Sage Journals: Discover world-class research

Abstract

Objective

The objective of this article is to evaluate whether statin use and vitamin D status is associated with severe headache or migraine in a nationally representative sample.

Methods

We conducted a cross-sectional study of US individuals aged ≥40 years for whom information on statin use, serum 25-hydroxy vitamin D (25(OH)D), and self-reported severe headache or migraine had been collected. We calculated prevalence estimates of headache according to statin and 25(OH)D, and conducted adjusted logistic regression analyses stratified by the median 25(OH)D (≤57 and >57 nmol/l).

Results

Among 5938 participants, multivariable-adjusted logistic regression showed that statin use was significantly associated with a lower prevalence of severe headache or migraine (OR 0.67; 95% CI 0.46, 0.98, p = 0.04). We found a significant interaction between statin use and 25(OH)D with the prevalence of severe headache or migraine (p for interaction = 0.005). Among participants who had serum 25(OH)D > 57 nmol/l, statin use was associated with a multivariable-adjusted odds ratio of 0.48 (95% CI 0.32, 0.71, p = 0.001) for having severe headache or migraine. Among those with 25(OH)D ≤ 57 nmol/l, no significant association was observed between statin use and severe headache or migraine.

Conclusion

Statin use in those with higher serum vitamin D levels is significantly associated with lower odds of having severe headache or migraine.

Keywords

Headache migraine statin 25-hydroxy vitamin D epidemiology

Introduction

Use of statin medications has been associated with both increased (1 –3) and decreased (4,5) risk for migraine and headache. The association of vitamin D status and headache is also mixed, with some (6 –8), but not all (9), observational studies showing low vitamin D levels may be associated with headache. Based on observations that statin-associated muscle pain is significantly less likely to occur in patients when vitamin D levels are higher (10), we hypothesized that statins may have a variable effect on headache related to an interaction between statin and vitamin D status. Specifically, we predicted that use of statins among individuals with low vitamin D status would be associated with a higher prevalence of experiencing severe headache or migraine, and that use of statin by individuals with higher vitamin D would be associated with a lower prevalence of severe headache or migraine.

There is currently no agreed on definition for optimal serum vitamin D levels (11). A 25(OH)D level <37.5 nmol/l or <50 nmol/l has frequently been used to define vitamin D deficiency (12,13). For optimal health, some experts advocate attaining a 25(OH)D level of at least 75 nmol/l (14).

Methods

This was a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES), a stratified multistage probability survey of the civilian, non-institutionalized United States population. The NHANES includes an in-home interview to collect demographic and detailed health information, followed by examination and laboratory testing in a mobile examination center. Public-use data files for this study were downloaded from the NHANES Website (http://www.cdc.gov/nchs/nhanes.htm). Consent was obtained from participants by the National Center for Health Statistics (NCHS) after approval by the NHANES Institutional Review Board/NCHS Research Ethics Review Board. These analyses were approved for exemption by our institutional review board based on 45 CFR 46.101(b) regulating the use of de-identified data.

We analyzed data from the 2001–2004 NHANES, as those were the only years for which information on primary exposures of interest, serum 25-hydroxy vitamin D (25(OH)D) and statin use, as well as the outcome, severe headache or migraine, was available. We restricted our analyses to participants ≥40 years, because people younger than 40 years rarely use statins.

During the in-home interview, participants were asked if they had severe headache or migraine in the three months prior to the interview. Information on statin and other prescription medications was queried from all participants by first asking if they used any prescription medication; those who answered in the affirmative were asked to show medication containers to the interviewer to ensure correct recording of medication names. Measurements of serum 25(OH)D were performed at the Centers for Disease Control in Atlanta, GA, using the DiaSorin RIA kit (Stillwater, MN). Adjusted measures of 25(OH)D were used, taking into account assay drifts due to reagent and calibration lot-to-lot variability over time (15). We included, a priori, stratification by vitamin D status to examine the hypothesized interaction and dichotomized 25(OH)D by the median, weighted to account for the population sampled (≤57 and >57 nmol/l).

