Thomas Berk, MD

Key clinical point: Both galcanezumab and rimegepant were effective as a preventive treatment for episodic migraine, with galcanezumab not being superior to rimegepant.

Major finding: Overall, 62% vs 61% of the patients receiving galcanezumab vs rimegepant achieved ≥ 50% reduction in monthly migraine headache days after 3 months, respectively, with no statistically significant difference between the groups (P = .70). Treatment-emergent adverse events were similar between study interventions and were mostly mild or moderate in severity.

Study details: Findings are from the CHALLENGE-MIG study including 580 patients with episodic migraine with or without aura who were randomly assigned to receive galcanezumab (n = 287) or rimegepant (n = 293) for 3 months.

Disclosures: This study was funded by Eli Lilly and Company, Indianapolis, IN, USA. Eight authors declared being employees of Eli Lilly and Company. Some other authors declared ties with various sources, including Eli Lilly and Company.

Source: Schwedt TJ et al. Comparing the efficacy and safety of galcanezumab versus rimegepant for prevention of episodic migraine: Results from a randomized, controlled clinical trial. Neurol Ther. 2023 (Nov 10). doi: 10.1007/s40120-023-00562-w

Key clinical point: Both galcanezumab and rimegepant were effective as a preventive treatment for episodic migraine, with galcanezumab not being superior to rimegepant.

Major finding: Overall, 62% vs 61% of the patients receiving galcanezumab vs rimegepant achieved ≥ 50% reduction in monthly migraine headache days after 3 months, respectively, with no statistically significant difference between the groups (P = .70). Treatment-emergent adverse events were similar between study interventions and were mostly mild or moderate in severity.

Study details: Findings are from the CHALLENGE-MIG study including 580 patients with episodic migraine with or without aura who were randomly assigned to receive galcanezumab (n = 287) or rimegepant (n = 293) for 3 months.

Disclosures: This study was funded by Eli Lilly and Company, Indianapolis, IN, USA. Eight authors declared being employees of Eli Lilly and Company. Some other authors declared ties with various sources, including Eli Lilly and Company.

Source: Schwedt TJ et al. Comparing the efficacy and safety of galcanezumab versus rimegepant for prevention of episodic migraine: Results from a randomized, controlled clinical trial. Neurol Ther. 2023 (Nov 10). doi: 10.1007/s40120-023-00562-w

Key clinical point: Both galcanezumab and rimegepant were effective as a preventive treatment for episodic migraine, with galcanezumab not being superior to rimegepant.

Major finding: Overall, 62% vs 61% of the patients receiving galcanezumab vs rimegepant achieved ≥ 50% reduction in monthly migraine headache days after 3 months, respectively, with no statistically significant difference between the groups (P = .70). Treatment-emergent adverse events were similar between study interventions and were mostly mild or moderate in severity.

Study details: Findings are from the CHALLENGE-MIG study including 580 patients with episodic migraine with or without aura who were randomly assigned to receive galcanezumab (n = 287) or rimegepant (n = 293) for 3 months.

Disclosures: This study was funded by Eli Lilly and Company, Indianapolis, IN, USA. Eight authors declared being employees of Eli Lilly and Company. Some other authors declared ties with various sources, including Eli Lilly and Company.

Source: Schwedt TJ et al. Comparing the efficacy and safety of galcanezumab versus rimegepant for prevention of episodic migraine: Results from a randomized, controlled clinical trial. Neurol Ther. 2023 (Nov 10). doi: 10.1007/s40120-023-00562-w

Depression is one of the most common comorbidities associated with migraine. Major depressive disorder is both a risk factor for chronic migraine and a condition that one is more likely to develop after being diagnosed with chronic migraine. The study by de Vries Lentsch and colleagues investigated the use of two of the calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) treatments — erenumab and fremanezumab — compared with a control group of patients with chronic migraine, with an eye on outcomes to measure depression. Of note, reduction in headache frequency (defined as reduction in monthly migraine days) was also investigated as an independent variable.

This was a single-center study performed at the University of Leiden Headache Center. It was not a randomized trial, but all patients were followed with an e-diary and Day 0 vs Day 90 questionnaires that tracked their headache frequency and severity as well as a number of metrics related to depression. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Center for Epidemiological Studies Depression Scale (CES-D). The Headache Impact Test (HIT-6) was used to follow headache-related impact and disability, and the Perceived Stress Scale (PSS) was used to measure the degree of stressful situations the patient was experiencing.

The baseline depression scales between the three groups were 70%, 60%, and 66%, respectively; there were similar baseline levels of migraine frequency and disability as well. Both intervention groups showed a significant decrease in the symptoms of depression, and having a greater level of depression was negatively associated with reduction in monthly migraine days after 3 months. Of note, logistic-regression analysis determined that the reduction in depressive symptoms was independent of the reduction in migraine frequency.

Nearly all headache care providers are faced with challenging situations on a daily basis; often this is due to the comorbidity of mood disorders and high-frequency migraine. A traditional approach has been to provide the patient with a migraine preventive medication in the antidepressant family, such as a tricyclic antidepressant or serotonin and norepinephrine reuptake inhibitor (SNRI). Although these can be helpful, they are less specific for migraine prevention. Many patients are also already taking antidepressant medications, and the addition of a migraine-preventive antidepressant would be contraindicated. This study broadens the possibilities for prevention in these complicated patients and shows that there is benefit in both migraine-related outcomes and markers for depression when using CGRP-based therapy.

The way headache medicine is practiced changed dramatically in 2018 with the advent of CGRP monoclonal antibody (mAb) treatments for migraine. These medications have allowed us to target migraine specifically, whereas all of the preventive medications for migraine prior to 2018 were developed for other conditions and only secondarily helped migraine. These include the antidepressant, antihypertensive, and antiepileptic classes of medications, as well as onabotulinum toxin A, which, although approved for migraine, is not targeting a migraine-specific factor. Moskatel and colleagues sought to better understand the changing patterns of prescribing the nonspecific, or "traditional," migraine preventive medications in light of the advent of CGRP treatment.

This was a retrospective cohort study using aggregated data from the Stanford headache center. The percentage of patients with chronic migraine who had been prescribed one of the 10 most prescribed oral preventive medications or onabotulinum toxin A, or any of the four CGRP mAb, were calculated relative to the total number of patients with chronic migraine who received a prescription for any medication from the clinic during the pre-CGRP mAb years of 2015-2017 and post-approval years of 2019-2021.

The Stanford (STARR) database was filtered, searching for patients living in a California ZIP code with a diagnosis of chronic migraine who were followed from 2015 to 2021. The 10 most common non-CGRP preventive medications were amitriptyline/nortriptyline, valproate, duloxetine, gabapentin, memantine, propranolol, venlafaxine, verapamil, and onabotulinumtoxinA.

Erenumab was noted to initially be the most prescribed CGRP monoclonal antibody medication, but this was overtaken by galcanezumab after the second quarter of 2020 and throughout 2021. There is a statistically significant decrease in the percentage of patients receiving any of the non-CGRP preventive medications since 2018. The most significant decreases were in the tricyclic antidepressant class, as well as valproate, duloxetine, memantine, and onabotulinum toxin A. There was no statistically significant change in venlafaxine or gabapentin prescriptions.

This study highlights the changing face of headache medicine, and having a new class of migraine-specific treatment has significantly affected prescribing patterns. Although there is a statistically significant decrease in the prescribing of these non–migraine-specific preventive medications, they are still often recommended due to step-therapy regulations from insurance formularies, or as part of a polypharmacy regimen that may be more beneficial for a patient. These medications do improve patient outcomes and will remain a mainstay in migraine treatment.

Nearly all patients with migraine are recommended an acute medication to treat migraine attacks abortively; some patients are also recommended preventive therapies if migraine frequency significantly affects their quality of life. The American Headache Society/American Academy of Neurology guidelines for prevention recommend the initiation of a preventive medication at a frequency of 4-5 headache days per month or approximately 1 per week. Lipton and colleagues sought to determine whether there were any efficacy concerns in combining a CGRP mAb for prevention with ubrogepant, an oral CGRP antagonist, for acute treatment.

This was a prospective, open-level observational study assessing pain relief, return to normal function, and treatment satisfaction with patients given 50 or 100 mg of ubrogepant while concomitantly being given a seizure or mAb medication. Patients were allowed to be taking onabotulinumtoxinA as well as a CGRP mAb. The patients in this study were asked to track their headache symptoms using the Migraine Buddy e-diary. Meaningful pain relief was defined as a rating of migraine-related pain with one of the following choices 4 hours after taking the medication: no pain, mild pain, moderate pain, or severe pain. Return to normal function was defined as whether the patient determined they were able to function normally relative to their baseline at specific times post intervention. This was based on a functional disability scale. Treatment satisfaction was determined on the basis of a seven-point rating scale for how satisfied the patient felt with the medication at the end of the trial period.

A total of 245 participants provided at least 30 days of data, with 44.5% of the patients taking erenumab, 35.1% taking galcanezumab, 18.0% taking fremanezumab, and 2.9% taking eptinezumab. Meaningful pain relief was achieved by 61.6% of patients at 2 hours and 80.4% of patients at 4 hours post dose for both the 50-mg and 100-mg dose of ubrogepant. Return to normal function was achieved by 34.7% of patients at 2 hours and 50.5% at 4 hours post dose as well. Patients reported a 72.7% satisfaction level with the medication.

When CGRP acute medications were first approved, there was concern about the use of a mAb together with an oral antagonist. It was thought that CGRP medications would be associated with fewer benefits than when these medications were used alone, due to the belief that only a specific amount of CGRP could be blocked at any specific time. This trial shows that the efficacy of CGRP acute medications is not affected by concomitant use of mAb. Many patients who respond well to CGRP mAb will benefit significantly from the additional abortive use of oral antagonists.

Depression is one of the most common comorbidities associated with migraine. Major depressive disorder is both a risk factor for chronic migraine and a condition that one is more likely to develop after being diagnosed with chronic migraine. The study by de Vries Lentsch and colleagues investigated the use of two of the calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) treatments — erenumab and fremanezumab — compared with a control group of patients with chronic migraine, with an eye on outcomes to measure depression. Of note, reduction in headache frequency (defined as reduction in monthly migraine days) was also investigated as an independent variable.

