Association between dietary caffeine intake and severe headache or migraine in US adults

The relationship between current dietary caffeine intake and severe headache or migraine is controversial. Therefore, we investigated the association between dietary caffeine intake and severe headaches or migraines among American adults. This cross-sectional study included 8993 adults (aged ≥ 20 years) with a dietary caffeine intake from the National Health and Nutrition Examination Surveys of America from 1999 to 2004. Covariates, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglycerides, were adjusted in multivariate logistic regression models. In US adults, after adjusting for potential confounders, a 100 mg/day increase in dietary caffeine intake was associated with a 5% increase in the prevalence of severe headache or migraine (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02–1.07). Further, the prevalence of severe headache or migraine was 42% higher with caffeine intake of ≥ 400 mg/day than with caffeine intake of ≥ 0 to < 40 mg/day (OR 1.42, 95% CI 1.16–1.75). Conclusively, dietary caffeine intake is positively associated with severe headaches or migraines in US adults.

Severe headache or migraine is a common neurological disorder that can seriously affect people's daily lives and heavily burden individuals and society 1 .Globally, severe headache or migraine ranks second among the causes of years lived with disability, with the greatest age-standardized prevalence in 1990 and 2017 2 .It is three times more common in women than men, with a lifetime prevalence of 43% and 18%, respectively 3 .It remains a serious public health issue in the United States (US), with an age-adjusted prevalence of 15.9% across all adults in 2018 4 .The financial strain of migraine is enormous; approximately 40% of US adults with migraine were unemployed in 2018, and a similar percentage were classified as poor or "near poor" 5 .Therefore, effective preventive measures and modifiable risk factors for severe headaches or migraines should be investigated.
Recent studies have shown that genetics, sleep, and diet are contributing factors to headaches [6][7][8] .Caffeine is an important area of concern in diet, and it occurs naturally in various foods, such as coffee beans, tea, kola nuts, mate leaves, and cocoa nuts 9 .Caffeine is an antagonist of adenosine, inhibiting the release of excitatory neurotransmitters, resulting in decreased cortical excitability 10,11 .Additionally, caffeine has psychostimulant effects via the modulation of dopaminergic neurons, and dopamine plays a role in the pathogenesis of migraine 12,13 .Headache attacks are related to changes in cerebral blood flow, and caffeine intake or withdrawal can change the speed of cerebral blood flow and aggravate headaches 14,15 , since it significantly affects the central nervous system 16,17 .
Previous studies have reported the wide use of caffeine for patients with headaches, either alone or in combination with other treatments 18 .The American Headache Society recommends over-the-counter (OTC) nonsteroidal anti-inflammatory drugs (NSAIDs) and combinations such as acetaminophen, aspirin, and caffeine as Level A recommendations for reducing migraine and other symptoms 19 .Derry et al. reported in a randomized double-blinded study that the addition of caffeine (≥ 100 mg) to standard doses of commonly used analgesics improved pain relief 20 ; however, this finding varies among studies.Shirlow et al. conducted a study on Australians and reported that the proportion of participants with headaches increased significantly with average caffeine intake 21 .However, Boardman et al. found no clear relationship between caffeine intake and headache in a crosssectional study in the United Kingdom (UK) 22 .In another study, Hoy et al. reported that caffeine preparations

Assessment of covariates
Covariates in this study, including age, triglycerides (TG), energy intake, protein intake, calcium intake, magnesium intake, iron intake, and sodium intake, were used as continuous variables.Categorical variables included education level (< high school, completed high school, > high school), race/ethnicity (non-Hispanic white, non-Hispanic black, or others), and marital status (married/living with a partner or widowed/divorced/separated/ never married).Poverty-income ratio (PIR) was defined as the ratio of family income to poverty threshold (< 1 indicating an income below the poverty threshold and ≥ 1 indicating an income above the poverty threshold; the latter category was further divided into two groups: 1.00 to < 2.00, ≥ 2.00).Body mass index (BMI) was measured as weight (kg) divided by height (m) squared (< 25.0 kg/m 2 indicating normal, 25.0 to < 30.0 kg/m 2 indicating overweight, ≥ 30.0 kg/m 2 indicating obese).Smoking status (never smoking, < 100 cigarettes; former smoker, not currently smoking but ≥ 100 cigarettes consumed previously; current smoker, ≥ 100 cigarettes and currently smoking every day or some days).Alcohol status was determined by whether the participant had at least 12 alcoholic drinks per year (yes or no).Cancer was judged by answering the following question: "Have you ever been told by a doctor or other health professional that you had cancer or a malignancy of any kind?"(yes or no).Hypertension (defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg) was determined by either three blood pressure measurements at different times, an existing diagnosis, or evidence of an existing antihypertensive medication regimen.

