Thomas Berk, MD

Since 2018, the field of headache medicine has changed significantly. The development of calcitonin gene-related peptide (CGRP)-targeting preventive medications has led to the ability to treat migraine in a much more specific manner. The development of CGRP acute oral medications over the past 2 years has allowed people with migraine the ability to use well-tolerated, migraine-specific, abortive treatments. Triptan medications were the first migraine-specific acute treatments developed, some of which were nonoral, such as injectable sumatriptan and intranasal sumatriptan and zolmitriptan. The study by Lipton and colleagues assesses the safety and tolerability of a novel acute CGRP antagonist nonoral treatment, zavegepant.

In this double-blind, randomized, multicentered trial, nearly 2000 participants were enrolled with a diagnosis of episodic migraine with or without aura; they were excluded if they had previously used another CGRP antagonist, either an injectable or oral medication, before enrolling in this study. In addition to assessing migraine pain, participants were asked to identify their otherwise most bothersome symptom, specifically photophobia, phonophobia, or nausea. They were given a nasal spray to self-administer and were assessed at 15 minutes after treatment and at multiple additional intervals, up to 48 hours after the initial dosing. The primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after treatment onset. There were 17 secondary endpoints.

At 2 hours after treatment onset, a statistically significant group had achieved freedom from pain. The percentage, however, did remain somewhat low: 24%. Freedom from the most bothersome symptom was also statistically significant but was up to 40%. For 13 of the 17 endpoints, the results were also statistically significant, including pain relief at 2 hours, sustained pain relief at 2-24 hours and 48 hours, functional improvement, and freedom from photophobia and phonophobia. The most common adverse effects were poor taste, nasal discomfort, and throat irritation. No serious adverse events were noted.

Zavegepant has been FDA approved for the acute treatment of migraine on the basis of these data. This is a novel, well-tolerated, nonoral acute treatment for migraine. We can now treat patients with very severe nausea or more sudden-onset pain with a CGRP option that can potentially treat their attacks more quickly.

One early finding in many of the CGRP studies was that a certain subpopulation of migraine patients have a robust and rapid preventive response to monoclonal antibody treatment. Raffaelli and colleagues sought to evaluate potential characteristics that would better predict the efficacy of CGRP antagonist monoclonal antibodies for the prevention of migraine.

In this study, the definition of a superresponse to CGRP antagonist treatment was a >75% reduction in monthly headache days after 3 months of treatment. Nonresponse was defined as <25% reduction over this same period. This was a retrospective cohort study at one headache center in Berlin, Germany. A total of 260 patients were enrolled, all with a diagnosis of migraine and all given a preventive CGRP monoclonal antibody.

There was no significant difference between nonresponders and superresponders when compared for sex, age, or time since migraine diagnosis. Erenumab was the most commonly prescribed CGRP antagonist medication, but all CGRP antagonists were included. There was no significant difference when CGRP receptor or ligand targeting antibodies were compared. Nonresponders were seen as more likely to have chronic migraine and higher monthly headache day and monthly migraine day frequencies. Superresponders were seen to have more "typical" migraine characteristics, such as unilateral or localized migraines or migraines with pulsating/throbbing characteristics, as well as the presence of photophobia and nausea; however, this was not statistically significant. Of note, superresponders were also significantly more likely to report improvement of their acute migraine attacks with triptan medications as compared with nonresponders.

Patients with less frequent migraine attacks and more classic migraine attacks appear to be much more likely to respond quickly and effectively to many preventive options; this appears to be most robust with the CGRP antibody class. Although the reason for this robust response is not entirely clear, it would certainly be best for providers to consider the initiation of CGRP antagonist preventive treatment in patients with these characteristics.

The newest generation of migraine-specific medications targets either the inflammatory neurotransmitter CGRP or the CGRP receptor. Erenumab is a CGRP receptor blocker, whereas both fremanezumab and galcanezumab block the CGRP ligand. Erenumab has been associated with constipation and high blood pressure, whereas the other CGRP antagonist medications are not associated with these side effects. Whether this is due to the difference in mechanism of action, and specifically whether the antibodies block the CGRP receptor or are an antagonist, is under consideration. Schiano di Cola and colleagues specifically sought to investigate the subtle differences between these two subclasses of treatment.

Patients with high-frequency episodic and chronic migraine were enrolled in this retrospective study; 6 months of data were included. The researchers here specifically looked at efficacy after 1, 3, and 6 months of treatment. They examined, as a primary outcome, monthly headache and migraine days, and migraine disability as based on the Migraine Disability Assessment Scale (MIDAS) and Headache Impact Test (HIT-6) score. Concomitant analgesic medication consumption and response rate relative to baseline were also compared.

A total of 152 patients were enrolled, 68 with CGRP ligand-targeting therapy and 84 with CGRP receptor-blocking therapy. Medication overuse was present in 73% of patients. Although a significant improvement from baseline was noted in monthly headache days, monthly migraine days, severity, analgesic consumption, and disability, MIDAS scores were significantly lower in the CGRP ligand-blocking group compared with the CGRP receptor group at 1 and 3 months. Number of monthly migraine days was also lower in the CGRP ligand-blocking group, but only after 3 months. The other variables, including monthly headache days per month, analgesic consumption, severity, and disability, were not statistically different.

Adverse events were not compared between the two groups, even though this was a prior noted difference between these two classes of medications. Although there are some slight differences in efficacy, the majority of outcome metrics did not appear to be significantly different in either group. One would be hard-pressed to choose a specific CGRP medication on the basis of these data.

Since 2018, the field of headache medicine has changed significantly. The development of calcitonin gene-related peptide (CGRP)-targeting preventive medications has led to the ability to treat migraine in a much more specific manner. The development of CGRP acute oral medications over the past 2 years has allowed people with migraine the ability to use well-tolerated, migraine-specific, abortive treatments. Triptan medications were the first migraine-specific acute treatments developed, some of which were nonoral, such as injectable sumatriptan and intranasal sumatriptan and zolmitriptan. The study by Lipton and colleagues assesses the safety and tolerability of a novel acute CGRP antagonist nonoral treatment, zavegepant.

In this double-blind, randomized, multicentered trial, nearly 2000 participants were enrolled with a diagnosis of episodic migraine with or without aura; they were excluded if they had previously used another CGRP antagonist, either an injectable or oral medication, before enrolling in this study. In addition to assessing migraine pain, participants were asked to identify their otherwise most bothersome symptom, specifically photophobia, phonophobia, or nausea. They were given a nasal spray to self-administer and were assessed at 15 minutes after treatment and at multiple additional intervals, up to 48 hours after the initial dosing. The primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after treatment onset. There were 17 secondary endpoints.

At 2 hours after treatment onset, a statistically significant group had achieved freedom from pain. The percentage, however, did remain somewhat low: 24%. Freedom from the most bothersome symptom was also statistically significant but was up to 40%. For 13 of the 17 endpoints, the results were also statistically significant, including pain relief at 2 hours, sustained pain relief at 2-24 hours and 48 hours, functional improvement, and freedom from photophobia and phonophobia. The most common adverse effects were poor taste, nasal discomfort, and throat irritation. No serious adverse events were noted.

Zavegepant has been FDA approved for the acute treatment of migraine on the basis of these data. This is a novel, well-tolerated, nonoral acute treatment for migraine. We can now treat patients with very severe nausea or more sudden-onset pain with a CGRP option that can potentially treat their attacks more quickly.

One early finding in many of the CGRP studies was that a certain subpopulation of migraine patients have a robust and rapid preventive response to monoclonal antibody treatment. Raffaelli and colleagues sought to evaluate potential characteristics that would better predict the efficacy of CGRP antagonist monoclonal antibodies for the prevention of migraine.

In this study, the definition of a superresponse to CGRP antagonist treatment was a >75% reduction in monthly headache days after 3 months of treatment. Nonresponse was defined as <25% reduction over this same period. This was a retrospective cohort study at one headache center in Berlin, Germany. A total of 260 patients were enrolled, all with a diagnosis of migraine and all given a preventive CGRP monoclonal antibody.

There was no significant difference between nonresponders and superresponders when compared for sex, age, or time since migraine diagnosis. Erenumab was the most commonly prescribed CGRP antagonist medication, but all CGRP antagonists were included. There was no significant difference when CGRP receptor or ligand targeting antibodies were compared. Nonresponders were seen as more likely to have chronic migraine and higher monthly headache day and monthly migraine day frequencies. Superresponders were seen to have more "typical" migraine characteristics, such as unilateral or localized migraines or migraines with pulsating/throbbing characteristics, as well as the presence of photophobia and nausea; however, this was not statistically significant. Of note, superresponders were also significantly more likely to report improvement of their acute migraine attacks with triptan medications as compared with nonresponders.

Patients with less frequent migraine attacks and more classic migraine attacks appear to be much more likely to respond quickly and effectively to many preventive options; this appears to be most robust with the CGRP antibody class. Although the reason for this robust response is not entirely clear, it would certainly be best for providers to consider the initiation of CGRP antagonist preventive treatment in patients with these characteristics.

The newest generation of migraine-specific medications targets either the inflammatory neurotransmitter CGRP or the CGRP receptor. Erenumab is a CGRP receptor blocker, whereas both fremanezumab and galcanezumab block the CGRP ligand. Erenumab has been associated with constipation and high blood pressure, whereas the other CGRP antagonist medications are not associated with these side effects. Whether this is due to the difference in mechanism of action, and specifically whether the antibodies block the CGRP receptor or are an antagonist, is under consideration. Schiano di Cola and colleagues specifically sought to investigate the subtle differences between these two subclasses of treatment.

Patients with high-frequency episodic and chronic migraine were enrolled in this retrospective study; 6 months of data were included. The researchers here specifically looked at efficacy after 1, 3, and 6 months of treatment. They examined, as a primary outcome, monthly headache and migraine days, and migraine disability as based on the Migraine Disability Assessment Scale (MIDAS) and Headache Impact Test (HIT-6) score. Concomitant analgesic medication consumption and response rate relative to baseline were also compared.

A total of 152 patients were enrolled, 68 with CGRP ligand-targeting therapy and 84 with CGRP receptor-blocking therapy. Medication overuse was present in 73% of patients. Although a significant improvement from baseline was noted in monthly headache days, monthly migraine days, severity, analgesic consumption, and disability, MIDAS scores were significantly lower in the CGRP ligand-blocking group compared with the CGRP receptor group at 1 and 3 months. Number of monthly migraine days was also lower in the CGRP ligand-blocking group, but only after 3 months. The other variables, including monthly headache days per month, analgesic consumption, severity, and disability, were not statistically different.

Adverse events were not compared between the two groups, even though this was a prior noted difference between these two classes of medications. Although there are some slight differences in efficacy, the majority of outcome metrics did not appear to be significantly different in either group. One would be hard-pressed to choose a specific CGRP medication on the basis of these data.

Since 2018, the field of headache medicine has changed significantly. The development of calcitonin gene-related peptide (CGRP)-targeting preventive medications has led to the ability to treat migraine in a much more specific manner. The development of CGRP acute oral medications over the past 2 years has allowed people with migraine the ability to use well-tolerated, migraine-specific, abortive treatments. Triptan medications were the first migraine-specific acute treatments developed, some of which were nonoral, such as injectable sumatriptan and intranasal sumatriptan and zolmitriptan. The study by Lipton and colleagues assesses the safety and tolerability of a novel acute CGRP antagonist nonoral treatment, zavegepant.

In this double-blind, randomized, multicentered trial, nearly 2000 participants were enrolled with a diagnosis of episodic migraine with or without aura; they were excluded if they had previously used another CGRP antagonist, either an injectable or oral medication, before enrolling in this study. In addition to assessing migraine pain, participants were asked to identify their otherwise most bothersome symptom, specifically photophobia, phonophobia, or nausea. They were given a nasal spray to self-administer and were assessed at 15 minutes after treatment and at multiple additional intervals, up to 48 hours after the initial dosing. The primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after treatment onset. There were 17 secondary endpoints.

At 2 hours after treatment onset, a statistically significant group had achieved freedom from pain. The percentage, however, did remain somewhat low: 24%. Freedom from the most bothersome symptom was also statistically significant but was up to 40%. For 13 of the 17 endpoints, the results were also statistically significant, including pain relief at 2 hours, sustained pain relief at 2-24 hours and 48 hours, functional improvement, and freedom from photophobia and phonophobia. The most common adverse effects were poor taste, nasal discomfort, and throat irritation. No serious adverse events were noted.

Zavegepant has been FDA approved for the acute treatment of migraine on the basis of these data. This is a novel, well-tolerated, nonoral acute treatment for migraine. We can now treat patients with very severe nausea or more sudden-onset pain with a CGRP option that can potentially treat their attacks more quickly.

One early finding in many of the CGRP studies was that a certain subpopulation of migraine patients have a robust and rapid preventive response to monoclonal antibody treatment. Raffaelli and colleagues sought to evaluate potential characteristics that would better predict the efficacy of CGRP antagonist monoclonal antibodies for the prevention of migraine.

In this study, the definition of a superresponse to CGRP antagonist treatment was a >75% reduction in monthly headache days after 3 months of treatment. Nonresponse was defined as <25% reduction over this same period. This was a retrospective cohort study at one headache center in Berlin, Germany. A total of 260 patients were enrolled, all with a diagnosis of migraine and all given a preventive CGRP monoclonal antibody.

There was no significant difference between nonresponders and superresponders when compared for sex, age, or time since migraine diagnosis. Erenumab was the most commonly prescribed CGRP antagonist medication, but all CGRP antagonists were included. There was no significant difference when CGRP receptor or ligand targeting antibodies were compared. Nonresponders were seen as more likely to have chronic migraine and higher monthly headache day and monthly migraine day frequencies. Superresponders were seen to have more "typical" migraine characteristics, such as unilateral or localized migraines or migraines with pulsating/throbbing characteristics, as well as the presence of photophobia and nausea; however, this was not statistically significant. Of note, superresponders were also significantly more likely to report improvement of their acute migraine attacks with triptan medications as compared with nonresponders.

Patients with less frequent migraine attacks and more classic migraine attacks appear to be much more likely to respond quickly and effectively to many preventive options; this appears to be most robust with the CGRP antibody class. Although the reason for this robust response is not entirely clear, it would certainly be best for providers to consider the initiation of CGRP antagonist preventive treatment in patients with these characteristics.

The newest generation of migraine-specific medications targets either the inflammatory neurotransmitter CGRP or the CGRP receptor. Erenumab is a CGRP receptor blocker, whereas both fremanezumab and galcanezumab block the CGRP ligand. Erenumab has been associated with constipation and high blood pressure, whereas the other CGRP antagonist medications are not associated with these side effects. Whether this is due to the difference in mechanism of action, and specifically whether the antibodies block the CGRP receptor or are an antagonist, is under consideration. Schiano di Cola and colleagues specifically sought to investigate the subtle differences between these two subclasses of treatment.

Patients with high-frequency episodic and chronic migraine were enrolled in this retrospective study; 6 months of data were included. The researchers here specifically looked at efficacy after 1, 3, and 6 months of treatment. They examined, as a primary outcome, monthly headache and migraine days, and migraine disability as based on the Migraine Disability Assessment Scale (MIDAS) and Headache Impact Test (HIT-6) score. Concomitant analgesic medication consumption and response rate relative to baseline were also compared.

A total of 152 patients were enrolled, 68 with CGRP ligand-targeting therapy and 84 with CGRP receptor-blocking therapy. Medication overuse was present in 73% of patients. Although a significant improvement from baseline was noted in monthly headache days, monthly migraine days, severity, analgesic consumption, and disability, MIDAS scores were significantly lower in the CGRP ligand-blocking group compared with the CGRP receptor group at 1 and 3 months. Number of monthly migraine days was also lower in the CGRP ligand-blocking group, but only after 3 months. The other variables, including monthly headache days per month, analgesic consumption, severity, and disability, were not statistically different.

Adverse events were not compared between the two groups, even though this was a prior noted difference between these two classes of medications. Although there are some slight differences in efficacy, the majority of outcome metrics did not appear to be significantly different in either group. One would be hard-pressed to choose a specific CGRP medication on the basis of these data.

Migraine is the single most common neurologic condition worldwide and is particularly predominant among women during their reproductive years. There are many important questions that arise when women with migraine start pregnancy planning, most of which involve acute and preventive medication use and red flags for headache in pregnancy. As of yet, there have been no large-scale epidemiologic studies looking at pregnancy risks for people with migraine. Specifically, if migraine is a statistically significant vascular risk factor, does it incur additional risks in pregnancy, which is a prothrombotic state?

Purdue-Smithe and colleagues reviewed a large longitudinal study, the Nurses' Health Study II, a biennial questionnaire that took place from 1989 to 2009 and in which the questions changed yearly. Migraine was assessed on the basis of whether the participants had been given a diagnosis of migraine (or migraine with aura) by a medical professional; outcomes of pregnancy were also determined on the basis of participants providing a comprehensive reproductive history, including pregnancy outcome, gestation length, birth weight, and pregnancy complications.

A total of 2234 participants were included in this study; 1989 of them reported a history of physician-diagnosed migraine, with 1078 classified as having migraine with aura and 1156 classified as having migraine without aura. Adverse pregnancy outcomes more frequently affect multiple gestations; a sensitivity analysis was conducted to restrict the data here to singleton pregnancies. Individuals with migraine were more likely to report a history of infertility, obesity, and oral contraceptive use than were those without migraine. A history of migraine was associated with greater risks for preterm delivery, gestational hypertension, and preeclampsia; however, it was not associated with gestational diabetes or low birth weight. Theses outcomes were independent of age during pregnancy.

This wide-ranging study does allow us to better discuss potential risks for our patients with migraine. In addition to discussions about estrogen contraception use and stroke risk, it is worth taking a minute to discuss potential pregnancy risks that are more associated with migraine. This will allow our patients to be better aligned with their obstetricians, who can determine if other factors may further elevate these risks. Highlighting areas of risk can allow for better recognition of these potential negative outcomes much earlier.

There is a well-known association between calcitonin gene related peptide (CGRP) and migraine, but what is less understood is how CGRP affects specific features of migraine. CGRP is found in the gut and is therefore thought to have an association with migraine-related nausea, but other migraine associated symptoms, such as photophobia, are less well understood. Schiano di Cola and colleagues sought to determine the effectiveness of galcanezumab specifically in regard to ictal photophobia pain.

They enrolled 80 patients with either high-frequency episodic migraine or chronic migraine who were taking galcanezumab; 47 were included as expressing photophobia as a significant migraine-associated symptom at baseline. The patients were evaluated after 3 months and again after 6 months of treatment. They were asked to record headache days, migraine days, consumption of acute medication, and pain intensity. Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores were also followed up. Improvement with photophobia was determined as either no improvement, slight improvement, moderate improvement, or high improvement. After 3 months of treatment, 68% of patients reported a significant improvement in ictal photophobia, 11 patients reported moderate improvement, and six patients a slight improvement. Two patients reported improvement only after 6 months of treatment.

Post hoc analysis revealed photophobia improvement was not statistically significant in patients who are considered responders to galcanezumab compared with nonresponders. Photophobia improvement was most apparent in patients who were considered triptan responders. It was also more common in people with high-frequency episodic migraine rather than in those with chronic migraine. Migraine disability scores were noted to be higher in participants who did not notice photophobia improvement.

This study highlights the necessity to focus on factors beyond simply migraine frequency and severity. Many of the most disabling characteristics of migraine may not be related to pain directly. More research is currently being undertaken regarding the mechanisms that underlie photophobia in migraine. Ultimately, this will lead to more focused treatment for patients who may have other disabling symptoms associated with their headache disorder.

So much has already been written regarding the association between migraine and vascular risk factors. Migraine is considered a statistically significant risk factor for stroke specifically; migraine with aura has been noted to have a stronger association. Acarsoy and colleagues longitudinally examined the risk for stroke for any cause as it relates to migraine in both middle-aged and older populations.

This prospective population-based trial was embedded in a large Netherlands-based study among middle-aged and older community residents of Rotterdam. A total of 7266 participants were interviewed; 6925 participants had both migraine and stroke information available. Migraine was assessed with a questionnaire based on The International Classification of Headache Disorders (ICHD) criteria. Stroke status was assessed based on World Health Organization criteria and verified from medical records. Participants in this study were continuously monitored for incident stroke through an automatic linking of the study database to national health database files.

Other risk factors selected were body mass index (BMI), smoking history, education level, and physical activity, as well as any history of coronary artery disease, hypertension, or hypercholesterolemia. The average age of the study population was 65.7 years. Among participants with migraine, 20% had a history of migraine with aura. Among all stroke events, 84% were ischemic, and 11% were hemorrhagic. There was no significant difference in stroke-free survival probability between people with and without migraine. Although there was an association between migraine and stroke risk in middle and older ages, this was not statistically significant.

