Clinical Edge Journal Scan Commentary: Migraine March 2022

The theme of the articles this month is migraine and blood vessels. Migraine is a known risk factor for vascular events, it is a known vasodilatory phenomenon, and it is commonly treated with vasoconstrictive medications. Genetic studies are further elucidating the connection between migraine and vascular risk factors. The following studies take this vascular connection to clinical relevance in different ways.

Previous studies have investigated the combination of simvastatin and vitamin D for migraine prevention. Statins have anti-inflammatory properties and migraine can partially be understood as an inflammatory vascular phenomenon. Vitamin D and simvastatin were previously shown to be effective in a randomized trial; this study¹ investigated the combination of atorvastatin with nortriptyline for migraine prevention. Patients were excluded if they had a vitamin D deficiency.

This was a triple-blinded study with one control group, one placebo plus notriptyline group, and one atorvastatin plus nortiptyline group. The nortiptyline dosage was 25mg nightly, and the interventions were given for 24 weeks. The primary outcome was decrease in headache day frequency; secondary outcomes were severity and quality of life as measured by the Migraine-Specific Quality of Life Questionnaire (MSQ).

Migraine frequency was seen to be significantly improved after 24 weeks in the statin group; however severity was not significantly affected. Adverse effects were mild and overall no subjects discontinued due to the intervention. Quality of life was also seen to be better in the combination statin/nortriptyline group.

The results of this study are compelling enough to consider the addition of a tricyclic antidepressant (TCA) for a patient already on a statin or to start a statin (in the appropriate clinical setting) on a patient already on a TCA. The main limiting factor may be the hesitation to use a TCA medication in an older patient, where the anticholinergic effects may be less predictable.

Caffeine has a controversial place in the headache world. Many patients either use caffeine as a way to treat their migraine attacks, or avoid it completely as they are told it is a migraine trigger. Most headache specialists recommend the avoidance of excessive caffeine use (typically considered >150 mg daily) and tell their patients to be consistent about when they consume caffeine. The effect of caffeine on migraine likely is due to its vasoactive property, specifically that it is vasoconstrictive in nature. These vasoactive properties may also be why many studies investigating cerebrovascular reactivity have been inconclusive in the past.

The authors in this study² recruited patients with episodic migraine and divided them based on caffeine use. All subjects underwent transcranial Doppler testing at baseline and after 3 months, caffeine users were instructed to discontinue caffeine in the interim. Doppler testing looked for differences in BHI (breath holding index) of the bilateral posterior cerebral arteries (PCA), which is a standard at their institution. Subjects were only investigated if they were headache-free and had not used a migraine abortive medication in the previous 48 hours. Preventive medications were not controlled for.

Although the investigators recommended discontinuation of caffeine for the caffeine users, only 28% of that subgroup did discontinue. They then subdivided the group of caffeine users into those whose caffeine intake increased, decreased, or stayed the same. Transcranial Doppler testing was performed in all subgroups.

The investigators found a lower BHI-PCA, or decrease in vasodilatory function, in the subgroups that remained on caffeine. Those who stopped caffeine had improvement in this metric, showing the possible reversibility that discontinuation of caffeine can have. It remains unclear precisely how caffeine is vasoactive, and the effects may be via adenosine receptors, endothelial function, neurotransmitter production, or regulation of the autonomic nervous system. The long-term vascular effects of caffeine are unknown, but they do appear to be reversible after a 3 month period.

Migraine, and especially migraine with aura, is well known as a vascular risk factor. The presence of migraine increases the odds ratio of stroke, myocardial ischemia, deep vein thrombosis and other vascular events significantly. The American College of Obstetrics and Gynecology recommends avoiding the use of any estrogen containing medication in the presence of migraine, due to estrogen itself being a pro-thrombotic hormone.  The precise mechanism that leads to this increased risk is unknown.

This study investigated the connection between migraine and large artery atherosclerosis (LAA). This group observed 415 consecutive patients aged 18-54 who presented for a first time ischemic stroke (other neurovascular events, such as cerebral venous sinus thrombosis, subarachnoid hemorrhage with secondary ischemia and transient ischemic attacks, were excluded). Data regarding these patient’s risks factors was collected and analyzed including elevated body mass index (BMI), hypertension, diabetes, tobacco use, and hyperlipidemia.

