Abstract
Background:
There is interest in whether supplements, including vitamin D and marine omega-3 (n-3) fatty acids, may be effective migraine prophylaxis. However, few studies have evaluated whether vitamin D or n-3 fatty acid supplementation may reduce migraine frequency or severity.
Methods:
Participants in the VITamin D and OmegA-3 TriaL (VITAL) were assigned to vitamin D3 (2000 IU/d) or marine n-3 fatty acid (1 g/d) supplementation in a two-by-two factorial design. Lifetime history of migraine was assessed a median of 4.6 years after the start of the trial. Individuals were asked to self-report changes in migraine frequency (no change, more frequent, or less frequent) and severity (no change, more severe, less severe) in the past 5 years. We used chi-square tests to compare proportions of individuals reporting changes in migraine frequency and severity between active and placebo groups.
Results:
Among the 25,871 participants in VITAL, 1032 participants had a history of probable migraine and provided information on changes in migraine frequency and severity. The percentage of individuals reporting decreases in migraine frequency did not differ between active (69.0%) and placebo vitamin D (68.4%) (p-value=0.54) or between active (67.8%) and placebo n-3 fatty acid (69.6%) (p-value=0.82). Similarly, the percentage of individuals reporting decreases in migraine severity did not differ between active (64.1%) and placebo vitamin D (65.0%) (p-value=0.86) or between active (64.5%) and placebo n-3 fatty acid (64.5%) (p-value=0.96).
Conclusions:
Neither vitamin D nor marine n-3 fatty acid supplementation, compared to placebo, affected migraine frequency or severity among middle-aged or older adults.
Keywords: Vitamin D, omega-3 fatty acids, migraine
Introduction
The prevalence of migraine is approximately 18% among women and 9% among men in the United States and is one of the leading causes of disability worldwide.1,2 To decrease the frequency of migraine attacks and decrease disability burden, individuals with migraine use a number of prophylactic medications, such as propranolol, topiramate, or calcitonin gene-related peptide (CGRP) inhibitors3,4 but recently, there has been growing interest in whether nonpharmacologic agents such as commonly used supplements, including vitamin D and marine omega-3 (n-3) fatty acids, may be effective for migraine prophylaxis. However, few studies have been conducted to evaluate whether vitamin D or n-3 fatty acid supplementation may prevent migraines or reduce migraine severity.
One small trial among presumed healthy individuals with headache noted that vitamin D supplementation, compared to placebo, resulted in less pain but did not impact the frequency of headache attacks.5 However, this study did not have information on migraine status of the participants. Another trial enrolled individuals with episodic migraine and assigned them to take either a combination therapy of simvastatin and vitamin D or placebo.6 This combination therapy showed a significant reduction in migraine days after 12 weeks and 24 weeks, but due to the design of the study, the authors were unable to examine the individual effect of vitamin D supplementation on migraine frequency.
A recent meta-analysis of randomized controlled trials of n-3 fatty acid intake found no significant effect of n-3 intake on migraine frequency or migraine severity, although there was a suggestion of reduction in migraine duration with n-3s.7 However, most of these trials were short-term (<3 months) and enrolled children or middle-aged individuals. The long-term effects on migraine of n-3 supplementation among middle aged or older individuals are unknown.
Using data from the VITamin D and OmegA-3 TriaL (VITAL), we performed post-hoc analyses to examine the effect of vitamin D and marine n-3 fatty acid supplementation on changes in migraine frequency and severity among middle aged and older adults.
Methods
The VITamin D and OmegA-3 TriaL (VITAL) was a randomized, double-blind, placebo-controlled trial to test the effects of vitamin D3 (cholecalciferol, 2,000 IU/day) and marine n-3 fatty acid (1 g/day fish-oil capsule containing 840 mg of n-3 fatty acids including eicosapentaenoic acid [EPA, 460 mg] + docosahexaenoic acid [DHA, 380 mg]) supplements in the primary prevention of cardiovascular disease and cancer in a multiethnic population of 25,871. The design and main results of the trial have been published previously. 8–10 In brief, the trial randomized a total of 25,871 men aged ≥50 and women aged ≥55 without a history of cancer (except non-melanoma skin cancer), myocardial infarction, stroke, transient ischemic attack, or coronary revascularization. Randomized treatment ended on December 31, 2017, with a median of 5.3 years of treatment and follow-up. VITAL was approved by the Institutional Review Board of Partners Healthcare/Brigham and Women’s Hospital, and the study agents have received Investigational New Drug Approval from the U.S. Food and Drug Administration. VITAL is registered at clinicaltrials.gov (NCT01169259).
