Commentary: Vasodilation, antihypertensive drugs, and caffeine in migraine, August 2023

Migraine is well known as a vascular phenomenon, but research over time has shown that vasodilation is a secondary feature of headache rather than the cause of headache pain. Calcitonin gene-related peptide (CGRP) and other vasoactive inflammatory proteins transmit nociceptive signals through the trigeminal system, and although vasodilation occurs, it is not essential for migraine attacks to occur. White matter changes on MRI are a common finding in people with migraine, and the burden of migraine often correlates with the amount of white matter changes seen. This connection highlights the indirect connection between migraine and vascular risks factors, and this study attempts to better quantify this, specifically with respect to stroke and myocardial infarction (MI).

The study by Fuglsang and colleagues was a registry-based nationwide population-based cohort study that included over 200,000 individuals with migraine, using data collected from 1996 to 2018. Participants were differentiated as having or not having migraine on the basis of prescriptions of preventive or acute migraine medications. Male and female participants were further subdivided, and these groups were compared to healthy controls. The primary endpoints were hazard ratio and absolute risk differences for developing hemorrhagic or ischemic stroke or MI among all groups.

The researchers found an increased risk for ischemic stroke that was equal among male and female participants. Hemorrhagic stroke and MI were seen to be increased in migraine, but primarily among women with migraine. This study specifically investigated what the researchers termed "premature" stroke and MI, and there remains a likelihood that estrogen could be the differentiating factor between the difference in risk between male and female participants with migraine. I have recently highlighted a number of studies investigating vascular risk factors associated with migraine; this study will help clinicians appropriately educate their patients with migraine regarding vascular risk.

The first medications reported as helpful preventively for migraine were antihypertensives, specifically beta-blockers (BB). A number of other medications in other antihypertensive subclasses have also subsequently been shown to be helpful for migraine prevention. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and alpha-blockers (AB). Carcel and colleagues conducted a meta-analysis that investigated a wide variety of antihypertensive medications in multiple classes and compared the reduction in headache frequency as defined as headache days per month.

This analysis reviewed 50 studies involving over 4000 participants. The majority of the studies (35 out 50 [70%]) had a cross-over design. The medications evaluated included clonidine (an alpha agonist), candesartan (an ARB), telmisartan (an ARB), propranolol (a BB), timolol (a BB), pindolol (a BB), metoprolol (a BB), bisoprolol (a BB), atenolol (a BB), alprenolol (a BB), nimodipine (a CCB), nifedipine (a CCB), verapamil (a CCB), nicardipine (a CCB), enalapril (an ACE inhibitor), and lisinopril (an ACE inhibitor). For each class of antihypertensive, there was a lower number of monthly headache days with treatment compared with placebo; the greatest reduction was for the CCB with a mean difference of about 2 days per month. BB on average decreased headache days per month by 0.7 days. For BB, there was no clear trend to increased efficacy with increased dose. Only six trials reported the difference in blood pressure: On average, there was a 9.3 mm Hg drop in systolic and 3.0 mm Hg drop in diastolic pressure.

The authors showed that there is statistical significance for the use of antihypertensive medications for decreasing migraine days per month, and this was statistically significant separately for numerous specific drugs within the classes: clonidine, candesartan, atenolol, bisoprolol, propranolol, timolol, nicardipine, and verapamil. Antihypertensive medications remain some of the most popular first-line preventive options for migraine, and although the benefit of this class as a whole is mild (slightly more than 1 day per month), it can be an excellent option for many patients

The relationship between migraine and caffeine is necessarily controversial. Caffeine is included as a component of many over-the-counter migraine treatments, and the beneficial effect of caffeine as an acute treatment for migraine has been documented for decades. Reduction in caffeine, however, has also been established as a helpful lifestyle modification for prevention of migraine attacks. Zhang and colleagues used data from the National Health and Nutrition Examination Survey database, a program conducted by the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States.

This study sought to quantify the relationship between dietary caffeine and "severe headache." For this study, "severe headache" was defined as answering yes to the question: During the past 3 months, did you have severe headaches or migraines? Dietary caffeine intake was collected through two 24-hour dietary recall interviews, one in person and one 3-10 days later via telephone. The amount of caffeine consumed was estimated in mg/day from all caffeine-containing foods and beverages, including coffee, tea, soda, and chocolate, using the US Department of Agriculture's Food and Nutrient Database. Each participant's mean caffeine intake was defined as the difference between the first and second dietary recalls.

A large number of covariates were assessed as well, 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 triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

Curiously, in this study, only male participants were included. The authors found a clear correlation between the amount of caffeine consumed over a 24-hour period and severe migraine attacks. Further evaluation should investigate the frequency of attacks rather than just individual experience over a 3-month period. Although caffeine is helpful acutely, higher dose consumption is a risk factor for worsening migraine.

