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      META ANALYSIS Year : 2023  |  Volume : 71  |  Issue : 4  |  Page : 655-661

Effects of Vitamin D on Migraine: A Meta-Analysis

Saibal Das1, Ayan Roy2, Sapan Kumar Behera1, Sandhiya Selvarajan2, Sadishkumar Kamalanathan1, Jaya Prakash Sahoo2, N Sreekumaran Nair3
1 Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
2 Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
3 Department of Biostatistics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India

Date of Submission16-Jan-2020Date of Decision04-May-2020Date of Acceptance06-Jun-2020Date of Web Publication18-Aug-2023

Correspondence Address:
Sandhiya Selvarajan
Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605 006
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/0028-3886.383862

Objective: The aim of this study was to evaluate the difference in mean serum 25-hydroxy vitamin D level between migraineurs and nonmigraineurs, the association between hypovitaminosis D and migraine, and the effects of oral vitamin D supplementation on migraine-related symptoms as compared to placebo.
Methods: Relevant databases were searched for observational studies and randomized-controlled trials (RCTs) which evaluated the difference in mean serum 25-hydroxy vitamin D level between migraineurs and nonmigraineurs; the association between hypovitaminosis D and migraine; and the effects of vitamin D supplementation on migraine-frequency, duration, and severity. Pooled mean difference and odds ratio were calculated (random-effects model, RevMan version 5.3).
Results: Ten observational studies and two RCTs were included. The serum 25-hydroxy vitamin D level in the migraineurs was significantly lower than that in the nonmigraineurs [mean difference − 4.44 ng/mL (95% CI: −6.11, −2.77)] (low-GRADE evidence). Hypovitaminosis D was found to be significantly associated with migraine [OR: 1.95 (95% CI: 1.07, 3.58)] (low-GRADE evidence). As compared to placebo, oral vitamin D supplementation significantly reduced the monthly migraine-frequency [mean difference: −2.20 (95% CI: −3.04, −1.36)], although it did not reduce the migraine-duration [mean difference: −16.00 hours per month (95% CI: −42.77, 10.76)] and migraine-severity score [standardized mean difference: −0.23 (95% CI: −0.79, 0.32)] (moderate-GRADE evidence).
Conclusion: Serum 25-hydroxy vitamin D level was significantly lower in the migraineurs than that in the nonmigraineurs, and hypovitaminosis D was significantly associated with migraine. Oral vitamin D supplementation significantly reduced migraine-frequency, but not its duration and severity.

Keywords: Association, headache, hypovitaminosis D, serum 25-hydroxy vitamin D level, supplementation
Key Message: Serum 25hydroxy vitamin D level was significantly lower in the migraineurs than that in the nonmigraineurs, and hypovitaminosis D was significantly associated with migraine. Oral vitamin D supplementation significantly reduced migrainefrequency, but not its duration and severity.

How to cite this article:
Das S, Roy A, Behera SK, Selvarajan S, Kamalanathan S, Sahoo JP, Nair N S. Effects of Vitamin D on Migraine: A Meta-Analysis. Neurol India 2023;71:655-61

The exact mechanisms contributing to the pathophysiology of migraine is elusive. Recent evidence supports the role of underlying neurogenic inflammation activating meningeal nociceptors[1] and vascular smooth muscle dysfunction.[2] Vitamin D is involved in the regulation of inflammation and oxidative stress by the reduction of tumor necrosis factor-α, interleukin-1β, nitric oxide synthase, and oxidative stress markers.[3] Apart from preventing neuronal loss by increasing the neurotrophic and neuroprotective factors, vitamin D is also implicated in the descending modulation of endogenous pain control.[3] Vitamin D receptors (VDR) and 1-α-hydroxylase (required for the production of the active form of vitamin D) are expressed both in the neurons and glia in the central nervous system. Animal studies have shown that VDRs are expressed in the neurons of dorsal ganglia, selectively in the small fiber neurons.[4] Some other studies have shown that VDR and 1-α-hydroxylase are present within the limbic system, basal ganglia, cerebellum, cerebral cortex, etc., of the human brain.[5]

In the last few years, several studies have exhibited the relationship between chronic pain and vitamin D deficiency. A recent meta-analysis has demonstrated that vitamin D supplementation may improve endothelial functions,[6] and thus, can provide beneficial results in the transmission and modulation of pain in migraine. However, several observational studies have reported an inconsistent and inconclusive association between serum 25-hydroxy vitamin D level and migraine. Further, the clinically significant contribution of vitamin D supplementation on migraine-related symptoms is not clear. Therefore, this meta-analysis was performed to evaluate the effects of vitamin D on migraine.