Statistical analysis
The main concern was whether dietary caffeine intake was associated with severe headaches or migraine after adjusting for other factors that may influence severe headaches or migraines.Continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as percentages.The χ 2 test was used to compare categorical variables between groups, a one-way analysis of variance was employed to compare normally distributed variables between groups, and the Kruskal-Wallis H test was utilized to compare variables with a skewed distribution between groups.Multivariable logistic regression analysis was performed to evaluate the independent association between dietary caffeine intake and severe headaches or migraine.Meet the methodological requirements.We used four levels of adjustment: Model 1 was adjusted for age and race/ethnicity; Model

Participant characteristics
In this study, 8993 participants were included (Figure S1).Table 1 shows the characteristics of the participants according to their dietary caffeine intake.We grouped the participants according to their caffeine intake based on previous literature.Walter's study defined 40-200 mg of caffeine per day as a "moderate" amount 29 .Further, Nawrot and van Dam RM research pointed out that more than 400 mg of caffeine daily is harmful to health 30,31 .Accordingly, we divided caffeine intake into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day.Statistically significant differences were observed in age, educational level, race/ethnicity, marital status, PIR, BMI, smoking status, alcohol status, cancer, TG, energy intake, protein intake, calcium intake, magnesium intake, iron intake, and sodium intake in the different dietary caffeine intake groups (P < 0.05).
Participants with the lowest dietary caffeine intake in group 1 (≥ 0 to < 40 mg/day) were likely to be younger, non-Hispanic white, less educated, living alone, poorer, and underweight, with less smoking, less drinking, no cancer, no hypertension, lower TG, and lower energy, protein, calcium, magnesium, iron, and sodium intake.

Association between dietary caffeine intake and severe headache or migraine
We investigated the individual effects of each covariate on severe headaches or migraine using univariate analyses separately for the males and females in Table 2.In males, the incidence of severe headaches or migraines was likely to be with higher education, married/living with a partner, relatively wealthy, with greater BMI, drinking, hypertension, and cancer patients.Also, the higher incidence of severe headaches or migraines in females may be higher education, those who lived alone, were relatively wealthy, with less BMI, drinking, hypertension, and cancer patients.
The fully adjusted model observed a linear relationship between dietary caffeine intake and severe headaches or migraines in US adults (males and females) (Figure S2).A scatter plot of dietary caffeine intake and severe headaches or migraine is shown in Figure S3.
The results of the multivariate logistic regression analysis are shown in Table 3.After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected in Models 1-4.In Model 4, all variables were adjusted; for every 100 mg/day increase in dietary caffeine intake, severe headache or migraine incidence increased by 5% (OR 1.05, 95% CI 1.02-1.07,P < 0.001) in all adults.Notably, for every 100 mg/day increase in dietary caffeine intake, severe headache or migraine incidence increased by 5% (OR 1.05, 95% CI 1.01-1.08,P = 0.006) and 7% (OR 1.07, 95% CI 1.02-1.11,P = 0.002) in males and females, respectively.
Among the groups of dietary caffeine intake in Model 4 compared with participants in the first group of dietary caffeine intake (≥ 0 to < 40 mg/day), while the fourth group of dietary caffeine intake (≥ 400 mg/day) was associated with severe headaches or migraine (OR 1.42, 95% CI 1.16-1.75,P < 0.001).These relationships are also found in males and females.
The results of subgroup analyses by age, educational level, race/ethnicity, marital status, BMI, cancer, and energy intake are presented in Table S2.A significant interaction of dietary caffeine intake with age was found (P < 0.05).