Other covariates

Principal confounders previously known or suspected to be associated with statin use or to affect the relationship between statin use and vitamin D were chosen a priori and included simultaneously in all multivariable adjusted models. These included age (continuous), sex (male/female), race/ethnicity (non-Hispanic white, non-Hispanic black, and other), educational attainment (less than high school diploma, high school diploma, more than high school diploma), self-reported health status (excellent/very good, good, poor/fair), physical activity (sedentary, moderate activity, vigorous activity), smoking (never, former, current), alcohol intake (continuous, average servings of drinks/week over the past year), body mass index (BMI) (continuous, based on measured height and weight), coronary heart disease (defined as having been told by a doctor/other health professional of a diagnosis of coronary artery disease, prior myocardial infarction, or angina), history of stroke, number of times seen by a doctor or other health professional during the past year (zero to one, two to three, or four or more times), number of concurrent medications used (continuous), use of specific medications that might be associated with pain relief and/or medication-overuse headache including: daily/near daily over-the-counter (OTC) analgesics (not including aspirin used alone), prescription nonsteroidal drugs, oral steroids, opioids, and use of specific medications commonly used for cardiovascular conditions, some of which may also prevent migraine including: beta-blockers, calcium channel blockers, angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers (ACE inhibitors/ARBs), and daily/near daily aspirin use. Daily/near daily use of aspirin or over-the-counter analgesics was defined as using these agents 15 days or more per month.

Sensitivity and post hoc analyses

We performed sensitivity analyses to explore if use of other medications or conditions influenced our results. Adjusting for all variables included in the main model we added, in separate models, the following: measured systolic blood pressure; diabetes (defined based on self-report of a doctor’s/health professional’s diagnosis, or measured glucose >200 mg/dl, or use of an antidiabetic medication); self-report of “depression/anxiety/emotional problem” that caused participant to have any difficulty or need help with activities; and, as a secondary proxy for mental health conditions, reporting having seen a mental health professional in the past year. Additionally, we examined whether use of preventive migraine therapy (which individuals regularly seeing a physician might be more likely to be prescribed) altered our findings. To perform these analyses, cardiovascular medications (except for statin and aspirin) were removed from the main model to avoid redundancy, and medications found to have Level A, B, or C evidence for migraine prevention were included (16). Specifically, this variable was defined as use of at least one of any of the following: divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, timolol, amitriptyline, venlafaxine, atenolol, nadolol, lisinopril, candesartan, clonidine, guanfacine, carbamazepine, nebivolol, pindolol, and cyproheptadine. To assess if post-menopausal status or exogenous hormones altered the results, we performed analyses restricting models (1) to age greater than 55 years, and (2) to women ≥40 years, while adding a variable for use of estrogen-containing contraceptives or hormone replacement therapy. Finally, we performed post hoc analyses examining 25(OH)D as a continuous linear variable.

All analyses were performed in SAS 9.3 and STATA 12 statistical software using survey weights to represent the population and to account for the complex sample design, non-response, and planned over-sampling of selected populations. We calculated prevalence estimates of headache according to 25(OH)D levels and to statin use, and conducted multivariable logistic regression analyses to adjust for multiple confounders.

Results

A total of 6238 participants aged ≥40 years were interviewed, examined, and had laboratory testing available for serum vitamin D levels. Of these, 300 individuals were excluded because they were missing information on at least one covariate of interest, resulting in 5938 participants being included in this study. Table 1 shows the characteristics of the study participants according to statin use. Participants using statins were more likely to be older, male, non-Hispanic white, former smokers, seen by a health professional multiple times in the past year, and were more likely to report poorer health, lower educational attainment, fewer servings of alcohol/week, and have histories of coronary heart disease and stroke. In addition they had higher BMIs and were more likely to use a greater number of concurrent medications, including higher use of OTC analgesics, prescription nonsteroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/ARBs, beta blockers, calcium channel blockers and daily/near daily aspirin.

Table 1.

Characteristics of the participants according to statin use (NHANES 2001–2004, ≥40 years).