All patients underwent magnetic resonance imaging (MRI), as well as either magnetic resonance angiography (MRA) or computed tomography angiography (CTA), and duplex ultrasound confirmed the images. Atherosclerosis was classified using a standardized system (ASCOD: atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection) that grades atheroslerotic lesions on a 0-3 scale.

The results may be considered counterintuitive. The presence of migraine was negatively associated with the presence of LAA: a history of migraine did not increase the risk of atherosclerosis. This was even the case when controlling for the traditional vascular risk factors. The authors theorize that likely the association between migraine and stroke and other vascular events is not related to atherosclerosis and may be due to other causes.

A genome-wide association study recently identified a specific polymorphism that was shared by migraine and coronary artery disease. But just like this study, the people with migraine had a negative association with coronary artery disease. If people with migraine do develop stroke or other vascular phenomena they typically present younger and healthier, and this may be why this negative correlation exists.

References

1. Sherafat M et al. The preventive effect of the combination of atorvastatin and nortriptyline in migraine-type headache: a randomized, triple-blind, placebo-controlled trial. Neurol Res. 2022 (Jan 17).
2. Gil Y-E et al. Effect of caffeine and caffeine cessation on cerebrovascular reactivity in patients with migraine. Headache. 2022;62(2):169-75 (Feb 3).
3. Gollion C et al. Migraine and large artery atherosclerosis in young adults with ischemic stroke. Headache. 2022;62(2):191-7 (Feb 5).

The theme of the articles this month is migraine and blood vessels. Migraine is a known risk factor for vascular events, it is a known vasodilatory phenomenon, and it is commonly treated with vasoconstrictive medications. Genetic studies are further elucidating the connection between migraine and vascular risk factors. The following studies take this vascular connection to clinical relevance in different ways.

Previous studies have investigated the combination of simvastatin and vitamin D for migraine prevention. Statins have anti-inflammatory properties and migraine can partially be understood as an inflammatory vascular phenomenon. Vitamin D and simvastatin were previously shown to be effective in a randomized trial; this study¹ investigated the combination of atorvastatin with nortriptyline for migraine prevention. Patients were excluded if they had a vitamin D deficiency.

This was a triple-blinded study with one control group, one placebo plus notriptyline group, and one atorvastatin plus nortiptyline group. The nortiptyline dosage was 25mg nightly, and the interventions were given for 24 weeks. The primary outcome was decrease in headache day frequency; secondary outcomes were severity and quality of life as measured by the Migraine-Specific Quality of Life Questionnaire (MSQ).

Migraine frequency was seen to be significantly improved after 24 weeks in the statin group; however severity was not significantly affected. Adverse effects were mild and overall no subjects discontinued due to the intervention. Quality of life was also seen to be better in the combination statin/nortriptyline group.

The results of this study are compelling enough to consider the addition of a tricyclic antidepressant (TCA) for a patient already on a statin or to start a statin (in the appropriate clinical setting) on a patient already on a TCA. The main limiting factor may be the hesitation to use a TCA medication in an older patient, where the anticholinergic effects may be less predictable.

Caffeine has a controversial place in the headache world. Many patients either use caffeine as a way to treat their migraine attacks, or avoid it completely as they are told it is a migraine trigger. Most headache specialists recommend the avoidance of excessive caffeine use (typically considered >150 mg daily) and tell their patients to be consistent about when they consume caffeine. The effect of caffeine on migraine likely is due to its vasoactive property, specifically that it is vasoconstrictive in nature. These vasoactive properties may also be why many studies investigating cerebrovascular reactivity have been inconclusive in the past.

The authors in this study² recruited patients with episodic migraine and divided them based on caffeine use. All subjects underwent transcranial Doppler testing at baseline and after 3 months, caffeine users were instructed to discontinue caffeine in the interim. Doppler testing looked for differences in BHI (breath holding index) of the bilateral posterior cerebral arteries (PCA), which is a standard at their institution. Subjects were only investigated if they were headache-free and had not used a migraine abortive medication in the previous 48 hours. Preventive medications were not controlled for.

Although the investigators recommended discontinuation of caffeine for the caffeine users, only 28% of that subgroup did discontinue. They then subdivided the group of caffeine users into those whose caffeine intake increased, decreased, or stayed the same. Transcranial Doppler testing was performed in all subgroups.