This study highlights, the appropriateness of educating migraine patients in regard to stroke risk. Specifically, patients should not be overly concerned regarding their migraine history. However, this study suggests that there does remain an association, but that this still remains somewhat unclear and less statistically significant in relation to age. When weighing vascular risk factors, more appropriate risks, such as elevated BMI, smoking history, hypertension, and the like should be highlighted, much more so than a history of migraine.

Migraine is the single most common neurologic condition worldwide and is particularly predominant among women during their reproductive years. There are many important questions that arise when women with migraine start pregnancy planning, most of which involve acute and preventive medication use and red flags for headache in pregnancy. As of yet, there have been no large-scale epidemiologic studies looking at pregnancy risks for people with migraine. Specifically, if migraine is a statistically significant vascular risk factor, does it incur additional risks in pregnancy, which is a prothrombotic state?

Purdue-Smithe and colleagues reviewed a large longitudinal study, the Nurses' Health Study II, a biennial questionnaire that took place from 1989 to 2009 and in which the questions changed yearly. Migraine was assessed on the basis of whether the participants had been given a diagnosis of migraine (or migraine with aura) by a medical professional; outcomes of pregnancy were also determined on the basis of participants providing a comprehensive reproductive history, including pregnancy outcome, gestation length, birth weight, and pregnancy complications.

A total of 2234 participants were included in this study; 1989 of them reported a history of physician-diagnosed migraine, with 1078 classified as having migraine with aura and 1156 classified as having migraine without aura. Adverse pregnancy outcomes more frequently affect multiple gestations; a sensitivity analysis was conducted to restrict the data here to singleton pregnancies. Individuals with migraine were more likely to report a history of infertility, obesity, and oral contraceptive use than were those without migraine. A history of migraine was associated with greater risks for preterm delivery, gestational hypertension, and preeclampsia; however, it was not associated with gestational diabetes or low birth weight. Theses outcomes were independent of age during pregnancy.

This wide-ranging study does allow us to better discuss potential risks for our patients with migraine. In addition to discussions about estrogen contraception use and stroke risk, it is worth taking a minute to discuss potential pregnancy risks that are more associated with migraine. This will allow our patients to be better aligned with their obstetricians, who can determine if other factors may further elevate these risks. Highlighting areas of risk can allow for better recognition of these potential negative outcomes much earlier.

There is a well-known association between calcitonin gene related peptide (CGRP) and migraine, but what is less understood is how CGRP affects specific features of migraine. CGRP is found in the gut and is therefore thought to have an association with migraine-related nausea, but other migraine associated symptoms, such as photophobia, are less well understood. Schiano di Cola and colleagues sought to determine the effectiveness of galcanezumab specifically in regard to ictal photophobia pain.

They enrolled 80 patients with either high-frequency episodic migraine or chronic migraine who were taking galcanezumab; 47 were included as expressing photophobia as a significant migraine-associated symptom at baseline. The patients were evaluated after 3 months and again after 6 months of treatment. They were asked to record headache days, migraine days, consumption of acute medication, and pain intensity. Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores were also followed up. Improvement with photophobia was determined as either no improvement, slight improvement, moderate improvement, or high improvement. After 3 months of treatment, 68% of patients reported a significant improvement in ictal photophobia, 11 patients reported moderate improvement, and six patients a slight improvement. Two patients reported improvement only after 6 months of treatment.

Post hoc analysis revealed photophobia improvement was not statistically significant in patients who are considered responders to galcanezumab compared with nonresponders. Photophobia improvement was most apparent in patients who were considered triptan responders. It was also more common in people with high-frequency episodic migraine rather than in those with chronic migraine. Migraine disability scores were noted to be higher in participants who did not notice photophobia improvement.

This study highlights the necessity to focus on factors beyond simply migraine frequency and severity. Many of the most disabling characteristics of migraine may not be related to pain directly. More research is currently being undertaken regarding the mechanisms that underlie photophobia in migraine. Ultimately, this will lead to more focused treatment for patients who may have other disabling symptoms associated with their headache disorder.

So much has already been written regarding the association between migraine and vascular risk factors. Migraine is considered a statistically significant risk factor for stroke specifically; migraine with aura has been noted to have a stronger association. Acarsoy and colleagues longitudinally examined the risk for stroke for any cause as it relates to migraine in both middle-aged and older populations.

This prospective population-based trial was embedded in a large Netherlands-based study among middle-aged and older community residents of Rotterdam. A total of 7266 participants were interviewed; 6925 participants had both migraine and stroke information available. Migraine was assessed with a questionnaire based on The International Classification of Headache Disorders (ICHD) criteria. Stroke status was assessed based on World Health Organization criteria and verified from medical records. Participants in this study were continuously monitored for incident stroke through an automatic linking of the study database to national health database files.

Other risk factors selected were body mass index (BMI), smoking history, education level, and physical activity, as well as any history of coronary artery disease, hypertension, or hypercholesterolemia. The average age of the study population was 65.7 years. Among participants with migraine, 20% had a history of migraine with aura. Among all stroke events, 84% were ischemic, and 11% were hemorrhagic. There was no significant difference in stroke-free survival probability between people with and without migraine. Although there was an association between migraine and stroke risk in middle and older ages, this was not statistically significant.

This study highlights, the appropriateness of educating migraine patients in regard to stroke risk. Specifically, patients should not be overly concerned regarding their migraine history. However, this study suggests that there does remain an association, but that this still remains somewhat unclear and less statistically significant in relation to age. When weighing vascular risk factors, more appropriate risks, such as elevated BMI, smoking history, hypertension, and the like should be highlighted, much more so than a history of migraine.

Migraine is the single most common neurologic condition worldwide and is particularly predominant among women during their reproductive years. There are many important questions that arise when women with migraine start pregnancy planning, most of which involve acute and preventive medication use and red flags for headache in pregnancy. As of yet, there have been no large-scale epidemiologic studies looking at pregnancy risks for people with migraine. Specifically, if migraine is a statistically significant vascular risk factor, does it incur additional risks in pregnancy, which is a prothrombotic state?

Purdue-Smithe and colleagues reviewed a large longitudinal study, the Nurses' Health Study II, a biennial questionnaire that took place from 1989 to 2009 and in which the questions changed yearly. Migraine was assessed on the basis of whether the participants had been given a diagnosis of migraine (or migraine with aura) by a medical professional; outcomes of pregnancy were also determined on the basis of participants providing a comprehensive reproductive history, including pregnancy outcome, gestation length, birth weight, and pregnancy complications.

A total of 2234 participants were included in this study; 1989 of them reported a history of physician-diagnosed migraine, with 1078 classified as having migraine with aura and 1156 classified as having migraine without aura. Adverse pregnancy outcomes more frequently affect multiple gestations; a sensitivity analysis was conducted to restrict the data here to singleton pregnancies. Individuals with migraine were more likely to report a history of infertility, obesity, and oral contraceptive use than were those without migraine. A history of migraine was associated with greater risks for preterm delivery, gestational hypertension, and preeclampsia; however, it was not associated with gestational diabetes or low birth weight. Theses outcomes were independent of age during pregnancy.

This wide-ranging study does allow us to better discuss potential risks for our patients with migraine. In addition to discussions about estrogen contraception use and stroke risk, it is worth taking a minute to discuss potential pregnancy risks that are more associated with migraine. This will allow our patients to be better aligned with their obstetricians, who can determine if other factors may further elevate these risks. Highlighting areas of risk can allow for better recognition of these potential negative outcomes much earlier.

There is a well-known association between calcitonin gene related peptide (CGRP) and migraine, but what is less understood is how CGRP affects specific features of migraine. CGRP is found in the gut and is therefore thought to have an association with migraine-related nausea, but other migraine associated symptoms, such as photophobia, are less well understood. Schiano di Cola and colleagues sought to determine the effectiveness of galcanezumab specifically in regard to ictal photophobia pain.

They enrolled 80 patients with either high-frequency episodic migraine or chronic migraine who were taking galcanezumab; 47 were included as expressing photophobia as a significant migraine-associated symptom at baseline. The patients were evaluated after 3 months and again after 6 months of treatment. They were asked to record headache days, migraine days, consumption of acute medication, and pain intensity. Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores were also followed up. Improvement with photophobia was determined as either no improvement, slight improvement, moderate improvement, or high improvement. After 3 months of treatment, 68% of patients reported a significant improvement in ictal photophobia, 11 patients reported moderate improvement, and six patients a slight improvement. Two patients reported improvement only after 6 months of treatment.

Post hoc analysis revealed photophobia improvement was not statistically significant in patients who are considered responders to galcanezumab compared with nonresponders. Photophobia improvement was most apparent in patients who were considered triptan responders. It was also more common in people with high-frequency episodic migraine rather than in those with chronic migraine. Migraine disability scores were noted to be higher in participants who did not notice photophobia improvement.

This study highlights the necessity to focus on factors beyond simply migraine frequency and severity. Many of the most disabling characteristics of migraine may not be related to pain directly. More research is currently being undertaken regarding the mechanisms that underlie photophobia in migraine. Ultimately, this will lead to more focused treatment for patients who may have other disabling symptoms associated with their headache disorder.

So much has already been written regarding the association between migraine and vascular risk factors. Migraine is considered a statistically significant risk factor for stroke specifically; migraine with aura has been noted to have a stronger association. Acarsoy and colleagues longitudinally examined the risk for stroke for any cause as it relates to migraine in both middle-aged and older populations.

This prospective population-based trial was embedded in a large Netherlands-based study among middle-aged and older community residents of Rotterdam. A total of 7266 participants were interviewed; 6925 participants had both migraine and stroke information available. Migraine was assessed with a questionnaire based on The International Classification of Headache Disorders (ICHD) criteria. Stroke status was assessed based on World Health Organization criteria and verified from medical records. Participants in this study were continuously monitored for incident stroke through an automatic linking of the study database to national health database files.

Other risk factors selected were body mass index (BMI), smoking history, education level, and physical activity, as well as any history of coronary artery disease, hypertension, or hypercholesterolemia. The average age of the study population was 65.7 years. Among participants with migraine, 20% had a history of migraine with aura. Among all stroke events, 84% were ischemic, and 11% were hemorrhagic. There was no significant difference in stroke-free survival probability between people with and without migraine. Although there was an association between migraine and stroke risk in middle and older ages, this was not statistically significant.

This study highlights, the appropriateness of educating migraine patients in regard to stroke risk. Specifically, patients should not be overly concerned regarding their migraine history. However, this study suggests that there does remain an association, but that this still remains somewhat unclear and less statistically significant in relation to age. When weighing vascular risk factors, more appropriate risks, such as elevated BMI, smoking history, hypertension, and the like should be highlighted, much more so than a history of migraine.

Migraine is a condition that particularly affects the population of reproductive-aged women. A significant amount of the literature discusses the effect of estrogen as a migraine trigger and specifically migraine with aura as a vascular risk factor. One topic that is not discussed in the literature is whether migraine could be a risk for miscarriage, also known as spontaneous abortion. The National Institutes of Health (NIH)-funded study by Crowe and colleagues looks at this risk, especially as it relates to the frequency of migraine, the use of acute migraine medications, and caffeine intake.

This was a broad study, including nearly 2000 patients with migraine, and was a continuation of a prior ongoing NIH-funded epidemiologic study. The initial study enrolled nearly 8000 participants, all of whom were women aged 21-45 years, were in a pregnancy planning stage, and were followed for up to 12 months or until a reported pregnancy. Questionnaires were given preconception, as well as early in pregnancy (defined as 8-9 weeks' gestation), and late in pregnancy (defined as 32 weeks' gestation).

During this study 19% of pregnancies ended in spontaneous abortion. A history of migraine preconception was not associated with spontaneous abortion risk on the basis of hazard ratios. There was a slight risk in those taking some migraine medication daily, either prophylactic or analgesic. Frequency of migraine itself was not noted as a risk for spontaneous abortion.

It is necessary that this important study be followed by further investigations looking at specific medication classes and their potential risk for spontaneous abortion. Migraine itself does not appear to be a risk for miscarriage; however, there remains the possibility that some preventive or acute medications may elevate this risk. At the current moment, there is not enough information to draw a conclusion. All clinicians who treat people with migraine, particularly women who are in their reproductive years, should continue to have conversations regarding pregnancy planning and the adjustment of both preventive and acute medications prior to conception.

Neck pain is a common comorbidity of both chronic and acute migraine, and botulinum toxin is a US Food and Drug Administration–approved treatment both for chronic migraine and certain painful neck conditions, including cervical dystonia. Migraine itself can be a disabling condition; when migraine is combined with other painful comorbidities the likelihood of disability becomes increased significantly. The standard PREEMPT protocol for botulinum toxin injection in chronic migraine of 155 units includes a number of injections in the trapezius and cervical paraspinal muscles. Many clinicians will give additional injections into these muscles and other areas around the neck, specifically targeting areas of neck and shoulder spasm and tenderness. Onan and colleagues investigated the quality of life and disability scores of patients who received these additional injections.

This was an open study, in which participants were given an additional 30 units of botulinum toxin into the general neck areas in a follow-the-pain protocol. The authors, used as a primary outcome, the reduction in the Migraine Disability Assessment (MIDAS) and Neck Disability Index (NDI) scores at 4 weeks and 3 months. The secondary outcome was the Headache Impact Test (HIT-6) score. An objective assessment of neck mobility or a quantification of trigger points were not calculated.

All scores, both the primary and secondary outcomes, were significantly decreased, and quality of life was also noted to be significantly improved with these additional injections. Most clinicians receive a 200-unit vial of botulinum toxin for each of their chronic migraine protocol injections. There is a growing body of evidence to argue that the additional units of botulinum toxin significantly improve outcomes, both regarding headache and neck pain. This study argues for delivering these additional injections of botulinum toxin, especially when neck pain is more prominent.

Much has been written about diet triggers and migraine recently. There has been some evidence for specific diet changes, ie, the addition of foods or nutrients that can be helpful or preventive for migraine. There is some evidence for the addition of omega-3 fatty acids. Huang and He investigated the effect of a high fiber diet on migraine frequency and severity.

This was a cross-sectional study involving data collected from the NIH/Centers for Disease Control and Prevention–sponsored National Health and Nutrition Examination Survey trial from 1999 to 2004. In the studied population, severe headache and migraine was present in approximately 20%, and dietary fiber intake was delineated on the basis of whether it was more than or less than 100 g/d. This study assessed dietary intake of fiber, via a 24-hour dietary recall that was conducted by trained interviewers during two interviews conducted over the course of 2 years.

A total of 12,000 participants were included in the study. There was a significant decrease in migraine severity between those with a higher and lower dietary fiber intake. The incidence of severe headache or migraine, as defined by frequency and severity, decreased in participants who had a dietary fiber intake > 100 g/d. The authors found that for every 10 g/d increase in dietary fiber intake, the prevalence of severe headache or migraine decreased by approximately 11%.

Although much has been written about the association between diet and migraine, most of the literature focuses on the avoidance of specific dietary triggers. A different consideration now exists, one that will likely increase compliance with dietary recommendations. Specifically, people treating patients with migraine can make recommendations regarding dietary changes that focus on adding specific healthy foods or other changes that can actually be associated with improving migraine frequency long-term. Recommending healthy fats, such as omega-3 fatty acids, and high fiber should be done for nearly all patients with migraine.

Migraine is a condition that particularly affects the population of reproductive-aged women. A significant amount of the literature discusses the effect of estrogen as a migraine trigger and specifically migraine with aura as a vascular risk factor. One topic that is not discussed in the literature is whether migraine could be a risk for miscarriage, also known as spontaneous abortion. The National Institutes of Health (NIH)-funded study by Crowe and colleagues looks at this risk, especially as it relates to the frequency of migraine, the use of acute migraine medications, and caffeine intake.

This was a broad study, including nearly 2000 patients with migraine, and was a continuation of a prior ongoing NIH-funded epidemiologic study. The initial study enrolled nearly 8000 participants, all of whom were women aged 21-45 years, were in a pregnancy planning stage, and were followed for up to 12 months or until a reported pregnancy. Questionnaires were given preconception, as well as early in pregnancy (defined as 8-9 weeks' gestation), and late in pregnancy (defined as 32 weeks' gestation).

During this study 19% of pregnancies ended in spontaneous abortion. A history of migraine preconception was not associated with spontaneous abortion risk on the basis of hazard ratios. There was a slight risk in those taking some migraine medication daily, either prophylactic or analgesic. Frequency of migraine itself was not noted as a risk for spontaneous abortion.

It is necessary that this important study be followed by further investigations looking at specific medication classes and their potential risk for spontaneous abortion. Migraine itself does not appear to be a risk for miscarriage; however, there remains the possibility that some preventive or acute medications may elevate this risk. At the current moment, there is not enough information to draw a conclusion. All clinicians who treat people with migraine, particularly women who are in their reproductive years, should continue to have conversations regarding pregnancy planning and the adjustment of both preventive and acute medications prior to conception.

Neck pain is a common comorbidity of both chronic and acute migraine, and botulinum toxin is a US Food and Drug Administration–approved treatment both for chronic migraine and certain painful neck conditions, including cervical dystonia. Migraine itself can be a disabling condition; when migraine is combined with other painful comorbidities the likelihood of disability becomes increased significantly. The standard PREEMPT protocol for botulinum toxin injection in chronic migraine of 155 units includes a number of injections in the trapezius and cervical paraspinal muscles. Many clinicians will give additional injections into these muscles and other areas around the neck, specifically targeting areas of neck and shoulder spasm and tenderness. Onan and colleagues investigated the quality of life and disability scores of patients who received these additional injections.

This was an open study, in which participants were given an additional 30 units of botulinum toxin into the general neck areas in a follow-the-pain protocol. The authors, used as a primary outcome, the reduction in the Migraine Disability Assessment (MIDAS) and Neck Disability Index (NDI) scores at 4 weeks and 3 months. The secondary outcome was the Headache Impact Test (HIT-6) score. An objective assessment of neck mobility or a quantification of trigger points were not calculated.

All scores, both the primary and secondary outcomes, were significantly decreased, and quality of life was also noted to be significantly improved with these additional injections. Most clinicians receive a 200-unit vial of botulinum toxin for each of their chronic migraine protocol injections. There is a growing body of evidence to argue that the additional units of botulinum toxin significantly improve outcomes, both regarding headache and neck pain. This study argues for delivering these additional injections of botulinum toxin, especially when neck pain is more prominent.

Much has been written about diet triggers and migraine recently. There has been some evidence for specific diet changes, ie, the addition of foods or nutrients that can be helpful or preventive for migraine. There is some evidence for the addition of omega-3 fatty acids. Huang and He investigated the effect of a high fiber diet on migraine frequency and severity.

This was a cross-sectional study involving data collected from the NIH/Centers for Disease Control and Prevention–sponsored National Health and Nutrition Examination Survey trial from 1999 to 2004. In the studied population, severe headache and migraine was present in approximately 20%, and dietary fiber intake was delineated on the basis of whether it was more than or less than 100 g/d. This study assessed dietary intake of fiber, via a 24-hour dietary recall that was conducted by trained interviewers during two interviews conducted over the course of 2 years.

A total of 12,000 participants were included in the study. There was a significant decrease in migraine severity between those with a higher and lower dietary fiber intake. The incidence of severe headache or migraine, as defined by frequency and severity, decreased in participants who had a dietary fiber intake > 100 g/d. The authors found that for every 10 g/d increase in dietary fiber intake, the prevalence of severe headache or migraine decreased by approximately 11%.

Although much has been written about the association between diet and migraine, most of the literature focuses on the avoidance of specific dietary triggers. A different consideration now exists, one that will likely increase compliance with dietary recommendations. Specifically, people treating patients with migraine can make recommendations regarding dietary changes that focus on adding specific healthy foods or other changes that can actually be associated with improving migraine frequency long-term. Recommending healthy fats, such as omega-3 fatty acids, and high fiber should be done for nearly all patients with migraine.

Migraine is a condition that particularly affects the population of reproductive-aged women. A significant amount of the literature discusses the effect of estrogen as a migraine trigger and specifically migraine with aura as a vascular risk factor. One topic that is not discussed in the literature is whether migraine could be a risk for miscarriage, also known as spontaneous abortion. The National Institutes of Health (NIH)-funded study by Crowe and colleagues looks at this risk, especially as it relates to the frequency of migraine, the use of acute migraine medications, and caffeine intake.