	No statin use n = 4869 % (SE) or mean (SE)	Statin use n = 1069 % (SE) or mean (SE)	p value
Age, years, mean	55.1 (0.2)	62.9 (0.5)	<0.001
Female	53.4 (0.8)	46.3 (1.7)	0.004
Race/ethnicity			<0.001
Non-Hispanic white	77.4 (2.1)	85.0 (1.8)
Non-Hispanic black	9.5 (1.2)	5.9 (0.9)
Other	13.1 (1.8)	9.1 (1.4)
Educational attainment			0.02
Less than high school diploma	17.7 (0.8)	20.1 (2.2)
High school diploma	25.5 (0.7)	29.3 (1.5)
More than high school diploma	57.0 (1.2)	50.2 (2.6)
Self-reported health status			<0.001
Very good/excellent	50.7 (1.5)	35.9 (2.7)
Good	30.3 (0.8)	31.2 (1.7)
Fair/poor	19.0 (1.1)	28.9 (3.0)
Physical activity			0.05
Sedentary	38.2 (1.2)	38.4 (2.4)
Moderate	33.5 (0.8)	40.2 (2.3)
Vigorous	28.4 (1.1)	21.5 (2.3)
Smoking status			<0.001
Never	47.6 (1.3)	41.0 (2.0)
Former	30.8 (1.2)	43.6 (1.6)
Current	21.6 (0.9)	15.4 (1.6)
Alcohol, average servings/week			<0.001
None	36.2 (2.5)	47.9 (2.8)
More than 0 to 1	24.1 (1.3)	19.5 (1.4)
More than 1 to 3	16.7 (1.1)	15.4 (1.5)
More than 3	22.0 (1.3)	17.2 (2.0)
Body mass index, kg/m², mean	28.6 (0.2)	29.8 (0.2)	<0.001
Coronary heart disease	6.4 (0.6)	31.0 (2.3)	<0.001
History of stroke	2.7 (0.3)	7.1 (1.3)	<0.001
Times seen a physician/health professional in past year			<0.001
0–1	32.9 (0.8)	9.4 (1.3)
2–3	53.0 (0.7)	66.9 (2.1)
≥4	14.1 (0.8)	23.7 (2.4)
Number of concurrent prescription medications, mean	2.0 (0.8)	5.1 (1.6)	<0.001
Analgesic/anti-inflammatory medications
Daily/near daily OTC analgesics	7.4 (0.6)	11.2 (1.4)	0.005
Prescription NSAIDs	11.8 (0.7)	18.9 (1.5)	<0.001
Opioids	6.8 (0.5)	8.1 (1.4)	0.26
Oral steroids	1.6 (0.2)	2.2 (0.5)	0.16
Medications-cardiovascular
ACE inhibitor/ARB	7.2 (0.7)	27.5 (2.3)	<0.001
Beta blocker	6.4 (0.6)	21.3 (1.9)	<0.001
Calcium channel blocker	3.7 (0.5)	10.5 (1.1)	<0.001
Daily/near daily aspirin	11.3 (0.8)	33.3 (1.5)	<0.001

NHANES: National Health and Nutrition Examination Survey; OTC analgesics: over-the-counter analgesics (not including aspirin used alone); NSAIDs: nonsteroidal anti-inflammatory drugs; ACE inhibitor/ARB: angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers.

Comparing characteristics of the population according to the other exposure of interest, serum vitamin D, (Table 2) shows that individuals with 25(OH)D > 57 nmol/l were more likely to be non-Hispanic white, never or former smokers, to have attained higher education, and were more likely to report better health status, moderate or vigorous physical activity, fewer times having been seen by a health professional in the past year, and fewer concurrent medications. In addition they had lower BMI, were less likely to be taking opioid medications, and were more likely to be taking daily/near daily aspirin.

Table 2.

Characteristics of the participants according to serum 25(OH)D (NHANES 2001–2004, ≥40 years).

	25(OH)D ≤ 57 nmol/l n = 3537 % (SE) or mean (SE)	25(OH)D > 57 nmol/l n = 2401 % (SE) or mean (SE)	p value
Age, years, mean	56.5 (0.3)	56.3 (0.3)	0.31
Female	55.1 (0.8)	49.3 (1.2)	0.001
Race/ethnicity			<0.001
Non-Hispanic white	70.0 (2.4)	89.9 (1.5)
Non-Hispanic black	15.0 (1.7)	2.5 (0.3)
Other	17.0 (2.0)	7.6 (1.5)
Educational attainment			0.001
Less than high school diploma	20.1 (1.0)	15.3 (1.5)
High school diploma	23.7 (0.8)	29.0 (1.1)
More than high school diploma	55.5 (1.3)	55.9 (1.8)
Self-reported health status			<0.001
Very good/excellent	41.4 (1.4)	55.5 (2.7)
Good	33.2 (0.8)	28.9 (1.2)
Fair/poor	25.4 (1.0)	15.6 (1.7)
Physical activity			<0.001
Sedentary	44.1 (1.2)	32.0 (1.6)
Moderate	32.6 (1.1)	36.7 (1.2)
Vigorous	23.3 (1.4)	31.4 (1.6)
Smoking status			0.03
Never	47.0 (1.3)	46.0 (1.8)
Former	30.7 (1.0)	35.4 (1.4)
Current	22.4 (1.2)	18.7 (1.3)
Alcohol, average servings/week			0.002
None	40.8 (1.8)	35.2 (3.6)
More than 0 to 1	25.3 (1.3)	21.3 (1.5)
More than 1 to 3	14.5 (0.8)	18.9 (1.6)
More than 3	19.4 (1.1)	24.6 (1.9)
Body mass index, kg/m², mean	29.9 (0.2)	27.5 (0.1)	<0.001
Coronary heart disease	11.0 (0.9)	9.9 (0.9)	0.28
History of stroke	3.6 (0.4)	3.2 (0.5)	0.42
Times seen a physician/health professional in past year			0.03
0–1	27.0 (1.1)	31.1 (1.2)
2–3	56.2 (0.9)	54.4 (1.2)
≥4	16.8 (0.9)	14.5 (1.1)
Number of concurrent prescription medications, mean	2.6 (1.2)	2.4 (0.8)	0.01
Analgesic/anti-inflammatory medications
Daily/near daily OTC analgesics	8.2 (0.6)	7.9 (0.9)	0.78
Prescription NSAIDs	13.5 (1.0)	12.4 (0.8)	0.32
Opioids	8.0 (0.7)	6.0 (0.8)	0.04
Oral steroids	1.8 (2.9)	1.6 (0.3)	0.63
Medications-cardiovascular
ACE inhibitor/ARB	11.3 (1.1)	9.9 (1.2)	0.07
Beta blocker	9.4 (0.9)	8.3 (0.8)	0.30
Calcium channel blocker	4.9 (0.6)	4.8 (0.7)	0.95
Daily/near daily aspirin	12.9 (0.8)	17.1 (1.2)	<0.001