The investigators found a lower BHI-PCA, or decrease in vasodilatory function, in the subgroups that remained on caffeine. Those who stopped caffeine had improvement in this metric, showing the possible reversibility that discontinuation of caffeine can have. It remains unclear precisely how caffeine is vasoactive, and the effects may be via adenosine receptors, endothelial function, neurotransmitter production, or regulation of the autonomic nervous system. The long-term vascular effects of caffeine are unknown, but they do appear to be reversible after a 3 month period.

Migraine, and especially migraine with aura, is well known as a vascular risk factor. The presence of migraine increases the odds ratio of stroke, myocardial ischemia, deep vein thrombosis and other vascular events significantly. The American College of Obstetrics and Gynecology recommends avoiding the use of any estrogen containing medication in the presence of migraine, due to estrogen itself being a pro-thrombotic hormone.  The precise mechanism that leads to this increased risk is unknown.

This study investigated the connection between migraine and large artery atherosclerosis (LAA). This group observed 415 consecutive patients aged 18-54 who presented for a first time ischemic stroke (other neurovascular events, such as cerebral venous sinus thrombosis, subarachnoid hemorrhage with secondary ischemia and transient ischemic attacks, were excluded). Data regarding these patient’s risks factors was collected and analyzed including elevated body mass index (BMI), hypertension, diabetes, tobacco use, and hyperlipidemia.

All patients underwent magnetic resonance imaging (MRI), as well as either magnetic resonance angiography (MRA) or computed tomography angiography (CTA), and duplex ultrasound confirmed the images. Atherosclerosis was classified using a standardized system (ASCOD: atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection) that grades atheroslerotic lesions on a 0-3 scale.

The results may be considered counterintuitive. The presence of migraine was negatively associated with the presence of LAA: a history of migraine did not increase the risk of atherosclerosis. This was even the case when controlling for the traditional vascular risk factors. The authors theorize that likely the association between migraine and stroke and other vascular events is not related to atherosclerosis and may be due to other causes.

A genome-wide association study recently identified a specific polymorphism that was shared by migraine and coronary artery disease. But just like this study, the people with migraine had a negative association with coronary artery disease. If people with migraine do develop stroke or other vascular phenomena they typically present younger and healthier, and this may be why this negative correlation exists.

References

1. Sherafat M et al. The preventive effect of the combination of atorvastatin and nortriptyline in migraine-type headache: a randomized, triple-blind, placebo-controlled trial. Neurol Res. 2022 (Jan 17).
2. Gil Y-E et al. Effect of caffeine and caffeine cessation on cerebrovascular reactivity in patients with migraine. Headache. 2022;62(2):169-75 (Feb 3).
3. Gollion C et al. Migraine and large artery atherosclerosis in young adults with ischemic stroke. Headache. 2022;62(2):191-7 (Feb 5).

The theme of the articles this month is migraine and blood vessels. Migraine is a known risk factor for vascular events, it is a known vasodilatory phenomenon, and it is commonly treated with vasoconstrictive medications. Genetic studies are further elucidating the connection between migraine and vascular risk factors. The following studies take this vascular connection to clinical relevance in different ways.

Previous studies have investigated the combination of simvastatin and vitamin D for migraine prevention. Statins have anti-inflammatory properties and migraine can partially be understood as an inflammatory vascular phenomenon. Vitamin D and simvastatin were previously shown to be effective in a randomized trial; this study¹ investigated the combination of atorvastatin with nortriptyline for migraine prevention. Patients were excluded if they had a vitamin D deficiency.

This was a triple-blinded study with one control group, one placebo plus notriptyline group, and one atorvastatin plus nortiptyline group. The nortiptyline dosage was 25mg nightly, and the interventions were given for 24 weeks. The primary outcome was decrease in headache day frequency; secondary outcomes were severity and quality of life as measured by the Migraine-Specific Quality of Life Questionnaire (MSQ).

Migraine frequency was seen to be significantly improved after 24 weeks in the statin group; however severity was not significantly affected. Adverse effects were mild and overall no subjects discontinued due to the intervention. Quality of life was also seen to be better in the combination statin/nortriptyline group.