  Methods 

This study was initiated after obtaining 'exemption from review' from the Institutional Ethics Committee, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India. The study protocol can be accessed in PROSPERO (ID: CRD42018116984).

Study design

The objectives of this study were to evaluate the difference in mean serum 25-hydroxy vitamin D level between migraineurs and nonmigraineurs, to assess the association between hypovitaminosis D and migraine, and to evaluate the effects of oral vitamin D supplementation on migraine-frequency, duration, and severity as compared to placebo. The inclusion criteria were: completed and published observational studies which evaluated the difference in mean serum 25-hydroxy vitamin D level between migraineurs (cases) and nonmigraineurs (controls) and/or evaluated the association between hypovitaminosis D (serum 25-hydroxy vitamin D level: <20 ng/ml) and migraine in patients aged ≥5 years of either gender (including a control group), as well as completed and published randomized-controlled trials (RCTs) which evaluated the effects of oral vitamin D supplementation on migraine-frequency, duration, and severity in patients aged ≥5 years of either gender. Studies involving any confounding diseases or co-medications were excluded.

Search strategy

MEDLINE/PubMed, IndMED, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and Cochrane Library [Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Methodology Register] were searched until 18th December 2019. The search terms used in various combinations were: “vitamin D”, “cholecalciferol”, “25-hydroxy vitamin D”, “headache”, and “migraine”. These search terms were adapted for use with different bibliographic databases in combination with database-specific filters for studies, if available. The search strategy was used to obtain the titles and the abstracts of the relevant studies in the English language, and they were independently screened by two authors, who subsequently retrieved abstracts, and if necessary, the full text of articles to determine the suitability. Disagreement resolution was done with a third author.

Data extraction and management

Data extraction was carried out independently by two authors using a pre-formatted data extraction spreadsheet. No assumptions or simplifications were made during data extraction. The included studies were assessed for the risk of bias by two authors independently using the Newcastle–Ottawa Scale for the observational studies[7] and Cochrane risk of bias tool[8] for the RCTs. The random-effects model was used to ensure the robustness of the model across various populations and susceptibility to outliers. The weighted mean difference in serum 25-hydroxy vitamin D level between migraineurs and nonmigraineurs was calculated. The association between hypovitaminosis D and migraine was evaluated by calculating the odds ratio. The weighted mean difference in migraine-frequency and duration and the standardized mean difference in migraine-severity between the groups receiving oral vitamin D supplementation and placebo were evaluated. All analyses were performed using RevMan version 5.3. Data regarding screened and randomized patients, as well as both intention-to-treat and per-protocol analysis, were evaluated. Attrition rates, such as dropouts, loss to follow-up, and withdrawals were investigated. Issues of missing data and imputation methods were critically appraised.[8] Heterogeneity was analyzed using χ2 test on n−1 degrees of freedom, with an α error of 5% used for statistical significance and with an i2 test.[9] The i2 values of 25%, 50%, and 75% corresponded to low, medium, and high levels of heterogeneity respectively. Funnel plots were used to assess the potential existence of small-study effects and reporting bias.[9] The GRADE approach (Grading of Recommendations Assessment, Development and Evaluation)[10],[11] was used to assess the quality of the generated evidence.

