Vitamin D3 might improve headache characteristics and protect against inflammation in migraine: a randomized clinical trial

Abstract

Introduction

Due to anti-inflammatory effects of vitamin D3, we aimed to explore the effects of supplementation with this vitamin on headache characteristics and serum levels of pro/anti-inflammatory markers in migraineurs.

Methods and materials

This placebo-controlled, double-blind study included 80 episodic migraineurs who randomly assigned into two equal groups to receive either daily dose of vitamin D3 2000 IU (50 μg) or placebo for 12 weeks. At baseline and after the trial, headache characteristics were determined using diaries and serum levels of interleukin (IL)-10, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (Cox-2) were assessed via ELISA method.

Results

At the end of trial, analysis of covariance (ANCOVA) adjusted for baseline values, and confounders revealed that vitamin D3 supplemented group experienced significantly lower headache days per month (4.71), reduced attacks duration (12.99 h/attack), less severe headaches (5.47, visual analog scale), and lower analgesics use/month (2.85) than placebo group (6.43, 18.32, 6.38 and 4.87, respectively) (P values < 0.05). Using ANCOVA adjusted for baseline levels and confounding variables, it was found that serum levels of IL-10 and Cox-2 did not significantly differ between groups after the experiment; whereas, iNOS serum level was significantly reduced in the intervention group (106.06 U/L) comparing to the controls (156.18 U/L P : 0.001). Also, the patients receiving vitamin D3 yielded a marginally significant lower IL-6 serum concentration (76.43 ng/L) compared to placebo (93.10 ng/L) (P value:0.055).

Conclusion

Based on the results of this study, we found that 2000 IU (50 μg)/day vitamin D3 supplementation for 12 weeks could improve headache characteristics and might reduce neuro-inflammation in episodic migraine.

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References

  1. 1.

    Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z (2018) Migraine is first cause of disability in under 50s: will health politicians now take notice? J Headache Pain 19(1):17

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A et al (2007) The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27(3):193–210

    PubMed  Article  Google Scholar 

  3. 3.

    Vetvik KG, MacGregor EA (2017) Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol 16(1):76–87

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Headache Classification Committee of the International Headache Society (IHS) (2018) The International Classification of Headache Disorders, 3rd edition. Cephalalgia : an international journal of headache 38(1):1–211

  5. 5.

    Dodick DW (2018) A phase-by-phase review of migraine pathophysiology. Headache 58(Suppl 1):4–16

    PubMed  Article  Google Scholar 

  6. 6.

    Waeber C, Moskowitz MA (2005) Migraine as an inflammatory disorder. Neurology 64(10 suppl 2):S9–S15

    PubMed  Article  Google Scholar 

  7. 7.

    Peroutka SJ (2005) Neurogenic inflammation and migraine: implications for the therapeutics. Mol Interv 5(5):304–311

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Bruno P, Carpino F, Carpino G, Zicari A (2007) An overview on immune system and migraine. Eur Rev Med Pharmacol Sci 11(4):245–248

    CAS  PubMed  Google Scholar 

  9. 9.

    Ramachandran R (2018) Neurogenic inflammation and its role in migraine. Semin Immunopathol 40(3):301–314

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Pietrobon D (2005) Migraine: new molecular mechanisms. Neuroscientist 11(4):373–386

  11. 11.

    Ceylan M, Bayraktutan OF, Becel S, Atis O, Yalcin A, Kotan D (2016) Serum levels of pentraxin-3 and other inflammatory biomarkers in migraine: association with migraine characteristics. Cephalalgia 36(6):518–525

    PubMed  Article  Google Scholar 

  12. 12.