The overall weighted prevalence of severe headache or migraine in this population was 20.1%. Figure 1 shows the weighted prevalence of severe headache or migraine in the population by age. Prevalence of severe headache or migraine varied between those who used statins and those who did not. Among 1069 statin users, 16.1% reported severe headache or migraine, compared to 20.9% of those who did not use a statin. Among those who had a 25(OH)D ≤ 57 nmol/l and those who had 25(OH)D > 57 nmol/l, the prevalence of severe headache or migraine was 21.1% and 19.1%, respectively.

Figure 1.

Three-month prevalence of severe headache or migraine according to age (NHANES 2001–2004, ≥40 years). NHANES: National Health and Nutrition Examination Survey.

Figure 2 illustrates the prevalence of severe headache or migraine among statin users versus non-users according to quartiles of 25(OH)D. Among statin users, the prevalence of severe headache or migraine was highest among participants in the lowest quartile of 25(OH)D and was lowest among participants in the highest 25(OH)D quartiles. Among non-statin users, the prevalence of severe headache or migraine was not substantially different across 25(OH)D quartiles.

Figure 2.

Three-month prevalence of severe headache or migraine among statin users and non-users according to serum 25(OH)D quartiles.

In multivariable analyses adjusted for all a priori covariates, we found a significant association between statin use and a lower prevalence of severe headache or migraine, adjusted odds ratio (OR): 0.67 (95% confidence interval (CI): 0.46, 0.98). Including an interaction term in the model between statin use and 25(OH)D ≤ or >57 nmol/l confirmed a statistically significant interaction between these factors, with a lower prevalence of severe headache or migraine for statin use and 25(OH)D > 57 nmol/l (p for interaction = 0.005). In post-hoc analysis, modeling 25(OH)D as a continuous linear variable attenuated the interaction between statin and 25(OH)D (p for interaction = 0.05).

Table 3 shows multivariable adjusted models for the effect of statins, as well as other cardiovascular medications, in the overall sample and stratified according to 25(OH)D ≤ 57 nmol/l and 25(OH)D > 57 nmol/l. In addition to statin, calcium channel blocker use was independently associated with a lower risk for severe headache or migraine in the overall population. The strongest association, however, was found for statin use in those with 25(OH)D > 57 nmol/l (OR 0.48; 95% CI: 0.32, 0.71).

Table 3.

Adjusted^a odds ratios (OR) and 95% confidence intervals (CI) of the effect of statin and other cardiovascular medications on severe headache or migraine in the overall sample and stratified by vitamin D status (National Health and Nutrition Examination Survey, 2001–2004, ≥40 years).