  Results 

A total of 75 studies were screened and of that, ten observational studies[12],[13],[14],[15],[16],[17],[18],[19],[20],[21] and two RCTs[22],[23] were included in the final analyses [Figure 1]. The characteristics of the included studies are enumerated in [Table 1]. Eight among the ten observational studies were of 'good quality', while the remaining two were of 'fair quality'. Both the included RCTs had low risks of bias [Figure s1]. In the overall population, serum 25-hydroxy vitamin D level was significantly lower in the migraineurs than that in the nonmigraineurs [mean difference: −4.44 ng/mL (95% CI: −6.11, −2.77)] [Figure 2]a (low-GRADE evidence). Hypovitaminosis D (serum 25-hydroxy vitamin D level < 20 ng/ml) was significantly associated with migraine in the overall population [OR: 1.95 (95% CI: 1.07, 3.58)] [Figure 2]b (low-GRADE evidence).

Figure 1: Study flow chart depicting the steps of synthesis of evidence from the literature

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Figure 2: Mean difference in serum 25-hydroxy vitamin D level between migraineurs and nonmigraineurs (a), and the association between hypovitaminosis D and migraine (b)

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As compared to placebo, oral vitamin D supplementation significantly reduced the monthly migraine-frequency [mean difference: −2.20 (95% CI: −3.04, −1.36)] [Figure 3]a, although it did not reduce the migraine-duration [mean difference: −16.00 hours per month (95% CI: −42.77, 10.76)] [Figure 3]b and the migraine-severity score [standardized mean difference: −0.23 (95% CI: −0.79, 0.32)] (moderate-GRADE evidence) [Figure 3]c. The heterogeneity was, however, high with most of the analyzed outcomes. The funnel plots of all the parameters assessed are represented in [Figure s2] and [Figure s3].

Figure 3: Effects of oral vitamin D supplementation on migraine-frequency (a), migraine-duration (b), and migraine-severity (standardized mean difference was used for severity) (c)

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  Discussion 

In this meta-analysis, we aimed to evaluate the difference in mean serum 25-hydroxy vitamin D level between migraineurs and nonmigraineurs, the association between hypovitaminosis D and migraine, and the effects of oral vitamin D supplementation on migraine-related symptoms. We found a significantly lower level of serum 25-hydroxy vitamin D in the migraineurs as compared to that in the nonmigraineurs. Our results are similar to a previous study which reported that 40% of the migraineurs had vitamin D deficiency as compared to the nonmigraineurs.[24] Vitamin D deficiency was also found in a study involving patients with chronic tension-type headache.[25] A study conducted in patients on statin therapy found lower odds of having migraine with a higher serum 25-hydroxy vitamin D level.[26] Another study demonstrated the relationship between the duration of migraine and vitamin D deficiency.[27] In a study, pediatric migraine patients with irritable bowel syndrome were found to have low serum 25-hydroxy vitamin D levels than the controls.[28] A marked correlation between pediatric migraine and serum 25-hydroxy vitamin D level was found in another study, and furthermore, vitamin D supplementation was found to be beneficial in children with migraine.[29] On the contrary, Krusz, et al. demonstrated no difference in serum 25-hydroxy vitamin D levels between migraineurs and patients with any other pain disorders.[30]

The mechanisms underlying the association between hypovitaminosis D and migraine remain to be fully elucidated. Vitamin D modulates brain-derived reactive oxygen species production, regulates calcium signaling in the brain, and also stimulates neurotrophic factor production.[31] Hypovitaminosis D is associated with lower serum magnesium levels, which is also associated with migraine attacks.[32],[33] Diverse neurological diseases, such as fibromyalgia and depression, which are associated with vitamin D deficiency, are often closely associated with migraine.[34] There is also growing evidence regarding the role of endothelial dysfunction in the pathophysiology of migraine implying that migraine is attributed to vascular smooth muscle dysfunction[35] with which vitamin D deficiency is often associated.[36]