The results of this study are compelling enough to consider the addition of a tricyclic antidepressant (TCA) for a patient already on a statin or to start a statin (in the appropriate clinical setting) on a patient already on a TCA. The main limiting factor may be the hesitation to use a TCA medication in an older patient, where the anticholinergic effects may be less predictable.

Caffeine has a controversial place in the headache world. Many patients either use caffeine as a way to treat their migraine attacks, or avoid it completely as they are told it is a migraine trigger. Most headache specialists recommend the avoidance of excessive caffeine use (typically considered >150 mg daily) and tell their patients to be consistent about when they consume caffeine. The effect of caffeine on migraine likely is due to its vasoactive property, specifically that it is vasoconstrictive in nature. These vasoactive properties may also be why many studies investigating cerebrovascular reactivity have been inconclusive in the past.

The authors in this study² recruited patients with episodic migraine and divided them based on caffeine use. All subjects underwent transcranial Doppler testing at baseline and after 3 months, caffeine users were instructed to discontinue caffeine in the interim. Doppler testing looked for differences in BHI (breath holding index) of the bilateral posterior cerebral arteries (PCA), which is a standard at their institution. Subjects were only investigated if they were headache-free and had not used a migraine abortive medication in the previous 48 hours. Preventive medications were not controlled for.

Although the investigators recommended discontinuation of caffeine for the caffeine users, only 28% of that subgroup did discontinue. They then subdivided the group of caffeine users into those whose caffeine intake increased, decreased, or stayed the same. Transcranial Doppler testing was performed in all subgroups.

The investigators found a lower BHI-PCA, or decrease in vasodilatory function, in the subgroups that remained on caffeine. Those who stopped caffeine had improvement in this metric, showing the possible reversibility that discontinuation of caffeine can have. It remains unclear precisely how caffeine is vasoactive, and the effects may be via adenosine receptors, endothelial function, neurotransmitter production, or regulation of the autonomic nervous system. The long-term vascular effects of caffeine are unknown, but they do appear to be reversible after a 3 month period.

Migraine, and especially migraine with aura, is well known as a vascular risk factor. The presence of migraine increases the odds ratio of stroke, myocardial ischemia, deep vein thrombosis and other vascular events significantly. The American College of Obstetrics and Gynecology recommends avoiding the use of any estrogen containing medication in the presence of migraine, due to estrogen itself being a pro-thrombotic hormone.  The precise mechanism that leads to this increased risk is unknown.

This study investigated the connection between migraine and large artery atherosclerosis (LAA). This group observed 415 consecutive patients aged 18-54 who presented for a first time ischemic stroke (other neurovascular events, such as cerebral venous sinus thrombosis, subarachnoid hemorrhage with secondary ischemia and transient ischemic attacks, were excluded). Data regarding these patient’s risks factors was collected and analyzed including elevated body mass index (BMI), hypertension, diabetes, tobacco use, and hyperlipidemia.

All patients underwent magnetic resonance imaging (MRI), as well as either magnetic resonance angiography (MRA) or computed tomography angiography (CTA), and duplex ultrasound confirmed the images. Atherosclerosis was classified using a standardized system (ASCOD: atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection) that grades atheroslerotic lesions on a 0-3 scale.

The results may be considered counterintuitive. The presence of migraine was negatively associated with the presence of LAA: a history of migraine did not increase the risk of atherosclerosis. This was even the case when controlling for the traditional vascular risk factors. The authors theorize that likely the association between migraine and stroke and other vascular events is not related to atherosclerosis and may be due to other causes.

A genome-wide association study recently identified a specific polymorphism that was shared by migraine and coronary artery disease. But just like this study, the people with migraine had a negative association with coronary artery disease. If people with migraine do develop stroke or other vascular phenomena they typically present younger and healthier, and this may be why this negative correlation exists.

References

1. Sherafat M et al. The preventive effect of the combination of atorvastatin and nortriptyline in migraine-type headache: a randomized, triple-blind, placebo-controlled trial. Neurol Res. 2022 (Jan 17).
2. Gil Y-E et al. Effect of caffeine and caffeine cessation on cerebrovascular reactivity in patients with migraine. Headache. 2022;62(2):169-75 (Feb 3).
3. Gollion C et al. Migraine and large artery atherosclerosis in young adults with ischemic stroke. Headache. 2022;62(2):191-7 (Feb 5).