This was a broad study, including nearly 2000 patients with migraine, and was a continuation of a prior ongoing NIH-funded epidemiologic study. The initial study enrolled nearly 8000 participants, all of whom were women aged 21-45 years, were in a pregnancy planning stage, and were followed for up to 12 months or until a reported pregnancy. Questionnaires were given preconception, as well as early in pregnancy (defined as 8-9 weeks' gestation), and late in pregnancy (defined as 32 weeks' gestation).

During this study 19% of pregnancies ended in spontaneous abortion. A history of migraine preconception was not associated with spontaneous abortion risk on the basis of hazard ratios. There was a slight risk in those taking some migraine medication daily, either prophylactic or analgesic. Frequency of migraine itself was not noted as a risk for spontaneous abortion.

It is necessary that this important study be followed by further investigations looking at specific medication classes and their potential risk for spontaneous abortion. Migraine itself does not appear to be a risk for miscarriage; however, there remains the possibility that some preventive or acute medications may elevate this risk. At the current moment, there is not enough information to draw a conclusion. All clinicians who treat people with migraine, particularly women who are in their reproductive years, should continue to have conversations regarding pregnancy planning and the adjustment of both preventive and acute medications prior to conception.

Neck pain is a common comorbidity of both chronic and acute migraine, and botulinum toxin is a US Food and Drug Administration–approved treatment both for chronic migraine and certain painful neck conditions, including cervical dystonia. Migraine itself can be a disabling condition; when migraine is combined with other painful comorbidities the likelihood of disability becomes increased significantly. The standard PREEMPT protocol for botulinum toxin injection in chronic migraine of 155 units includes a number of injections in the trapezius and cervical paraspinal muscles. Many clinicians will give additional injections into these muscles and other areas around the neck, specifically targeting areas of neck and shoulder spasm and tenderness. Onan and colleagues investigated the quality of life and disability scores of patients who received these additional injections.

This was an open study, in which participants were given an additional 30 units of botulinum toxin into the general neck areas in a follow-the-pain protocol. The authors, used as a primary outcome, the reduction in the Migraine Disability Assessment (MIDAS) and Neck Disability Index (NDI) scores at 4 weeks and 3 months. The secondary outcome was the Headache Impact Test (HIT-6) score. An objective assessment of neck mobility or a quantification of trigger points were not calculated.

All scores, both the primary and secondary outcomes, were significantly decreased, and quality of life was also noted to be significantly improved with these additional injections. Most clinicians receive a 200-unit vial of botulinum toxin for each of their chronic migraine protocol injections. There is a growing body of evidence to argue that the additional units of botulinum toxin significantly improve outcomes, both regarding headache and neck pain. This study argues for delivering these additional injections of botulinum toxin, especially when neck pain is more prominent.

Much has been written about diet triggers and migraine recently. There has been some evidence for specific diet changes, ie, the addition of foods or nutrients that can be helpful or preventive for migraine. There is some evidence for the addition of omega-3 fatty acids. Huang and He investigated the effect of a high fiber diet on migraine frequency and severity.

This was a cross-sectional study involving data collected from the NIH/Centers for Disease Control and Prevention–sponsored National Health and Nutrition Examination Survey trial from 1999 to 2004. In the studied population, severe headache and migraine was present in approximately 20%, and dietary fiber intake was delineated on the basis of whether it was more than or less than 100 g/d. This study assessed dietary intake of fiber, via a 24-hour dietary recall that was conducted by trained interviewers during two interviews conducted over the course of 2 years.

A total of 12,000 participants were included in the study. There was a significant decrease in migraine severity between those with a higher and lower dietary fiber intake. The incidence of severe headache or migraine, as defined by frequency and severity, decreased in participants who had a dietary fiber intake > 100 g/d. The authors found that for every 10 g/d increase in dietary fiber intake, the prevalence of severe headache or migraine decreased by approximately 11%.

Although much has been written about the association between diet and migraine, most of the literature focuses on the avoidance of specific dietary triggers. A different consideration now exists, one that will likely increase compliance with dietary recommendations. Specifically, people treating patients with migraine can make recommendations regarding dietary changes that focus on adding specific healthy foods or other changes that can actually be associated with improving migraine frequency long-term. Recommending healthy fats, such as omega-3 fatty acids, and high fiber should be done for nearly all patients with migraine.

January's theme is migraine triggers. We'll take a look at three recent studies that have tried to better determine the nature of specific triggers for headache.

One of the most common and reportedly consistent migraine triggers is exposure to alcohol, and the International Classification of Headache Disorders (ICHD-3) includes alcohol-induced headache as a secondary headache. Little is known regarding the association between migraine and alcohol. Vives-Mestres and colleagues investigated the alcohol intake of people using a digital health diary for headache. They specifically looked at the 48 hours preceding a migraine attack and whether alcohol was consumed, and also the number of beverages consumed. This was further adjusted for sex, age, and average weekly alcohol intake.

The N1-Headache Tracker is a digital headache diary that patients use to track their daily headache symptoms and inform them of potential migraine risk factors. Over a 90-day period, this study followed patients that did not meet the criteria for a diagnosis of chronic migraine. They also reported on their intake to the platform that they regularly consume alcohol. Of note, persons who never tracked alcohol consumption were excluded from this study. On intake to the platform, alcohol exposure was characterized both as whether daily consumption of alcohol was occurring and as the total daily number of alcoholic beverages.

The primary outcome of this study was migraine attack 1 day after alcohol consumption. Participants were specifically asked if their headaches were diagnosed as migraine by a physician. Migraine attack onset was considered binary, and a logistic model was used to estimate the probability of having a migraine attack on any given day with the association of alcohol intake for up to 48 hours prior to that day.

A total of 487 people with migraine were included in this trial and they collectively contributed over 43,000 diary days; almost 6000 were first days of a migraine attack. Overall alcohol consumption was not considered high and was noted to vary between groups; people with lower frequency migraine tended to have higher rates of alcohol intake. No significant correlation was observed between the presence of migraine attacks within 48 hours after alcohol consumption. This did not vary among different probability models; a population-level model showed that the probability of a migraine attack 2 days after alcohol intake was 25% lower than the probability of an attack with no alcohol consumption. This was also true after adjustment for age, sex, and average number of alcoholic beverages per week.

The association between migraine and alcohol is complicated, and the concept of migraine triggers in general is very complex. Although over 70% of people with migraine say that they have a consistent trigger, and alcohol is consistently at the top of the list of those reported triggers, there does not appear to be a direct correlation between migraine and alcohol exposure. The greatest caveat of this study is the fact that people with chronic migraine were excluded. Further research should specifically investigate triggers such as alcohol in this population.

The use of proton pump inhibitors (PPI) has been shown in previous studies over the past few years to be associated with a number of neurologic events and risks, including impaired hearing, vision, and memory, as well as migraine occurrence. The specifics of this association are not well known — specifically, whether the duration of use is the main factor, or whether it is acute exposure to a PPI medication that is a trigger. Kang and colleagues reviewed data in the Korean national database and developed a case-control model to study this association specifically.

The migraine and control groups were equally matched: They had the same demographics, smoking status, alcohol consumption, blood pressure range, fasting glucose, and total cholesterol. Past and current PPI use and comparisons of migraine occurrence were further differentiated among patients who were exposed to PPI medications for < 30 days, 30-365 days, and > 365 days.

The use of PPI treatments was noted to be linked to increased migraine regardless of duration, and regardless of the acute presence of the PPI. Even a history of prior PPI use was noted to increase the odds ratio of migraine development. This was significant among all subgroups, independent of age, sex, and other comorbidities. There was no difference in the presence of aura associated with migraine.

As we noted above, the concept of migraine triggers is overall poorly understood. This is even more the case when it comes to historical exposures. Although the use of PPI medications appears to be associated with the occurrence of migraine in this population, these medications are necessary in many instances, including in patients with severe gastritis and gastroesophageal reflux refractory to diet changes. It remains to be seen precisely how PPI medications would potentially lead to a higher incidence of migraine.

Among many of the triggers discussed, specific foods are commonly thought to be associated with migraine. Although there is scant evidence for a specific diet to improve migraine frequency, many patients are very interested in potential dietary changes that may help them. Prior studies and reviews have looked at gluten-free, dairy-free, low-carbohydrate, low-tyramine, and elimination diets — all of which were not associated with a significant improvement in migraine frequency or severity. Bakıran and colleagues sought to investigate an antioxidant-rich diet that included polyphenols and carotenoids — substances that may improve systemic inflammation, glucose metabolism, and oxidative stress.

Phytochemical-rich foods include fruits and vegetables (excluding potatoes) as well as nuts, whole grains, pulses, and olive oil. The phytochemical index is a tool used by dietitians and nutritionists to assess the phytochemical content in a diet.

A total of 90 patients who had a diagnosis of episodic migraine by a neurologist were enrolled. Individuals were excluded if they had a body mass index > 40 or < 18 or had other significant chronic comorbidities, such as hypertension, diabetes, hepatic or renal disease, or other neurologic conditions. Participants filled out a headache diary over 3 months; the Migraine Disability Assessment (MIDAS) questionnaire was also followed in order to assess migraine-related disability. Diet quality was cataloged as per patient records; patients also filled out a 3-day nonconsecutive food diary. This information was added to a food software program that calculated specific nutrients, including the phytochemical index.

Participants were divided into groups with good diet quality and poor diet quality based on their phytochemical index. No differences were seen in migraine frequency or disability between these groups, although mean attack duration was lower in those with poor diet quality. Severity was noted to be higher in those with poor diet quality; 75% of participants with poor diet quality experienced severe attacks.

Overall, the results of this study are very mixed. Participants on the recommended high phytochemical diet were seen to have lower severity of migraine but a prolonged duration of attack. There also was no correlation between this diet and either frequency or disability. This was a small study, and further research should focus on this among other diet changes that have the possibility to improve the quality of life of people with migraine.

January's theme is migraine triggers. We'll take a look at three recent studies that have tried to better determine the nature of specific triggers for headache.

One of the most common and reportedly consistent migraine triggers is exposure to alcohol, and the International Classification of Headache Disorders (ICHD-3) includes alcohol-induced headache as a secondary headache. Little is known regarding the association between migraine and alcohol. Vives-Mestres and colleagues investigated the alcohol intake of people using a digital health diary for headache. They specifically looked at the 48 hours preceding a migraine attack and whether alcohol was consumed, and also the number of beverages consumed. This was further adjusted for sex, age, and average weekly alcohol intake.

The N1-Headache Tracker is a digital headache diary that patients use to track their daily headache symptoms and inform them of potential migraine risk factors. Over a 90-day period, this study followed patients that did not meet the criteria for a diagnosis of chronic migraine. They also reported on their intake to the platform that they regularly consume alcohol. Of note, persons who never tracked alcohol consumption were excluded from this study. On intake to the platform, alcohol exposure was characterized both as whether daily consumption of alcohol was occurring and as the total daily number of alcoholic beverages.

The primary outcome of this study was migraine attack 1 day after alcohol consumption. Participants were specifically asked if their headaches were diagnosed as migraine by a physician. Migraine attack onset was considered binary, and a logistic model was used to estimate the probability of having a migraine attack on any given day with the association of alcohol intake for up to 48 hours prior to that day.

A total of 487 people with migraine were included in this trial and they collectively contributed over 43,000 diary days; almost 6000 were first days of a migraine attack. Overall alcohol consumption was not considered high and was noted to vary between groups; people with lower frequency migraine tended to have higher rates of alcohol intake. No significant correlation was observed between the presence of migraine attacks within 48 hours after alcohol consumption. This did not vary among different probability models; a population-level model showed that the probability of a migraine attack 2 days after alcohol intake was 25% lower than the probability of an attack with no alcohol consumption. This was also true after adjustment for age, sex, and average number of alcoholic beverages per week.

The association between migraine and alcohol is complicated, and the concept of migraine triggers in general is very complex. Although over 70% of people with migraine say that they have a consistent trigger, and alcohol is consistently at the top of the list of those reported triggers, there does not appear to be a direct correlation between migraine and alcohol exposure. The greatest caveat of this study is the fact that people with chronic migraine were excluded. Further research should specifically investigate triggers such as alcohol in this population.

The use of proton pump inhibitors (PPI) has been shown in previous studies over the past few years to be associated with a number of neurologic events and risks, including impaired hearing, vision, and memory, as well as migraine occurrence. The specifics of this association are not well known — specifically, whether the duration of use is the main factor, or whether it is acute exposure to a PPI medication that is a trigger. Kang and colleagues reviewed data in the Korean national database and developed a case-control model to study this association specifically.

The migraine and control groups were equally matched: They had the same demographics, smoking status, alcohol consumption, blood pressure range, fasting glucose, and total cholesterol. Past and current PPI use and comparisons of migraine occurrence were further differentiated among patients who were exposed to PPI medications for < 30 days, 30-365 days, and > 365 days.

The use of PPI treatments was noted to be linked to increased migraine regardless of duration, and regardless of the acute presence of the PPI. Even a history of prior PPI use was noted to increase the odds ratio of migraine development. This was significant among all subgroups, independent of age, sex, and other comorbidities. There was no difference in the presence of aura associated with migraine.

As we noted above, the concept of migraine triggers is overall poorly understood. This is even more the case when it comes to historical exposures. Although the use of PPI medications appears to be associated with the occurrence of migraine in this population, these medications are necessary in many instances, including in patients with severe gastritis and gastroesophageal reflux refractory to diet changes. It remains to be seen precisely how PPI medications would potentially lead to a higher incidence of migraine.

Among many of the triggers discussed, specific foods are commonly thought to be associated with migraine. Although there is scant evidence for a specific diet to improve migraine frequency, many patients are very interested in potential dietary changes that may help them. Prior studies and reviews have looked at gluten-free, dairy-free, low-carbohydrate, low-tyramine, and elimination diets — all of which were not associated with a significant improvement in migraine frequency or severity. Bakıran and colleagues sought to investigate an antioxidant-rich diet that included polyphenols and carotenoids — substances that may improve systemic inflammation, glucose metabolism, and oxidative stress.

Phytochemical-rich foods include fruits and vegetables (excluding potatoes) as well as nuts, whole grains, pulses, and olive oil. The phytochemical index is a tool used by dietitians and nutritionists to assess the phytochemical content in a diet.

A total of 90 patients who had a diagnosis of episodic migraine by a neurologist were enrolled. Individuals were excluded if they had a body mass index > 40 or < 18 or had other significant chronic comorbidities, such as hypertension, diabetes, hepatic or renal disease, or other neurologic conditions. Participants filled out a headache diary over 3 months; the Migraine Disability Assessment (MIDAS) questionnaire was also followed in order to assess migraine-related disability. Diet quality was cataloged as per patient records; patients also filled out a 3-day nonconsecutive food diary. This information was added to a food software program that calculated specific nutrients, including the phytochemical index.

Participants were divided into groups with good diet quality and poor diet quality based on their phytochemical index. No differences were seen in migraine frequency or disability between these groups, although mean attack duration was lower in those with poor diet quality. Severity was noted to be higher in those with poor diet quality; 75% of participants with poor diet quality experienced severe attacks.

Overall, the results of this study are very mixed. Participants on the recommended high phytochemical diet were seen to have lower severity of migraine but a prolonged duration of attack. There also was no correlation between this diet and either frequency or disability. This was a small study, and further research should focus on this among other diet changes that have the possibility to improve the quality of life of people with migraine.

January's theme is migraine triggers. We'll take a look at three recent studies that have tried to better determine the nature of specific triggers for headache.

One of the most common and reportedly consistent migraine triggers is exposure to alcohol, and the International Classification of Headache Disorders (ICHD-3) includes alcohol-induced headache as a secondary headache. Little is known regarding the association between migraine and alcohol. Vives-Mestres and colleagues investigated the alcohol intake of people using a digital health diary for headache. They specifically looked at the 48 hours preceding a migraine attack and whether alcohol was consumed, and also the number of beverages consumed. This was further adjusted for sex, age, and average weekly alcohol intake.

The N1-Headache Tracker is a digital headache diary that patients use to track their daily headache symptoms and inform them of potential migraine risk factors. Over a 90-day period, this study followed patients that did not meet the criteria for a diagnosis of chronic migraine. They also reported on their intake to the platform that they regularly consume alcohol. Of note, persons who never tracked alcohol consumption were excluded from this study. On intake to the platform, alcohol exposure was characterized both as whether daily consumption of alcohol was occurring and as the total daily number of alcoholic beverages.

The primary outcome of this study was migraine attack 1 day after alcohol consumption. Participants were specifically asked if their headaches were diagnosed as migraine by a physician. Migraine attack onset was considered binary, and a logistic model was used to estimate the probability of having a migraine attack on any given day with the association of alcohol intake for up to 48 hours prior to that day.

A total of 487 people with migraine were included in this trial and they collectively contributed over 43,000 diary days; almost 6000 were first days of a migraine attack. Overall alcohol consumption was not considered high and was noted to vary between groups; people with lower frequency migraine tended to have higher rates of alcohol intake. No significant correlation was observed between the presence of migraine attacks within 48 hours after alcohol consumption. This did not vary among different probability models; a population-level model showed that the probability of a migraine attack 2 days after alcohol intake was 25% lower than the probability of an attack with no alcohol consumption. This was also true after adjustment for age, sex, and average number of alcoholic beverages per week.

The association between migraine and alcohol is complicated, and the concept of migraine triggers in general is very complex. Although over 70% of people with migraine say that they have a consistent trigger, and alcohol is consistently at the top of the list of those reported triggers, there does not appear to be a direct correlation between migraine and alcohol exposure. The greatest caveat of this study is the fact that people with chronic migraine were excluded. Further research should specifically investigate triggers such as alcohol in this population.

The use of proton pump inhibitors (PPI) has been shown in previous studies over the past few years to be associated with a number of neurologic events and risks, including impaired hearing, vision, and memory, as well as migraine occurrence. The specifics of this association are not well known — specifically, whether the duration of use is the main factor, or whether it is acute exposure to a PPI medication that is a trigger. Kang and colleagues reviewed data in the Korean national database and developed a case-control model to study this association specifically.

The migraine and control groups were equally matched: They had the same demographics, smoking status, alcohol consumption, blood pressure range, fasting glucose, and total cholesterol. Past and current PPI use and comparisons of migraine occurrence were further differentiated among patients who were exposed to PPI medications for < 30 days, 30-365 days, and > 365 days.

The use of PPI treatments was noted to be linked to increased migraine regardless of duration, and regardless of the acute presence of the PPI. Even a history of prior PPI use was noted to increase the odds ratio of migraine development. This was significant among all subgroups, independent of age, sex, and other comorbidities. There was no difference in the presence of aura associated with migraine.

As we noted above, the concept of migraine triggers is overall poorly understood. This is even more the case when it comes to historical exposures. Although the use of PPI medications appears to be associated with the occurrence of migraine in this population, these medications are necessary in many instances, including in patients with severe gastritis and gastroesophageal reflux refractory to diet changes. It remains to be seen precisely how PPI medications would potentially lead to a higher incidence of migraine.

Among many of the triggers discussed, specific foods are commonly thought to be associated with migraine. Although there is scant evidence for a specific diet to improve migraine frequency, many patients are very interested in potential dietary changes that may help them. Prior studies and reviews have looked at gluten-free, dairy-free, low-carbohydrate, low-tyramine, and elimination diets — all of which were not associated with a significant improvement in migraine frequency or severity. Bakıran and colleagues sought to investigate an antioxidant-rich diet that included polyphenols and carotenoids — substances that may improve systemic inflammation, glucose metabolism, and oxidative stress.

Phytochemical-rich foods include fruits and vegetables (excluding potatoes) as well as nuts, whole grains, pulses, and olive oil. The phytochemical index is a tool used by dietitians and nutritionists to assess the phytochemical content in a diet.

A total of 90 patients who had a diagnosis of episodic migraine by a neurologist were enrolled. Individuals were excluded if they had a body mass index > 40 or < 18 or had other significant chronic comorbidities, such as hypertension, diabetes, hepatic or renal disease, or other neurologic conditions. Participants filled out a headache diary over 3 months; the Migraine Disability Assessment (MIDAS) questionnaire was also followed in order to assess migraine-related disability. Diet quality was cataloged as per patient records; patients also filled out a 3-day nonconsecutive food diary. This information was added to a food software program that calculated specific nutrients, including the phytochemical index.

Participants were divided into groups with good diet quality and poor diet quality based on their phytochemical index. No differences were seen in migraine frequency or disability between these groups, although mean attack duration was lower in those with poor diet quality. Severity was noted to be higher in those with poor diet quality; 75% of participants with poor diet quality experienced severe attacks.

Overall, the results of this study are very mixed. Participants on the recommended high phytochemical diet were seen to have lower severity of migraine but a prolonged duration of attack. There also was no correlation between this diet and either frequency or disability. This was a small study, and further research should focus on this among other diet changes that have the possibility to improve the quality of life of people with migraine.