The questionnaire that included questions on migraine features was returned a median of 4.6 years after randomization. A total of 21,983 individuals were mailed the questionnaire, of which 19,567 (89%) responded. Participants were first asked “Have you ever experienced recurring (repeated) headaches?” If they responded yes, they were further asked about the characteristics of these headaches, including: duration of 4 to 72 hours, pain worse on one side of the head, pain that is pounding, pulsating, or throbbing, moderate or severe pain intensity, aggravation by routine physical activity, sensitivity to light, sensitivity to sound, and nausea and/or vomiting. Using these headache characteristics, 1287 met the International Classification of Headache Disorders – Third Edition (ICHD-3) criteria for probable migraine11 (Figure 1).
Figure 1:
In addition to assessing the characteristics listed above, we also assessed aura status by asking “How often have you experienced aura around the time of your recurring headaches (i.e., seen things like spots, stars, lines, flashing lights, zigzag lines, or “heat waves”)?” Possible response options were never, sometimes, or always which was then dichotomized as never experiencing aura versus sometimes or always experiencing aura.
On the same questionnaire, we assessed changes in the severity and frequency of the recurring headaches over the past five years. Individuals who reported recurring headaches were asked “On average, have your recurring headaches changed in the past 5 years with respect to frequency or severity?” with possible response options for frequency of: “no change in frequency over past five years”, “I have more headache days per month now”, and “I have fewer headache days per month now”; and for severity of: “No change in severity over past 5 years”, “My headaches are more severe now”, and “My headaches are less severe now.” 1032 individuals provided information on changes in migraine frequency and severity and were included in our analyses (Figure 1).
We calculated the percentage of individuals in each response category by randomized treatment assignment and used chi-square tests for trend to determine if the proportion of individuals reporting each outcome differed by randomized treatment assignment. We also performed sensitivity analyses adjusting for age, sex, and the other randomized treatment assignment using multinomial logistic regression because adjusting for covariates predictive of the outcome can result in increased power to detect associations.12
We explored whether the associations between randomized treatment assignments and changes in migraine frequency and severity were modified by migraine aura status, age, sex, baseline body mass index, and race. We additionally explored whether baseline fish intake modified the effect of randomized treatment assignment to marine n-3 fatty acid supplementation on migraine frequency or severity and whether baseline vitamin D levels modified the effect of randomized treatment assignment to vitamin D on migraine frequency and severity.
To test possible effect modification by statin use, as suggested by previous research,6 we performed additional analyses in which we categorized individuals based on their randomized treatment assignment and self-reported statin use at baseline. Possible exposure categories were placebo vitamin D and no statin use, statin use only, vitamin D only, and vitamin D and statin use. Chi-squared tests were used to determine if the proportion of individuals reporting each outcome differed by exposure status. We also performed sensitivity analyses adjusting for age, sex, and the other randomized treatment assignment using multinomial logistic regression.12
Results
The average age of the 1032 individuals included in these analyses was 65.6 years; 74.5% were women and 89.6% were white. The baseline characteristics of the individuals included in these analyses were similar across the randomized treatment groups (Table 1).
Table 1.
Baseline characteristics and aura status of those with a history of migraine according to randomized treatment assignment.
