Type Headache Patients. Open Access Maced J Med Sci [Internet]. 2017Oct.7 [cited 2020Sep.30];5(6):757-61. Available from: https://www.id-press.eu/mjms/article/view/oamjms.2017.172
B - Clinical Sciences