This was a single-center study performed at the University of Leiden Headache Center. It was not a randomized trial, but all patients were followed with an e-diary and Day 0 vs Day 90 questionnaires that tracked their headache frequency and severity as well as a number of metrics related to depression. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Center for Epidemiological Studies Depression Scale (CES-D). The Headache Impact Test (HIT-6) was used to follow headache-related impact and disability, and the Perceived Stress Scale (PSS) was used to measure the degree of stressful situations the patient was experiencing.

The baseline depression scales between the three groups were 70%, 60%, and 66%, respectively; there were similar baseline levels of migraine frequency and disability as well. Both intervention groups showed a significant decrease in the symptoms of depression, and having a greater level of depression was negatively associated with reduction in monthly migraine days after 3 months. Of note, logistic-regression analysis determined that the reduction in depressive symptoms was independent of the reduction in migraine frequency.

Nearly all headache care providers are faced with challenging situations on a daily basis; often this is due to the comorbidity of mood disorders and high-frequency migraine. A traditional approach has been to provide the patient with a migraine preventive medication in the antidepressant family, such as a tricyclic antidepressant or serotonin and norepinephrine reuptake inhibitor (SNRI). Although these can be helpful, they are less specific for migraine prevention. Many patients are also already taking antidepressant medications, and the addition of a migraine-preventive antidepressant would be contraindicated. This study broadens the possibilities for prevention in these complicated patients and shows that there is benefit in both migraine-related outcomes and markers for depression when using CGRP-based therapy.

The way headache medicine is practiced changed dramatically in 2018 with the advent of CGRP monoclonal antibody (mAb) treatments for migraine. These medications have allowed us to target migraine specifically, whereas all of the preventive medications for migraine prior to 2018 were developed for other conditions and only secondarily helped migraine. These include the antidepressant, antihypertensive, and antiepileptic classes of medications, as well as onabotulinum toxin A, which, although approved for migraine, is not targeting a migraine-specific factor. Moskatel and colleagues sought to better understand the changing patterns of prescribing the nonspecific, or "traditional," migraine preventive medications in light of the advent of CGRP treatment.

This was a retrospective cohort study using aggregated data from the Stanford headache center. The percentage of patients with chronic migraine who had been prescribed one of the 10 most prescribed oral preventive medications or onabotulinum toxin A, or any of the four CGRP mAb, were calculated relative to the total number of patients with chronic migraine who received a prescription for any medication from the clinic during the pre-CGRP mAb years of 2015-2017 and post-approval years of 2019-2021.

The Stanford (STARR) database was filtered, searching for patients living in a California ZIP code with a diagnosis of chronic migraine who were followed from 2015 to 2021. The 10 most common non-CGRP preventive medications were amitriptyline/nortriptyline, valproate, duloxetine, gabapentin, memantine, propranolol, venlafaxine, verapamil, and onabotulinumtoxinA.

Erenumab was noted to initially be the most prescribed CGRP monoclonal antibody medication, but this was overtaken by galcanezumab after the second quarter of 2020 and throughout 2021. There is a statistically significant decrease in the percentage of patients receiving any of the non-CGRP preventive medications since 2018. The most significant decreases were in the tricyclic antidepressant class, as well as valproate, duloxetine, memantine, and onabotulinum toxin A. There was no statistically significant change in venlafaxine or gabapentin prescriptions.

This study highlights the changing face of headache medicine, and having a new class of migraine-specific treatment has significantly affected prescribing patterns. Although there is a statistically significant decrease in the prescribing of these non–migraine-specific preventive medications, they are still often recommended due to step-therapy regulations from insurance formularies, or as part of a polypharmacy regimen that may be more beneficial for a patient. These medications do improve patient outcomes and will remain a mainstay in migraine treatment.

Nearly all patients with migraine are recommended an acute medication to treat migraine attacks abortively; some patients are also recommended preventive therapies if migraine frequency significantly affects their quality of life. The American Headache Society/American Academy of Neurology guidelines for prevention recommend the initiation of a preventive medication at a frequency of 4-5 headache days per month or approximately 1 per week. Lipton and colleagues sought to determine whether there were any efficacy concerns in combining a CGRP mAb for prevention with ubrogepant, an oral CGRP antagonist, for acute treatment.

This was a prospective, open-level observational study assessing pain relief, return to normal function, and treatment satisfaction with patients given 50 or 100 mg of ubrogepant while concomitantly being given a seizure or mAb medication. Patients were allowed to be taking onabotulinumtoxinA as well as a CGRP mAb. The patients in this study were asked to track their headache symptoms using the Migraine Buddy e-diary. Meaningful pain relief was defined as a rating of migraine-related pain with one of the following choices 4 hours after taking the medication: no pain, mild pain, moderate pain, or severe pain. Return to normal function was defined as whether the patient determined they were able to function normally relative to their baseline at specific times post intervention. This was based on a functional disability scale. Treatment satisfaction was determined on the basis of a seven-point rating scale for how satisfied the patient felt with the medication at the end of the trial period.

A total of 245 participants provided at least 30 days of data, with 44.5% of the patients taking erenumab, 35.1% taking galcanezumab, 18.0% taking fremanezumab, and 2.9% taking eptinezumab. Meaningful pain relief was achieved by 61.6% of patients at 2 hours and 80.4% of patients at 4 hours post dose for both the 50-mg and 100-mg dose of ubrogepant. Return to normal function was achieved by 34.7% of patients at 2 hours and 50.5% at 4 hours post dose as well. Patients reported a 72.7% satisfaction level with the medication.

When CGRP acute medications were first approved, there was concern about the use of a mAb together with an oral antagonist. It was thought that CGRP medications would be associated with fewer benefits than when these medications were used alone, due to the belief that only a specific amount of CGRP could be blocked at any specific time. This trial shows that the efficacy of CGRP acute medications is not affected by concomitant use of mAb. Many patients who respond well to CGRP mAb will benefit significantly from the additional abortive use of oral antagonists.

Depression is one of the most common comorbidities associated with migraine. Major depressive disorder is both a risk factor for chronic migraine and a condition that one is more likely to develop after being diagnosed with chronic migraine. The study by de Vries Lentsch and colleagues investigated the use of two of the calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) treatments — erenumab and fremanezumab — compared with a control group of patients with chronic migraine, with an eye on outcomes to measure depression. Of note, reduction in headache frequency (defined as reduction in monthly migraine days) was also investigated as an independent variable.

This was a single-center study performed at the University of Leiden Headache Center. It was not a randomized trial, but all patients were followed with an e-diary and Day 0 vs Day 90 questionnaires that tracked their headache frequency and severity as well as a number of metrics related to depression. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Center for Epidemiological Studies Depression Scale (CES-D). The Headache Impact Test (HIT-6) was used to follow headache-related impact and disability, and the Perceived Stress Scale (PSS) was used to measure the degree of stressful situations the patient was experiencing.

The baseline depression scales between the three groups were 70%, 60%, and 66%, respectively; there were similar baseline levels of migraine frequency and disability as well. Both intervention groups showed a significant decrease in the symptoms of depression, and having a greater level of depression was negatively associated with reduction in monthly migraine days after 3 months. Of note, logistic-regression analysis determined that the reduction in depressive symptoms was independent of the reduction in migraine frequency.

Nearly all headache care providers are faced with challenging situations on a daily basis; often this is due to the comorbidity of mood disorders and high-frequency migraine. A traditional approach has been to provide the patient with a migraine preventive medication in the antidepressant family, such as a tricyclic antidepressant or serotonin and norepinephrine reuptake inhibitor (SNRI). Although these can be helpful, they are less specific for migraine prevention. Many patients are also already taking antidepressant medications, and the addition of a migraine-preventive antidepressant would be contraindicated. This study broadens the possibilities for prevention in these complicated patients and shows that there is benefit in both migraine-related outcomes and markers for depression when using CGRP-based therapy.

The way headache medicine is practiced changed dramatically in 2018 with the advent of CGRP monoclonal antibody (mAb) treatments for migraine. These medications have allowed us to target migraine specifically, whereas all of the preventive medications for migraine prior to 2018 were developed for other conditions and only secondarily helped migraine. These include the antidepressant, antihypertensive, and antiepileptic classes of medications, as well as onabotulinum toxin A, which, although approved for migraine, is not targeting a migraine-specific factor. Moskatel and colleagues sought to better understand the changing patterns of prescribing the nonspecific, or "traditional," migraine preventive medications in light of the advent of CGRP treatment.

This was a retrospective cohort study using aggregated data from the Stanford headache center. The percentage of patients with chronic migraine who had been prescribed one of the 10 most prescribed oral preventive medications or onabotulinum toxin A, or any of the four CGRP mAb, were calculated relative to the total number of patients with chronic migraine who received a prescription for any medication from the clinic during the pre-CGRP mAb years of 2015-2017 and post-approval years of 2019-2021.

The Stanford (STARR) database was filtered, searching for patients living in a California ZIP code with a diagnosis of chronic migraine who were followed from 2015 to 2021. The 10 most common non-CGRP preventive medications were amitriptyline/nortriptyline, valproate, duloxetine, gabapentin, memantine, propranolol, venlafaxine, verapamil, and onabotulinumtoxinA.

Erenumab was noted to initially be the most prescribed CGRP monoclonal antibody medication, but this was overtaken by galcanezumab after the second quarter of 2020 and throughout 2021. There is a statistically significant decrease in the percentage of patients receiving any of the non-CGRP preventive medications since 2018. The most significant decreases were in the tricyclic antidepressant class, as well as valproate, duloxetine, memantine, and onabotulinum toxin A. There was no statistically significant change in venlafaxine or gabapentin prescriptions.

This study highlights the changing face of headache medicine, and having a new class of migraine-specific treatment has significantly affected prescribing patterns. Although there is a statistically significant decrease in the prescribing of these non–migraine-specific preventive medications, they are still often recommended due to step-therapy regulations from insurance formularies, or as part of a polypharmacy regimen that may be more beneficial for a patient. These medications do improve patient outcomes and will remain a mainstay in migraine treatment.

Nearly all patients with migraine are recommended an acute medication to treat migraine attacks abortively; some patients are also recommended preventive therapies if migraine frequency significantly affects their quality of life. The American Headache Society/American Academy of Neurology guidelines for prevention recommend the initiation of a preventive medication at a frequency of 4-5 headache days per month or approximately 1 per week. Lipton and colleagues sought to determine whether there were any efficacy concerns in combining a CGRP mAb for prevention with ubrogepant, an oral CGRP antagonist, for acute treatment.