This month, we will take a look at three new studies investigating risk factors and treatments for headache in children.

Stress has long been noted to be one of the most consistent triggers for migraine attacks. Much has been written and studied regarding the effect of migraine on mood in adults; however, few studies have done the same in the pediatric and adolescent population. Childhood trauma has been associated with the development of chronic migraine as an adult, and behavioral treatments, such as cognitive-behavioral therapy and biofeedback, are considered as effective or more effective for migraine prevention in children compared with preventive medications. Falla and colleagues have quantified the risk for anxiety and depression in children and adolescents with migraine.

The "internalization of symptoms" is defined by the authors as an individual's tendency to react to stress with physical symptoms, including anxiety and depression. These are thought to be elevated in children and adolescents with many effects, including migraine. However, no correlation has yet been shown. Beyond the internalization of symptoms, specific psychiatric diagnoses may also be more prominent in this population.

This study was a meta-analysis of data pooled from studies that assessed migraine-related symptoms as they relate to disorders on the spectrum of anxiety, depression, and trauma-related disorders. Any studies with participants older than 18 years were excluded from this analysis. A total of 80 studies were included. Anxiety symptoms were seen to be significantly higher in children and adolescents with migraine compared to controls and the odds of having an anxiety disorder were higher among those with migraine compared with controls. Depressive symptoms were also significantly higher; however, this effect size was much smaller. The incidence of migraine was not different than that of other headache disorders.

Many patients describe stress as a trigger for migraine and other headache attacks. Mood disorders and childhood trauma are associated with the development of chronic migraine as an adult. This study reveals a two-way connection between mood disorders and headache diagnoses in children. Screening for the underlying symptoms of depression and anxiety should be done when evaluating children and adolescents for headache disorders, and there should be a focus on the treatment of these conditions in addition to treating the headache symptoms.

There are, unfortunately, very few acute pediatric migraine trials. Only a handful of medications have actually been investigated for the treatment of migraine in children younger than 12 years, and only one migraine-specific medication, rizatriptan, is approved in the United States for pediatric use. Because of this, many argue that children and adolescents with migraines end up overusing over-the-counter medication options, increasing the risk for medication overuse headache. In addition, many patients need nonoral acute migraine treatments due to nausea and vomiting or rapid onset migraine attacks.

Yonker and colleagues conducted a phase 3, randomized, double-blind, multicenter trial that only enrolled patients aged 6-11 years, all of whom had a diagnosis of episodic migraine (< 15 days of migraine per month). Children that weighed < 50 kg were given a randomly assigned lower dose of 1 mg or 2.5 mg zolmitriptan nasal spray, and those who weighed > 50 kg were randomly assigned to either 2.5 mg or 5 mg, which is the standard adult dose.

The primary outcome was a standard 2-hour pain freedom level; secondary outcomes included the proportion of improvement at 0.5, 1, and 24 hours post-dose, as well as sustained headache response for the following 2-24 hours and time to rescue medication use. Although 300 patients were enrolled and taken through the run-in process, 114 were discontinued either due to placebo response or because they had no treated migraine during the run-in phase. The mean age was 9.2 years and half of the patients were girls (of note, this is considered an appropriate proportion for pediatric migraine).

The primary endpoint of 2-hour pain freedom was not met; however, more patients in the high-dose treatment group were pain-free after 2 hours than in the placebo group. Several secondary endpoints did achieve statistical significance, including pain-free status at 1 hour post-dose, as well as headache response at 0.5, 1, and 2 hours — all of which were lower in the high-dose treatment group. The lower-dose treatment group was statistically similar to placebo for all the timepoints noted above. Treatment-related adverse events were rare in all groups.

This study did not meet its primary efficacy endpoint. However, it does show safety and effectiveness, enough at least to broaden the use of zolmitriptan for pediatric migraine. Many more effective medications for migraine treatment in adults should follow the lead of this group to find better and more specific treatments for children with migraine.

As we noted above, childhood trauma is associated with the development of chronic migraine in adulthood. Prior studies have defined childhood trauma as physical or emotional abuse primarily, and the correlation between childhood illnesses and headache disorder has not previously been determined. Davidsson and colleagues published a study in the Journal of Cancer Epidemiology that reviewed nationwide database registers longitudinally to better understand this potential risk factor.

The Danish Cancer Register was reviewed for the purpose of identifying anyone in the general Danish population who developed a diagnosis of cancer before age 20 years. The individual identification numbers in that register were linked to data in other nationwide registers for the purpose of determining whether those individuals initiated migraine-specific medications or were admitted for an inpatient hospitalization for migraine. Study participants were also grouped based on cancer type, specifically hematologic cancers involving chemotherapy and central nervous system-directed therapies, brain tumors needing intracranial surgery or radiation to the brain, blastomas or other solid tumors outside of the central nervous system, sarcomas treated with an alkylating chemotherapy, and all other carcinomas.

Among all individuals diagnosed with a childhood cancer, there was a significant increase in overall risk for the need to initiate antimigraine medication. Of interest, this was higher in those diagnosed in their teenage years. Migraine hospitalization was also noted to be higher in nearly all strata, with the exception of those diagnosed with cancer prior to the age of 5 years. The highest risk was also noted in individuals with hematologic cancers, blastomas, and brain tumors as opposed to those with sarcomas and other carcinomas. The highest cumulative risk for migraine remains in those who were diagnosed with cancer between ages 15 and 19 years.

This month, we will take a look at three new studies investigating risk factors and treatments for headache in children.

Stress has long been noted to be one of the most consistent triggers for migraine attacks. Much has been written and studied regarding the effect of migraine on mood in adults; however, few studies have done the same in the pediatric and adolescent population. Childhood trauma has been associated with the development of chronic migraine as an adult, and behavioral treatments, such as cognitive-behavioral therapy and biofeedback, are considered as effective or more effective for migraine prevention in children compared with preventive medications. Falla and colleagues have quantified the risk for anxiety and depression in children and adolescents with migraine.

The "internalization of symptoms" is defined by the authors as an individual's tendency to react to stress with physical symptoms, including anxiety and depression. These are thought to be elevated in children and adolescents with many effects, including migraine. However, no correlation has yet been shown. Beyond the internalization of symptoms, specific psychiatric diagnoses may also be more prominent in this population.

This study was a meta-analysis of data pooled from studies that assessed migraine-related symptoms as they relate to disorders on the spectrum of anxiety, depression, and trauma-related disorders. Any studies with participants older than 18 years were excluded from this analysis. A total of 80 studies were included. Anxiety symptoms were seen to be significantly higher in children and adolescents with migraine compared to controls and the odds of having an anxiety disorder were higher among those with migraine compared with controls. Depressive symptoms were also significantly higher; however, this effect size was much smaller. The incidence of migraine was not different than that of other headache disorders.

Many patients describe stress as a trigger for migraine and other headache attacks. Mood disorders and childhood trauma are associated with the development of chronic migraine as an adult. This study reveals a two-way connection between mood disorders and headache diagnoses in children. Screening for the underlying symptoms of depression and anxiety should be done when evaluating children and adolescents for headache disorders, and there should be a focus on the treatment of these conditions in addition to treating the headache symptoms.

There are, unfortunately, very few acute pediatric migraine trials. Only a handful of medications have actually been investigated for the treatment of migraine in children younger than 12 years, and only one migraine-specific medication, rizatriptan, is approved in the United States for pediatric use. Because of this, many argue that children and adolescents with migraines end up overusing over-the-counter medication options, increasing the risk for medication overuse headache. In addition, many patients need nonoral acute migraine treatments due to nausea and vomiting or rapid onset migraine attacks.

Yonker and colleagues conducted a phase 3, randomized, double-blind, multicenter trial that only enrolled patients aged 6-11 years, all of whom had a diagnosis of episodic migraine (< 15 days of migraine per month). Children that weighed < 50 kg were given a randomly assigned lower dose of 1 mg or 2.5 mg zolmitriptan nasal spray, and those who weighed > 50 kg were randomly assigned to either 2.5 mg or 5 mg, which is the standard adult dose.

The primary outcome was a standard 2-hour pain freedom level; secondary outcomes included the proportion of improvement at 0.5, 1, and 24 hours post-dose, as well as sustained headache response for the following 2-24 hours and time to rescue medication use. Although 300 patients were enrolled and taken through the run-in process, 114 were discontinued either due to placebo response or because they had no treated migraine during the run-in phase. The mean age was 9.2 years and half of the patients were girls (of note, this is considered an appropriate proportion for pediatric migraine).

The primary endpoint of 2-hour pain freedom was not met; however, more patients in the high-dose treatment group were pain-free after 2 hours than in the placebo group. Several secondary endpoints did achieve statistical significance, including pain-free status at 1 hour post-dose, as well as headache response at 0.5, 1, and 2 hours — all of which were lower in the high-dose treatment group. The lower-dose treatment group was statistically similar to placebo for all the timepoints noted above. Treatment-related adverse events were rare in all groups.

This study did not meet its primary efficacy endpoint. However, it does show safety and effectiveness, enough at least to broaden the use of zolmitriptan for pediatric migraine. Many more effective medications for migraine treatment in adults should follow the lead of this group to find better and more specific treatments for children with migraine.

As we noted above, childhood trauma is associated with the development of chronic migraine in adulthood. Prior studies have defined childhood trauma as physical or emotional abuse primarily, and the correlation between childhood illnesses and headache disorder has not previously been determined. Davidsson and colleagues published a study in the Journal of Cancer Epidemiology that reviewed nationwide database registers longitudinally to better understand this potential risk factor.

The Danish Cancer Register was reviewed for the purpose of identifying anyone in the general Danish population who developed a diagnosis of cancer before age 20 years. The individual identification numbers in that register were linked to data in other nationwide registers for the purpose of determining whether those individuals initiated migraine-specific medications or were admitted for an inpatient hospitalization for migraine. Study participants were also grouped based on cancer type, specifically hematologic cancers involving chemotherapy and central nervous system-directed therapies, brain tumors needing intracranial surgery or radiation to the brain, blastomas or other solid tumors outside of the central nervous system, sarcomas treated with an alkylating chemotherapy, and all other carcinomas.

Among all individuals diagnosed with a childhood cancer, there was a significant increase in overall risk for the need to initiate antimigraine medication. Of interest, this was higher in those diagnosed in their teenage years. Migraine hospitalization was also noted to be higher in nearly all strata, with the exception of those diagnosed with cancer prior to the age of 5 years. The highest risk was also noted in individuals with hematologic cancers, blastomas, and brain tumors as opposed to those with sarcomas and other carcinomas. The highest cumulative risk for migraine remains in those who were diagnosed with cancer between ages 15 and 19 years.

This month, we will take a look at three new studies investigating risk factors and treatments for headache in children.

Stress has long been noted to be one of the most consistent triggers for migraine attacks. Much has been written and studied regarding the effect of migraine on mood in adults; however, few studies have done the same in the pediatric and adolescent population. Childhood trauma has been associated with the development of chronic migraine as an adult, and behavioral treatments, such as cognitive-behavioral therapy and biofeedback, are considered as effective or more effective for migraine prevention in children compared with preventive medications. Falla and colleagues have quantified the risk for anxiety and depression in children and adolescents with migraine.

The "internalization of symptoms" is defined by the authors as an individual's tendency to react to stress with physical symptoms, including anxiety and depression. These are thought to be elevated in children and adolescents with many effects, including migraine. However, no correlation has yet been shown. Beyond the internalization of symptoms, specific psychiatric diagnoses may also be more prominent in this population.

This study was a meta-analysis of data pooled from studies that assessed migraine-related symptoms as they relate to disorders on the spectrum of anxiety, depression, and trauma-related disorders. Any studies with participants older than 18 years were excluded from this analysis. A total of 80 studies were included. Anxiety symptoms were seen to be significantly higher in children and adolescents with migraine compared to controls and the odds of having an anxiety disorder were higher among those with migraine compared with controls. Depressive symptoms were also significantly higher; however, this effect size was much smaller. The incidence of migraine was not different than that of other headache disorders.

Many patients describe stress as a trigger for migraine and other headache attacks. Mood disorders and childhood trauma are associated with the development of chronic migraine as an adult. This study reveals a two-way connection between mood disorders and headache diagnoses in children. Screening for the underlying symptoms of depression and anxiety should be done when evaluating children and adolescents for headache disorders, and there should be a focus on the treatment of these conditions in addition to treating the headache symptoms.

There are, unfortunately, very few acute pediatric migraine trials. Only a handful of medications have actually been investigated for the treatment of migraine in children younger than 12 years, and only one migraine-specific medication, rizatriptan, is approved in the United States for pediatric use. Because of this, many argue that children and adolescents with migraines end up overusing over-the-counter medication options, increasing the risk for medication overuse headache. In addition, many patients need nonoral acute migraine treatments due to nausea and vomiting or rapid onset migraine attacks.

Yonker and colleagues conducted a phase 3, randomized, double-blind, multicenter trial that only enrolled patients aged 6-11 years, all of whom had a diagnosis of episodic migraine (< 15 days of migraine per month). Children that weighed < 50 kg were given a randomly assigned lower dose of 1 mg or 2.5 mg zolmitriptan nasal spray, and those who weighed > 50 kg were randomly assigned to either 2.5 mg or 5 mg, which is the standard adult dose.

The primary outcome was a standard 2-hour pain freedom level; secondary outcomes included the proportion of improvement at 0.5, 1, and 24 hours post-dose, as well as sustained headache response for the following 2-24 hours and time to rescue medication use. Although 300 patients were enrolled and taken through the run-in process, 114 were discontinued either due to placebo response or because they had no treated migraine during the run-in phase. The mean age was 9.2 years and half of the patients were girls (of note, this is considered an appropriate proportion for pediatric migraine).

The primary endpoint of 2-hour pain freedom was not met; however, more patients in the high-dose treatment group were pain-free after 2 hours than in the placebo group. Several secondary endpoints did achieve statistical significance, including pain-free status at 1 hour post-dose, as well as headache response at 0.5, 1, and 2 hours — all of which were lower in the high-dose treatment group. The lower-dose treatment group was statistically similar to placebo for all the timepoints noted above. Treatment-related adverse events were rare in all groups.

This study did not meet its primary efficacy endpoint. However, it does show safety and effectiveness, enough at least to broaden the use of zolmitriptan for pediatric migraine. Many more effective medications for migraine treatment in adults should follow the lead of this group to find better and more specific treatments for children with migraine.

As we noted above, childhood trauma is associated with the development of chronic migraine in adulthood. Prior studies have defined childhood trauma as physical or emotional abuse primarily, and the correlation between childhood illnesses and headache disorder has not previously been determined. Davidsson and colleagues published a study in the Journal of Cancer Epidemiology that reviewed nationwide database registers longitudinally to better understand this potential risk factor.

The Danish Cancer Register was reviewed for the purpose of identifying anyone in the general Danish population who developed a diagnosis of cancer before age 20 years. The individual identification numbers in that register were linked to data in other nationwide registers for the purpose of determining whether those individuals initiated migraine-specific medications or were admitted for an inpatient hospitalization for migraine. Study participants were also grouped based on cancer type, specifically hematologic cancers involving chemotherapy and central nervous system-directed therapies, brain tumors needing intracranial surgery or radiation to the brain, blastomas or other solid tumors outside of the central nervous system, sarcomas treated with an alkylating chemotherapy, and all other carcinomas.

Among all individuals diagnosed with a childhood cancer, there was a significant increase in overall risk for the need to initiate antimigraine medication. Of interest, this was higher in those diagnosed in their teenage years. Migraine hospitalization was also noted to be higher in nearly all strata, with the exception of those diagnosed with cancer prior to the age of 5 years. The highest risk was also noted in individuals with hematologic cancers, blastomas, and brain tumors as opposed to those with sarcomas and other carcinomas. The highest cumulative risk for migraine remains in those who were diagnosed with cancer between ages 15 and 19 years.

Calcitonin gene-related peptide (CGRP) antagonist medications are becoming more and more of a mainstay of both migraine prevention and acute treatment. Four CGRP monoclonal antibody medications and three oral CGRP antagonists are now available for prevention and acute treatment of migraine. When this class of medications was developed, many patients and providers were initially concerned regarding any potentially unanticipated long-term adverse events. The first CGRP antagonist medication, erenumab, was associated with constipation, and, although this has not been formally reported with other CGRP medications, there is some anecdotal evidence of gastrointestinal (GI) discomfort with both oral and other monoclonal antibody medications in this class. In 2021, erenumab was also reported to be associated with hypertension and a formal warning was issued for this.

Before CGRP was used for migraine prevention, it had been known to be a potent vasodilator. Although the randomized controlled trials (RCT) for all CGRP medications included a longitudinal review of blood pressure (BP) measures, none of those initial trials revealed an increased risk for hypertension or other cardiovascular events or concerns. Some of the initial trials even included patients at higher cardiovascular risk. Migraine itself is associated with an increased vascular risk; it is therefore extremely important to determine whether a potential treatment may be increasing this risk further.

In the study by de Vries and colleagues, all patients were started on either erenumab or fremanezumab and were included if they had a follow-up blood pressure measurement within 6 months. All patients had at least8 migraine days per month and had used four or more preventive medications. Patients taking erenumab were first started at 70 mg monthly and were optionally increased to 140 mg after 3 months. Fremanezumab was always given at a dose of 225 mg monthly (as opposed to 675 mg every 3 months). BP data were collected at baseline and followed up at every visit, with a maximum of 12 months of review. Patients were excluded if their baseline BP was measured while they were undergoing tapering an antihypertensive medication at the same time that they were starting the CGRP antagonist. Patients already treated for hypertension were included only if there were no changes to their hypertensive regimen.

Patients were also compared with a control group with a similar distribution in sex, age, and diagnosis, and who were not taking any migraine preventive medication that would affect their BP. Control group BP was also measured at least two different time points 1-3 months from baseline.

A total of 211 patients were enrolled: 109 in the erenumab group and 87 in the fremanezumab group. The erenumab group was also associated with an increase in both systolic BP (SBP) and diastolic BP (DBP) (SBP ≤ 9 mm Hg; DBP ≤ 6.3 mm Hg). The fremanezumab group had a lower increase in SBP (1 mm Hg) and no increase in DBP. Nine patients were started on antihypertensive medications, five of them after the baseline BP recording only. There was no change over time in the control group.

As noted, CGRP has a potent vasodilatory effect. Although not proven, a theory has been posited that CGRP receptor antagonist medications are somewhat more likely to lead to systemic adverse effects than are ligand-blocking medications. This may, at least in part, explain why erenumab appears to have more associated GI discomfort and constipation as well as a vascular effect with hypertension. In light of these findings, it is absolutely necessary for the additional CGRP medications to also be studied for these potential risk factors.

With the advent of novel acute treatments for migraine, many providers ask themselves what the potential risks and benefits are for each new class of drugs developed and approved over the past few years. Johnston and colleagues reviewed five recently published RCT to compare risk-benefit profiles for lasmiditan, rimegepant, and ubrogepant. Lasmiditan is the only medication in the ditan class, a serotonin (5HT-1F) receptor agonist medication approved for the acute treatment of migraine. Rimegepant and ubrogepant are oral CGRP antagonists.

Lasmiditan does have a potential risk for impairment while driving due to excessive sedation and dizziness; it is also more likely than the CGRP medications to lead to the development of medication overuse headache. The CGRP medications, however, are associated with a smaller responder rate for headache freedom at 2 hours. The investigators reviewed the data published in five RCT to develop a statistically based decision-making process that correlates with the number needed to treat vs the number needed to harm for all three of these medications. The number needed to treat is a statistically defined parameter that characterizes the number of patients that need to be treated with an intervention to achieve a positive event. The number needed to harm refers to an additional negative event relative to the reference treatment (placebo in the case of an RCT).

The reviewed studies compared multiple dosages of these medications. Efficacy outcomes were pain relief and pain freedom at 2 hours, sustained pain relief from 2 to 24 hours, and freedom from the most bothersome symptom at 2 hours. Safety outcomes were dizziness and nausea.

The number needed to treat was the lowest for 200 mg lasmiditan (twice the highest recommended acute dose), followed by 75 mg rimegepant. The number needed to harm was highest for 25 mg ubrogepant (half of the lowest recommended acute dose). Nausea was lowest for 75 mg rimegepant.

An individualized approach is always recommended when considering both preventive and acute treatments for migraine. It is definitely worth keeping these results in mind when discussing potential acute treatment options with patients. This is especially true when considering patients who may be more likely to experience either dizziness or nausea with other acute treatments. It is also worth individualizing a potential acute treatment when a patient experiences rapid-onset migraine symptoms. Further investigations into both acute and preventive treatments would enlighten and further individualize our clinical approaches.