    Palm-Meinders IH, Koppen H, Terwindt GM, Launer LJ, Konishi J, Moonen JM, Bakkers JT, Hofman PA, van Lew B, Middelkoop HA, van Buchem M, Ferrari MD, Kruit MC (2012) Structural brain changes in migraine. Jama 308(18):1889–1897

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Sadeghi O, Nasiri M, Maghsoudi Z, Pahlavani N, Rezaie M, Askari G (2015) Effects of pyridoxine supplementation on severity, frequency and duration of migraine attacks in migraine patients with aura: a double-blind randomized clinical trial study in Iran. Iran J Neurol 14(2):74–80

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Eren Y, Dirik E, Neselioglu S, Erel O (2015) Oxidative stress and decreased thiol level in patients with migraine: cross-sectional study. Acta Neurol Belg 115(4):643–649

    PubMed  Article  Google Scholar 

  15. 15.

    Ghorbani Z, Togha M, Rafiee P, Ahmadi ZS, Rasekh Magham R, Haghighi S, et al (2019) Vitamin D in migraine headache: a comprehensive review on literature. Neurol Sci

  16. 16.

    Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(7):1911–1930

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Anjum I, Jaffery SS, Fayyaz M, Samoo Z, Anjum S (2018) The Role of Vitamin D in Brain Health: A Mini Literature Review. Cureus 10(7):e2960-e

    Google Scholar 

  18. 18.

    van Harten-Gerritsen AS, Balvers MG, Witkamp RF, Kampman E, van Duijnhoven FJ (2015) Vitamin D, Inflammation, and colorectal Cancer progression: a review of mechanistic studies and future directions for epidemiological studies. Cancer Epidemiol Biomark Prev 24(12):1820–1828

    Article  CAS  Google Scholar 

  19. 19.

    Helde-Frankling M, Bjorkhem-Bergman L (2017) Vitamin D in Pain Management. Int J Mol Sci 18(10):2170

    PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Martin KR, Reid DM (2017) Is there role for vitamin D in the treatment of chronic pain? Ther Adv Musculoskelet Dis 9(6):131–135

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Togha M, Razeghi Jahromi S, Ghorbani Z, Martami F, Seifishahpar M (2018) Serum vitamin D status in a Group of Migraine Patients Compared with Healthy Controls: a case-control study. Headache 58(10):1530–1540

    PubMed  Article  Google Scholar 

  22. 22.

    Martami F, Razeghi Jahromi S, Togha M, Ghorbani Z, Seifishahpar M, Saidpour A (2018) The serum level of inflammatory markers in chronic and episodic migraine: a case-control study. Neurol Sci 39(10):1741–1749

    PubMed  Article  Google Scholar 

  23. 23.

    Sarchielli P, Alberti A, Baldi A, Coppola F, Rossi C, Pierguidi L et al (2006) Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally. Headache: J Head Face Pain 46(2):200–207

    Article  Google Scholar 

  24. 24.

    Fidan I, Yuksel S, Ymir T, Irkec C, Aksakal FN (2006) The importance of cytokines, chemokines and nitric oxide in pathophysiology of migraine. J Neuroimmunol 171(1–2):184–188

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Tietjen G, Khubchandani J, Khan A, Herial N (2010) Adiponectin and Inflammatory Cytokines in Young Women with Migraine

  26. 26.

    Yücel M, Kotan D, Çiftçi GG, Çiftçi I, Cikriklar H (2016) Serum levels of endocan, claudin-5 and cytokines in migraine. Eur Rev Med Pharmacol Sci 20(5):930–936

    PubMed  Google Scholar 

  27. 27.

    Uzar E, Evliyaoglu O, Yucel Y, Ugur Cevik M, Acar A, Guzel I et al (2011) Serum cytokine and pro-brain natriuretic peptide (BNP) levels in patients with migraine. Eur Rev Med Pharmacol Sci 15(10):1111–1116

    CAS  PubMed  Google Scholar 

  28. 28.

    Oliveira AB, Bachi ALL, Ribeiro RT, Mello MT, Tufik S, Peres MFP (2017) Unbalanced plasma TNF-α and IL-12/IL-10 profile in women with migraine is associated with psychological and physiological outcomes. J Neuroimmunol 313:138–144

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Jahromi SR, Abolhasani M, Ghorbani Z, Sadre-Jahani S, Alizadeh Z, Talebpour M et al (2017) Bariatric surgery promising in migraine control: a controlled trial on weight loss and its effect on migraine headache. Obes Surg:1–10

  30. 30.