| Active Vitamin D (N=526) | Placebo Vitamin D (N=506) | Active n-3 fatty acid (N=516) | Placebo n-3 fatty acid (N=516) | |
|---|---|---|---|---|
| Age, mean (SD) | 65.8 (6.0) | 65.4 (5.5) | 65.7 (5.8) | 65.6 (5.7) |
| Female sex, N (%) | 402 (76.4) | 367 (72.5) | 376 (72.9) | 393 (76.2) |
| Race, N (%) | ||||
| White | 471 (89.9) | 454 (90.3) | 466 (90.5) | 459 (89.7) |
| Black | 45 (8.6) | 37 (7.4) | 43 (8.4) | 39 (7.6) |
| Other | 8 (1.5) | 12 (2.4) | 6 (1.2) | 14 (2.7) |
| BMI (mean, SD) | 27.9 (6.0) | 28.0 (5.8) | 28.1 (5.8) | 27.7 (5.9) |
| Current smoker, N (%) | 20 (3.8) | 22 (4.4) | 24 (4.7) | 18 (3.5) |
| Any alcohol use, N (%) | 321 (61.7) | 326 (64.8) | 329 (64.4) | 318 (61.1) |
| Use of hypertension medication, N (%) | 282 (53.7) | 258 (51.1) | 274 (53.2) | 266 (51.7) |
| Statin use, N (%) | 181 (34.9) | 169 (33.6) | 171 (33.6) | 179 (34.9) |
| Experience aura, N (%) | 282 (54.1) | 277 (55.0) | 281 (55.0) | 278 (54.1) |
Table 2 shows the proportion of individuals reporting changes in migraine frequency or severity by randomized treatment assignment to vitamin D. Among those assigned to placebo vitamin D, 20.4% reported no change in migraine frequency, 11.3% reported an increase in migraine frequency, and 68.4% reported a decrease in migraine frequency. Among those assigned to active vitamin D, 21.7% reported no change in migraine frequency, 9.3% reported an increase in migraine frequency, and 69.0% reported a decrease in migraine frequency. A similar pattern of results was seen for migraine severity with most individuals reporting decreases in migraine severity. We observed no significant differences in the proportions of individuals reporting changes in migraine frequency (p-value=0.54) or severity (p-value=0.86) by randomized treatment assignment to vitamin D. Sensitivity analyses using multinomial logistic regression did not show an significant associations between randomized treatment assignments and changes in migraine frequency or severity (results not shown).
Table 2.
Effect of randomized treatment assignment to vitamin D on migraine frequency and severity among those with a history of migraine.
| Change in migraine frequency | |||||||
| Decrease in frequency | No Change | Increase in frequency | p-value for trend | ||||
| N | % | N | % | N | % | ||
| Placebo Vitamin D | 346 | 68.4 | 103 | 20.4 | 57 | 11.3 | 0.54 |
| Active Vitamin D | 363 | 69.0 | 114 | 21.7 | 49 | 9.3 | |
| Change in migraine severity | |||||||
| Decrease in severity | No Change | Increase in severity | p-value for trend | ||||
| N | % | N | % | N | % | ||
| Placebo Vitamin D | 329 | 65.0 | 139 | 27.5 | 38 | 7.5 | 0.86 |
| Active Vitamin D | 337 | 64.1 | 158 | 30.0 | 31 | 5.9 | |
Table 3 shows the proportion of individuals reporting changes in migraine frequency and severity by randomized treatment assignment to marine n-3 fatty acid supplementation. Among those assigned to placebo marine n-3 fatty acid, 19.8% reported no change in migraine frequency, 10.7% reported an increase in migraine frequency, and 69.6% reported a decrease in migraine frequency. Among those assigned to active marine n-3 fatty acid, 22.3% reported no change in migraine frequency, 9.9% reported an increase in migraine frequency, and 67.8% reported a decrease in migraine frequency. A similar pattern of results was seen for migraine severity with most individuals reporting decreases in migraine severity. No significant differences were seen between the two groups for either migraine frequency (p-value=0.82) or severity (p-value=0.96).
Table 3.
Effect of randomized treatment assignment to n-3 fatty acid supplementation on migraine frequency and severity among those with a history of migraine.
| Change in migraine frequency | |||||||
| Decrease in frequency | No Change | Increase in frequency | p-value for trend | ||||
| N | % | N | % | N | % | ||
| Placebo n-3 fatty acid | 359 | 69.6 | 102 | 19.8 | 55 | 10.7 | 0.82 |
| n-3 fatty acid | 350 | 67.8 | 115 | 22.3 | 51 | 9.9 | |
| Change in migraine severity | |||||||
| Decrease in severity | No Change | Increase in severity | p-value for trend | ||||
| N | % | N | % | N | % | ||
| Placebo n-3 fatty acid | 333 | 64.5 | 148 | 28.7 | 35 | 6.8 | 0.96 |
| n-3 fatty acid | 333 | 64.5 | 149 | 28.9 | 34 | 6.6 | |
Five hundred fifty-nine individuals reported always or sometimes experiencing aura, 466 reported never experiencing aura and 7 did not answer the question assessing aura. We did not observe any significant differences in the effect of vitamin D or marine n-3 fatty acid supplementation on changes in migraine frequency or severity when we stratified by aura status (Table 4) or when we stratified by age, sex, race, or baseline body mass index (Supplemental Table 1–4). Baseline level of 25-hydroxy-D did not modify the effect of vitamin D supplementation on changes in migraine frequency and severity (Supplemental Table 5). Baseline fish consumption did not modify the effect of marine n-3 fatty acid supplementation on changes in migraine frequency and severity (Supplemental Table 6)
Table 4.