This was a prospective, open-level observational study assessing pain relief, return to normal function, and treatment satisfaction with patients given 50 or 100 mg of ubrogepant while concomitantly being given a seizure or mAb medication. Patients were allowed to be taking onabotulinumtoxinA as well as a CGRP mAb. The patients in this study were asked to track their headache symptoms using the Migraine Buddy e-diary. Meaningful pain relief was defined as a rating of migraine-related pain with one of the following choices 4 hours after taking the medication: no pain, mild pain, moderate pain, or severe pain. Return to normal function was defined as whether the patient determined they were able to function normally relative to their baseline at specific times post intervention. This was based on a functional disability scale. Treatment satisfaction was determined on the basis of a seven-point rating scale for how satisfied the patient felt with the medication at the end of the trial period.

A total of 245 participants provided at least 30 days of data, with 44.5% of the patients taking erenumab, 35.1% taking galcanezumab, 18.0% taking fremanezumab, and 2.9% taking eptinezumab. Meaningful pain relief was achieved by 61.6% of patients at 2 hours and 80.4% of patients at 4 hours post dose for both the 50-mg and 100-mg dose of ubrogepant. Return to normal function was achieved by 34.7% of patients at 2 hours and 50.5% at 4 hours post dose as well. Patients reported a 72.7% satisfaction level with the medication.

When CGRP acute medications were first approved, there was concern about the use of a mAb together with an oral antagonist. It was thought that CGRP medications would be associated with fewer benefits than when these medications were used alone, due to the belief that only a specific amount of CGRP could be blocked at any specific time. This trial shows that the efficacy of CGRP acute medications is not affected by concomitant use of mAb. Many patients who respond well to CGRP mAb will benefit significantly from the additional abortive use of oral antagonists.

Inpatient headache admissions are often considered a last-case scenario option for patients with chronic refractory migraine. Initially described by Raskin,¹ the admission typically consists of repetitive infusions of dihydroergotamine (DHE) with a pretreatment of antihistamine, neuroleptic, and other antinausea medications in addition to anti-inflammatory or steroid medications, IV fluids, and magnesium. Often this is superimposed on a continuous infusion of lidocaine or ketamine. One common concern is whether the use of DHE is safe for patients at a higher risk for vascular disease. Wang and colleagues reported on the incidence of cardiovascular adverse events in this population receiving repetitive intravenous DHE.

They present findings based on the Jefferson Headache Center (Philadelphia, Pennsylvania) Inpatient Headache Protocol, looking at patients admitted from January through October 2019. Of the 347 patients admitted during this period, 64 were identified as having either an elevated or low risk for atherosclerotic vascular disease. The degree of vascular risk was determined on the basis of an atherosclerotic cardiovascular disease calculation, using body mass index values, cholesterol level, and mean arterial blood pressure readings, as well as smoking and diabetes history. A score < 5.0% was designated low risk, while elevated risk included scores up to 20%. DHE was not offered to patients with a history of moderate to severe ischemic heart disease, coronary vasospasm, peripheral artery disease, Raynaud phenomenon, or ischemic stroke.

The primary outcome was treatment effectiveness, determined by an 11-point pain scale; secondary outcomes included tolerability, as defined by change in the patient's QTc (corrected QT interval) based on their daily ECG monitoring, the incidence of chest pain or shortness of breath, and whether DHE needed to be tapered or discontinued. The researchers noted that the elevated-vascular-risk group had fewer patients receiving the maximum dose of DHE and receiving less DHE over the course of their admission as compared with the low-risk group. They also reported lower response rates and less freedom from pain after admission. No clinically significant adverse events were noted in either group, and only three patients had sustained ECG changes from baseline.

DHE remains an effective treatment for the most chronic and refractory migraine cases, and it can be provided safely and effectively in an appropriately monitored setting. Although there still are contraindications for receiving DHE, those who can receive it may benefit significantly. Ideally, this should be done with cardiac clearance if there is any doubt regarding the vascular risk for any individual patient.

The frequency and severity of migraine can fluctuate due to a myriad of factors. When faced with worsening migraine, most healthcare providers ask their patients about specific triggers or other potential causes that may have led to the recent subacute worsening. Many healthcare providers will also investigate further, and when appropriate, order serum lab testing to determine whether any potential metabolic derangement, vitamin deficiency, or other abnormality could be contributing. Subclinical hypothyroidism is a common finding when investigating for these potential causes of worsening migraine, and often our internal medicine or endocrinology colleagues will discount these findings as "borderline" or still within normal limits. Dev and colleagues sought to determine whether low-dose thyroid replacement was beneficial for migraine prevention in this situation.

This study defined subclinical hypothyroidism as a thyroid-stimulating hormone (TSH) level of 4.5-10.0 mIU/L with a normal free thyroxine (T4), measured twice within 6 weeks for confirmation. Patients with prior thyroid disease were excluded from the study. Participants were randomly assigned to take 25 μg levothyroxine supplementation or placebo and were allowed to continue their migraine treatments. The primary outcomes were reduction in headache duration, frequency, severity, and Migraine Disability Assessment (MIDAS) score after 3 months.

A total of 87 patients with migraine and subclinical hypothyroidism were recruited, and the investigators noted a statistically significant improvement in all parameters (migraine frequency, severity, duration, MIDAS score) after 3 months of low-dose thyroid supplementation. This was maintained at a 3-month follow-up visit as well. TSH levels normalized in 87% of participants after repeat testing 3 months after the intervention.

When evaluating patients with worsening migraine who had been stable, it is wise to consider subclinical hypothyroidism as a potential etiology. Low-dose thyroid hormone supplementation appears to be well tolerated and effective for normalizing both TSH levels and, importantly, the migrainous exacerbation. Clinicians often will start or add preventive medications, ignoring the reason that there was an exacerbation in the first place, even though many of our colleagues choose not to treat this degree of hypothyroidism.

Many variants of migraine are better recognized and understood now; chief among these is vestibular migraine (VM). VM is a migraine subtype characterized by frequent or near-constant vestibular symptoms (vertigo, lightheadedness, disequilibrium, or rocking) with superimposed headache symptoms with some migrainous features. VM is generally considered to be more difficult to treat and more treatment-refractory than episodic or chronic migraine without vestibular symptoms. There are few treatments that are specific for this variant of migraine. Chen and colleagues sought to better understand the evidence of specific treatments for VM via meta-analysis.

Only randomized controlled trials were included in this meta-analysis; seven studies that specifically recruited patients with vestibular migraine using International Classification of Headache Disorders (ICHD) criteria were included. The outcomes of the studies were changes in frequency or severity of vestibular migraine attacks. The studies that were included were published from 2014 to 2022 and comprised multiple treatment comparisons, including metoprolol, venlafaxine, valproic acid, propranolol, flunarizine, a probiotic, and relaxation techniques.

Three interventions were noted to be significantly beneficial for VM prevention, specifically a decrease in migraine frequency: valproic acid, propranolol, and venlafaxine. Valproic acid yielded the greatest decrease in VM frequency among all interventions. None of the interventions were associated with improvement in VM severity, and none of the treatments were associated with significantly different adverse-event and dropout rates.

VM is widely thought to be underdiagnosed and should be considered more frequently. This includes situations in which the headache component of the patient's complaints is relatively mild but still associated with features of migraines, such as sensitivities to light and sound, nausea, or unilateral presentations of pain. There remain very few high-quality VM studies, but this meta-analysis should highlight potential treatment options and raise the profile for this diagnosis in order for further trials to be performed.

Additional Reference

1. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995-997. doi: 10.1212/WNL.36.7.995

Inpatient headache admissions are often considered a last-case scenario option for patients with chronic refractory migraine. Initially described by Raskin,¹ the admission typically consists of repetitive infusions of dihydroergotamine (DHE) with a pretreatment of antihistamine, neuroleptic, and other antinausea medications in addition to anti-inflammatory or steroid medications, IV fluids, and magnesium. Often this is superimposed on a continuous infusion of lidocaine or ketamine. One common concern is whether the use of DHE is safe for patients at a higher risk for vascular disease. Wang and colleagues reported on the incidence of cardiovascular adverse events in this population receiving repetitive intravenous DHE.

They present findings based on the Jefferson Headache Center (Philadelphia, Pennsylvania) Inpatient Headache Protocol, looking at patients admitted from January through October 2019. Of the 347 patients admitted during this period, 64 were identified as having either an elevated or low risk for atherosclerotic vascular disease. The degree of vascular risk was determined on the basis of an atherosclerotic cardiovascular disease calculation, using body mass index values, cholesterol level, and mean arterial blood pressure readings, as well as smoking and diabetes history. A score < 5.0% was designated low risk, while elevated risk included scores up to 20%. DHE was not offered to patients with a history of moderate to severe ischemic heart disease, coronary vasospasm, peripheral artery disease, Raynaud phenomenon, or ischemic stroke.

The primary outcome was treatment effectiveness, determined by an 11-point pain scale; secondary outcomes included tolerability, as defined by change in the patient's QTc (corrected QT interval) based on their daily ECG monitoring, the incidence of chest pain or shortness of breath, and whether DHE needed to be tapered or discontinued. The researchers noted that the elevated-vascular-risk group had fewer patients receiving the maximum dose of DHE and receiving less DHE over the course of their admission as compared with the low-risk group. They also reported lower response rates and less freedom from pain after admission. No clinically significant adverse events were noted in either group, and only three patients had sustained ECG changes from baseline.

DHE remains an effective treatment for the most chronic and refractory migraine cases, and it can be provided safely and effectively in an appropriately monitored setting. Although there still are contraindications for receiving DHE, those who can receive it may benefit significantly. Ideally, this should be done with cardiac clearance if there is any doubt regarding the vascular risk for any individual patient.

The frequency and severity of migraine can fluctuate due to a myriad of factors. When faced with worsening migraine, most healthcare providers ask their patients about specific triggers or other potential causes that may have led to the recent subacute worsening. Many healthcare providers will also investigate further, and when appropriate, order serum lab testing to determine whether any potential metabolic derangement, vitamin deficiency, or other abnormality could be contributing. Subclinical hypothyroidism is a common finding when investigating for these potential causes of worsening migraine, and often our internal medicine or endocrinology colleagues will discount these findings as "borderline" or still within normal limits. Dev and colleagues sought to determine whether low-dose thyroid replacement was beneficial for migraine prevention in this situation.

This study defined subclinical hypothyroidism as a thyroid-stimulating hormone (TSH) level of 4.5-10.0 mIU/L with a normal free thyroxine (T4), measured twice within 6 weeks for confirmation. Patients with prior thyroid disease were excluded from the study. Participants were randomly assigned to take 25 μg levothyroxine supplementation or placebo and were allowed to continue their migraine treatments. The primary outcomes were reduction in headache duration, frequency, severity, and Migraine Disability Assessment (MIDAS) score after 3 months.