    Mottaghi T, Askari G, Khorvash F, Maracy MR (2015) Effect of vitamin D supplementation on symptoms and C-reactive protein in migraine patients. J Res Med Sci 20(5):477–482

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Gazerani P, Fuglsang R, Pedersen JG, Sorensen J, Kjeldsen JL, Yassin H et al (2019) A randomized, double-blinded, placebo-controlled, parallel trial of vitamin D3 supplementation in adult patients with migraine. Curr Med Res Opin 35(4):715–723

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Buettner C, Nir RR, Bertisch SM, Bernstein C, Schain A, Mittleman MA et al (2015) Simvastatin and vitamin D for migraine prevention: a randomized, controlled trial. Ann Neurol 78(6):970–981

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Wang M (2013) Cortical spreading depression and calcitonin gene-related peptide: a brief review of current progress. Neuropeptides 47(6):463–466

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Close LN, Eftekhari S, Wang M, Charles AC, Russo AFJC (2018) Cortical spreading depression as a site of origin for migraine: Role of CGRP 0333102418774299

  35. 35.

    (2015) Pathophysiology of Headaches From Molecule to Man. Paolo Martelletti RJ (ed). Springer, Cham

  36. 36.

    Vanmolkot F, De Hoon J (2007) Increased C-reactive protein in young adult patients with migraine. Cephalalgia 27(7):843–846

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Kurth T, Ridker P, Buring J (2008) Migraine and biomarkers of cardiovascular disease in women. Cephalalgia 28(1):49–56

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Hamed SA, Hamed EA, Eldin AME, Mahmoud NM (2010) Vascular risk factors, endothelial function, and carotid thickness in patients with migraine: relationship to atherosclerosis. J Stroke Cerebrovasc Dis 19(2):92–103

    PubMed  Article  Google Scholar 

  39. 39.

    Tietjen GE, Khubchandani J (2015) Vascular biomarkers in migraine. Cephalalgia 35(2):95–117

    PubMed  Article  Google Scholar 

  40. 40.

    Güzel I, Taşdemir N, Çelik Y (2013) Evaluation of serum transforming growth factor β1 and C-reactive protein levels in migraine patients. Neurol Neurochir Pol 47(4):357–362

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Covelli V, Munno I, Pellegrino N, Altamura M, Decandia P, Marcuccio C, di Venere A, Jirillo E (1991) Are TNF-alpha and IL-1 beta relevant in the pathogenesis of migraine without aura? Acta Neurol 13(2):205–211

    CAS  Google Scholar 

  42. 42.

    Perini F, D'andrea G, Galloni E, Pignatelli F, Billo G, Alba S et al (2005) Plasma cytokine levels in migraineurs and controls. Headache: J Head Face Pain 45(7):926–931

    Article  Google Scholar 

  43. 43.

    Malhotra R (2016) Understanding migraine: potential role of neurogenic inflammation. Ann Indian Acad Neurol 19(2):175–182

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Olesen J (2008) The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther 120(2):157–171

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Al-Daghri NM, Bukhari I, Yakout SM, Sabico S, Khattak MNK, Aziz I et al (2018) Associations of serum nitric oxide with vitamin D and other metabolic factors in apparently healthy adolescents. Biomed Res Int 2018:1489132

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Golden TN (2016) The role of inducible nitric oxide synthase in macrophage activation following acute lung injury

  47. 47.

    de Oliveira DL, Hirotsu C, Tufik S, Andersen ML (2017) The interfaces between vitamin D, sleep and pain. J Endocrinol 234(1):R23–R36

    PubMed  Article  Google Scholar 

  48. 48.