Erenumab currently carries a prescriber warning for constipation. Although there has been some anecdotal evidence for constipation with other CGRP antagonists, this has never fully been investigated. Currently, the other CGRP medication options have fewer side effects and not all  are associated with constipation. Kudrow and colleagues sought to review the incidence of constipation, and GI motility in general, with both erenumab and galcanezumab. Their hypothesis was that a single dose of erenumab would be associated with delayed GI motility and a single dose of galcanezumab would not be.

This study was conducted as a multicenter trial with single-blinding. A total of 65 patients were enrolled and given either 140 mg erenumab or 240 mg galcanezumab (the loading dose). GI motility was measured via a wireless motility capsule at baseline before treatment and repeated at 2 weeks. This test is approved by the US Food and Drug Administration for evaluation of gastric transit time in patients with suspected gastroparesis and for evaluation of colonic transit time in patients with chronic idiopathic constipation. Patients with prior GI symptoms were excluded, as were patients taking a tricyclic antidepressant or a calcium-channel blocker, owing to known constipation with these agents.

The primary endpoint in this study was change from a baseline colonic transit time 2 weeks after injection with the CGRP monoclonal antibody. Secondary endpoints included change from baseline in whole-gut transit time, gastric emptying time, small-bowel transfer time, and combined small- and large-bowel transfer time. The Gastrointestinal Symptom Rating Scale (GSRS) was also used, evaluating abdominal pain, reflux, indigestion, constipation, and diarrhea based on a 7-point response, ranging from no discomfort to very severe discomfort.

The primary endpoint of baseline change in colonic transit time was not statistically significant between the groups: A mean change of 5.8 hours was noted for erenumab and 5.4 hours for galcanezumab. Most secondary endpoints were also not statistically significantly different between the two groups. Small-bowel transit time was  decreased in the galcanezumab group. When the patient-reported scales were reviewed, spontaneous bowel movements decreased significantly in the erenumab group, a finding that was not seen in the galcanezumab group and was statistically significant. The GSRS also showed a small but statistically significant change in the erenumab group.

This study does appear to show a significant difference in the two CGRP antagonist medications. The full side-effect profiles of the four CGRP monoclonal antibodies and three oral CGRP blocking medications available remain unknown. Further head-to-head comparisons will allow better differentiation of these options and better individualization of patient care.

Calcitonin gene-related peptide (CGRP) antagonist medications are becoming more and more of a mainstay of both migraine prevention and acute treatment. Four CGRP monoclonal antibody medications and three oral CGRP antagonists are now available for prevention and acute treatment of migraine. When this class of medications was developed, many patients and providers were initially concerned regarding any potentially unanticipated long-term adverse events. The first CGRP antagonist medication, erenumab, was associated with constipation, and, although this has not been formally reported with other CGRP medications, there is some anecdotal evidence of gastrointestinal (GI) discomfort with both oral and other monoclonal antibody medications in this class. In 2021, erenumab was also reported to be associated with hypertension and a formal warning was issued for this.

Before CGRP was used for migraine prevention, it had been known to be a potent vasodilator. Although the randomized controlled trials (RCT) for all CGRP medications included a longitudinal review of blood pressure (BP) measures, none of those initial trials revealed an increased risk for hypertension or other cardiovascular events or concerns. Some of the initial trials even included patients at higher cardiovascular risk. Migraine itself is associated with an increased vascular risk; it is therefore extremely important to determine whether a potential treatment may be increasing this risk further.

In the study by de Vries and colleagues, all patients were started on either erenumab or fremanezumab and were included if they had a follow-up blood pressure measurement within 6 months. All patients had at least8 migraine days per month and had used four or more preventive medications. Patients taking erenumab were first started at 70 mg monthly and were optionally increased to 140 mg after 3 months. Fremanezumab was always given at a dose of 225 mg monthly (as opposed to 675 mg every 3 months). BP data were collected at baseline and followed up at every visit, with a maximum of 12 months of review. Patients were excluded if their baseline BP was measured while they were undergoing tapering an antihypertensive medication at the same time that they were starting the CGRP antagonist. Patients already treated for hypertension were included only if there were no changes to their hypertensive regimen.

Patients were also compared with a control group with a similar distribution in sex, age, and diagnosis, and who were not taking any migraine preventive medication that would affect their BP. Control group BP was also measured at least two different time points 1-3 months from baseline.

A total of 211 patients were enrolled: 109 in the erenumab group and 87 in the fremanezumab group. The erenumab group was also associated with an increase in both systolic BP (SBP) and diastolic BP (DBP) (SBP ≤ 9 mm Hg; DBP ≤ 6.3 mm Hg). The fremanezumab group had a lower increase in SBP (1 mm Hg) and no increase in DBP. Nine patients were started on antihypertensive medications, five of them after the baseline BP recording only. There was no change over time in the control group.

As noted, CGRP has a potent vasodilatory effect. Although not proven, a theory has been posited that CGRP receptor antagonist medications are somewhat more likely to lead to systemic adverse effects than are ligand-blocking medications. This may, at least in part, explain why erenumab appears to have more associated GI discomfort and constipation as well as a vascular effect with hypertension. In light of these findings, it is absolutely necessary for the additional CGRP medications to also be studied for these potential risk factors.

With the advent of novel acute treatments for migraine, many providers ask themselves what the potential risks and benefits are for each new class of drugs developed and approved over the past few years. Johnston and colleagues reviewed five recently published RCT to compare risk-benefit profiles for lasmiditan, rimegepant, and ubrogepant. Lasmiditan is the only medication in the ditan class, a serotonin (5HT-1F) receptor agonist medication approved for the acute treatment of migraine. Rimegepant and ubrogepant are oral CGRP antagonists.

Lasmiditan does have a potential risk for impairment while driving due to excessive sedation and dizziness; it is also more likely than the CGRP medications to lead to the development of medication overuse headache. The CGRP medications, however, are associated with a smaller responder rate for headache freedom at 2 hours. The investigators reviewed the data published in five RCT to develop a statistically based decision-making process that correlates with the number needed to treat vs the number needed to harm for all three of these medications. The number needed to treat is a statistically defined parameter that characterizes the number of patients that need to be treated with an intervention to achieve a positive event. The number needed to harm refers to an additional negative event relative to the reference treatment (placebo in the case of an RCT).

The reviewed studies compared multiple dosages of these medications. Efficacy outcomes were pain relief and pain freedom at 2 hours, sustained pain relief from 2 to 24 hours, and freedom from the most bothersome symptom at 2 hours. Safety outcomes were dizziness and nausea.

The number needed to treat was the lowest for 200 mg lasmiditan (twice the highest recommended acute dose), followed by 75 mg rimegepant. The number needed to harm was highest for 25 mg ubrogepant (half of the lowest recommended acute dose). Nausea was lowest for 75 mg rimegepant.

An individualized approach is always recommended when considering both preventive and acute treatments for migraine. It is definitely worth keeping these results in mind when discussing potential acute treatment options with patients. This is especially true when considering patients who may be more likely to experience either dizziness or nausea with other acute treatments. It is also worth individualizing a potential acute treatment when a patient experiences rapid-onset migraine symptoms. Further investigations into both acute and preventive treatments would enlighten and further individualize our clinical approaches.

Erenumab currently carries a prescriber warning for constipation. Although there has been some anecdotal evidence for constipation with other CGRP antagonists, this has never fully been investigated. Currently, the other CGRP medication options have fewer side effects and not all  are associated with constipation. Kudrow and colleagues sought to review the incidence of constipation, and GI motility in general, with both erenumab and galcanezumab. Their hypothesis was that a single dose of erenumab would be associated with delayed GI motility and a single dose of galcanezumab would not be.

This study was conducted as a multicenter trial with single-blinding. A total of 65 patients were enrolled and given either 140 mg erenumab or 240 mg galcanezumab (the loading dose). GI motility was measured via a wireless motility capsule at baseline before treatment and repeated at 2 weeks. This test is approved by the US Food and Drug Administration for evaluation of gastric transit time in patients with suspected gastroparesis and for evaluation of colonic transit time in patients with chronic idiopathic constipation. Patients with prior GI symptoms were excluded, as were patients taking a tricyclic antidepressant or a calcium-channel blocker, owing to known constipation with these agents.

The primary endpoint in this study was change from a baseline colonic transit time 2 weeks after injection with the CGRP monoclonal antibody. Secondary endpoints included change from baseline in whole-gut transit time, gastric emptying time, small-bowel transfer time, and combined small- and large-bowel transfer time. The Gastrointestinal Symptom Rating Scale (GSRS) was also used, evaluating abdominal pain, reflux, indigestion, constipation, and diarrhea based on a 7-point response, ranging from no discomfort to very severe discomfort.

The primary endpoint of baseline change in colonic transit time was not statistically significant between the groups: A mean change of 5.8 hours was noted for erenumab and 5.4 hours for galcanezumab. Most secondary endpoints were also not statistically significantly different between the two groups. Small-bowel transit time was  decreased in the galcanezumab group. When the patient-reported scales were reviewed, spontaneous bowel movements decreased significantly in the erenumab group, a finding that was not seen in the galcanezumab group and was statistically significant. The GSRS also showed a small but statistically significant change in the erenumab group.

This study does appear to show a significant difference in the two CGRP antagonist medications. The full side-effect profiles of the four CGRP monoclonal antibodies and three oral CGRP blocking medications available remain unknown. Further head-to-head comparisons will allow better differentiation of these options and better individualization of patient care.

Calcitonin gene-related peptide (CGRP) antagonist medications are becoming more and more of a mainstay of both migraine prevention and acute treatment. Four CGRP monoclonal antibody medications and three oral CGRP antagonists are now available for prevention and acute treatment of migraine. When this class of medications was developed, many patients and providers were initially concerned regarding any potentially unanticipated long-term adverse events. The first CGRP antagonist medication, erenumab, was associated with constipation, and, although this has not been formally reported with other CGRP medications, there is some anecdotal evidence of gastrointestinal (GI) discomfort with both oral and other monoclonal antibody medications in this class. In 2021, erenumab was also reported to be associated with hypertension and a formal warning was issued for this.

Before CGRP was used for migraine prevention, it had been known to be a potent vasodilator. Although the randomized controlled trials (RCT) for all CGRP medications included a longitudinal review of blood pressure (BP) measures, none of those initial trials revealed an increased risk for hypertension or other cardiovascular events or concerns. Some of the initial trials even included patients at higher cardiovascular risk. Migraine itself is associated with an increased vascular risk; it is therefore extremely important to determine whether a potential treatment may be increasing this risk further.

In the study by de Vries and colleagues, all patients were started on either erenumab or fremanezumab and were included if they had a follow-up blood pressure measurement within 6 months. All patients had at least8 migraine days per month and had used four or more preventive medications. Patients taking erenumab were first started at 70 mg monthly and were optionally increased to 140 mg after 3 months. Fremanezumab was always given at a dose of 225 mg monthly (as opposed to 675 mg every 3 months). BP data were collected at baseline and followed up at every visit, with a maximum of 12 months of review. Patients were excluded if their baseline BP was measured while they were undergoing tapering an antihypertensive medication at the same time that they were starting the CGRP antagonist. Patients already treated for hypertension were included only if there were no changes to their hypertensive regimen.

Patients were also compared with a control group with a similar distribution in sex, age, and diagnosis, and who were not taking any migraine preventive medication that would affect their BP. Control group BP was also measured at least two different time points 1-3 months from baseline.

A total of 211 patients were enrolled: 109 in the erenumab group and 87 in the fremanezumab group. The erenumab group was also associated with an increase in both systolic BP (SBP) and diastolic BP (DBP) (SBP ≤ 9 mm Hg; DBP ≤ 6.3 mm Hg). The fremanezumab group had a lower increase in SBP (1 mm Hg) and no increase in DBP. Nine patients were started on antihypertensive medications, five of them after the baseline BP recording only. There was no change over time in the control group.

As noted, CGRP has a potent vasodilatory effect. Although not proven, a theory has been posited that CGRP receptor antagonist medications are somewhat more likely to lead to systemic adverse effects than are ligand-blocking medications. This may, at least in part, explain why erenumab appears to have more associated GI discomfort and constipation as well as a vascular effect with hypertension. In light of these findings, it is absolutely necessary for the additional CGRP medications to also be studied for these potential risk factors.

With the advent of novel acute treatments for migraine, many providers ask themselves what the potential risks and benefits are for each new class of drugs developed and approved over the past few years. Johnston and colleagues reviewed five recently published RCT to compare risk-benefit profiles for lasmiditan, rimegepant, and ubrogepant. Lasmiditan is the only medication in the ditan class, a serotonin (5HT-1F) receptor agonist medication approved for the acute treatment of migraine. Rimegepant and ubrogepant are oral CGRP antagonists.

Lasmiditan does have a potential risk for impairment while driving due to excessive sedation and dizziness; it is also more likely than the CGRP medications to lead to the development of medication overuse headache. The CGRP medications, however, are associated with a smaller responder rate for headache freedom at 2 hours. The investigators reviewed the data published in five RCT to develop a statistically based decision-making process that correlates with the number needed to treat vs the number needed to harm for all three of these medications. The number needed to treat is a statistically defined parameter that characterizes the number of patients that need to be treated with an intervention to achieve a positive event. The number needed to harm refers to an additional negative event relative to the reference treatment (placebo in the case of an RCT).

The reviewed studies compared multiple dosages of these medications. Efficacy outcomes were pain relief and pain freedom at 2 hours, sustained pain relief from 2 to 24 hours, and freedom from the most bothersome symptom at 2 hours. Safety outcomes were dizziness and nausea.

The number needed to treat was the lowest for 200 mg lasmiditan (twice the highest recommended acute dose), followed by 75 mg rimegepant. The number needed to harm was highest for 25 mg ubrogepant (half of the lowest recommended acute dose). Nausea was lowest for 75 mg rimegepant.

An individualized approach is always recommended when considering both preventive and acute treatments for migraine. It is definitely worth keeping these results in mind when discussing potential acute treatment options with patients. This is especially true when considering patients who may be more likely to experience either dizziness or nausea with other acute treatments. It is also worth individualizing a potential acute treatment when a patient experiences rapid-onset migraine symptoms. Further investigations into both acute and preventive treatments would enlighten and further individualize our clinical approaches.

Erenumab currently carries a prescriber warning for constipation. Although there has been some anecdotal evidence for constipation with other CGRP antagonists, this has never fully been investigated. Currently, the other CGRP medication options have fewer side effects and not all  are associated with constipation. Kudrow and colleagues sought to review the incidence of constipation, and GI motility in general, with both erenumab and galcanezumab. Their hypothesis was that a single dose of erenumab would be associated with delayed GI motility and a single dose of galcanezumab would not be.

This study was conducted as a multicenter trial with single-blinding. A total of 65 patients were enrolled and given either 140 mg erenumab or 240 mg galcanezumab (the loading dose). GI motility was measured via a wireless motility capsule at baseline before treatment and repeated at 2 weeks. This test is approved by the US Food and Drug Administration for evaluation of gastric transit time in patients with suspected gastroparesis and for evaluation of colonic transit time in patients with chronic idiopathic constipation. Patients with prior GI symptoms were excluded, as were patients taking a tricyclic antidepressant or a calcium-channel blocker, owing to known constipation with these agents.

The primary endpoint in this study was change from a baseline colonic transit time 2 weeks after injection with the CGRP monoclonal antibody. Secondary endpoints included change from baseline in whole-gut transit time, gastric emptying time, small-bowel transfer time, and combined small- and large-bowel transfer time. The Gastrointestinal Symptom Rating Scale (GSRS) was also used, evaluating abdominal pain, reflux, indigestion, constipation, and diarrhea based on a 7-point response, ranging from no discomfort to very severe discomfort.

The primary endpoint of baseline change in colonic transit time was not statistically significant between the groups: A mean change of 5.8 hours was noted for erenumab and 5.4 hours for galcanezumab. Most secondary endpoints were also not statistically significantly different between the two groups. Small-bowel transit time was  decreased in the galcanezumab group. When the patient-reported scales were reviewed, spontaneous bowel movements decreased significantly in the erenumab group, a finding that was not seen in the galcanezumab group and was statistically significant. The GSRS also showed a small but statistically significant change in the erenumab group.

This study does appear to show a significant difference in the two CGRP antagonist medications. The full side-effect profiles of the four CGRP monoclonal antibodies and three oral CGRP blocking medications available remain unknown. Further head-to-head comparisons will allow better differentiation of these options and better individualization of patient care.

Lasmiditan—the first migraine treatment in the new ditan class— is a serotonin receptor agonist, similar to triptan medications. However, it is specific for the 5HT_1F receptor rather than the 5HT_1B/1D receptor. The main purpose of this specificity is that it leads to less vascular risk; specifically, this medication should be safer for populations at higher risk for vascular events, such as myocardial infarction and stroke.

Only one triptan, naratriptan, had previously been studied for the treatment of menstrual migraine, at a recommended dose of 2.5 mg twice daily as a bridge. A new study by MacGregor and colleagues looked at taking 50, 100, or 200 mg of lasmiditan vs placebo for an individual premenstrual attack.

The participants in the study were recruited from the intention-to-treat population of two prior studies for this drug, a phase 2 trial and a phase 3 trial. The menstrual calendars of the female participants were reviewed, followed by randomization into one of the four groups. Patients with chronic migraine were excluded from the study. The primary outcome was freedom from pain at 2 hours; secondary outcomes were freedom from the most bothersome symptom and reduction in pain severity.

Of the four populations followed, all three intervention groups noted significant results in freedom from pain at 2 hours compared with placebo. The 2-hour responder rate was 33.6% for the 200 mg group, 16.7% for the 50 mg and 100 mg groups, and 7.6% for the placebo group. Freedom from the most bothersome symptom and pain reduction were also significant in these populations.

Menstruation-associated migraine and worsening headache attacks due to patients' hormonal fluctuations are some of the most common issues and triggers that neurologists and headache specialists confront. Although the responder rates for freedom from pain at 2 hours were not very robust, lasmiditan does appear to be significantly effective in this population, and in those with menstrual triggers specifically. The field of headache medicine would be even better served by additional studies on both preventive and more acute medications in association with hormonal triggers.

Another very common trigger for migraine is changes in sleep patterns. An astute headache specialist will always ask about sleep quantity and quality during an initial assessment of a patient. Many headache centers have sleep-specific questionnaires that patients fill out during intake. The precise association between migraine and sleep deserves more elucidation. Duan and colleagues specifically set out to reveal whether differences in sleep quality affect migraine frequency; whether this is the same among different gender and age groups; and whether headache disability, severity, mood, and quality of life are related to underlying sleep changes independent of other factors.

A total of 134 participants with migraine and 70 without migraine or any other headache disorder were enrolled in the study. Sleep quality was assessed through The Pittsburgh Sleep Quality Index (PSQI) questionnaire. This is a commonly used self-reported questionnaire for assessing quality and quantity of sleep over the past month and is considered the standard of care in most sleep centers. The investigators here sought to determine the predictive value of the PSQI in regard to migraine. Migraine disability was assessed via the Migraine Disability Assessment (MIDAS) scale as well as the Headache Impact Test (HIT-6). Statistical analysis was performed with logistical regression, t test, and χ² squared test.

There strongest correlations between poor sleep quality and risk of migraine were found in women, patients over 35 years old, and those with lower education levels. The results revealed that the migraine group had poorer sleep quality, as well as higher anxiety and depression scores, compared with the control group. A low PSQI score (eg, poorer sleep quality) was associated with higher migraine frequency; this was independent of body mass index (BMI), weekly exercise time, and smoking or drinking history. After participants were divided into good and poor sleep quality subgroups, the PSQI score was found to increase the odds ratio of migraine by a factor of 6.

The investigators were able to show the predictive quality of the PSQI score. Worse sleep quality was found to be associated with a higher MIDAS score and HIT-6 score as well as total pain burden, pain severity, decreased quality of life, depression, and anxiety. Although most headache specialists spend a significant amount of time discussing sleep as it relates to migraine, it may be worth considering following a sleep quality scale, such as the PSQI, over time as we monitor our patients. This may allow us to take a more proactive role and be able to prognosticate our patients' migraine journey somewhat better. Although sleep triggers and associations with migraine can be very difficult to discuss and treat, this study very clearly argues for the importance of focusing on sleep with our patients.

Although the most common aura our patients with migraine experience is visual, many patients with migraine will also experience non-aura visual changes. These can range from short-lasting episodes of blurred vision, such as transient visual obscurations, or other transient visual disturbances that do not fit the criteria of aura as defined by the International Classification of Headache Disorders (ICHD).