Migraine is well known as a vascular phenomenon, but research over time has shown that vasodilation is a secondary feature of headache rather than the cause of headache pain. Calcitonin gene-related peptide (CGRP) and other vasoactive inflammatory proteins transmit nociceptive signals through the trigeminal system, and although vasodilation occurs, it is not essential for migraine attacks to occur. White matter changes on MRI are a common finding in people with migraine, and the burden of migraine often correlates with the amount of white matter changes seen. This connection highlights the indirect connection between migraine and vascular risks factors, and this study attempts to better quantify this, specifically with respect to stroke and myocardial infarction (MI).

The study by Fuglsang and colleagues was a registry-based nationwide population-based cohort study that included over 200,000 individuals with migraine, using data collected from 1996 to 2018. Participants were differentiated as having or not having migraine on the basis of prescriptions of preventive or acute migraine medications. Male and female participants were further subdivided, and these groups were compared to healthy controls. The primary endpoints were hazard ratio and absolute risk differences for developing hemorrhagic or ischemic stroke or MI among all groups.

The researchers found an increased risk for ischemic stroke that was equal among male and female participants. Hemorrhagic stroke and MI were seen to be increased in migraine, but primarily among women with migraine. This study specifically investigated what the researchers termed "premature" stroke and MI, and there remains a likelihood that estrogen could be the differentiating factor between the difference in risk between male and female participants with migraine. I have recently highlighted a number of studies investigating vascular risk factors associated with migraine; this study will help clinicians appropriately educate their patients with migraine regarding vascular risk.

The first medications reported as helpful preventively for migraine were antihypertensives, specifically beta-blockers (BB). A number of other medications in other antihypertensive subclasses have also subsequently been shown to be helpful for migraine prevention. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and alpha-blockers (AB). Carcel and colleagues conducted a meta-analysis that investigated a wide variety of antihypertensive medications in multiple classes and compared the reduction in headache frequency as defined as headache days per month.

This analysis reviewed 50 studies involving over 4000 participants. The majority of the studies (35 out 50 [70%]) had a cross-over design. The medications evaluated included clonidine (an alpha agonist), candesartan (an ARB), telmisartan (an ARB), propranolol (a BB), timolol (a BB), pindolol (a BB), metoprolol (a BB), bisoprolol (a BB), atenolol (a BB), alprenolol (a BB), nimodipine (a CCB), nifedipine (a CCB), verapamil (a CCB), nicardipine (a CCB), enalapril (an ACE inhibitor), and lisinopril (an ACE inhibitor). For each class of antihypertensive, there was a lower number of monthly headache days with treatment compared with placebo; the greatest reduction was for the CCB with a mean difference of about 2 days per month. BB on average decreased headache days per month by 0.7 days. For BB, there was no clear trend to increased efficacy with increased dose. Only six trials reported the difference in blood pressure: On average, there was a 9.3 mm Hg drop in systolic and 3.0 mm Hg drop in diastolic pressure.

The authors showed that there is statistical significance for the use of antihypertensive medications for decreasing migraine days per month, and this was statistically significant separately for numerous specific drugs within the classes: clonidine, candesartan, atenolol, bisoprolol, propranolol, timolol, nicardipine, and verapamil. Antihypertensive medications remain some of the most popular first-line preventive options for migraine, and although the benefit of this class as a whole is mild (slightly more than 1 day per month), it can be an excellent option for many patients

The relationship between migraine and caffeine is necessarily controversial. Caffeine is included as a component of many over-the-counter migraine treatments, and the beneficial effect of caffeine as an acute treatment for migraine has been documented for decades. Reduction in caffeine, however, has also been established as a helpful lifestyle modification for prevention of migraine attacks. Zhang and colleagues used data from the National Health and Nutrition Examination Survey database, a program conducted by the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States.

This study sought to quantify the relationship between dietary caffeine and "severe headache." For this study, "severe headache" was defined as answering yes to the question: During the past 3 months, did you have severe headaches or migraines? Dietary caffeine intake was collected through two 24-hour dietary recall interviews, one in person and one 3-10 days later via telephone. The amount of caffeine consumed was estimated in mg/day from all caffeine-containing foods and beverages, including coffee, tea, soda, and chocolate, using the US Department of Agriculture's Food and Nutrient Database. Each participant's mean caffeine intake was defined as the difference between the first and second dietary recalls.

A large number of covariates were assessed as well, 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 triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

Curiously, in this study, only male participants were included. The authors found a clear correlation between the amount of caffeine consumed over a 24-hour period and severe migraine attacks. Further evaluation should investigate the frequency of attacks rather than just individual experience over a 3-month period. Although caffeine is helpful acutely, higher dose consumption is a risk factor for worsening migraine.