A total of 87 patients with migraine and subclinical hypothyroidism were recruited, and the investigators noted a statistically significant improvement in all parameters (migraine frequency, severity, duration, MIDAS score) after 3 months of low-dose thyroid supplementation. This was maintained at a 3-month follow-up visit as well. TSH levels normalized in 87% of participants after repeat testing 3 months after the intervention.

When evaluating patients with worsening migraine who had been stable, it is wise to consider subclinical hypothyroidism as a potential etiology. Low-dose thyroid hormone supplementation appears to be well tolerated and effective for normalizing both TSH levels and, importantly, the migrainous exacerbation. Clinicians often will start or add preventive medications, ignoring the reason that there was an exacerbation in the first place, even though many of our colleagues choose not to treat this degree of hypothyroidism.

Many variants of migraine are better recognized and understood now; chief among these is vestibular migraine (VM). VM is a migraine subtype characterized by frequent or near-constant vestibular symptoms (vertigo, lightheadedness, disequilibrium, or rocking) with superimposed headache symptoms with some migrainous features. VM is generally considered to be more difficult to treat and more treatment-refractory than episodic or chronic migraine without vestibular symptoms. There are few treatments that are specific for this variant of migraine. Chen and colleagues sought to better understand the evidence of specific treatments for VM via meta-analysis.

Only randomized controlled trials were included in this meta-analysis; seven studies that specifically recruited patients with vestibular migraine using International Classification of Headache Disorders (ICHD) criteria were included. The outcomes of the studies were changes in frequency or severity of vestibular migraine attacks. The studies that were included were published from 2014 to 2022 and comprised multiple treatment comparisons, including metoprolol, venlafaxine, valproic acid, propranolol, flunarizine, a probiotic, and relaxation techniques.

Three interventions were noted to be significantly beneficial for VM prevention, specifically a decrease in migraine frequency: valproic acid, propranolol, and venlafaxine. Valproic acid yielded the greatest decrease in VM frequency among all interventions. None of the interventions were associated with improvement in VM severity, and none of the treatments were associated with significantly different adverse-event and dropout rates.

VM is widely thought to be underdiagnosed and should be considered more frequently. This includes situations in which the headache component of the patient's complaints is relatively mild but still associated with features of migraines, such as sensitivities to light and sound, nausea, or unilateral presentations of pain. There remain very few high-quality VM studies, but this meta-analysis should highlight potential treatment options and raise the profile for this diagnosis in order for further trials to be performed.

Additional Reference

1. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995-997. doi: 10.1212/WNL.36.7.995

Inpatient headache admissions are often considered a last-case scenario option for patients with chronic refractory migraine. Initially described by Raskin,¹ the admission typically consists of repetitive infusions of dihydroergotamine (DHE) with a pretreatment of antihistamine, neuroleptic, and other antinausea medications in addition to anti-inflammatory or steroid medications, IV fluids, and magnesium. Often this is superimposed on a continuous infusion of lidocaine or ketamine. One common concern is whether the use of DHE is safe for patients at a higher risk for vascular disease. Wang and colleagues reported on the incidence of cardiovascular adverse events in this population receiving repetitive intravenous DHE.

They present findings based on the Jefferson Headache Center (Philadelphia, Pennsylvania) Inpatient Headache Protocol, looking at patients admitted from January through October 2019. Of the 347 patients admitted during this period, 64 were identified as having either an elevated or low risk for atherosclerotic vascular disease. The degree of vascular risk was determined on the basis of an atherosclerotic cardiovascular disease calculation, using body mass index values, cholesterol level, and mean arterial blood pressure readings, as well as smoking and diabetes history. A score < 5.0% was designated low risk, while elevated risk included scores up to 20%. DHE was not offered to patients with a history of moderate to severe ischemic heart disease, coronary vasospasm, peripheral artery disease, Raynaud phenomenon, or ischemic stroke.

The primary outcome was treatment effectiveness, determined by an 11-point pain scale; secondary outcomes included tolerability, as defined by change in the patient's QTc (corrected QT interval) based on their daily ECG monitoring, the incidence of chest pain or shortness of breath, and whether DHE needed to be tapered or discontinued. The researchers noted that the elevated-vascular-risk group had fewer patients receiving the maximum dose of DHE and receiving less DHE over the course of their admission as compared with the low-risk group. They also reported lower response rates and less freedom from pain after admission. No clinically significant adverse events were noted in either group, and only three patients had sustained ECG changes from baseline.

DHE remains an effective treatment for the most chronic and refractory migraine cases, and it can be provided safely and effectively in an appropriately monitored setting. Although there still are contraindications for receiving DHE, those who can receive it may benefit significantly. Ideally, this should be done with cardiac clearance if there is any doubt regarding the vascular risk for any individual patient.

The frequency and severity of migraine can fluctuate due to a myriad of factors. When faced with worsening migraine, most healthcare providers ask their patients about specific triggers or other potential causes that may have led to the recent subacute worsening. Many healthcare providers will also investigate further, and when appropriate, order serum lab testing to determine whether any potential metabolic derangement, vitamin deficiency, or other abnormality could be contributing. Subclinical hypothyroidism is a common finding when investigating for these potential causes of worsening migraine, and often our internal medicine or endocrinology colleagues will discount these findings as "borderline" or still within normal limits. Dev and colleagues sought to determine whether low-dose thyroid replacement was beneficial for migraine prevention in this situation.

This study defined subclinical hypothyroidism as a thyroid-stimulating hormone (TSH) level of 4.5-10.0 mIU/L with a normal free thyroxine (T4), measured twice within 6 weeks for confirmation. Patients with prior thyroid disease were excluded from the study. Participants were randomly assigned to take 25 μg levothyroxine supplementation or placebo and were allowed to continue their migraine treatments. The primary outcomes were reduction in headache duration, frequency, severity, and Migraine Disability Assessment (MIDAS) score after 3 months.

A total of 87 patients with migraine and subclinical hypothyroidism were recruited, and the investigators noted a statistically significant improvement in all parameters (migraine frequency, severity, duration, MIDAS score) after 3 months of low-dose thyroid supplementation. This was maintained at a 3-month follow-up visit as well. TSH levels normalized in 87% of participants after repeat testing 3 months after the intervention.

When evaluating patients with worsening migraine who had been stable, it is wise to consider subclinical hypothyroidism as a potential etiology. Low-dose thyroid hormone supplementation appears to be well tolerated and effective for normalizing both TSH levels and, importantly, the migrainous exacerbation. Clinicians often will start or add preventive medications, ignoring the reason that there was an exacerbation in the first place, even though many of our colleagues choose not to treat this degree of hypothyroidism.

Many variants of migraine are better recognized and understood now; chief among these is vestibular migraine (VM). VM is a migraine subtype characterized by frequent or near-constant vestibular symptoms (vertigo, lightheadedness, disequilibrium, or rocking) with superimposed headache symptoms with some migrainous features. VM is generally considered to be more difficult to treat and more treatment-refractory than episodic or chronic migraine without vestibular symptoms. There are few treatments that are specific for this variant of migraine. Chen and colleagues sought to better understand the evidence of specific treatments for VM via meta-analysis.

Only randomized controlled trials were included in this meta-analysis; seven studies that specifically recruited patients with vestibular migraine using International Classification of Headache Disorders (ICHD) criteria were included. The outcomes of the studies were changes in frequency or severity of vestibular migraine attacks. The studies that were included were published from 2014 to 2022 and comprised multiple treatment comparisons, including metoprolol, venlafaxine, valproic acid, propranolol, flunarizine, a probiotic, and relaxation techniques.

Three interventions were noted to be significantly beneficial for VM prevention, specifically a decrease in migraine frequency: valproic acid, propranolol, and venlafaxine. Valproic acid yielded the greatest decrease in VM frequency among all interventions. None of the interventions were associated with improvement in VM severity, and none of the treatments were associated with significantly different adverse-event and dropout rates.

VM is widely thought to be underdiagnosed and should be considered more frequently. This includes situations in which the headache component of the patient's complaints is relatively mild but still associated with features of migraines, such as sensitivities to light and sound, nausea, or unilateral presentations of pain. There remain very few high-quality VM studies, but this meta-analysis should highlight potential treatment options and raise the profile for this diagnosis in order for further trials to be performed.

Additional Reference

1. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995-997. doi: 10.1212/WNL.36.7.995

This month we will discuss "migraine plus" conditions: menstrual migraine as well as migraine-associated symptoms, including allodynia, photophobia, and nausea.

Migraine is one of the most common and disabling conditions worldwide, and it is three times more likely to be found in women than men. This is even more so during reproductive years, where many women experience hormonally triggered migraine attacks. Although some women will experience migraine exclusively perimenstrually, most women who experience menstrual migraine attacks also will have migraine attacks that are not hormonally triggered. It is often challenging to find the correct acute treatment for specific kinds of migraine attacks, and many women will describe specific acute medications as more effective for their nonmenstrual or "regular" migraine attacks compared with their perimenstrual attacks. The study by MacGregor and colleagues investigated the use of ubrogepant and compared its effect between these two subtypes of attacks.

This trial was an extension of the initial phase 3 trial of ubrogepant, called ACHIEVE II. Initial investigators enrolled over 700 patients into an open-label extension, and the participants were randomly assigned 1:1:1 to their "usual care," 50 mg ubrogepant, or 100 mg ubrogepant. Participants were blinded to the dose of ubrogepant even though they knew that they were taking ubrogepant or their standard acute medication. The purpose of the "usual care" arm was not to collect efficacy results; rather, it was for safety, specifically to evaluate the long-term hepatic safety with ubrogepant.

Participants were allowed to treat up to eight migraine attacks per 4-week interval. The duration of the trial was 52 weeks, and a second dose of medication was allowed, identical to the initial dose. Women in this trial recorded their menstrual start date and whether they treated menstrually related attacks. An attack was considered menstrually related if the headache was within a 5-day window of the onset of menstruation. Of the 734 women enrolled in the intention-to-treat population, 354 reported at least one menstrual cycle start date with a headache day. Efficacy outcome measures included pain freedom at 2 hours post-dose, pain relief at 2 hours post-dose, absence of photophobia, phonophobia, and nausea at 2 hours post-dose, normal function at 2 hours post-dose, and use of rescue medication within 24 hours of the initial dose. All information was collected via an electronic diary.