    Linden J, Granasen G, Salzer J, Svenningsson A, Sundstrom P (2019) Inflammatory activity and vitamin D levels in an MS population treated with rituximab. Mult Scler J Exp Transl Clin 5(1):2055217319826598

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Wang Y, Yang S, Zhou Q, Zhang H, Yi B (2019) Effects of vitamin D supplementation on renal function, inflammation and glycemic control in patients with diabetic nephropathy: a systematic review and meta-analysis. Kidney Blood Press Res 44(1):72–87

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Filgueiras MS, Rocha NP, Novaes JF, Bressan J (2018) Vitamin D status, oxidative stress, and inflammation in children and adolescents: a systematic review. Crit Rev Food Sci Nutr 1–10

  51. 51.

    Chen N, Wan Z, Han SF, Li BY, Zhang ZL, Qin LQ (2014) Effect of vitamin D supplementation on the level of circulating high-sensitivity C-reactive protein: a meta-analysis of randomized controlled trials. Nutrients 6(6):2206–2216

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Sepidarkish M, Farsi F, Akbari-Fakhrabadi M, Namazi N, Almasi-Hashiani A, Maleki Hagiagha A, Heshmati J (2019) The effect of vitamin D supplementation on oxidative stress parameters: a systematic review and meta-analysis of clinical trials. Pharmacol Res 139:141–152

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Akbari M, Ostadmohammadi V, Lankarani KB, Tabrizi R, Kolahdooz F, Heydari ST et al (2018) The effects of vitamin D supplementation on biomarkers of inflammation and oxidative stress among women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Horm Metab Res 50(4):271–279

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Colotta F, Jansson B, Bonelli F (2017) Modulation of inflammatory and immune responses by vitamin D. J Autoimmun 85:78–97

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Sarchielli P, Floridi A, Mancini M, Rossi C, Coppola F, Baldi A, Pini LA, Calabresi P (2006) NF-κB activity and iNOS expression in monocytes from internal jugular blood of migraine without Aura patients during attacks. Cephalalgia 26(9):1071–1079

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Dursun E, Gezen-Ak D, Yilmazer S (2014) The influence of vitamin D treatment on the inducible nitric oxide synthase (INOS) expression in primary hippocampal neurons. Noro Psikiyatri Arsivi 51(2):163–168

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Shipton EA, Shipton EE (2015) Vitamin D and Pain: Vitamin D and Its Role in the Aetiology and Maintenance of Chronic Pain States and Associated Comorbidities. Pain Res Treat 2015:904967

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Pradhan AA, Bertels Z, Akerman S (2018) Targeted nitric oxide synthase inhibitors for migraine. Neurotherapeutics 15(2):391–401

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Andrukhova O, Slavic S, Zeitz U, Riesen SC, Heppelmann MS, Ambrisko TD et al (2014) Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice. Mol Endocrinol (Baltimore, Md) 28(1):53–64

    Article  CAS  Google Scholar 

  60. 60.

    Bikle D (2009) Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94(1):26–34

    CAS  PubMed  Article  Google Scholar 

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Funding

This research has been supported by Tehran University of Medical Sciences & health Services grant 96-04-161-37647 and 96-04-54-36870.

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Correspondence to Maryam Mahmoudi.

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Compliance with ethical standards

The study protocol was reviewed and approved by ethics committee of vice-chancellor in research affairs, Tehran University of Medical Sciences (ethics code: IR.TUMS.VCR.REC.1397.170). Before undergoing any study procedure, all patients gave written informed consent.

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The authors declare that they have no conflict of interest.

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Ghorbani, Z., Togha, M., Rafiee, P. et al. Vitamin D3 might improve headache characteristics and protect against inflammation in migraine: a randomized clinical trial. Neurol Sci 41, 1183–1192 (2020). https://doi.org/10.1007/s10072-019-04220-8

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Keywords

  • Analgesics
  • Cholecalciferol
  • Frequency
  • Headache attacks
  • Inflammation
  • Severity