Discussion
The results of this cross-sectional study of adult males in the US showed the association between dietary caffeine intake and severe headaches or migraine for the first time in a nationally representative sample.After adjusting for other variables, we found a linear relationship between dietary caffeine intake and severe headaches or migraines from 1999 to 2004.We also found that age modified the association.
The study investigated increased odds of severe headaches or migraine with increasing dietary caffeine intake in adults.
Our data were obtained from the NHANES database, which surveys a nationally representative sample of various health and nutrition measures covering diverse demographic characteristics such as multi-ethnicity 28 .Furthermore, the database is comprehensive, and its results are representative.
Caffeine is structurally similar to adenosine 12 , which plays important roles in regulating neurotransmitter release in the brain, movement, reward, sleep/wakefulness, cognition, and analgesia 32 .When caffeine binds to adenosine receptors on the cell surface, it acts as an adenosine receptor antagonist, which in turn induces cortical hyperexcitability and maintains arousal in the brain 11,13 .The main effect of caffeine in the neuroendocrine control system is the activation of distinct neuronal pathways by altering neurotransmitter release, which causes headaches and dependence 33 .Dehydration is also considered a possible contributor to migraine, and higher doses of caffeine can induce acute diuresis, which may subsequently lead to dehydration 34,35 .Chronic caffeine intake promotes a nociceptive state of cortical hyperexcitability and excitable neurons by antagonizing G proteincoupled purinergic (P1) receptors, which induces or exacerbates headaches 14,36  www.nature.com/scientificreports/exposure to caffeine increases the risk of developing analgesic-overuse headaches, chronic daily headaches, and physical dependency [37][38][39] .Age may affect the relationship between dietary caffeine intake and severe headaches or migraine; in the subgroup analysis, we found a stronger relationship in age < 60 years, and the interaction is significant among females.Hormones, such as menarche, oral contraceptive use, pregnancy, menopause, etc., greatly influence females' migraines 40 , mainly involving young and middle-aged people ≥ 20 to < 60 years.Studies also have shown www.nature.com/scientificreports/ that caffeine intake affects the levels of luteal progesterone levels, luteal total, and free estradiol in premenopausal women; in postmenopausal females, no significant associations were detected with these hormones 41 , which may have implications for the relationship between dietary caffeine intake and severe headaches or migraine in adults non-elderly.However, its impact mechanism is still unclear, and it is necessary to conduct further studies to explore this conclusively.This study had some limitations.First, this was a cross-sectional study; thus, we could not determine a causal relationship between dietary caffeine intake and severe headaches or migraine.Second, the data were obtained from questionnaires; therefore, there could be significant recall bias.Third, severe headache or migraine is based on self-reports and cannot be distinguished by type.Fourth, the caffeine intake calculated by food conversion may be inaccurate.However, the data used in this study came from the NHANES database, a research program designed to assess the health and nutritional status of adults and children in the US, and is intended to be accurate 42 .Fifth, the results may have been influenced by uncontrolled confounding, such as non-alcoholic fatty liver disease (NAFLD) 43 .Sixth, the data is nearly 20 years old at this point and may not be reflective of the current population, so our next study will include more recent data.

Conclusions
Our study showed that higher dietary caffeine intake is positively associated with a higher prevalence of severe headaches or migraines in US adults.However, further prospective studies are needed to clarify whether increased dietary caffeine intake increases the risk of severe headaches or migraine.

Table 1 .
Characteristics of study participants aged ≥ 20 years from 1999 to 2004 National Health and Nutrition Examination Survey.SD standard deviation, PIR poverty-income ratio (ratio of family income to poverty threshold), BMI body mass index (calculated as weight in kilograms divided by the square of height in meters), TG triglycerides.

Table 2 .
Effects of factors on severe headache or migraine in adults.SD standard deviation, PIR povertyincome ratio, BMI body mass index, TG triglyceride, CI confidence interval, OR odds ratio.

Table 3 .
Associations of caffeine intake with severe headache or migraine.CI confidence interval, OR odds ratio.
a Model 1: Adjust for age and race/ethnicity.b Model 2: Adjusted for the variables in Model 1 plus body mass index, poverty-income ratio, educational level, marital status, alcohol status, and smoking status.c Model 3: Adjusted for the variables in Model 2 plus hypertension, cancer, and triglycerides.d Model 4: Adjusted for the variables in Model 3 plus energy intake, protein intake, calcium intake, magnesium intake, iron intake, and sodium intake.