There was no statistically significant difference between 2-hour pain freedom outcomes of menstrual and nonmenstrual migraine attacks, although there was a numerically higher mean percentage of menstrual attacks that was not statistically significant. This was noted for both doses of ubrogepant. This was also the case for 2-hour pain relief; the migraine-associated symptoms of photophobia, phonophobia, and nausea; for functional disability; and the use of a rescue medication. Among all outcomes it appears that both doses of ubrogepant are equally effective for both menstrual and nonmenstrual migraine attacks. On the basis of this evidence, clinicians may be able to consolidate different acute medications for different migraine subtypes and consider the use of this calcitonin gene-related peptide (CGRP) antagonist for all the patient's attacks.

Allodynia is a condition whereby a nonpainful stimulus is perceived as painful. In the context of migraine, this often will occur in the head and neck region and as a result of the chronification of migraine — headache frequency increasing to > 15 days per month. One significant risk factor for the development of chronic migraine is medication overuse, when an acute medication for migraine is used more often than its recommended use. Pijpers and colleagues sought to determine whether the presence of allodynia was predictive for the prognosis of chronic migraine complicated by medication overuse.

This study was a subset of the Chronification And Reversibility of Migraine (CHARM) study, a randomized, double-blind, placebo-controlled trial that aimed to investigate whether treatment with botulinum toxin A was of added value in addition to withdrawal therapy in chronic migraine patients with medication overuse headache. Diagnoses were made in consultation with headache experts and confirmed by a headache diary. Exclusion criteria were: (1) other primary headache or neurologic disorders; (2) other chronic pain disorders with medium to high pain intensity or requiring pain medication; (3) major psychiatric disorders other than depression; (4) major cognitive, behavioral, or oncologic disorders; (5) contraindications for treatment or inability to adhere to the study protocol; (6) (planned) pregnancy or breastfeeding; (7) use of ergots, opioids, or barbiturates; or (8) abuse of drugs in the past 12 months. Allodynia was determined by the Allodynia Symptom Checklist (ASC) .

The primary outcome was reversion from chronic to episodic migraine; secondary outcomes were > 50% reduction in monthly migraine days and reduction in number of monthly headache days. A total of 173 participants in the CHARM trial provided baseline allodynia data and were included in this current study. Participants with cutaneous allodynia were mainly women and did not differ significantly in age, number of monthly migraine or headache days, age of onset, use of acute or prophylactic treatment, or being treated with botulinum toxin.

The absence of cutaneous allodynia was predictive for good outcome after 12 weeks. For the primary endpoint, the odds for reversion from chronic migraine to episodic migraine were 2.5 times higher for participants without allodynia vs with allodynia. In all, 75.0% of participants without allodynia vs 57.4% of participants with allodynia reverted to episodic migraine. These helpful data will allow us to better predict accurately the disease process and better set expectations for our patients with chronic migraine.

In the earlier days of headache treatment, the focus for both acute and preventive medications was a decrease in the severity or frequency of pain. As time has progressed and our understanding of migraine has broadened, we now consider pain one of the many features of migraine, albeit usually the most prominent feature. The CGRP antagonist class of migraine medications has revolutionized how migraine is treated, both acutely and preventively; however, the initial studies all focused on pain-related outcomes. Alpuente and colleagues sought to better determine the effect of CGRP monoclonal antibody medications on other migraine-associated symptoms, specifically photophobia, photophobia, nausea, dizziness, and aura.

All injectable CGRP antibody medications were studied. Responses were recorded in an electronic diary. Patients were followed at 3 and 6 months and were excluded if their diary was < 80% complete; a total of 158 patients were included in this study. At 3 months, groups of patients were further divided between those who had > 50% decrease in monthly headache days and those that had < 50% reduction.

The > 50% group showed statistically significant reductions in the ratios of photophobia, phonophobia, and aura after 6 months of treatment, and, of note, these symptoms decreased at a higher rate than the reduction in headache days per month after 6 months. Rates of nausea and dizziness only reduced proportionally to the monthly headache days. For the < 50% group, there was a rebound of dizziness in between months 3 and 6, but all other outcomes decreased in proportion to the monthly headache days.

Our patients all experience symptoms other than headache pain as part of their migraine attacks. When we discuss the risks and benefits of a new treatment, we can now more accurately address many of the other associated symptoms and explain what our patients are likely to expect when starting a new medication. Similar studies have described these findings with the oral CGRP antagonists as well, and most acute migraine studies now use "most bothersome symptom" rather than pain severity as their primary outcome.

This month we will discuss "migraine plus" conditions: menstrual migraine as well as migraine-associated symptoms, including allodynia, photophobia, and nausea.

Migraine is one of the most common and disabling conditions worldwide, and it is three times more likely to be found in women than men. This is even more so during reproductive years, where many women experience hormonally triggered migraine attacks. Although some women will experience migraine exclusively perimenstrually, most women who experience menstrual migraine attacks also will have migraine attacks that are not hormonally triggered. It is often challenging to find the correct acute treatment for specific kinds of migraine attacks, and many women will describe specific acute medications as more effective for their nonmenstrual or "regular" migraine attacks compared with their perimenstrual attacks. The study by MacGregor and colleagues investigated the use of ubrogepant and compared its effect between these two subtypes of attacks.

This trial was an extension of the initial phase 3 trial of ubrogepant, called ACHIEVE II. Initial investigators enrolled over 700 patients into an open-label extension, and the participants were randomly assigned 1:1:1 to their "usual care," 50 mg ubrogepant, or 100 mg ubrogepant. Participants were blinded to the dose of ubrogepant even though they knew that they were taking ubrogepant or their standard acute medication. The purpose of the "usual care" arm was not to collect efficacy results; rather, it was for safety, specifically to evaluate the long-term hepatic safety with ubrogepant.

Participants were allowed to treat up to eight migraine attacks per 4-week interval. The duration of the trial was 52 weeks, and a second dose of medication was allowed, identical to the initial dose. Women in this trial recorded their menstrual start date and whether they treated menstrually related attacks. An attack was considered menstrually related if the headache was within a 5-day window of the onset of menstruation. Of the 734 women enrolled in the intention-to-treat population, 354 reported at least one menstrual cycle start date with a headache day. Efficacy outcome measures included pain freedom at 2 hours post-dose, pain relief at 2 hours post-dose, absence of photophobia, phonophobia, and nausea at 2 hours post-dose, normal function at 2 hours post-dose, and use of rescue medication within 24 hours of the initial dose. All information was collected via an electronic diary.

There was no statistically significant difference between 2-hour pain freedom outcomes of menstrual and nonmenstrual migraine attacks, although there was a numerically higher mean percentage of menstrual attacks that was not statistically significant. This was noted for both doses of ubrogepant. This was also the case for 2-hour pain relief; the migraine-associated symptoms of photophobia, phonophobia, and nausea; for functional disability; and the use of a rescue medication. Among all outcomes it appears that both doses of ubrogepant are equally effective for both menstrual and nonmenstrual migraine attacks. On the basis of this evidence, clinicians may be able to consolidate different acute medications for different migraine subtypes and consider the use of this calcitonin gene-related peptide (CGRP) antagonist for all the patient's attacks.

Allodynia is a condition whereby a nonpainful stimulus is perceived as painful. In the context of migraine, this often will occur in the head and neck region and as a result of the chronification of migraine — headache frequency increasing to > 15 days per month. One significant risk factor for the development of chronic migraine is medication overuse, when an acute medication for migraine is used more often than its recommended use. Pijpers and colleagues sought to determine whether the presence of allodynia was predictive for the prognosis of chronic migraine complicated by medication overuse.

This study was a subset of the Chronification And Reversibility of Migraine (CHARM) study, a randomized, double-blind, placebo-controlled trial that aimed to investigate whether treatment with botulinum toxin A was of added value in addition to withdrawal therapy in chronic migraine patients with medication overuse headache. Diagnoses were made in consultation with headache experts and confirmed by a headache diary. Exclusion criteria were: (1) other primary headache or neurologic disorders; (2) other chronic pain disorders with medium to high pain intensity or requiring pain medication; (3) major psychiatric disorders other than depression; (4) major cognitive, behavioral, or oncologic disorders; (5) contraindications for treatment or inability to adhere to the study protocol; (6) (planned) pregnancy or breastfeeding; (7) use of ergots, opioids, or barbiturates; or (8) abuse of drugs in the past 12 months. Allodynia was determined by the Allodynia Symptom Checklist (ASC) .

The primary outcome was reversion from chronic to episodic migraine; secondary outcomes were > 50% reduction in monthly migraine days and reduction in number of monthly headache days. A total of 173 participants in the CHARM trial provided baseline allodynia data and were included in this current study. Participants with cutaneous allodynia were mainly women and did not differ significantly in age, number of monthly migraine or headache days, age of onset, use of acute or prophylactic treatment, or being treated with botulinum toxin.

The absence of cutaneous allodynia was predictive for good outcome after 12 weeks. For the primary endpoint, the odds for reversion from chronic migraine to episodic migraine were 2.5 times higher for participants without allodynia vs with allodynia. In all, 75.0% of participants without allodynia vs 57.4% of participants with allodynia reverted to episodic migraine. These helpful data will allow us to better predict accurately the disease process and better set expectations for our patients with chronic migraine.

In the earlier days of headache treatment, the focus for both acute and preventive medications was a decrease in the severity or frequency of pain. As time has progressed and our understanding of migraine has broadened, we now consider pain one of the many features of migraine, albeit usually the most prominent feature. The CGRP antagonist class of migraine medications has revolutionized how migraine is treated, both acutely and preventively; however, the initial studies all focused on pain-related outcomes. Alpuente and colleagues sought to better determine the effect of CGRP monoclonal antibody medications on other migraine-associated symptoms, specifically photophobia, photophobia, nausea, dizziness, and aura.

All injectable CGRP antibody medications were studied. Responses were recorded in an electronic diary. Patients were followed at 3 and 6 months and were excluded if their diary was < 80% complete; a total of 158 patients were included in this study. At 3 months, groups of patients were further divided between those who had > 50% decrease in monthly headache days and those that had < 50% reduction.

The > 50% group showed statistically significant reductions in the ratios of photophobia, phonophobia, and aura after 6 months of treatment, and, of note, these symptoms decreased at a higher rate than the reduction in headache days per month after 6 months. Rates of nausea and dizziness only reduced proportionally to the monthly headache days. For the < 50% group, there was a rebound of dizziness in between months 3 and 6, but all other outcomes decreased in proportion to the monthly headache days.