	Overall sample^b n = 5938		25(OH)D ≤ 57 nmol/l^b n = 3237		25(OH)D > 57 nmol/l^b n = 2401
	OR (95% CI)	p value	OR (95% CI)	p value	OR (95% CI)	p value
Statin	0.67 (0.46, 0.98)	0.04	0.84 (0.52, 1.36)	0.47	0.48 (0.32, 0.71)	0.001
ACE inhibitor/ARB	0.70 (0.48, 1.02)	0.06	0.80 (0.53, 1.22)	0.29	0.56 (0.30, 1.03)	0.06
Beta-blocker	1.28 (0.87, 1.87)	0.20	1.35 (0.84, 2.11)	0.21	1.16 (0.72, 1.87)	0.52
Calcium channel blocker	0.55 (0.32, 0.91)	0.02	0.58 (0.33, 1.04)	0.07	0.52 (0.22, 1.23)	0.13
Daily aspirin	0.88 (0.61, 1.25)	0.46	0.91 (0.56, 1.47)	0.68	0.94 (0.57, 1.56)	0.80

Adjusted for all medications in above table and for age, sex, race/ethnicity (non-Hispanic white, non-Hispanic black, other), educational attainment (less than high school diploma, high school diploma, more than high school diploma), self-reported health status (excellent/very good, good, poor/fair), physical activity (sedentary, moderate, vigorous), smoking status (never, former, current), alcohol intake, body mass index, coronary heart disease, stroke, times seen by a health professional in last year (0–1, 2–3, ≥4), number of concurrent medications used, use of daily/near daily over-the-counter analgesics, use of prescription nonsteroidal drugs, use of opioids, and use of oral steroids.

^bPrevalence of severe headache or migraine in each group: Overall sample, n = 1069; 25(OH)D ≤ 57 nmol/l, n = 675; 25(OH)D > 57 nmol/l, n = 394). ACE inhibitor/ARB: angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers.

Bold denotes significant findings at p value < 0.05.

Further adjustment for measured systolic blood pressure; diabetes; depression/anxiety; or having seen a mental health professional in the past year, and using alternative modeling to examine the use of preventive migraine medications, did not materially affect the results in the overall model or stratified models.

To account for the possibility that endogenous or exogenous estrogen influenced our results, we also performed multivariable adjusted models in subpopulations: (1) Restricting age to ≥55 years in men and women. These analyses revealed an OR of 0.62 (95% CI: 0.41, 0.95) for the effect of statin on the outcome of severe headache or migraine in the overall model, an OR of 0.82 (95%CI: 0.50, 1.37) for those with 25(OH)D ≤ 57 nmol/l, and an OR of 0.33 (95% CI: 0.17, 0.66) for those with 25(OH)D > 57 nmol/l; and (2) restricting the sample to women only, for ages ≥40 years, and including use of exogenous estrogen (defined as use of estrogen-containing contraception or hormone replacement therapy) as a covariate in the models. These analyses revealed an OR of 0.71 (95% CI: 0.43, 1.16) for the effect of statin on the outcome of severe headache or migraine in the overall model, an OR of 0.91 (95% CI: 0.52, 1.57) for those with 25(OH)D ≤ 57 nmol/l, and an OR of 0.43 (95% CI: 0.20, 0.91) for those with 25(OH)D > 57 nmol/l.

Discussion

In the presence of higher levels of vitamin D, statin use was associated with a significantly lower prevalence of severe headache or migraine. This association remains after adjusting for multiple confounders.

The outcome for this study, prevalence of severe headache or migraine in the prior three months, was based on self-report; therefore, we can interpret our findings only in the context of severe headache. However, considering that most headaches are classified as migraine when headache specialists evaluate headaches described by patients as severe (17), it is reasonable to propose that most headaches reported in this study were migraine. Other headaches likely include severe tension-type headache, and to a much lesser extent, uncommon primary and secondary headaches (18 –20).

Options for migraine prophylaxis remain unsatisfactory, with patients citing lack of effectiveness and significant side effects as the most common reasons for discontinuing their use (21). Thus, efforts to identify more effective treatments with low side effects remain urgent. This current study supports the idea of investigating if statin and vitamin D supplementation could be an effective, well-tolerated therapy for preventing migraine.

The overall rationale for this study is based on the association between migraine with aura and the risk for developing vascular disease, most notably stroke and suggested associations between vascular diseases and any migraine (22 –25), although the latter remains controversial. Statins have demonstrated benefits in preventing and improving vascular diseases via lipid (26) and lipid-independent (27 –31) effects on the endothelium. As a hypothetical mechanism, endothelial dysfunction, which is a precursor to vascular disease, may be both a consequence of migraine and a possible cause/contributor of migraine pathogenesis (32). Evidence for endothelial dysfunction in migraine patients includes increased markers of inflammation (tumor necrosis factor (TNF)alpha, and interleukin (IL)-1) (33), thrombosis (von Willebrand factor (vWF) activity (34), and plasminogen activator antigen (32), and alterations in the nitric oxide pathway (35,36), which mediates vascular smooth muscle tone. Additionally, several studies have shown an association of migraine with increased augmentation index (AIx), a measure of arterial stiffness (37 –41). Accordingly, in the context of migraine, statin may reduce attack frequency by improving endothelial function (42), arterial stiffness (28,43), and vascular tone (28), and through the ability to reduce inflammatory responses (44 –48), and decrease platelet aggregation and thrombosis (49).