Effect of randomized treatment assignment to vitamin D and n-3 fatty acid supplementation on migraine frequency and severity stratified by migraine aura status.
| Migraine with aura (n=559) | Migraine without aura (N=466) | |||||||||||||
| Change in migraine frequency | ||||||||||||||
| Decrease in frequency | No change | Increase in frequency | p-value | Decrease in frequency | No change | Increase in frequency | p-value | |||||||
| N | % | N | % | N | % | N | % | N | % | N | % | |||
| Placebo Vitamin D | 205 | 74.0 | 49 | 17.7 | 23 | 8.3 | 0.29 | 139 | 61.2 | 54 | 23.8 | 34 | 15.0 | 0.05 |
| Active Vitamin D | 195 | 69.2 | 61 | 21.6 | 26 | 9.2 | 164 | 68.6 | 52 | 21.8 | 23 | 9.6 | ||
| Placebo n-3 fatty acid | 205 | 73.7 | 47 | 16.9 | 26 | 9.4 | 0.56 | 152 | 64.4 | 55 | 23.3 | 29 | 13.3 | 0.83 |
| n-3 fatty acid | 195 | 69.4 | 63 | 22.4 | 23 | 8.2 | 151 | 65.7 | 51 | 22.2 | 28 | 12.2 | ||
| Change in migraine severity | ||||||||||||||
| Decrease in severity | No change | Increase in severity | p-value | Decrease in severity | No change | Increase in severity | p-value | |||||||
| N | % | N | % | N | % | N | % | N | % | N | % | |||
| Placebo Vitamin D | 195 | 70.4 | 61 | 22.0 | 21 | 7.6 | 0.37 | 133 | 58.6 | 77 | 33.9 | 17 | 7.5 | 0.25 |
| Active Vitamin D | 180 | 63.8 | 86 | 30.5 | 16 | 5.7 | 153 | 64.0 | 71 | 29.7 | 15 | 6.3 | ||
| Placebo n-3 fatty acid | 191 | 68.7 | 69 | 24.8 | 18 | 6.5 | 0.50 | 141 | 59.8 | 78 | 33.1 | 17 | 7.2 | 0.49 |
| n-3 fatty acid | 184 | 65.5 | 78 | 27.8 | 19 | 6.8 | 145 | 63.0 | 70 | 30.4 | 15 | 6.5 | ||
Table 5 presents results by categories of statin use and randomized treatment assignment to vitamin D. The proportions of individuals reporting decreases in migraine frequency and severity were similar across all groups and we observed no significant effects between our exposure categories and migraine frequency or severity. Sensitivity analyses using multinomial logistic regression did not show significant associations between categories of statin use and randomized treatment assignment to vitamin D and changes in migraine frequency or severity (results not shown).
Table 5.
Effect of randomized treatment assignment to vitamin D and BASELINE statin use on migraine frequency and severity among those with a history of migraine (N=1022).
| Change in migraine frequency | |||||||
| Decrease in frequency | No Change | Increase in frequency | p-value for trend | ||||
| N | % | N | % | N | % | ||
| Placebo + no statin use | 227 | 68.0 | 69 | 20.7 | 38 | 11.4 | |
| Statin use only | 117 | 69.2 | 34 | 20.1 | 18 | 10.7 | 0.99 |
| Vitamin D only | 238 | 70.4 | 72 | 21.3 | 28 | 8.3 | 0.22 |
| Vitamin D + statin use | 121 | 66.9 | 39 | 21.6 | 21 | 11.6 | 0.47 |
| Change in migraine severity | |||||||
| Decrease in severity | No Change | Increase in severity | p-value for trend | ||||
| N | % | N | % | N | % | ||
| Placebo + no statin use | 215 | 64.4 | 93 | 27.8 | 26 | 7.8 | |
| Statin use only | 112 | 66.3 | 45 | 26.6 | 12 | 7.1 | 0.76 |
| Vitamin D only | 216 | 63.9 | 101 | 29.9 | 21 | 6.2 | 0.96 |
| Vitamin D + statin use | 117 | 64.6 | 54 | 29.8 | 10 | 5.5 | 0.76 |
Discussion
We observed no significant effects of randomized treatment assignment to vitamin D or marine n-3 fatty acid supplementation on self-reported changes in migraine frequency or severity in this large study of middle aged or older adults.