Our patients all experience symptoms other than headache pain as part of their migraine attacks. When we discuss the risks and benefits of a new treatment, we can now more accurately address many of the other associated symptoms and explain what our patients are likely to expect when starting a new medication. Similar studies have described these findings with the oral CGRP antagonists as well, and most acute migraine studies now use "most bothersome symptom" rather than pain severity as their primary outcome.

This month we will discuss "migraine plus" conditions: menstrual migraine as well as migraine-associated symptoms, including allodynia, photophobia, and nausea.

Migraine is one of the most common and disabling conditions worldwide, and it is three times more likely to be found in women than men. This is even more so during reproductive years, where many women experience hormonally triggered migraine attacks. Although some women will experience migraine exclusively perimenstrually, most women who experience menstrual migraine attacks also will have migraine attacks that are not hormonally triggered. It is often challenging to find the correct acute treatment for specific kinds of migraine attacks, and many women will describe specific acute medications as more effective for their nonmenstrual or "regular" migraine attacks compared with their perimenstrual attacks. The study by MacGregor and colleagues investigated the use of ubrogepant and compared its effect between these two subtypes of attacks.

This trial was an extension of the initial phase 3 trial of ubrogepant, called ACHIEVE II. Initial investigators enrolled over 700 patients into an open-label extension, and the participants were randomly assigned 1:1:1 to their "usual care," 50 mg ubrogepant, or 100 mg ubrogepant. Participants were blinded to the dose of ubrogepant even though they knew that they were taking ubrogepant or their standard acute medication. The purpose of the "usual care" arm was not to collect efficacy results; rather, it was for safety, specifically to evaluate the long-term hepatic safety with ubrogepant.

Participants were allowed to treat up to eight migraine attacks per 4-week interval. The duration of the trial was 52 weeks, and a second dose of medication was allowed, identical to the initial dose. Women in this trial recorded their menstrual start date and whether they treated menstrually related attacks. An attack was considered menstrually related if the headache was within a 5-day window of the onset of menstruation. Of the 734 women enrolled in the intention-to-treat population, 354 reported at least one menstrual cycle start date with a headache day. Efficacy outcome measures included pain freedom at 2 hours post-dose, pain relief at 2 hours post-dose, absence of photophobia, phonophobia, and nausea at 2 hours post-dose, normal function at 2 hours post-dose, and use of rescue medication within 24 hours of the initial dose. All information was collected via an electronic diary.

There was no statistically significant difference between 2-hour pain freedom outcomes of menstrual and nonmenstrual migraine attacks, although there was a numerically higher mean percentage of menstrual attacks that was not statistically significant. This was noted for both doses of ubrogepant. This was also the case for 2-hour pain relief; the migraine-associated symptoms of photophobia, phonophobia, and nausea; for functional disability; and the use of a rescue medication. Among all outcomes it appears that both doses of ubrogepant are equally effective for both menstrual and nonmenstrual migraine attacks. On the basis of this evidence, clinicians may be able to consolidate different acute medications for different migraine subtypes and consider the use of this calcitonin gene-related peptide (CGRP) antagonist for all the patient's attacks.

Allodynia is a condition whereby a nonpainful stimulus is perceived as painful. In the context of migraine, this often will occur in the head and neck region and as a result of the chronification of migraine — headache frequency increasing to > 15 days per month. One significant risk factor for the development of chronic migraine is medication overuse, when an acute medication for migraine is used more often than its recommended use. Pijpers and colleagues sought to determine whether the presence of allodynia was predictive for the prognosis of chronic migraine complicated by medication overuse.

This study was a subset of the Chronification And Reversibility of Migraine (CHARM) study, a randomized, double-blind, placebo-controlled trial that aimed to investigate whether treatment with botulinum toxin A was of added value in addition to withdrawal therapy in chronic migraine patients with medication overuse headache. Diagnoses were made in consultation with headache experts and confirmed by a headache diary. Exclusion criteria were: (1) other primary headache or neurologic disorders; (2) other chronic pain disorders with medium to high pain intensity or requiring pain medication; (3) major psychiatric disorders other than depression; (4) major cognitive, behavioral, or oncologic disorders; (5) contraindications for treatment or inability to adhere to the study protocol; (6) (planned) pregnancy or breastfeeding; (7) use of ergots, opioids, or barbiturates; or (8) abuse of drugs in the past 12 months. Allodynia was determined by the Allodynia Symptom Checklist (ASC) .

The primary outcome was reversion from chronic to episodic migraine; secondary outcomes were > 50% reduction in monthly migraine days and reduction in number of monthly headache days. A total of 173 participants in the CHARM trial provided baseline allodynia data and were included in this current study. Participants with cutaneous allodynia were mainly women and did not differ significantly in age, number of monthly migraine or headache days, age of onset, use of acute or prophylactic treatment, or being treated with botulinum toxin.

The absence of cutaneous allodynia was predictive for good outcome after 12 weeks. For the primary endpoint, the odds for reversion from chronic migraine to episodic migraine were 2.5 times higher for participants without allodynia vs with allodynia. In all, 75.0% of participants without allodynia vs 57.4% of participants with allodynia reverted to episodic migraine. These helpful data will allow us to better predict accurately the disease process and better set expectations for our patients with chronic migraine.

In the earlier days of headache treatment, the focus for both acute and preventive medications was a decrease in the severity or frequency of pain. As time has progressed and our understanding of migraine has broadened, we now consider pain one of the many features of migraine, albeit usually the most prominent feature. The CGRP antagonist class of migraine medications has revolutionized how migraine is treated, both acutely and preventively; however, the initial studies all focused on pain-related outcomes. Alpuente and colleagues sought to better determine the effect of CGRP monoclonal antibody medications on other migraine-associated symptoms, specifically photophobia, photophobia, nausea, dizziness, and aura.

All injectable CGRP antibody medications were studied. Responses were recorded in an electronic diary. Patients were followed at 3 and 6 months and were excluded if their diary was < 80% complete; a total of 158 patients were included in this study. At 3 months, groups of patients were further divided between those who had > 50% decrease in monthly headache days and those that had < 50% reduction.

The > 50% group showed statistically significant reductions in the ratios of photophobia, phonophobia, and aura after 6 months of treatment, and, of note, these symptoms decreased at a higher rate than the reduction in headache days per month after 6 months. Rates of nausea and dizziness only reduced proportionally to the monthly headache days. For the < 50% group, there was a rebound of dizziness in between months 3 and 6, but all other outcomes decreased in proportion to the monthly headache days.

Our patients all experience symptoms other than headache pain as part of their migraine attacks. When we discuss the risks and benefits of a new treatment, we can now more accurately address many of the other associated symptoms and explain what our patients are likely to expect when starting a new medication. Similar studies have described these findings with the oral CGRP antagonists as well, and most acute migraine studies now use "most bothersome symptom" rather than pain severity as their primary outcome.

The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.

This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.

The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.

This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.

CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.

This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.

This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.

Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.

The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.

This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.

A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.

Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.

The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.

This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.

The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.

This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.

CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.

This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.

This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.

Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.

The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.

This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.

A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.

Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.

The calcitonin gene-related peptide (CGRP) antagonist class of medications has changed the face of migraine treatment — and there are now both acute and preventive options that are available in oral and injectable formulations. The gepant subclass of CGRP antagonists are small-molecule medications, in contrast to the CGRP monoclonal antibodies. Atogepant was developed as the first oral migraine-specific preventive medication, and the initial trials allowed for an initial approval by the US Food and Drug Administration for episodic migraine alone. The study by Pozo-Rosich and colleagues extended the patient population to patients with chronic migraine.

This was an international, multicenter, randomized controlled study of two dosages of atogepant (30 mg twice daily and 60 mg daily) compared with placebo over 12 weeks. The primary endpoint was change in mean monthly migraine days. There was a safety population as well that received a single dose of medication. Nearly 800 participants were enrolled equally into these three groups, and the authors used a modified intention-to-treat format that included all participants with at least 1 month of e-diary data and took at least one dose of the study medication.

The baseline number of mean monthly migraine days in this chronic migraine population was 18.6 days per month. After 12 weeks, the three groups showed decreases of 7.5, 6.1, and 5.1 days per month, which was statistically significant for the two intervention groups. The most common side effects were constipation and nausea, with up to 10% of the study population experiencing some gastrointestinal symptoms. Weight loss of 7% of body weight was also noticed in the two intervention groups.

This study describes the benefit of atogepant extending beyond the indication of episodic migraine. This chronic migraine population showed significant benefit in the decrease of mean monthly migraine days per month after 12 weeks. One additional benefit is weight loss even after 12 weeks. Compared with the monoclonal antibody class of CGRP antagonist, this medication appears to be approximately equally effective, with the additional benefit of weight loss. Because many preventive medications for migraine may be associated with weight gain — particularly the antidepressant and potentially the antihypertensive classes of medications — this can be a differentiating factor when choosing an appropriate preventive medication for your patients with chronic migraine.

CGRP is a known inflammatory modulator that also plays a significant role in the propagation of migraine. CGRP blockade has been associated, in some studies, with upper respiratory tract infection symptoms, raising the question of whether blocking CGRP chronically may increase the risk for infection. A prior study revealed that CGRP levels were decreased in patients with severe COVID-19, and another study did not find significant differences in COVID-19 disease, progression, or severity among migraine patients on CGRP antagonists. Wang and colleagues specifically sought to determine any potential association or risk between the use of CGRP antagonist medications and COVID.

This retrospective cohort study was performed in the US Veterans Affairs (VA) hospital system. It analyzed the electronic medical records of veterans diagnosed with migraine between January and May 2022. The participants' exposure to CGRP medications and the 30-day odds of hospitalization, as well as use of mechanical ventilation, were calculated. CGRP prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL), which were the only CGRP medications available at that point in the VA system. The primary outcome was cumulative incidence of SARS-CoV-2 infection; occurrences of SARS-CoV-2 infection were obtained from the VA COVID-19 Shared Data Resource. Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result.

This analysis revealed that CGRP monoclonal antibody use was not associated with risk for COVID-19, and among participants who tested positive for COVID-19, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between those who were receiving CGRP medications and those who were not. Although another prior study implied that CGRP blockade may decrease the risk for severe disease related to a cytokine storm, those results were only in vitro, and no results from human or animal trials have replicated these data. There is, therefore, no contraindication to using CGRP antagonist medications in people at high risk for development of COVID-19.