Statins are best known as cholesterol-lowering agents, and an association between hypercholesterolemia and migraine has previously been reported (50 –54). However, the few studies that have further explored the association between cholesterol and frequency of migraine have not found a correlation (52,53). Therefore, it seems unlikely that statins might decrease migraine via a direct action on cholesterol reduction, suggesting further investigations on lipid-independent actions would be of most interest.

We did not find significant modification of statin’s effects by vitamin D when modeling 25(OH)D as a simple linear continuous variable; this was not surprising given prevailing evidence suggesting a threshold effect of vitamin D on various health outcomes (55). Regarding the observed interaction between statin and 25(OH)D > 57 nmol/l, it may be reasonable to speculate that the effects of statin are facilitated by vitamin D, which has overall anti-inflammatory effects on cytokines (56,57). Another speculation on how vitamin D might interact with statin to reduce migraine involves muscle pain, a suspected trigger of migraine when occurring in the neck (58). Muscle pain in general is common among statin users with low vitamin D level, but is significantly less common among statin users with higher vitamin D levels (10). Because the pathophysiology of migraine-associated muscle tenderness is largely unknown, more research is needed to understand whether and how statin and vitamin D interact to reduce migraine through actions on muscles.

Finally, it is possible that low vitamin D status serves as a surrogate marker for long-term disease states or long-term poor health in general, and those individuals with longer-term poor health or disease may be less likely to respond to pleiotropic effects of statin. Although we controlled for several health measures and health risks in this study, a cross-sectional study lacks the dimension of time. Therefore, investigation into the relationship between statin, vitamin D status, and migraine in large longitudinal cohorts and randomized, controlled trials would be of great interest.

Study limitations

First, this study included only people ≥40 years in order to evaluate statin use, thus our findings may not be generalizable to younger individuals with severe headache or migraine. Second, although we adjusted for several confounders, residual confounding may exist. Third, the outcome of having severe headache or migraine in the past three months was based on self-report. As noted above, no further information was available to discern headache classifications or apply International Classification Headache Disorders criteria. Thus, misclassification is possible. Fourth, although 25(OH)D showed a normal distribution, the range was relatively narrow, which prevented us from examining higher levels, e.g. 25(OH)D levels 75 nmol/l or higher, recommended by some for optimal health (14). Fifth, our findings of dichotomized versus linear models of 25(OH)D are consistent with the notion that the effect of 25(OH)D on statin use is nonlinear; however, the exact threshold at which severe headache or migraine may decrease remains unclear. Finally, as a cross-sectional study, this study cannot address causality or the direction of the association we observed between statin use and vitamin D with lower prevalence of severe headache or migraine.

Results from this study suggest the combination of statin treatment and vitamin D supplementation should be explored as a possible headache/migraine preventive. Additionally, among individuals using a statin who experience an increase in or worsening of migraine or headache, testing for vitamin D may be reasonable and, if vitamin D deficiency were to be identified, supplementation would be prudent.

Conclusion

Our preliminary findings indicate that people who have serum 25(OH)D > 57 nmol/l and use a statin have a lower prevalence of severe headache or migraine. It remains to be seen whether combined treatment with statin and vitamin D supplementation might serve as a therapy to prevent headache or migraine.

Clinical implications

Statins have a variable effect on the prevalence of severe headache or migraine that depends on vitamin D status.

Statin use in those with higher serum vitamin D levels is significantly associated with a lower prevalence of having severe headache or migraine.

Footnotes

Funding

Dr Buettner’s time was supported by a National Institutes of Health (NIH) K23 Career Development Award (K23AR055664) and by the Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center. Dr Burstein was supported by an NIH Award (R37 NS079678). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University and its affiliated academic health care centers or the National Institutes of Health.

Conflicts of interest

Dr Buettner and Dr Burstein have applied for a patent for the combination of statin and vitamin D as a prophylactic treatment in migraine. Dr Burstein has received funding from the NIH, Merck, Allergan and GlaxoSmithKline.

References

Rapoport

. Unrecognized adverse drug reactions. CMAJ 1993; 149: 1233–1233.

Ramsey

Snyder

. Altitude-induced migraine headache secondary to pravastatin: Case report. Aviat Space Environ Med 1998; 69: 603–606.

Shuster

. Lipid-lowering drugs and headache. Nursing 1998; 28: 32–32.