A prior study by Tsao and colleagues had revealed that almost half of headache patients experienced some headache-related visual change, the most common of which were short-lasting flickering lights or a movable, monochromatic scotoma. As opposed to visual aura, these transient disturbances were shorter in onset and duration and typically occurred during the headache phase of a migraine attack. In the current study, Tsao and colleagues sought to determine whether the presence of these findings was associated with a different headache burden from that typically found in migraine with aura.

The participants in this study were enrolled over a 10-year period from May 2010 to July 2020. They initially underwent a visual phenomenon questionnaire and then a thorough clinical interview to determine their headache diagnosis per ICHD criteria — specifically whether they had an underlying diagnosis of migraine with aura or migraine without aura. Participants were also separately diagnosed with chronic migraine or medication overuse headache. A visual rating scale was used in the initial questionnaires. This scale posed questions about the duration of symptoms; whether the symptoms develop gradually or suddenly; and whether the visual change was a scotoma, zigzag lines, or in a unilateral or bilateral visual field. A prior study by these investigators determined this visual rating scale to be highly sensitive and specific for diagnosing migraine with aura.

Participants were also given the MIDAS questionnaire and were assessed with the HIT-6 scale, a migraine photophobia score, and the Beck Depression Inventory. A total of 12,255 patients were enrolled, 9946 with migraine, who were subdivided on the basis of diagnosis of migraine with or without aura. Blurred vision was the most common visual complaint among all migraine patients. Patients who had transient visual disturbances that did not fit the criteria of migraine with aura were noted to have a statistically significant higher headache frequency, more severe headache-related disability, a higher likelihood of developing medication overuse headache, and a greater incidence of anxiety and depression.

An important distinction that all headache specialists make is whether their patients experience migraine with or without aura. The primary purpose for this distinction is to determine the appropriateness of specific medications (estrogen or vasoconstrictive medications), as migraine aura relates to vascular risk. We usually delve deeply into whether the visual symptoms that our patients experience do or do not fit into the ICHD criteria of migraine aura. We should not discard or think less of non-aura visual disturbances; these authors argue very clearly that these kinds of visual changes can be very relevant prognostically.

Lasmiditan—the first migraine treatment in the new ditan class— is a serotonin receptor agonist, similar to triptan medications. However, it is specific for the 5HT_1F receptor rather than the 5HT_1B/1D receptor. The main purpose of this specificity is that it leads to less vascular risk; specifically, this medication should be safer for populations at higher risk for vascular events, such as myocardial infarction and stroke.

Only one triptan, naratriptan, had previously been studied for the treatment of menstrual migraine, at a recommended dose of 2.5 mg twice daily as a bridge. A new study by MacGregor and colleagues looked at taking 50, 100, or 200 mg of lasmiditan vs placebo for an individual premenstrual attack.

The participants in the study were recruited from the intention-to-treat population of two prior studies for this drug, a phase 2 trial and a phase 3 trial. The menstrual calendars of the female participants were reviewed, followed by randomization into one of the four groups. Patients with chronic migraine were excluded from the study. The primary outcome was freedom from pain at 2 hours; secondary outcomes were freedom from the most bothersome symptom and reduction in pain severity.

Of the four populations followed, all three intervention groups noted significant results in freedom from pain at 2 hours compared with placebo. The 2-hour responder rate was 33.6% for the 200 mg group, 16.7% for the 50 mg and 100 mg groups, and 7.6% for the placebo group. Freedom from the most bothersome symptom and pain reduction were also significant in these populations.

Menstruation-associated migraine and worsening headache attacks due to patients' hormonal fluctuations are some of the most common issues and triggers that neurologists and headache specialists confront. Although the responder rates for freedom from pain at 2 hours were not very robust, lasmiditan does appear to be significantly effective in this population, and in those with menstrual triggers specifically. The field of headache medicine would be even better served by additional studies on both preventive and more acute medications in association with hormonal triggers.

Another very common trigger for migraine is changes in sleep patterns. An astute headache specialist will always ask about sleep quantity and quality during an initial assessment of a patient. Many headache centers have sleep-specific questionnaires that patients fill out during intake. The precise association between migraine and sleep deserves more elucidation. Duan and colleagues specifically set out to reveal whether differences in sleep quality affect migraine frequency; whether this is the same among different gender and age groups; and whether headache disability, severity, mood, and quality of life are related to underlying sleep changes independent of other factors.

A total of 134 participants with migraine and 70 without migraine or any other headache disorder were enrolled in the study. Sleep quality was assessed through The Pittsburgh Sleep Quality Index (PSQI) questionnaire. This is a commonly used self-reported questionnaire for assessing quality and quantity of sleep over the past month and is considered the standard of care in most sleep centers. The investigators here sought to determine the predictive value of the PSQI in regard to migraine. Migraine disability was assessed via the Migraine Disability Assessment (MIDAS) scale as well as the Headache Impact Test (HIT-6). Statistical analysis was performed with logistical regression, t test, and χ² squared test.

There strongest correlations between poor sleep quality and risk of migraine were found in women, patients over 35 years old, and those with lower education levels. The results revealed that the migraine group had poorer sleep quality, as well as higher anxiety and depression scores, compared with the control group. A low PSQI score (eg, poorer sleep quality) was associated with higher migraine frequency; this was independent of body mass index (BMI), weekly exercise time, and smoking or drinking history. After participants were divided into good and poor sleep quality subgroups, the PSQI score was found to increase the odds ratio of migraine by a factor of 6.

The investigators were able to show the predictive quality of the PSQI score. Worse sleep quality was found to be associated with a higher MIDAS score and HIT-6 score as well as total pain burden, pain severity, decreased quality of life, depression, and anxiety. Although most headache specialists spend a significant amount of time discussing sleep as it relates to migraine, it may be worth considering following a sleep quality scale, such as the PSQI, over time as we monitor our patients. This may allow us to take a more proactive role and be able to prognosticate our patients' migraine journey somewhat better. Although sleep triggers and associations with migraine can be very difficult to discuss and treat, this study very clearly argues for the importance of focusing on sleep with our patients.

Although the most common aura our patients with migraine experience is visual, many patients with migraine will also experience non-aura visual changes. These can range from short-lasting episodes of blurred vision, such as transient visual obscurations, or other transient visual disturbances that do not fit the criteria of aura as defined by the International Classification of Headache Disorders (ICHD).

A prior study by Tsao and colleagues had revealed that almost half of headache patients experienced some headache-related visual change, the most common of which were short-lasting flickering lights or a movable, monochromatic scotoma. As opposed to visual aura, these transient disturbances were shorter in onset and duration and typically occurred during the headache phase of a migraine attack. In the current study, Tsao and colleagues sought to determine whether the presence of these findings was associated with a different headache burden from that typically found in migraine with aura.

The participants in this study were enrolled over a 10-year period from May 2010 to July 2020. They initially underwent a visual phenomenon questionnaire and then a thorough clinical interview to determine their headache diagnosis per ICHD criteria — specifically whether they had an underlying diagnosis of migraine with aura or migraine without aura. Participants were also separately diagnosed with chronic migraine or medication overuse headache. A visual rating scale was used in the initial questionnaires. This scale posed questions about the duration of symptoms; whether the symptoms develop gradually or suddenly; and whether the visual change was a scotoma, zigzag lines, or in a unilateral or bilateral visual field. A prior study by these investigators determined this visual rating scale to be highly sensitive and specific for diagnosing migraine with aura.

Participants were also given the MIDAS questionnaire and were assessed with the HIT-6 scale, a migraine photophobia score, and the Beck Depression Inventory. A total of 12,255 patients were enrolled, 9946 with migraine, who were subdivided on the basis of diagnosis of migraine with or without aura. Blurred vision was the most common visual complaint among all migraine patients. Patients who had transient visual disturbances that did not fit the criteria of migraine with aura were noted to have a statistically significant higher headache frequency, more severe headache-related disability, a higher likelihood of developing medication overuse headache, and a greater incidence of anxiety and depression.

An important distinction that all headache specialists make is whether their patients experience migraine with or without aura. The primary purpose for this distinction is to determine the appropriateness of specific medications (estrogen or vasoconstrictive medications), as migraine aura relates to vascular risk. We usually delve deeply into whether the visual symptoms that our patients experience do or do not fit into the ICHD criteria of migraine aura. We should not discard or think less of non-aura visual disturbances; these authors argue very clearly that these kinds of visual changes can be very relevant prognostically.

Lasmiditan—the first migraine treatment in the new ditan class— is a serotonin receptor agonist, similar to triptan medications. However, it is specific for the 5HT_1F receptor rather than the 5HT_1B/1D receptor. The main purpose of this specificity is that it leads to less vascular risk; specifically, this medication should be safer for populations at higher risk for vascular events, such as myocardial infarction and stroke.

Only one triptan, naratriptan, had previously been studied for the treatment of menstrual migraine, at a recommended dose of 2.5 mg twice daily as a bridge. A new study by MacGregor and colleagues looked at taking 50, 100, or 200 mg of lasmiditan vs placebo for an individual premenstrual attack.

The participants in the study were recruited from the intention-to-treat population of two prior studies for this drug, a phase 2 trial and a phase 3 trial. The menstrual calendars of the female participants were reviewed, followed by randomization into one of the four groups. Patients with chronic migraine were excluded from the study. The primary outcome was freedom from pain at 2 hours; secondary outcomes were freedom from the most bothersome symptom and reduction in pain severity.

Of the four populations followed, all three intervention groups noted significant results in freedom from pain at 2 hours compared with placebo. The 2-hour responder rate was 33.6% for the 200 mg group, 16.7% for the 50 mg and 100 mg groups, and 7.6% for the placebo group. Freedom from the most bothersome symptom and pain reduction were also significant in these populations.

Menstruation-associated migraine and worsening headache attacks due to patients' hormonal fluctuations are some of the most common issues and triggers that neurologists and headache specialists confront. Although the responder rates for freedom from pain at 2 hours were not very robust, lasmiditan does appear to be significantly effective in this population, and in those with menstrual triggers specifically. The field of headache medicine would be even better served by additional studies on both preventive and more acute medications in association with hormonal triggers.

Another very common trigger for migraine is changes in sleep patterns. An astute headache specialist will always ask about sleep quantity and quality during an initial assessment of a patient. Many headache centers have sleep-specific questionnaires that patients fill out during intake. The precise association between migraine and sleep deserves more elucidation. Duan and colleagues specifically set out to reveal whether differences in sleep quality affect migraine frequency; whether this is the same among different gender and age groups; and whether headache disability, severity, mood, and quality of life are related to underlying sleep changes independent of other factors.

A total of 134 participants with migraine and 70 without migraine or any other headache disorder were enrolled in the study. Sleep quality was assessed through The Pittsburgh Sleep Quality Index (PSQI) questionnaire. This is a commonly used self-reported questionnaire for assessing quality and quantity of sleep over the past month and is considered the standard of care in most sleep centers. The investigators here sought to determine the predictive value of the PSQI in regard to migraine. Migraine disability was assessed via the Migraine Disability Assessment (MIDAS) scale as well as the Headache Impact Test (HIT-6). Statistical analysis was performed with logistical regression, t test, and χ² squared test.

There strongest correlations between poor sleep quality and risk of migraine were found in women, patients over 35 years old, and those with lower education levels. The results revealed that the migraine group had poorer sleep quality, as well as higher anxiety and depression scores, compared with the control group. A low PSQI score (eg, poorer sleep quality) was associated with higher migraine frequency; this was independent of body mass index (BMI), weekly exercise time, and smoking or drinking history. After participants were divided into good and poor sleep quality subgroups, the PSQI score was found to increase the odds ratio of migraine by a factor of 6.

The investigators were able to show the predictive quality of the PSQI score. Worse sleep quality was found to be associated with a higher MIDAS score and HIT-6 score as well as total pain burden, pain severity, decreased quality of life, depression, and anxiety. Although most headache specialists spend a significant amount of time discussing sleep as it relates to migraine, it may be worth considering following a sleep quality scale, such as the PSQI, over time as we monitor our patients. This may allow us to take a more proactive role and be able to prognosticate our patients' migraine journey somewhat better. Although sleep triggers and associations with migraine can be very difficult to discuss and treat, this study very clearly argues for the importance of focusing on sleep with our patients.

Although the most common aura our patients with migraine experience is visual, many patients with migraine will also experience non-aura visual changes. These can range from short-lasting episodes of blurred vision, such as transient visual obscurations, or other transient visual disturbances that do not fit the criteria of aura as defined by the International Classification of Headache Disorders (ICHD).

A prior study by Tsao and colleagues had revealed that almost half of headache patients experienced some headache-related visual change, the most common of which were short-lasting flickering lights or a movable, monochromatic scotoma. As opposed to visual aura, these transient disturbances were shorter in onset and duration and typically occurred during the headache phase of a migraine attack. In the current study, Tsao and colleagues sought to determine whether the presence of these findings was associated with a different headache burden from that typically found in migraine with aura.

The participants in this study were enrolled over a 10-year period from May 2010 to July 2020. They initially underwent a visual phenomenon questionnaire and then a thorough clinical interview to determine their headache diagnosis per ICHD criteria — specifically whether they had an underlying diagnosis of migraine with aura or migraine without aura. Participants were also separately diagnosed with chronic migraine or medication overuse headache. A visual rating scale was used in the initial questionnaires. This scale posed questions about the duration of symptoms; whether the symptoms develop gradually or suddenly; and whether the visual change was a scotoma, zigzag lines, or in a unilateral or bilateral visual field. A prior study by these investigators determined this visual rating scale to be highly sensitive and specific for diagnosing migraine with aura.

Participants were also given the MIDAS questionnaire and were assessed with the HIT-6 scale, a migraine photophobia score, and the Beck Depression Inventory. A total of 12,255 patients were enrolled, 9946 with migraine, who were subdivided on the basis of diagnosis of migraine with or without aura. Blurred vision was the most common visual complaint among all migraine patients. Patients who had transient visual disturbances that did not fit the criteria of migraine with aura were noted to have a statistically significant higher headache frequency, more severe headache-related disability, a higher likelihood of developing medication overuse headache, and a greater incidence of anxiety and depression.

An important distinction that all headache specialists make is whether their patients experience migraine with or without aura. The primary purpose for this distinction is to determine the appropriateness of specific medications (estrogen or vasoconstrictive medications), as migraine aura relates to vascular risk. We usually delve deeply into whether the visual symptoms that our patients experience do or do not fit into the ICHD criteria of migraine aura. We should not discard or think less of non-aura visual disturbances; these authors argue very clearly that these kinds of visual changes can be very relevant prognostically.

The theme of this month's commentary is alternative outcomes measures for future migraine studies. The traditional outcomes measures, such as headache frequency measured in headache days, have long been considered gold standards when evaluating the efficacy of preventive interventions. When headache conditions are complicated by interictal pain or other symptoms, or when medication overuse adds a higher frequency or greater severity, those traditional measures are somewhat less exact and specific. Meaningful change for patients with higher frequency of attacks, near-continuous pain, or other migraine symptoms is quite different from that for those without these complications.

Ailani and colleagues reviewed post hoc data from the CONQUER trial, a prior study evaluating the safety and efficacy of galcanezumab vs placebo in patients who had previously not benefited from two to four categories of migraine preventive medication. This refractory population was initially noted to have 4.1 fewer headache days per month than patients taking placebo, but the authors now attempted to review these data with a focus on a different measure: total pain burden (TPB). They defined daily TPB as a single composite measure assessing the frequency, duration, and severity of migraine, calculated by multiplying the number of hours of migraine by the maximum daily migraine pain severity score. The monthly TPB was calculated by adding the daily pain burden over the entire month. The Migraine Disability Assessment questionnaire (MIDAS) and Migraine-Specific Quality of Life Questionnaire (MSQ) scores were also included to compare migraine-related disability and quality of life.

The patients who received galcanezumab were noted to have a significantly lower TPB, both in episodic and chronic migraine. Significantly greater reductions in monthly TPB relative to placebo were observed at each individual month as well. The change from baseline TPB was also noted to be significantly improved in the galcanezumab group compared with the placebo group. The reduction in TPB was noted even when migraine-day reductions were accounted for as part of a sensitivity analysis.

Preventive trials for migraine treatment focus primarily on migraine-day reduction, and for many patients with higher-frequency migraine, this measure does not adequately account for their disease-related disability. This unique way of looking at pain as part of a bigger picture is much more significant and meaningful for this patient population. Migraine frequency is still a very important outcomes measure, but it would be wise to add TBP or another measure that looks more globally at disease-related disability, especially when investigating preventive options in patients with chronic migraine.

When considering whether an intervention is helpful, most patients and clinicians follow the headache frequency, severity, or quality-of-life factors. As most patients will readily report, not all "headache-free days" are created equal. Although most people with migraine will experience days with absolutely no headache pain or other migraine-associated symptoms, on many days they will still have some symptoms of migraine. Lee and colleagues attempted to quantify the difference between headache-free days and crystal-clear days.

Most headache studies use the frequency of headache days as a primary or secondary outcome. This study collected data on both headache days and crystal-clear days, using data from a questionnaire-based large South Korean nationwide population study that evaluated headache and sleep. The study questions were validated for migraine and aura, and included: "How many days have you had a headache during the previous 30 days?" and "How many days have you had crystal-clear days without headache during the previous 30 days?" The data were then analyzed and compared with the widespread pain index (criteria for fibromyalgia) as well as sleep duration, sleep quality, depression and anxiety scales, and an allodynia checklist.

A little over 3000 respondents completed the surveys; 1938 had experienced headache over the past year, 170 were classified as having a diagnosis of migraine, and 50 of those were diagnosed with aura as well. Out of the patients with migraine, 97% had "unclear days." This was higher than the rate of those with non-migraine headaches (91%). Nearly all people surveyed had some crystal-clear days (99.4%).

The number of crystal-clear days per 30 days was significantly lower in participants with migraine than in those with non-migraine headache. Participants with migraine also had higher frequencies of cutaneous allodynia, anxiety, and depression. The weekly average sleep duration in participants with migraine did not significantly differ from that in participants with non-migraine headaches. The widespread pain index rate was much higher in those with migraine as well.

Most patients will definitely understand the difference between crystal-clear and unclear headache days. Many of the newer outcomes studies in migraine have started focusing on the most bothersome symptom, as headache pain is far from the only significant or disabling symptom associated with migraine. This study makes clear that further outcomes changes are necessary, and that a potentially more meaningful result in migraine studies may actually be crystal-clear days rather than simply headache-free days.

Although there are more acute options available for headache treatment, medication overuse headache remains a major complicating factor for most clinicians who treat headache. When educating patients, there is always a strong emphasis on guidelines for acute medication use. Many patients struggle with knowing when to use an acute treatment and when to alternate with a different treatment, and often they will withhold treatment completely due to fear of medication overuse. The new class of calcitonin gene-related peptide (CGRP) antagonist medications has shown some potential benefit as a preventive option for both medication overuse headache and migraine.

The prospective study by Curone and colleagues enrolled 300 patients with confirmed medication overuse headache who did not undergo withdrawal of the overused acute medication. Patients who are already taking preventive medications were excluded, as were patients with diagnoses other than chronic migraine or medication overuse. Patients were given one of the three injectable CGRP antagonist medications for prevention and were followed up at 3, 6, 9, and 12 months. The primary outcome was MIDAS score as well as monthly headache days and analgesic consumption.

Out of 303 patients, 242 (80%) showed both a ≥50% reduction of monthly headache days and ≥50% reduction in analgesic intake at 3-month follow-up visit. At 9 months, 198 (65%) were still responders. Monthly analgesic intake decreased ≥50% in 268 of 303 patients (88%) at 3 months and in 241 of 303 patients (79%) at the 6-month follow-up.

For years there has been a debate regarding whether withdrawal of an overused medication is necessary for effective treatment of medication overuse headache. Many preventive treatments are less effective when medication overuse is ongoing. The CGRP class of medications does appear to be effective even with ongoing acute medication overuse. This class of medications should definitely be considered when withdrawing an overused medication is complicated, or when a patient needs to continue to take analgesic medications for another condition.

The theme of this month's commentary is alternative outcomes measures for future migraine studies. The traditional outcomes measures, such as headache frequency measured in headache days, have long been considered gold standards when evaluating the efficacy of preventive interventions. When headache conditions are complicated by interictal pain or other symptoms, or when medication overuse adds a higher frequency or greater severity, those traditional measures are somewhat less exact and specific. Meaningful change for patients with higher frequency of attacks, near-continuous pain, or other migraine symptoms is quite different from that for those without these complications.