Migraine is well known as a vascular phenomenon, but research over time has shown that vasodilation is a secondary feature of headache rather than the cause of headache pain. Calcitonin gene-related peptide (CGRP) and other vasoactive inflammatory proteins transmit nociceptive signals through the trigeminal system, and although vasodilation occurs, it is not essential for migraine attacks to occur. White matter changes on MRI are a common finding in people with migraine, and the burden of migraine often correlates with the amount of white matter changes seen. This connection highlights the indirect connection between migraine and vascular risks factors, and this study attempts to better quantify this, specifically with respect to stroke and myocardial infarction (MI).

The study by Fuglsang and colleagues was a registry-based nationwide population-based cohort study that included over 200,000 individuals with migraine, using data collected from 1996 to 2018. Participants were differentiated as having or not having migraine on the basis of prescriptions of preventive or acute migraine medications. Male and female participants were further subdivided, and these groups were compared to healthy controls. The primary endpoints were hazard ratio and absolute risk differences for developing hemorrhagic or ischemic stroke or MI among all groups.

The researchers found an increased risk for ischemic stroke that was equal among male and female participants. Hemorrhagic stroke and MI were seen to be increased in migraine, but primarily among women with migraine. This study specifically investigated what the researchers termed "premature" stroke and MI, and there remains a likelihood that estrogen could be the differentiating factor between the difference in risk between male and female participants with migraine. I have recently highlighted a number of studies investigating vascular risk factors associated with migraine; this study will help clinicians appropriately educate their patients with migraine regarding vascular risk.

The first medications reported as helpful preventively for migraine were antihypertensives, specifically beta-blockers (BB). A number of other medications in other antihypertensive subclasses have also subsequently been shown to be helpful for migraine prevention. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and alpha-blockers (AB). Carcel and colleagues conducted a meta-analysis that investigated a wide variety of antihypertensive medications in multiple classes and compared the reduction in headache frequency as defined as headache days per month.

This analysis reviewed 50 studies involving over 4000 participants. The majority of the studies (35 out 50 [70%]) had a cross-over design. The medications evaluated included clonidine (an alpha agonist), candesartan (an ARB), telmisartan (an ARB), propranolol (a BB), timolol (a BB), pindolol (a BB), metoprolol (a BB), bisoprolol (a BB), atenolol (a BB), alprenolol (a BB), nimodipine (a CCB), nifedipine (a CCB), verapamil (a CCB), nicardipine (a CCB), enalapril (an ACE inhibitor), and lisinopril (an ACE inhibitor). For each class of antihypertensive, there was a lower number of monthly headache days with treatment compared with placebo; the greatest reduction was for the CCB with a mean difference of about 2 days per month. BB on average decreased headache days per month by 0.7 days. For BB, there was no clear trend to increased efficacy with increased dose. Only six trials reported the difference in blood pressure: On average, there was a 9.3 mm Hg drop in systolic and 3.0 mm Hg drop in diastolic pressure.

The authors showed that there is statistical significance for the use of antihypertensive medications for decreasing migraine days per month, and this was statistically significant separately for numerous specific drugs within the classes: clonidine, candesartan, atenolol, bisoprolol, propranolol, timolol, nicardipine, and verapamil. Antihypertensive medications remain some of the most popular first-line preventive options for migraine, and although the benefit of this class as a whole is mild (slightly more than 1 day per month), it can be an excellent option for many patients

The relationship between migraine and caffeine is necessarily controversial. Caffeine is included as a component of many over-the-counter migraine treatments, and the beneficial effect of caffeine as an acute treatment for migraine has been documented for decades. Reduction in caffeine, however, has also been established as a helpful lifestyle modification for prevention of migraine attacks. Zhang and colleagues used data from the National Health and Nutrition Examination Survey database, a program conducted by the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States.

This study sought to quantify the relationship between dietary caffeine and "severe headache." For this study, "severe headache" was defined as answering yes to the question: During the past 3 months, did you have severe headaches or migraines? Dietary caffeine intake was collected through two 24-hour dietary recall interviews, one in person and one 3-10 days later via telephone. The amount of caffeine consumed was estimated in mg/day from all caffeine-containing foods and beverages, including coffee, tea, soda, and chocolate, using the US Department of Agriculture's Food and Nutrient Database. Each participant's mean caffeine intake was defined as the difference between the first and second dietary recalls.

A large number of covariates were assessed as well, 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 triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

Curiously, in this study, only male participants were included. The authors found a clear correlation between the amount of caffeine consumed over a 24-hour period and severe migraine attacks. Further evaluation should investigate the frequency of attacks rather than just individual experience over a 3-month period. Although caffeine is helpful acutely, higher dose consumption is a risk factor for worsening migraine.