We found that hypovitaminosis D was significantly associated with migraine. For estimating the association between hypovitaminosis D and migraine, we selected only those studies where the cut-off serum 25-hydroxy vitamin D level of 20 ng/mL was considered as a deficiency.[37] Our results are similar to a previous study which demonstrated that migraineurs tend to have a high rate of hypovitaminosis D.[38] Virtanen, et al. have shown that low serum 25-hydroxy vitamin D level was associated with a markedly higher risk of frequent headache including migraine.[39] In a Korean study, the duration of migraine was found to be related to vitamin D deficiency.[27] In a large nationwide retrospective study conducted in the United States, a significant association between hypovitaminosis D with migraine was found. The authors further recommended providing early preventive measures to reduce disability in patients.[40] Consistent with our results, two recent systematic reviews have stressed the role of vitamin D in migraine and advocated that vitamin D supplementation might produce beneficial effects in migraine.[41],[42] However, Mottaghi, et al. demonstrated that there was no significant relationship between serum 25-hydroxy vitamin D level and migraine severity.[43] Two other systematic reviews also could not demonstrate a lower serum 25-hydroxy vitamin D level in the migraineurs than that in the nonmigraineurs or any association between hypovitaminosis D and migraine.[44],[45] This could be attributed to the inclusion of case reports and a few observational and case-control studies. It is pertinent to mention here that fixing the cut-off serum 25-hydroxy vitamin D level for defining deficiency and choosing the assay for estimation of serum 25-hydroxy vitamin D level are the two critical issues to consider. The high heterogeneity in our results could have been resulted because of the inclusion of the nonrandomized (observational) studies, the inclusion of patients from different geographical areas of different latitude having a direct influence on serum 25-hydroxy vitamin D level which is associated with headache,[46] and the presence of other confounding factors affecting the serum 25-hydroxy vitamin D level.

We further found that vitamin D supplementation resulted in a statistically significant reduction in migraine frequency as compared to placebo. The probable explanation of this finding is due to a favorable change in the cytokine milieu after vitamin D supplementation resulting in reduced inflammation and pain. Vitamin D, via its active metabolite 1,25-dihydroxy vitamin D, is known to modify the sensitivity of nociception through a reduction in nitric oxide generation and its interactions with calcitonin gene-related peptide, thereby reducing the headache frequency in the migraineurs[45] Two previous case-reports have shown that treatment with vitamin D and calcium have significantly reduced the frequency and severity of migraine.[47],[48] Vitamin D in addition to amitriptyline was found to significantly reduce the frequency of migraine as compared to amitriptyline monotherapy.[49] Vitamin D deficiency is known to be associated with interleukin-1, interleukin-6, tumor necrosis factor-α, and nitric oxide production.[50] These results support the idea of utilizing the anti-inflammatory effects of vitamin D in inflammatory diseases, such as migraine as a primary drug or as an adjunct therapy with other drugs exerting pleiotropic effects, such as statins.[51] However, we found that vitamin D intervention did not produce any beneficial effects on the duration and severity of migraine as compared to placebo. Hence, although vitamin D supplementation was found to be effective in reducing the frequency of migraine attacks, it appears not to have any beneficial effects once a migraine attack occurs, thereby suggesting a prophylactic rather than a therapeutic role. In our analysis, only two RCTs were available and the high heterogeneity in the results could be because of the differences in the dose and duration of vitamin D treatment, as well as the difference in baseline serum 25-hydroxy vitamin D level.

There are a few limitations to this study. We could not adjust the different confounding factors affecting the serum 25-hydroxy vitamin D level, such as age, gender, body mass index, diet, sunlight exposure, etc. The sample sizes of the two RCTs were less, and the dose and duration of 25-hydroxy vitamin D treatment varied. The heterogeneity was also high with some of the outcomes.

  Conclusion 

To the best of our knowledge, this is the first meta-analysis to demonstrate that serum 25-hydroxy vitamin D was significantly lower in the migraineurs than that in the nonmigraineurs, and hypovitaminosis D was significantly associated with migraine. Further, oral vitamin D supplementation, as compared to placebo, was found to reduce migraine-frequency.

Financial support and sponsorship

Nil.

Conflicts interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. This work was presented as a poster presentation at the 19th Congress of the International Headache Society, Dublin on 7th September 2019. However, the work has been updated.

 

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  [Figure 1], [Figure 2], [Figure 3]
 
 
  [Table 1]