Ailani and colleagues reviewed post hoc data from the CONQUER trial, a prior study evaluating the safety and efficacy of galcanezumab vs placebo in patients who had previously not benefited from two to four categories of migraine preventive medication. This refractory population was initially noted to have 4.1 fewer headache days per month than patients taking placebo, but the authors now attempted to review these data with a focus on a different measure: total pain burden (TPB). They defined daily TPB as a single composite measure assessing the frequency, duration, and severity of migraine, calculated by multiplying the number of hours of migraine by the maximum daily migraine pain severity score. The monthly TPB was calculated by adding the daily pain burden over the entire month. The Migraine Disability Assessment questionnaire (MIDAS) and Migraine-Specific Quality of Life Questionnaire (MSQ) scores were also included to compare migraine-related disability and quality of life.

The patients who received galcanezumab were noted to have a significantly lower TPB, both in episodic and chronic migraine. Significantly greater reductions in monthly TPB relative to placebo were observed at each individual month as well. The change from baseline TPB was also noted to be significantly improved in the galcanezumab group compared with the placebo group. The reduction in TPB was noted even when migraine-day reductions were accounted for as part of a sensitivity analysis.

Preventive trials for migraine treatment focus primarily on migraine-day reduction, and for many patients with higher-frequency migraine, this measure does not adequately account for their disease-related disability. This unique way of looking at pain as part of a bigger picture is much more significant and meaningful for this patient population. Migraine frequency is still a very important outcomes measure, but it would be wise to add TBP or another measure that looks more globally at disease-related disability, especially when investigating preventive options in patients with chronic migraine.

When considering whether an intervention is helpful, most patients and clinicians follow the headache frequency, severity, or quality-of-life factors. As most patients will readily report, not all "headache-free days" are created equal. Although most people with migraine will experience days with absolutely no headache pain or other migraine-associated symptoms, on many days they will still have some symptoms of migraine. Lee and colleagues attempted to quantify the difference between headache-free days and crystal-clear days.

Most headache studies use the frequency of headache days as a primary or secondary outcome. This study collected data on both headache days and crystal-clear days, using data from a questionnaire-based large South Korean nationwide population study that evaluated headache and sleep. The study questions were validated for migraine and aura, and included: "How many days have you had a headache during the previous 30 days?" and "How many days have you had crystal-clear days without headache during the previous 30 days?" The data were then analyzed and compared with the widespread pain index (criteria for fibromyalgia) as well as sleep duration, sleep quality, depression and anxiety scales, and an allodynia checklist.

A little over 3000 respondents completed the surveys; 1938 had experienced headache over the past year, 170 were classified as having a diagnosis of migraine, and 50 of those were diagnosed with aura as well. Out of the patients with migraine, 97% had "unclear days." This was higher than the rate of those with non-migraine headaches (91%). Nearly all people surveyed had some crystal-clear days (99.4%).

The number of crystal-clear days per 30 days was significantly lower in participants with migraine than in those with non-migraine headache. Participants with migraine also had higher frequencies of cutaneous allodynia, anxiety, and depression. The weekly average sleep duration in participants with migraine did not significantly differ from that in participants with non-migraine headaches. The widespread pain index rate was much higher in those with migraine as well.

Most patients will definitely understand the difference between crystal-clear and unclear headache days. Many of the newer outcomes studies in migraine have started focusing on the most bothersome symptom, as headache pain is far from the only significant or disabling symptom associated with migraine. This study makes clear that further outcomes changes are necessary, and that a potentially more meaningful result in migraine studies may actually be crystal-clear days rather than simply headache-free days.

Although there are more acute options available for headache treatment, medication overuse headache remains a major complicating factor for most clinicians who treat headache. When educating patients, there is always a strong emphasis on guidelines for acute medication use. Many patients struggle with knowing when to use an acute treatment and when to alternate with a different treatment, and often they will withhold treatment completely due to fear of medication overuse. The new class of calcitonin gene-related peptide (CGRP) antagonist medications has shown some potential benefit as a preventive option for both medication overuse headache and migraine.

The prospective study by Curone and colleagues enrolled 300 patients with confirmed medication overuse headache who did not undergo withdrawal of the overused acute medication. Patients who are already taking preventive medications were excluded, as were patients with diagnoses other than chronic migraine or medication overuse. Patients were given one of the three injectable CGRP antagonist medications for prevention and were followed up at 3, 6, 9, and 12 months. The primary outcome was MIDAS score as well as monthly headache days and analgesic consumption.

Out of 303 patients, 242 (80%) showed both a ≥50% reduction of monthly headache days and ≥50% reduction in analgesic intake at 3-month follow-up visit. At 9 months, 198 (65%) were still responders. Monthly analgesic intake decreased ≥50% in 268 of 303 patients (88%) at 3 months and in 241 of 303 patients (79%) at the 6-month follow-up.

For years there has been a debate regarding whether withdrawal of an overused medication is necessary for effective treatment of medication overuse headache. Many preventive treatments are less effective when medication overuse is ongoing. The CGRP class of medications does appear to be effective even with ongoing acute medication overuse. This class of medications should definitely be considered when withdrawing an overused medication is complicated, or when a patient needs to continue to take analgesic medications for another condition.

The theme of this month's commentary is alternative outcomes measures for future migraine studies. The traditional outcomes measures, such as headache frequency measured in headache days, have long been considered gold standards when evaluating the efficacy of preventive interventions. When headache conditions are complicated by interictal pain or other symptoms, or when medication overuse adds a higher frequency or greater severity, those traditional measures are somewhat less exact and specific. Meaningful change for patients with higher frequency of attacks, near-continuous pain, or other migraine symptoms is quite different from that for those without these complications.

Ailani and colleagues reviewed post hoc data from the CONQUER trial, a prior study evaluating the safety and efficacy of galcanezumab vs placebo in patients who had previously not benefited from two to four categories of migraine preventive medication. This refractory population was initially noted to have 4.1 fewer headache days per month than patients taking placebo, but the authors now attempted to review these data with a focus on a different measure: total pain burden (TPB). They defined daily TPB as a single composite measure assessing the frequency, duration, and severity of migraine, calculated by multiplying the number of hours of migraine by the maximum daily migraine pain severity score. The monthly TPB was calculated by adding the daily pain burden over the entire month. The Migraine Disability Assessment questionnaire (MIDAS) and Migraine-Specific Quality of Life Questionnaire (MSQ) scores were also included to compare migraine-related disability and quality of life.

The patients who received galcanezumab were noted to have a significantly lower TPB, both in episodic and chronic migraine. Significantly greater reductions in monthly TPB relative to placebo were observed at each individual month as well. The change from baseline TPB was also noted to be significantly improved in the galcanezumab group compared with the placebo group. The reduction in TPB was noted even when migraine-day reductions were accounted for as part of a sensitivity analysis.

Preventive trials for migraine treatment focus primarily on migraine-day reduction, and for many patients with higher-frequency migraine, this measure does not adequately account for their disease-related disability. This unique way of looking at pain as part of a bigger picture is much more significant and meaningful for this patient population. Migraine frequency is still a very important outcomes measure, but it would be wise to add TBP or another measure that looks more globally at disease-related disability, especially when investigating preventive options in patients with chronic migraine.

When considering whether an intervention is helpful, most patients and clinicians follow the headache frequency, severity, or quality-of-life factors. As most patients will readily report, not all "headache-free days" are created equal. Although most people with migraine will experience days with absolutely no headache pain or other migraine-associated symptoms, on many days they will still have some symptoms of migraine. Lee and colleagues attempted to quantify the difference between headache-free days and crystal-clear days.

Most headache studies use the frequency of headache days as a primary or secondary outcome. This study collected data on both headache days and crystal-clear days, using data from a questionnaire-based large South Korean nationwide population study that evaluated headache and sleep. The study questions were validated for migraine and aura, and included: "How many days have you had a headache during the previous 30 days?" and "How many days have you had crystal-clear days without headache during the previous 30 days?" The data were then analyzed and compared with the widespread pain index (criteria for fibromyalgia) as well as sleep duration, sleep quality, depression and anxiety scales, and an allodynia checklist.

A little over 3000 respondents completed the surveys; 1938 had experienced headache over the past year, 170 were classified as having a diagnosis of migraine, and 50 of those were diagnosed with aura as well. Out of the patients with migraine, 97% had "unclear days." This was higher than the rate of those with non-migraine headaches (91%). Nearly all people surveyed had some crystal-clear days (99.4%).

The number of crystal-clear days per 30 days was significantly lower in participants with migraine than in those with non-migraine headache. Participants with migraine also had higher frequencies of cutaneous allodynia, anxiety, and depression. The weekly average sleep duration in participants with migraine did not significantly differ from that in participants with non-migraine headaches. The widespread pain index rate was much higher in those with migraine as well.

Most patients will definitely understand the difference between crystal-clear and unclear headache days. Many of the newer outcomes studies in migraine have started focusing on the most bothersome symptom, as headache pain is far from the only significant or disabling symptom associated with migraine. This study makes clear that further outcomes changes are necessary, and that a potentially more meaningful result in migraine studies may actually be crystal-clear days rather than simply headache-free days.

Although there are more acute options available for headache treatment, medication overuse headache remains a major complicating factor for most clinicians who treat headache. When educating patients, there is always a strong emphasis on guidelines for acute medication use. Many patients struggle with knowing when to use an acute treatment and when to alternate with a different treatment, and often they will withhold treatment completely due to fear of medication overuse. The new class of calcitonin gene-related peptide (CGRP) antagonist medications has shown some potential benefit as a preventive option for both medication overuse headache and migraine.

The prospective study by Curone and colleagues enrolled 300 patients with confirmed medication overuse headache who did not undergo withdrawal of the overused acute medication. Patients who are already taking preventive medications were excluded, as were patients with diagnoses other than chronic migraine or medication overuse. Patients were given one of the three injectable CGRP antagonist medications for prevention and were followed up at 3, 6, 9, and 12 months. The primary outcome was MIDAS score as well as monthly headache days and analgesic consumption.

Out of 303 patients, 242 (80%) showed both a ≥50% reduction of monthly headache days and ≥50% reduction in analgesic intake at 3-month follow-up visit. At 9 months, 198 (65%) were still responders. Monthly analgesic intake decreased ≥50% in 268 of 303 patients (88%) at 3 months and in 241 of 303 patients (79%) at the 6-month follow-up.

For years there has been a debate regarding whether withdrawal of an overused medication is necessary for effective treatment of medication overuse headache. Many preventive treatments are less effective when medication overuse is ongoing. The CGRP class of medications does appear to be effective even with ongoing acute medication overuse. This class of medications should definitely be considered when withdrawing an overused medication is complicated, or when a patient needs to continue to take analgesic medications for another condition.

Migraine is a unique neurologic condition, in that a person can't prove they have it and there are few objective tools neurologists have to guide their diagnostic process. The recognition of the role of the vasoactive peptide calcitonin gene-related peptide (CGRP) in the 1990s changed the way many researchers and clinicians conceptualized migraine. Subsequent studies have used CGRP as a human model for migraine, and most recently pituitary adenylate cyclase–activating polypeptide 38 (PACAP-38) has also been recognized for its important role in migraine propagation. All of the existing data have been in adults, and no studies until now have specifically investigated the presence of these peptides in children with migraine.

Pediatric migraine is unique in a number of ways. Children with migraine present less unilaterally, the duration of their attacks is typically shorter, and the associated symptoms can often be more prominent than the headache pain during an attack. There are unique pediatric migraine subtypes that are exceptionally rare in adults, such as periodic paralysis attacks and abdominal migraine. For this reason, it is not entirely clear whether the same biomarkers of disease in adults would also be present in the pediatric population.

In the study by Liu and colleagues, the investigators enrolled 76 pediatric patients with migraine (the diagnosis was confirmed by at least two neurologists). Patients were excluded if there was any analgesic medication use over the past 2 months; if there was concern for secondary headache; or any underlying mood disorders, congenital disease, or other major medical conditions. An additional 77 controls were matched for age and sex. Blood was collected from all participants after an 8-hour fast to avoid collecting after potentially ingesting a food trigger. Blood samples were obtained during an ictal period (within 8 hours of a migraine attack) as well as interictally (not taken if the participant had a migraine attack within the past 24 hours).

The plasma CGRP and PACAP-38 levels were significantly higher in pediatric patients with migraine than in those without a migraine history, in both the ictal state and the interictal state. Among patients with migraine, there was a nonsignificant trend toward a higher CGRP level in the ictal phase, and no difference in these phases with PACAP-38. There was no difference in the CGRP or PACAP-38 levels between participants with and those without aura. When different aura groups were compared (with the participants separated on the basis of a history of motor vs vision vs sensory aura), no difference was seen among the different aura groups. Binary logistic regression testing and analysis of variance also showed that CGRP and PACAP-38 are independent risk factors for pediatric migraine, and specific levels of each were associated with an 11 and a 13 times increased risk, respectively.

Biomarker testing is still not clinically performed for migraine either in adults or children. This is primarily due to cost and the fact that most commercially available laboratories do not currently offer these tests. The results above do shed additional light on migraine pathogenesis and indicate that the phenotypic differences seen in pediatric migraine are less likely related to differences in brain function in children.

Levetiracetam is a commonly used antiepileptic medication. Prior studies have investigated the use of this medication for migraine, both acutely and preventively. Other antiepileptic medications have been shown to be very effective for both of these indications. Topiramate and valproic acid are both commonly used for migraine: topiramate primarily preventively and valproic acid both for prevention and, commonly in its intravenous form, for acute treatment. Levetiracetam is currently not commonly used for migraine, although some institutions will use the intravenous formulation for severe refractory status migrainosus.

Evers and colleagues investigated the open label use of levetiracetam for migraine prevention at a dose of 1000 mg twice daily in a small population of 50 persons. The study participants were started at a dose of 500 mg twice daily for 4 weeks, then increased to 1000 mg twice daily for a total of 12 weeks. The primary endpoint was migraine attack frequency during the last 4 weeks of treatment.

A 50% reduction in headache frequency was seen in 46% of the enrolled participants. The most common reported side effects were sedation, nausea, and weight gain, as well as cognitive change (five patients dropped out of the study owing to intolerance of the treatment). A post hoc comparison between the patients with and without response to levetiracetam revealed that those who responded were those with a less refractory history — they had tried fewer medications and were using fewer acute medications as well.

The antiepileptic class of preventive migraine medications is notorious for issues with tolerance. Among the antiepileptic medications, levetiracetam is commonly used but also commonly stopped owing to mood and cognitive complaints. Although the researchers here do show early evidence for a moderate amount of efficacy for treating migraine, the fact that there are now more migraine-specific preventive medications that are better tolerated and overall more efficacious make choosing levetiracetam for prevention less necessary.

Now that there are multiple classes of migraine-specific acute medications, the outstanding question remains: What are the potential benefits and drawbacks for the use of triptans compared with the oral CGRP receptor antagonists (gepants)? Most obviously, triptan medications are contraindicated in patients with significant vascular risk factors; however, what is not known is whether some of the other adverse events associated with triptans are more or less prominent with gepant use. Lee and colleagues conducted a meta-analysis of 15 studies to review this data.

A previous meta-analysis demonstrated that oral CGRP receptor antagonists are more effective than placebo, but less effective than triptans against acute migraine. The most common intolerances for gepants are nausea, somnolence, and dry mouth, but the safety and tolerability of gepants have not been compared with that of triptans. These authors pooled the data on five gepant medications (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant). The primary outcome was incidence of treatment-related adverse events and the secondary outcome was the incidence of the specific intolerances of diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting.

Compared with placebo, the relative risk for any adverse event was found to be low, at 1.15, and the relative risk for treatment-related adverse events was only slightly higher, at 1.18. Gepants were found to be significantly more associated with an increased risk for fatigue, nausea, and somnolence vs placebo. Compared with triptans, the CGRP antagonists were associated with significantly less treatment-related adverse events as well as any adverse event. There was no significant difference in the incidence of diarrhea, nausea, and vomiting between the two groups.

This study helps elucidate some of the differences between the two classes of migraine-specific acute medications. As noted above, a prior meta-analysis did reveal some benefits with the triptan class, specifically better effectiveness. When choosing a better-tolerated medication for your patients, you may want to consider a gepant; when considering a stronger or more potent option, you might stick with a triptan.

Migraine is a unique neurologic condition, in that a person can't prove they have it and there are few objective tools neurologists have to guide their diagnostic process. The recognition of the role of the vasoactive peptide calcitonin gene-related peptide (CGRP) in the 1990s changed the way many researchers and clinicians conceptualized migraine. Subsequent studies have used CGRP as a human model for migraine, and most recently pituitary adenylate cyclase–activating polypeptide 38 (PACAP-38) has also been recognized for its important role in migraine propagation. All of the existing data have been in adults, and no studies until now have specifically investigated the presence of these peptides in children with migraine.

Pediatric migraine is unique in a number of ways. Children with migraine present less unilaterally, the duration of their attacks is typically shorter, and the associated symptoms can often be more prominent than the headache pain during an attack. There are unique pediatric migraine subtypes that are exceptionally rare in adults, such as periodic paralysis attacks and abdominal migraine. For this reason, it is not entirely clear whether the same biomarkers of disease in adults would also be present in the pediatric population.

In the study by Liu and colleagues, the investigators enrolled 76 pediatric patients with migraine (the diagnosis was confirmed by at least two neurologists). Patients were excluded if there was any analgesic medication use over the past 2 months; if there was concern for secondary headache; or any underlying mood disorders, congenital disease, or other major medical conditions. An additional 77 controls were matched for age and sex. Blood was collected from all participants after an 8-hour fast to avoid collecting after potentially ingesting a food trigger. Blood samples were obtained during an ictal period (within 8 hours of a migraine attack) as well as interictally (not taken if the participant had a migraine attack within the past 24 hours).

The plasma CGRP and PACAP-38 levels were significantly higher in pediatric patients with migraine than in those without a migraine history, in both the ictal state and the interictal state. Among patients with migraine, there was a nonsignificant trend toward a higher CGRP level in the ictal phase, and no difference in these phases with PACAP-38. There was no difference in the CGRP or PACAP-38 levels between participants with and those without aura. When different aura groups were compared (with the participants separated on the basis of a history of motor vs vision vs sensory aura), no difference was seen among the different aura groups. Binary logistic regression testing and analysis of variance also showed that CGRP and PACAP-38 are independent risk factors for pediatric migraine, and specific levels of each were associated with an 11 and a 13 times increased risk, respectively.

Biomarker testing is still not clinically performed for migraine either in adults or children. This is primarily due to cost and the fact that most commercially available laboratories do not currently offer these tests. The results above do shed additional light on migraine pathogenesis and indicate that the phenotypic differences seen in pediatric migraine are less likely related to differences in brain function in children.

Levetiracetam is a commonly used antiepileptic medication. Prior studies have investigated the use of this medication for migraine, both acutely and preventively. Other antiepileptic medications have been shown to be very effective for both of these indications. Topiramate and valproic acid are both commonly used for migraine: topiramate primarily preventively and valproic acid both for prevention and, commonly in its intravenous form, for acute treatment. Levetiracetam is currently not commonly used for migraine, although some institutions will use the intravenous formulation for severe refractory status migrainosus.

Evers and colleagues investigated the open label use of levetiracetam for migraine prevention at a dose of 1000 mg twice daily in a small population of 50 persons. The study participants were started at a dose of 500 mg twice daily for 4 weeks, then increased to 1000 mg twice daily for a total of 12 weeks. The primary endpoint was migraine attack frequency during the last 4 weeks of treatment.

A 50% reduction in headache frequency was seen in 46% of the enrolled participants. The most common reported side effects were sedation, nausea, and weight gain, as well as cognitive change (five patients dropped out of the study owing to intolerance of the treatment). A post hoc comparison between the patients with and without response to levetiracetam revealed that those who responded were those with a less refractory history — they had tried fewer medications and were using fewer acute medications as well.

The antiepileptic class of preventive migraine medications is notorious for issues with tolerance. Among the antiepileptic medications, levetiracetam is commonly used but also commonly stopped owing to mood and cognitive complaints. Although the researchers here do show early evidence for a moderate amount of efficacy for treating migraine, the fact that there are now more migraine-specific preventive medications that are better tolerated and overall more efficacious make choosing levetiracetam for prevention less necessary.

Now that there are multiple classes of migraine-specific acute medications, the outstanding question remains: What are the potential benefits and drawbacks for the use of triptans compared with the oral CGRP receptor antagonists (gepants)? Most obviously, triptan medications are contraindicated in patients with significant vascular risk factors; however, what is not known is whether some of the other adverse events associated with triptans are more or less prominent with gepant use. Lee and colleagues conducted a meta-analysis of 15 studies to review this data.