Many patients with migraine are recommended specific treatments for the prevention of migraine attacks and for the acute treatment of their attacks. Very few studies have investigated specific combinations of acute and preventive treatments. Although logically, there should be no contraindication to most treatment combinations, there may be some additional synergistic benefit to the combination of specific classes of medications. We have previously discussed a synergy between the CGRP antagonist class and onabotulinumtoxinA (Botox) for the prevention of chronic migraine; Manack Adams and colleagues sought to quantify the efficacy of ubrogepant when the patients were also administered botulinum toxin.

The joint American Academy of Neurology/American Headache Society consensus statement recommends starting preventive medication for anyone with migraine who experiences > 4-5 days of headache per month. It also recommends a migraine-specific acute treatment for anyone who experiences migraine attacks. Botulinum toxin is approved by the US Food and Drug Administration for the prevention of chronic migraine at a dose of 155 units injected every 3 months; ubrogepant is a CGRP oral small-molecule antagonist that is approved for the acute treatment of migraine.

This study investigated the effectiveness of ubrogepant, with a primary endpoint of meaningful pain relief and return to normal function 2 and 4 hours after an initial dose of 50 or 100 mg. Meaningful pain relief was defined as answering "yes" to a question about whether the patient experienced meaningful pain relief. This has been a pre-reported endpoint in other acute migraine treatment trials. Return to normal function was defined as the time point where the patient could perform their daily activities on the basis of a functional disability scale. Achieving normal function was classified as either remaining free of disability or by reporting functional disability before taking ubrogepant and then indicating a return to normal function at 2 and 4 hours post-dose.

A total of 134 patients were enrolled, taking both ubrogepant and botulinum toxin; patients were included if they were treated with ubrogepant at least once. Meaningful pain relief was achieved in 53.3% of patients at 2 hours and in 76.2% of patients at 4 hours post-dose. Return to normal function was achieved by 30.1% of patients at 2 hours and by 52.1% of patients at 4 hours post-dose. Both meaningful pain relief and return to normal function were seen to be statistically significant and stable across up to 10 attacks per person.

Headache treatment providers typically need to consider different classes of medications for prevention and acute treatment. A growing body of evidence describes a synergy between the CGRP class of medications and botulinum toxin. This appears to be true both when CGRP antagonists are used preventively and, in this case, when they are used for acute events. This certainly would be a safe and effective choice in many instances for many patients.

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

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

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

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

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

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

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

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

A large number of covariates were assessed as well, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

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

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

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

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

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

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

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

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

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

A large number of covariates were assessed as well, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

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

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

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

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

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

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

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

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

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

A large number of covariates were assessed as well, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

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

Calcitonin gene-related peptide (CGRP) antagonist medications have revolutionized migraine therapy since being introduced in 2018. The initial preventive trials for monoclonal antibodies (mAb) excluded older adults, with a cutoff in all studies at age 65 years. Long-term safety studies have not revealed signals for concern related to vascular or other adverse events. The study by Muñoz-Vendrell and colleagues investigated the efficacy of CGRP mAb in treatment-refractory older adults.

This was an observational retrospective study in participants older than 65 years that had previously used three or more prior migraine preventives unsuccessfully. The primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and acute medication frequency as well as improvement in patient reported outcomes.

A total of 162 participants were followed at 18 different headache centers throughout Spain. All patients had at least 8 headache days per month and had been treated unsuccessfully with three prior medications for migraine prevention, one of which was botulinum toxin. The median age was 68 years, and over 80% had chronic migraine. The reduction in mean headache days was 10 days per month; 72% continued to use their CGRP mAb after using it for 6 months. Participants were compared relative to medication overuse but no significant differences were found between those who overused medication and others.

This study highlights the efficacy of CGRP medications in those outside of the initially studied population. Other preventive medications may be contraindicated in this population, but CGRP antagonists do appear to be safe and effective options for older adults.

Opiate medications are typically considered inappropriate as an acute treatment for migraine. Even infrequent use of opiate medications has been shown to be associated with worse migraine outcomes, specifically higher frequency and a higher likelihood to convert from episodic to chronic migraine. Van Welie and colleagues performed a cross-sectional questionnaire-based study assessing levels of opioid use in patients with migraine.

Participants were selected from the Leiden Headache Center and fit the diagnostic criteria of migraine. They were given an e-questionnaire to determine their use of these opiates: buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol, and tramadol (codeine was not included in this list). Patients were separately divided between chronic and episodic migraine groups. The primary outcome was assessing for current acute treatment of migraine with an opiate; secondary outcomes were association of chronicity of migraine and likelihood of medication overuse with opiate use.

Only approximately 1.8% of participants reported that they currently use an opiate for acute migraine treatment; 12.5% reported that they previously have used an opiate and 25.7% reported using an opiate for another pain condition. Tramadol was the most commonly used opiate medication, followed by oxycodone and morphine; 2.4% of patients reported that their opiate use was not prescribed by their doctor. Primary care doctors were the most common prescribers of the opiate medications; 16% of the time, patients were told that it was a preventive treatment for migraine. Opiate use was more frequent in patients with a diagnosis of chronic migraine, and the duration of use was greater.

Opiate medications remain a poor acute choice of treatment for migraine, and this study shows a correlation between higher opiate use and chronic migraine. There are many other acute medications now available for migraine, many of them migraine-specific treatments, such as triptans, gepants, and ditans. This research again shows that opiates should be avoided if at all possible for migraine.

Patients with medication overuse headache are more likely to be treatment-refractory, and the addition of acute medications often can be less effective if they remain on the overused medication. There has been a long-standing debate whether it is best to wean medications first or start a preventive initially when faced with medication overuse. The CGRP antagonists may be one of the better preventive options in this situation, and one mAb (fremenezumab) reported positive data in a small medication overuse trial. The study by Guerzoni and colleagues investigated the effectiveness of galcanezumab in chronic migraine with medication overuse.

This was a prospective trial conducted at the University Hospital of Modena. A total of 78 patients with a diagnosis of chronic migraine and medication overuse were enrolled for 15 months, with follow-up every 3 months. At each follow-up appointment, they completed a questionnaire asking them details about: mean migraine days per month, mean number of painkillers taken per month, mean days per month taking a painkiller, average migraine severity, and the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questions. Patients were given the standard-dosing regimen of glacanezumab for migraine and were not blinded; this was an open-label study.

The mean migraine days per month were significantly reduced after 3, 6, 9, and 12 months. The amount of painkillers used per month and days of painkillers per month both reduced significantly as well. Migraine-related disability on HIT-6 and MIDAS were all reduced significantly as well. The most significant improvement long-term was noted in patients who improved the most during the initial 3 months of treatment.

The debate regarding the best treatment for patients with medication overuse will continue, but this study highlights the effectiveness of CGRP mAb use in this population. Patients were able to decrease the use of acute medications without a strict wean off of their previous medication. Ideally, a similar study should also be done for additional mAb and oral CGRP antagonists.

Calcitonin gene-related peptide (CGRP) antagonist medications have revolutionized migraine therapy since being introduced in 2018. The initial preventive trials for monoclonal antibodies (mAb) excluded older adults, with a cutoff in all studies at age 65 years. Long-term safety studies have not revealed signals for concern related to vascular or other adverse events. The study by Muñoz-Vendrell and colleagues investigated the efficacy of CGRP mAb in treatment-refractory older adults.

This was an observational retrospective study in participants older than 65 years that had previously used three or more prior migraine preventives unsuccessfully. The primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and acute medication frequency as well as improvement in patient reported outcomes.

A total of 162 participants were followed at 18 different headache centers throughout Spain. All patients had at least 8 headache days per month and had been treated unsuccessfully with three prior medications for migraine prevention, one of which was botulinum toxin. The median age was 68 years, and over 80% had chronic migraine. The reduction in mean headache days was 10 days per month; 72% continued to use their CGRP mAb after using it for 6 months. Participants were compared relative to medication overuse but no significant differences were found between those who overused medication and others.

This study highlights the efficacy of CGRP medications in those outside of the initially studied population. Other preventive medications may be contraindicated in this population, but CGRP antagonists do appear to be safe and effective options for older adults.

Opiate medications are typically considered inappropriate as an acute treatment for migraine. Even infrequent use of opiate medications has been shown to be associated with worse migraine outcomes, specifically higher frequency and a higher likelihood to convert from episodic to chronic migraine. Van Welie and colleagues performed a cross-sectional questionnaire-based study assessing levels of opioid use in patients with migraine.

Participants were selected from the Leiden Headache Center and fit the diagnostic criteria of migraine. They were given an e-questionnaire to determine their use of these opiates: buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol, and tramadol (codeine was not included in this list). Patients were separately divided between chronic and episodic migraine groups. The primary outcome was assessing for current acute treatment of migraine with an opiate; secondary outcomes were association of chronicity of migraine and likelihood of medication overuse with opiate use.

Only approximately 1.8% of participants reported that they currently use an opiate for acute migraine treatment; 12.5% reported that they previously have used an opiate and 25.7% reported using an opiate for another pain condition. Tramadol was the most commonly used opiate medication, followed by oxycodone and morphine; 2.4% of patients reported that their opiate use was not prescribed by their doctor. Primary care doctors were the most common prescribers of the opiate medications; 16% of the time, patients were told that it was a preventive treatment for migraine. Opiate use was more frequent in patients with a diagnosis of chronic migraine, and the duration of use was greater.

Opiate medications remain a poor acute choice of treatment for migraine, and this study shows a correlation between higher opiate use and chronic migraine. There are many other acute medications now available for migraine, many of them migraine-specific treatments, such as triptans, gepants, and ditans. This research again shows that opiates should be avoided if at all possible for migraine.

Patients with medication overuse headache are more likely to be treatment-refractory, and the addition of acute medications often can be less effective if they remain on the overused medication. There has been a long-standing debate whether it is best to wean medications first or start a preventive initially when faced with medication overuse. The CGRP antagonists may be one of the better preventive options in this situation, and one mAb (fremenezumab) reported positive data in a small medication overuse trial. The study by Guerzoni and colleagues investigated the effectiveness of galcanezumab in chronic migraine with medication overuse.

This was a prospective trial conducted at the University Hospital of Modena. A total of 78 patients with a diagnosis of chronic migraine and medication overuse were enrolled for 15 months, with follow-up every 3 months. At each follow-up appointment, they completed a questionnaire asking them details about: mean migraine days per month, mean number of painkillers taken per month, mean days per month taking a painkiller, average migraine severity, and the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questions. Patients were given the standard-dosing regimen of glacanezumab for migraine and were not blinded; this was an open-label study.