Similar to our study, a meta-analysis of trials enrolling children and young or middle-aged adults reported no effect of n-3 fatty acid supplementation on migraine frequency or severity.7 In contrast, there is some evidence from prior trials that vitamin D supplementation may affect headache severity or migraine frequency. One trial among immigrants from South Asia, the Middle East, and Africa living in Norway found that vitamin D supplementation (either 10 μg/day or 25μg/day [400 or 1000 IU/d]) compared to placebo was associated with decreases in headache severity.5 In another trial, randomized assignment to a combination of a vitamin D supplement (1000 IU twice per day) and simvastatin (20 mg) resulted in lower migraine frequency compared to placebo.6 The median ages in these trials ranged from 28 to 40 years. In contrast, our study population was much older (mean age 65.6 years). Adults over the age of 60 are less likely to report having experienced a migraine headache in the past year than those between the ages of 20 and 60.12 This supports observations that the frequency of migraine may decrease with age.13 Most individuals in our study, regardless of randomized treatment assignment, reported decreases in migraine frequency and severity over time. This decline in migraine frequency and severity seen with aging may have been stronger than any effect of vitamin D on migraine frequency or severity.
Strengths to this study include randomized assignment to vitamin D and marine n-3 fatty acid supplementation, which limited confounding by baseline characteristics, and the enrollment of both men and women. In addition, this trial was of longer duration (a median of 5.3 years) than any prior trials of vitamin D or marine n-3 fatty acid supplementation on migraine. We further asked about migraine characteristics, which allowed us to classify individuals as having probable migraine using the ICHD-3 criteria.11
Some important limitations to this study should be noted. First, migraine was not assessed on the baseline questionnaire and was only assessed a median of 4.6 years after the start of the study. As a result, individuals who were randomized towards the end of enrollment in the main trial did not receive the questionnaire assessing migraine and therefore we were unable to assess migraine status on all individuals enrolled in VITAL. Second, we did not quantitatively measure migraine frequency or severity and all changes in migraine frequency and severity are based on self-report. It is possible that individuals may not accurately remember changes in migraine frequency or severity, but this should not vary by randomized treatment assignment because individuals were blinded to their treatment status. Third, although our questionnaire asked about ever history of recurring, repeated headache, the overall migraine prevalence in our sample was only 11.6% and it is possible that individuals may have underreported their lifetime experience with headaches. However, we observed no association between randomized treatment assignment and reporting of probable migraine.
In conclusion, supplementation with vitamin D and/or marine n-3 fatty acids did not affect migraine frequency or severity in this large cohort of middle-aged or older adults. Based on our and other data, these supplements are unlikely to be of benefit for this purpose.
Supplementary Material
Clinical Significance.
There is interest in whether vitamin D and marine omega-3 fatty acids may be effective migraine prophylaxis.
Using data from the VITamin D and OmegA-3 TriaL (VITAL), we determined the effect of vitamin D or marine omega-3 fatty acid supplementation on changes in migraine frequency and severity.
Neither vitamin D nor marine omega-3 fatty acid supplementation affected migraine frequency or severity among middle-aged or older adults.
Acknowledgements:
The authors thank the VITAL investigators, staff, and the trial participants for their outstanding dedication and commitment. Pharmavite donated vitamin D and Pronova BioPharma and BASF donated the omega-3 fatty acids (Omacor); the companies also donated matching placebos and packaging in the form of calendar packs. Quest Diagnostics measured the serum 25-hydroxyvitamin D levels plasma n−3 index at no cost to the trial.
Funding Sources: VITAL was supported by grants U01 CA138962 and R01 CA138962, which included support from the National Cancer Institute, National Heart, Lung and Blood Institute, Office of Dietary Supplements, National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health.
Pharmavite donated vitamin D and Pronova BioPharma and BASF donated fish oil (Omacor); the companies also donated matching placebos and packaging in the form of calendar packs. Quest Diagnostics measured the plasma n−3 index at no cost to the trial. None of the donating companies had any role in the trial design or conduct, the data collection or analysis, or the manuscript preparation or review.
Dr. Rist was supported by K01 HL128791.
Disclosures: TK reports having contributed to an advisory board of CoLucid and a research project funded by Amgen, for which the Charité – Universitätsmedizin Berlin received an unrestricted compensation. He further reports having received honoraria from Lilly, Newsenselab, and Total for providing methodological advice, from Novartis and from Daiichi Sankyo for providing a lecture on neuroepidemiology and research methods, and from the BMJ for editorial services. The other authors declare that they have no conflicts of interest.
Footnotes
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