A previous meta-analysis demonstrated that oral CGRP receptor antagonists are more effective than placebo, but less effective than triptans against acute migraine. The most common intolerances for gepants are nausea, somnolence, and dry mouth, but the safety and tolerability of gepants have not been compared with that of triptans. These authors pooled the data on five gepant medications (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant). The primary outcome was incidence of treatment-related adverse events and the secondary outcome was the incidence of the specific intolerances of diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting.

Compared with placebo, the relative risk for any adverse event was found to be low, at 1.15, and the relative risk for treatment-related adverse events was only slightly higher, at 1.18. Gepants were found to be significantly more associated with an increased risk for fatigue, nausea, and somnolence vs placebo. Compared with triptans, the CGRP antagonists were associated with significantly less treatment-related adverse events as well as any adverse event. There was no significant difference in the incidence of diarrhea, nausea, and vomiting between the two groups.

This study helps elucidate some of the differences between the two classes of migraine-specific acute medications. As noted above, a prior meta-analysis did reveal some benefits with the triptan class, specifically better effectiveness. When choosing a better-tolerated medication for your patients, you may want to consider a gepant; when considering a stronger or more potent option, you might stick with a triptan.

Migraine is a unique neurologic condition, in that a person can't prove they have it and there are few objective tools neurologists have to guide their diagnostic process. The recognition of the role of the vasoactive peptide calcitonin gene-related peptide (CGRP) in the 1990s changed the way many researchers and clinicians conceptualized migraine. Subsequent studies have used CGRP as a human model for migraine, and most recently pituitary adenylate cyclase–activating polypeptide 38 (PACAP-38) has also been recognized for its important role in migraine propagation. All of the existing data have been in adults, and no studies until now have specifically investigated the presence of these peptides in children with migraine.

Pediatric migraine is unique in a number of ways. Children with migraine present less unilaterally, the duration of their attacks is typically shorter, and the associated symptoms can often be more prominent than the headache pain during an attack. There are unique pediatric migraine subtypes that are exceptionally rare in adults, such as periodic paralysis attacks and abdominal migraine. For this reason, it is not entirely clear whether the same biomarkers of disease in adults would also be present in the pediatric population.

In the study by Liu and colleagues, the investigators enrolled 76 pediatric patients with migraine (the diagnosis was confirmed by at least two neurologists). Patients were excluded if there was any analgesic medication use over the past 2 months; if there was concern for secondary headache; or any underlying mood disorders, congenital disease, or other major medical conditions. An additional 77 controls were matched for age and sex. Blood was collected from all participants after an 8-hour fast to avoid collecting after potentially ingesting a food trigger. Blood samples were obtained during an ictal period (within 8 hours of a migraine attack) as well as interictally (not taken if the participant had a migraine attack within the past 24 hours).

The plasma CGRP and PACAP-38 levels were significantly higher in pediatric patients with migraine than in those without a migraine history, in both the ictal state and the interictal state. Among patients with migraine, there was a nonsignificant trend toward a higher CGRP level in the ictal phase, and no difference in these phases with PACAP-38. There was no difference in the CGRP or PACAP-38 levels between participants with and those without aura. When different aura groups were compared (with the participants separated on the basis of a history of motor vs vision vs sensory aura), no difference was seen among the different aura groups. Binary logistic regression testing and analysis of variance also showed that CGRP and PACAP-38 are independent risk factors for pediatric migraine, and specific levels of each were associated with an 11 and a 13 times increased risk, respectively.

Biomarker testing is still not clinically performed for migraine either in adults or children. This is primarily due to cost and the fact that most commercially available laboratories do not currently offer these tests. The results above do shed additional light on migraine pathogenesis and indicate that the phenotypic differences seen in pediatric migraine are less likely related to differences in brain function in children.

Levetiracetam is a commonly used antiepileptic medication. Prior studies have investigated the use of this medication for migraine, both acutely and preventively. Other antiepileptic medications have been shown to be very effective for both of these indications. Topiramate and valproic acid are both commonly used for migraine: topiramate primarily preventively and valproic acid both for prevention and, commonly in its intravenous form, for acute treatment. Levetiracetam is currently not commonly used for migraine, although some institutions will use the intravenous formulation for severe refractory status migrainosus.

Evers and colleagues investigated the open label use of levetiracetam for migraine prevention at a dose of 1000 mg twice daily in a small population of 50 persons. The study participants were started at a dose of 500 mg twice daily for 4 weeks, then increased to 1000 mg twice daily for a total of 12 weeks. The primary endpoint was migraine attack frequency during the last 4 weeks of treatment.

A 50% reduction in headache frequency was seen in 46% of the enrolled participants. The most common reported side effects were sedation, nausea, and weight gain, as well as cognitive change (five patients dropped out of the study owing to intolerance of the treatment). A post hoc comparison between the patients with and without response to levetiracetam revealed that those who responded were those with a less refractory history — they had tried fewer medications and were using fewer acute medications as well.

The antiepileptic class of preventive migraine medications is notorious for issues with tolerance. Among the antiepileptic medications, levetiracetam is commonly used but also commonly stopped owing to mood and cognitive complaints. Although the researchers here do show early evidence for a moderate amount of efficacy for treating migraine, the fact that there are now more migraine-specific preventive medications that are better tolerated and overall more efficacious make choosing levetiracetam for prevention less necessary.

Now that there are multiple classes of migraine-specific acute medications, the outstanding question remains: What are the potential benefits and drawbacks for the use of triptans compared with the oral CGRP receptor antagonists (gepants)? Most obviously, triptan medications are contraindicated in patients with significant vascular risk factors; however, what is not known is whether some of the other adverse events associated with triptans are more or less prominent with gepant use. Lee and colleagues conducted a meta-analysis of 15 studies to review this data.

A previous meta-analysis demonstrated that oral CGRP receptor antagonists are more effective than placebo, but less effective than triptans against acute migraine. The most common intolerances for gepants are nausea, somnolence, and dry mouth, but the safety and tolerability of gepants have not been compared with that of triptans. These authors pooled the data on five gepant medications (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant). The primary outcome was incidence of treatment-related adverse events and the secondary outcome was the incidence of the specific intolerances of diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting.

Compared with placebo, the relative risk for any adverse event was found to be low, at 1.15, and the relative risk for treatment-related adverse events was only slightly higher, at 1.18. Gepants were found to be significantly more associated with an increased risk for fatigue, nausea, and somnolence vs placebo. Compared with triptans, the CGRP antagonists were associated with significantly less treatment-related adverse events as well as any adverse event. There was no significant difference in the incidence of diarrhea, nausea, and vomiting between the two groups.

This study helps elucidate some of the differences between the two classes of migraine-specific acute medications. As noted above, a prior meta-analysis did reveal some benefits with the triptan class, specifically better effectiveness. When choosing a better-tolerated medication for your patients, you may want to consider a gepant; when considering a stronger or more potent option, you might stick with a triptan.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

Most headache specialists are familiar with the "standard" or PREEMPT onabotulinumtoxinA (Botox) paradigm used preventively for migraine. This protocol uses 155 units of onabotulinumtoxinA over 31 sites in seven muscle groups. OnabotulinumtoxinA vials typically come in 100 or 200 units, and when preparing onabotulinumtoxinA for patients who are being injected most providers are forced to discard most or all of the remaining 45 units. Anecdotally, some providers do inject the entire 200-unit vial, and the additional injection sites are either given in another standard protocol or in a follow-the-pain manner.

The study by Zandieh and colleagues followed 175 patients with chronic migraine who first received three injections of 150 units of onabotulinumtoxinA, then three injections of 200 units of this agent. The additional 50 units were injected into the temporalis and occipitalis muscles — the standard sites were used, but additional units were injected into each of the sites. The majority of patients experienced primarily frontal pain; the injections were not given in specific areas where more pain was manifesting.

The average number of headache days per month decreased significantly when the onabotulinumtoxinA dose was increased; patients tolerated the medication over the 3-month period as well. In practice, many providers use the additional units of onabotulinumtoxinA. This study argues that there is a minimal risk, and probably a potential significant benefit, when using up to 200 units every 3 months. Providers should, however, be aware that in rare instances, some insurances will only cover a 155-unit injection, and the use of additional units may jeopardize reimbursement for those plans.

Many patients anecdotally will use cold or heat as a treatment for acute migraine pain; however, the topical use of temperature has not been well studied for this purpose. Cold stimulus has, importantly, been known to be a trigger of migraine as well as other headache disorders classified in the International Classification of Headache Disorders, third edition (ICHD-3), including external cold stimulus headache and "brain freeze" or internal cold stimulus headache. Hsu and colleagues produced a meta-analysis and systematic review on the use of cold for acute treatment of migraine.

Six studies were found to be eligible for this review. The cold stimulus could be placed anywhere on the head, and the studies could have considered its use for any migraine-associated symptom. This includes headache, eye pain, nausea, or vomiting. The interventions used cold somewhat differently, including as ice packing, cooling compression, soaking, and as a rinse. Both randomized and nonrandomized trials were included in the systematic review; however, only randomized controlled trials were used for the meta-analysis.

The primary outcome evaluated by the authors was pain intensity; secondary outcomes were duration of migraine pain as well as associated symptoms (eg, nausea, vomiting). The meta-analysis revealed that cold interventions reduce migraine pain by 3.21 points on an analog scale, and this was found to be effective within 30 minutes. At 1-2 hours after the intervention, the effect was not seen to be significant. At 24 hours, the effect of cold intervention was marginal. Cold was not seen to significantly reduce nausea or vomiting at 2 hours after intervention.

Although cold treatments are commonly used by patients, there appears to be benefit only early in the onset of a migraine attack. Headache specialists typically recommend early treatment with a migraine-specific acute medication; however, the medication may take minutes to hours before taking effect. Cold can be recommended to patients during that intervening period, and it may help until the time that their acute medications take effect.

Chronic refractory migraine remains one of the most debilitating neurologic disorders and is a challenge even for the best trained neurologist or headache specialist. There are few headache centers with inpatient headache units around the United States, and those that remain use treatments that most neurologists are not familiar with. Schwenk and colleagues retrospectively reviewed the data of a major academic headache center and revealed impressive outcomes in this very difficult-to-treat population.

This study reviewed the outcomes of 609 consecutive patients admitted to the Thomas Jefferson University inpatient headache unit from 2017 to 2021. These patients all received continuous lidocaine infusions that were titrated according to an internal protocol that balanced daily plasma lidocaine levels, tolerability, and pain relief. Hospital discharge occurred when patients were pain-free for 12-24 hours or had a minimal response after 5 days of treatment. All patients had at least eight severe headaches per month for at least 6 consecutive months and had tried one to seven preventive medications, with the result of either intolerance or ineffectiveness.

The primary outcome was change from baseline to discharge pain level. Patients were admitted with an average score of 7.0 of 10 on admission and were discharged at a score of 1.0 of 10. Secondary outcomes were average pain at post-discharge appointment vs baseline (5.5 vs 7.0), number of monthly headache days at post-discharge appointment (22.5 vs 26.8), and current and average pain levels at the post-discharge appointment, which were both significantly lower as well. The most common adverse effect was nausea; others noted were cardiovascular changes, hallucinations or nightmares, sedation, anxiety, and chest pain.

This is an important retrospective on the effectiveness of an inpatient lidocaine protocol for refractory chronic migraine. When considering this population, especially if multiple lines of preventive and acute medications are not effective, referral to an academic inpatient headache center should definitely be considered. This patient population does not respond effectively to most treatment modalities, and this is cause to give them hope.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

Most headache specialists are familiar with the "standard" or PREEMPT onabotulinumtoxinA (Botox) paradigm used preventively for migraine. This protocol uses 155 units of onabotulinumtoxinA over 31 sites in seven muscle groups. OnabotulinumtoxinA vials typically come in 100 or 200 units, and when preparing onabotulinumtoxinA for patients who are being injected most providers are forced to discard most or all of the remaining 45 units. Anecdotally, some providers do inject the entire 200-unit vial, and the additional injection sites are either given in another standard protocol or in a follow-the-pain manner.

The study by Zandieh and colleagues followed 175 patients with chronic migraine who first received three injections of 150 units of onabotulinumtoxinA, then three injections of 200 units of this agent. The additional 50 units were injected into the temporalis and occipitalis muscles — the standard sites were used, but additional units were injected into each of the sites. The majority of patients experienced primarily frontal pain; the injections were not given in specific areas where more pain was manifesting.

The average number of headache days per month decreased significantly when the onabotulinumtoxinA dose was increased; patients tolerated the medication over the 3-month period as well. In practice, many providers use the additional units of onabotulinumtoxinA. This study argues that there is a minimal risk, and probably a potential significant benefit, when using up to 200 units every 3 months. Providers should, however, be aware that in rare instances, some insurances will only cover a 155-unit injection, and the use of additional units may jeopardize reimbursement for those plans.

Many patients anecdotally will use cold or heat as a treatment for acute migraine pain; however, the topical use of temperature has not been well studied for this purpose. Cold stimulus has, importantly, been known to be a trigger of migraine as well as other headache disorders classified in the International Classification of Headache Disorders, third edition (ICHD-3), including external cold stimulus headache and "brain freeze" or internal cold stimulus headache. Hsu and colleagues produced a meta-analysis and systematic review on the use of cold for acute treatment of migraine.

Six studies were found to be eligible for this review. The cold stimulus could be placed anywhere on the head, and the studies could have considered its use for any migraine-associated symptom. This includes headache, eye pain, nausea, or vomiting. The interventions used cold somewhat differently, including as ice packing, cooling compression, soaking, and as a rinse. Both randomized and nonrandomized trials were included in the systematic review; however, only randomized controlled trials were used for the meta-analysis.

The primary outcome evaluated by the authors was pain intensity; secondary outcomes were duration of migraine pain as well as associated symptoms (eg, nausea, vomiting). The meta-analysis revealed that cold interventions reduce migraine pain by 3.21 points on an analog scale, and this was found to be effective within 30 minutes. At 1-2 hours after the intervention, the effect was not seen to be significant. At 24 hours, the effect of cold intervention was marginal. Cold was not seen to significantly reduce nausea or vomiting at 2 hours after intervention.

Although cold treatments are commonly used by patients, there appears to be benefit only early in the onset of a migraine attack. Headache specialists typically recommend early treatment with a migraine-specific acute medication; however, the medication may take minutes to hours before taking effect. Cold can be recommended to patients during that intervening period, and it may help until the time that their acute medications take effect.

Chronic refractory migraine remains one of the most debilitating neurologic disorders and is a challenge even for the best trained neurologist or headache specialist. There are few headache centers with inpatient headache units around the United States, and those that remain use treatments that most neurologists are not familiar with. Schwenk and colleagues retrospectively reviewed the data of a major academic headache center and revealed impressive outcomes in this very difficult-to-treat population.

This study reviewed the outcomes of 609 consecutive patients admitted to the Thomas Jefferson University inpatient headache unit from 2017 to 2021. These patients all received continuous lidocaine infusions that were titrated according to an internal protocol that balanced daily plasma lidocaine levels, tolerability, and pain relief. Hospital discharge occurred when patients were pain-free for 12-24 hours or had a minimal response after 5 days of treatment. All patients had at least eight severe headaches per month for at least 6 consecutive months and had tried one to seven preventive medications, with the result of either intolerance or ineffectiveness.

The primary outcome was change from baseline to discharge pain level. Patients were admitted with an average score of 7.0 of 10 on admission and were discharged at a score of 1.0 of 10. Secondary outcomes were average pain at post-discharge appointment vs baseline (5.5 vs 7.0), number of monthly headache days at post-discharge appointment (22.5 vs 26.8), and current and average pain levels at the post-discharge appointment, which were both significantly lower as well. The most common adverse effect was nausea; others noted were cardiovascular changes, hallucinations or nightmares, sedation, anxiety, and chest pain.

This is an important retrospective on the effectiveness of an inpatient lidocaine protocol for refractory chronic migraine. When considering this population, especially if multiple lines of preventive and acute medications are not effective, referral to an academic inpatient headache center should definitely be considered. This patient population does not respond effectively to most treatment modalities, and this is cause to give them hope.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

Most headache specialists are familiar with the "standard" or PREEMPT onabotulinumtoxinA (Botox) paradigm used preventively for migraine. This protocol uses 155 units of onabotulinumtoxinA over 31 sites in seven muscle groups. OnabotulinumtoxinA vials typically come in 100 or 200 units, and when preparing onabotulinumtoxinA for patients who are being injected most providers are forced to discard most or all of the remaining 45 units. Anecdotally, some providers do inject the entire 200-unit vial, and the additional injection sites are either given in another standard protocol or in a follow-the-pain manner.

The study by Zandieh and colleagues followed 175 patients with chronic migraine who first received three injections of 150 units of onabotulinumtoxinA, then three injections of 200 units of this agent. The additional 50 units were injected into the temporalis and occipitalis muscles — the standard sites were used, but additional units were injected into each of the sites. The majority of patients experienced primarily frontal pain; the injections were not given in specific areas where more pain was manifesting.

The average number of headache days per month decreased significantly when the onabotulinumtoxinA dose was increased; patients tolerated the medication over the 3-month period as well. In practice, many providers use the additional units of onabotulinumtoxinA. This study argues that there is a minimal risk, and probably a potential significant benefit, when using up to 200 units every 3 months. Providers should, however, be aware that in rare instances, some insurances will only cover a 155-unit injection, and the use of additional units may jeopardize reimbursement for those plans.

Many patients anecdotally will use cold or heat as a treatment for acute migraine pain; however, the topical use of temperature has not been well studied for this purpose. Cold stimulus has, importantly, been known to be a trigger of migraine as well as other headache disorders classified in the International Classification of Headache Disorders, third edition (ICHD-3), including external cold stimulus headache and "brain freeze" or internal cold stimulus headache. Hsu and colleagues produced a meta-analysis and systematic review on the use of cold for acute treatment of migraine.

Six studies were found to be eligible for this review. The cold stimulus could be placed anywhere on the head, and the studies could have considered its use for any migraine-associated symptom. This includes headache, eye pain, nausea, or vomiting. The interventions used cold somewhat differently, including as ice packing, cooling compression, soaking, and as a rinse. Both randomized and nonrandomized trials were included in the systematic review; however, only randomized controlled trials were used for the meta-analysis.

The primary outcome evaluated by the authors was pain intensity; secondary outcomes were duration of migraine pain as well as associated symptoms (eg, nausea, vomiting). The meta-analysis revealed that cold interventions reduce migraine pain by 3.21 points on an analog scale, and this was found to be effective within 30 minutes. At 1-2 hours after the intervention, the effect was not seen to be significant. At 24 hours, the effect of cold intervention was marginal. Cold was not seen to significantly reduce nausea or vomiting at 2 hours after intervention.

Although cold treatments are commonly used by patients, there appears to be benefit only early in the onset of a migraine attack. Headache specialists typically recommend early treatment with a migraine-specific acute medication; however, the medication may take minutes to hours before taking effect. Cold can be recommended to patients during that intervening period, and it may help until the time that their acute medications take effect.

Chronic refractory migraine remains one of the most debilitating neurologic disorders and is a challenge even for the best trained neurologist or headache specialist. There are few headache centers with inpatient headache units around the United States, and those that remain use treatments that most neurologists are not familiar with. Schwenk and colleagues retrospectively reviewed the data of a major academic headache center and revealed impressive outcomes in this very difficult-to-treat population.

This study reviewed the outcomes of 609 consecutive patients admitted to the Thomas Jefferson University inpatient headache unit from 2017 to 2021. These patients all received continuous lidocaine infusions that were titrated according to an internal protocol that balanced daily plasma lidocaine levels, tolerability, and pain relief. Hospital discharge occurred when patients were pain-free for 12-24 hours or had a minimal response after 5 days of treatment. All patients had at least eight severe headaches per month for at least 6 consecutive months and had tried one to seven preventive medications, with the result of either intolerance or ineffectiveness.

The primary outcome was change from baseline to discharge pain level. Patients were admitted with an average score of 7.0 of 10 on admission and were discharged at a score of 1.0 of 10. Secondary outcomes were average pain at post-discharge appointment vs baseline (5.5 vs 7.0), number of monthly headache days at post-discharge appointment (22.5 vs 26.8), and current and average pain levels at the post-discharge appointment, which were both significantly lower as well. The most common adverse effect was nausea; others noted were cardiovascular changes, hallucinations or nightmares, sedation, anxiety, and chest pain.

This is an important retrospective on the effectiveness of an inpatient lidocaine protocol for refractory chronic migraine. When considering this population, especially if multiple lines of preventive and acute medications are not effective, referral to an academic inpatient headache center should definitely be considered. This patient population does not respond effectively to most treatment modalities, and this is cause to give them hope.