Liberopoulos

Mikhailidis

. Could statins be useful in the treatment of patients with migraine? Headache 2006; 46: 672–675.

Medeiros

Valença

. Simvastatin for migraine prevention. Headache 2007; 47: 855–856.

Kjaergaard

Eggen

Mathiesen

. Association between headache and serum 25-hydroxyvitamin D: The Tromsø Study: Tromsø 6. Headache 2012; 52: 1499–1505.

Knutsen

Brekke

Gjelstad

. Vitamin D status in patients with musculoskeletal pain, fatigue and headache: A cross-sectional descriptive study in a multi-ethnic general practice in Norway. Scand J Prim Health Care 2010; 28: 166–171.

Prakash

Shah

. Chronic tension-type headache with vitamin D deficiency: Casual or causal association? Headache 2009; 49: 1214–1222.

Zandifar

Masjedi

Banihashemi

. Vitamin D status in migraine patients: A case-control study. Biomed Res Int 2014; 2014: 514782–514782.

10.

Palamaner Subash Shantha

Ramos

Thomas-Hemak

. Association of vitamin D and incident statin induced myalgia—a retrospective cohort study. PloS One 2014; 9: e88877–e88877.

11.

Dawson-Hughes

Heaney

Holick

. Estimates of optimal vitamin D status. Osteoporos Int 2005; 16: 713–716.

12.

Thomas

Lloyd-Jones

Thadhani

. Hypovitaminosis D in medical inpatients. N Engl J Med 1998; 338: 777–783.

13.

Centers for Disease Control and Prevention. National report on biochemical indicators of diet and nutrition in the U.S. population 1999–2002. Atlanta, GA, 2008.

14.

Bischoff-Ferrari

Giovannucci

Willett

. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006; 84: 18–28.

15.

National Health and Nutrition Examination Survey. Revised analytical note for NHANES 2000–2006 and NHANES III (1988–1994) 25-hydroxyvitamin D analysis, www.cdc.gov/nchs/data/nhanes/nhanes3/VitaminD_analyticnote.pdf. (2008, accessed 25 March 2014).

16.

Silberstein

Holland

Freitag

. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012; 78: 1337–1345.

17.

Tepper

Dahlof

Dowson

. Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: Data from the Landmark Study. Headache 2004; 44: 856–864.

18.

Lipton

Bigal

Diamond

. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007; 68: 343–349.

19.

Schwartz

Stewart

Simon

. Epidemiology of tension-type headache. JAMA 1998; 279: 381–383.

20.

Vos

Flaxman

Naghavi

. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2163–2196.

21.

Blumenfeld

Bloudek

Becker

. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: Results from the second international burden of migraine study (IBMS-II). Headache 2013; 53: 644–655.

22.

Sacco

Ripa

Grassi

. Peripheral vascular dysfunction in migraine: A review. J Headache Pain 2013; 14: 80–80.

23.

Schillaci

Sarchielli

Corbelli

. Aortic stiffness and pulse wave reflection in young subjects with migraine: A case-control study. Neurology 2010; 75: 960–966.

24.

Schürks

Rist

Bigal

. Migraine and cardiovascular disease: Systematic review and meta-analysis. BMJ 2009; 339: b3914–b3914.

25.

Tietjen

. Migraine as a systemic vasculopathy. Cephalalgia 2009; 29: 987–996.

26.

Baigent

Keech

Kearney

. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–1278.

27.

Halcox

Deanfield

. Beyond the laboratory: Clinical implications for statin pleiotropy. Circulation 2004; 109(21 Suppl): II42–II48.

28.

Kanaki

Sarafidis

Georgianos

. Effects of low-dose atorvastatin on arterial stiffness and central aortic pressure augmentation in patients with hypertension and hypercholesterolemia. Am J Hypertens 2013; 26: 608–616.

29.

Moon

Kim

Cho

. Antioxidant effects of statins in patients with atherosclerotic cerebrovascular disease. J Clin Neurol 2014; 10: 140–147.

30.

Tziomalos

Karagiannis

Athyros

. Effects of lipid-lowering agents on inflammation, haemostasis and blood pressure. Curr Pharm Des 2014; 20: 6306–6313.

31.

Undas

Brummel-Ziedins

Mann

. Anticoagulant effects of statins and their clinical implications. Thromb Haemost 2014; 111: 392–400.

32.

Tietjen

Herial

White

. Migraine and biomarkers of endothelial activation in young women. Stroke 2009; 40: 2977–2982.

33.

Perini

D’Andrea

Galloni

. Plasma cytokine levels in migraineurs and controls. Headache 2005; 45: 926–931.

34.

Tietjen

Al-Qasmi

Athanas

. Increased von Willebrand factor in migraine. Neurology 2001; 57: 334–336.

35.

Fidan

Yuksel

Ymir

. The importance of cytokines, chemokines and nitric oxide in pathophysiology of migraine. J Neuroimmunol 2006; 171: 184–188.

36.

Yetkin

Ozisik

Ozcan

. Increased dilator response to nitrate and decreased flow-mediated dilatation in migraineurs. Headache 2007; 47: 104–110.

37.

Vanmolkot

Van Bortel

de Hoon

. Altered arterial function in migraine of recent onset. Neurology 2007; 68: 1563–1570.

38.

Jiménez Caballero

Muñoz Escudero

. Peripheral endothelial function and arterial stiffness in patients with chronic migraine: A case-control study. J Headache Pain 2013; 14: 8–8.

39.

Liman

Neeb

Rosinski

. Peripheral endothelial function and arterial stiffness in women with migraine with aura: A case-control study. Cephalalgia 2012; 32: 459–466.

40.

Schillaci

Sarchielli

Corbelli

. Aortic stiffness and pulse wave reflection in young subjects with migraine: A case-control study. Neurology 2010; 75: 960–966.

41.

Nagai

Tabara

Igase

. Migraine is associated with enhanced arterial stiffness. Hypertens Res 2007; 30: 577–583.

42.

Wang

Liu

Liao

. Pleiotropic effects of statin therapy: Molecular mechanisms and clinical results. Trends Mol Med 2008; 14: 37–44.

43.

Tousoulis

Oikonomou

Siasos

. Dose-dependent effects of short term atorvastatin treatment on arterial wall properties and on indices of left ventricular remodeling in ischemic heart failure. Atherosclerosis 2013; 227: 367–372.

44.

Shishehbor

Brennan

Aviles

. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003; 108: 426–431.

45.

Chu

Guilianini

Barratt

. Pharmacogenetic determinants of statin-induced reductions in C-reactive protein. Circ Cardiovasc Genet 2012; 5: 58–65.

46.

Clockaerts

Van Osch

Bastiaansen-Jenniskens

. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study. Ann Rheum Dis 2012; 71: 642–647.

47.

Kadam

Blagojevic

Belcher

. Statin use and clinical osteoarthritis in the general population: A longitudinal study. J Gen Intern Med 2013; 28: 943–949.

48.

Gouveia

Scorza

Iha

. Lovastatin decreases the synthesis of inflammatory mediators during epileptogenesis in the hippocampus of rats submitted to pilocarpine-induced epilepsy. Epilepsy Behav 2014; 36: 68–73.

49.

Undas

Brummel

Musial

. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001; 103: 2248–2253.

50.

Scher

Terwindt

Picavet

. Cardiovascular risk factors and migraine: The GEM population-based study. Neurology 2005; 64: 614–620.

51.

Monastero

Pipia

Cefalù

. Association between plasma lipid levels and migraine in subjects aged >or =50 years: Preliminary data from the Zabùt Aging Project. Neurol Sci 2008; 29(Suppl 1): S179–S181.

52.

Kurth

Ridker

Buring

. Migraine and biomarkers of cardiovascular disease in women. Cephalalgia 2008; 28: 49–56.

53.

Gruber

Bernecker

Pailer

. Lipid profile in normal weight migraineurs—evidence for cardiovascular risk. Eur J Neurol 2010; 17: 419–425.

54.

Rist

Tzourio

Kurth

. Associations between lipid levels and migraine: Cross-sectional analysis in the epidemiology of vascular ageing study. Cephalalgia 2011; 31: 1459–1465.

55.

de Boer

Levin

Robinson-Cohen

. Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: A cohort study. Ann Intern Med 2012; 156: 627–634.

56.

Müller

Haahr

Diamant

. 1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level. Cytokine 1992; 4: 506–512.

57.

Canning

Grotenhuis

de Wit

. 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. Eur J Endocrinol 2001; 145: 351–357.

58.

Ashina S, Bendtsen L, Lyngberg AC, et al. Prevalence of neck pain in migraine and tension-type headache: A population study. Cephalalgia. Epub ahead of print 22 May 2014.

Association of statin use and risk for severe headache or migraine by serum vitamin D status: A cross-sectional population-based study

Abstract

Objective

Methods

Results

Conclusion

Keywords

Introduction

Methods

Other covariates

Sensitivity and post hoc analyses

Results

Discussion

Study limitations

Conclusion

Clinical implications

Footnotes

Funding

Conflicts of interest

References