The mean migraine days per month were significantly reduced after 3, 6, 9, and 12 months. The amount of painkillers used per month and days of painkillers per month both reduced significantly as well. Migraine-related disability on HIT-6 and MIDAS were all reduced significantly as well. The most significant improvement long-term was noted in patients who improved the most during the initial 3 months of treatment.

The debate regarding the best treatment for patients with medication overuse will continue, but this study highlights the effectiveness of CGRP mAb use in this population. Patients were able to decrease the use of acute medications without a strict wean off of their previous medication. Ideally, a similar study should also be done for additional mAb and oral CGRP antagonists.

Calcitonin gene-related peptide (CGRP) antagonist medications have revolutionized migraine therapy since being introduced in 2018. The initial preventive trials for monoclonal antibodies (mAb) excluded older adults, with a cutoff in all studies at age 65 years. Long-term safety studies have not revealed signals for concern related to vascular or other adverse events. The study by Muñoz-Vendrell and colleagues investigated the efficacy of CGRP mAb in treatment-refractory older adults.

This was an observational retrospective study in participants older than 65 years that had previously used three or more prior migraine preventives unsuccessfully. The primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and acute medication frequency as well as improvement in patient reported outcomes.

A total of 162 participants were followed at 18 different headache centers throughout Spain. All patients had at least 8 headache days per month and had been treated unsuccessfully with three prior medications for migraine prevention, one of which was botulinum toxin. The median age was 68 years, and over 80% had chronic migraine. The reduction in mean headache days was 10 days per month; 72% continued to use their CGRP mAb after using it for 6 months. Participants were compared relative to medication overuse but no significant differences were found between those who overused medication and others.

This study highlights the efficacy of CGRP medications in those outside of the initially studied population. Other preventive medications may be contraindicated in this population, but CGRP antagonists do appear to be safe and effective options for older adults.

Opiate medications are typically considered inappropriate as an acute treatment for migraine. Even infrequent use of opiate medications has been shown to be associated with worse migraine outcomes, specifically higher frequency and a higher likelihood to convert from episodic to chronic migraine. Van Welie and colleagues performed a cross-sectional questionnaire-based study assessing levels of opioid use in patients with migraine.

Participants were selected from the Leiden Headache Center and fit the diagnostic criteria of migraine. They were given an e-questionnaire to determine their use of these opiates: buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol, and tramadol (codeine was not included in this list). Patients were separately divided between chronic and episodic migraine groups. The primary outcome was assessing for current acute treatment of migraine with an opiate; secondary outcomes were association of chronicity of migraine and likelihood of medication overuse with opiate use.

Only approximately 1.8% of participants reported that they currently use an opiate for acute migraine treatment; 12.5% reported that they previously have used an opiate and 25.7% reported using an opiate for another pain condition. Tramadol was the most commonly used opiate medication, followed by oxycodone and morphine; 2.4% of patients reported that their opiate use was not prescribed by their doctor. Primary care doctors were the most common prescribers of the opiate medications; 16% of the time, patients were told that it was a preventive treatment for migraine. Opiate use was more frequent in patients with a diagnosis of chronic migraine, and the duration of use was greater.

Opiate medications remain a poor acute choice of treatment for migraine, and this study shows a correlation between higher opiate use and chronic migraine. There are many other acute medications now available for migraine, many of them migraine-specific treatments, such as triptans, gepants, and ditans. This research again shows that opiates should be avoided if at all possible for migraine.

Patients with medication overuse headache are more likely to be treatment-refractory, and the addition of acute medications often can be less effective if they remain on the overused medication. There has been a long-standing debate whether it is best to wean medications first or start a preventive initially when faced with medication overuse. The CGRP antagonists may be one of the better preventive options in this situation, and one mAb (fremenezumab) reported positive data in a small medication overuse trial. The study by Guerzoni and colleagues investigated the effectiveness of galcanezumab in chronic migraine with medication overuse.

This was a prospective trial conducted at the University Hospital of Modena. A total of 78 patients with a diagnosis of chronic migraine and medication overuse were enrolled for 15 months, with follow-up every 3 months. At each follow-up appointment, they completed a questionnaire asking them details about: mean migraine days per month, mean number of painkillers taken per month, mean days per month taking a painkiller, average migraine severity, and the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questions. Patients were given the standard-dosing regimen of glacanezumab for migraine and were not blinded; this was an open-label study.

The mean migraine days per month were significantly reduced after 3, 6, 9, and 12 months. The amount of painkillers used per month and days of painkillers per month both reduced significantly as well. Migraine-related disability on HIT-6 and MIDAS were all reduced significantly as well. The most significant improvement long-term was noted in patients who improved the most during the initial 3 months of treatment.

The debate regarding the best treatment for patients with medication overuse will continue, but this study highlights the effectiveness of CGRP mAb use in this population. Patients were able to decrease the use of acute medications without a strict wean off of their previous medication. Ideally, a similar study should also be done for additional mAb and oral CGRP antagonists.

The field of headache medicine has changed significantly since 2018 with the advent of calcitonin gene-related peptide (CGRP)–targeted medications. Although many patients improve after their first injection, and there is even a significant portion of "super responders" who can revert to nearly zero headache days per month, the majority of patients have a moderate response. Many patients who have not had a significant decrease in the frequency and severity of migraine attacks over 12 weeks wonder whether they will eventually achieve this on a CGRP medication. Barbanti and colleagues looked specifically at the subpopulation of late responders to CGRP treatments.

This was a multicenter, prospective study lasting 24 weeks, defining the differences in responders to CGRP treatments. Participants in this study had failed three or more prior preventive medications and had high-frequency, episodic, or chronic migraine. Their response rate was determined as follows: "responder" patients had a more than 50% reduction in baseline monthly migraine days between weeks 9 and 12, and "late responder" patients achieved that reduction after 12 weeks. All three injectable CGRP monoclonal antibodies were included in this trial.

Nearly 66% of patients treated with a CGRP monoclonal antibody had a 50% or greater response at 12 weeks. Of the study participants, 34% were considered nonresponders at 12 weeks, and 55% of those nonresponders did become responders between 13 and 24 weeks. This subpopulation of late responders was noted to have higher body mass index (BMI), more frequent prior treatment failures, as well as other pain and psychiatric comorbidities. Allodynia and unilateral cranial autonomic symptoms were also noted to be significantly higher in this population.

This study helps better determine the length of a CGRP trial for prevention. Patients with more treatment failures and comorbidities should be given additional time for this class of medications to work, even beyond the initial 12 weeks.

The COVID-19 pandemic has changed the way of life for everyone, and this is especially true for people with chronic medical conditions. Hrytsenko and colleagues sought to quantify the effect that COVID-19 had on patients with a history of episodic or chronic migraine. They used a scale to determine "psycho-emotional state deterioration" in patients with migraine with and without a history of COVID-19.

The investigators included 133 participants with a prior diagnosis of migraine, either chronic or episodic. Of these, 95 had a positive polymerase chain reaction (PCR) test for COVID-19, indicating SARS-CoV-2 infection; 38 did not. The Hamilton Anxiety Rating Scale (HARS) was used to assess the severity of perceived anxiety symptoms and was used to determine psycho-emotional state. The Migraine Disability Assessment test (MIDAS) was used to determine their quality of life and degree of disability related to migraine. Patients with a history of COVID-19 had an increased usage of antimigraine medications, increased frequency of attacks, and higher HARS ratings. The average MIDAS score also increased significantly.

Many of our patients who were struggling prior to the COVID-19 pandemic unfortunately have done much worse after SARS-CoV-2 infection. A number of potential explanations exist for this, including worsening neuroinflammation in the context of COVID-19, which can specifically increase the propagation of inflammatory neurotransmitters, such as CGRP. Patients with a history of migraine respond to this with heightened frequency and severity of migraine.

There is a notable growing connection between certain neurologic conditions and vasomotor symptoms. Specifically, there appears to be an increased incidence of migraine and certain hypertensive or tachycardic conditions. Migraine is well known to be a vascular risk factor and migraine with aura even more so. Faubion and colleagues sought to quantify this in a specific menopausal population.

This was a large cross-sectional study, with an older median age compared with average migraine studies: 52.8 years. Nearly 60% of participants were postmenopausal and were recruited from a Mayo Clinic menopause registry. Participants were evaluated for a history of migraine based on The International Classification of Headache Disorders, third edition (ICHD3), criteria. They also had their symptoms measured on a menopause rating scale (the symptoms measured included hot flashes, sleep problems, physical and mental exhaustion, joint and muscular discomfort, and mood). Additional information was cross-referenced, including BMI, race, ethnicity, education, marital status, hypertension, and menopause status.

A diagnosis of migraine was associated with hypertension. There was no association between hypertension and hot flash severity, and there was a suggestion that hot flash severity and migraine history were not associated. The presence of other pain disorders also did not correlate with any other vasomotor symptoms.

This study does again link vasomotor issues with migraines. This connection remains well-founded and relevant. Antihypertensive medications have been some of the first preventive options ever offered to people with migraine. CGRP medications may actually lead to an increase in the risk for hypertension. Disconnection remains relevant and is something to discuss with patients with migraine, especially if they are at a higher risk.

The field of headache medicine has changed significantly since 2018 with the advent of calcitonin gene-related peptide (CGRP)–targeted medications. Although many patients improve after their first injection, and there is even a significant portion of "super responders" who can revert to nearly zero headache days per month, the majority of patients have a moderate response. Many patients who have not had a significant decrease in the frequency and severity of migraine attacks over 12 weeks wonder whether they will eventually achieve this on a CGRP medication. Barbanti and colleagues looked specifically at the subpopulation of late responders to CGRP treatments.

This was a multicenter, prospective study lasting 24 weeks, defining the differences in responders to CGRP treatments. Participants in this study had failed three or more prior preventive medications and had high-frequency, episodic, or chronic migraine. Their response rate was determined as follows: "responder" patients had a more than 50% reduction in baseline monthly migraine days between weeks 9 and 12, and "late responder" patients achieved that reduction after 12 weeks. All three injectable CGRP monoclonal antibodies were included in this trial.

Nearly 66% of patients treated with a CGRP monoclonal antibody had a 50% or greater response at 12 weeks. Of the study participants, 34% were considered nonresponders at 12 weeks, and 55% of those nonresponders did become responders between 13 and 24 weeks. This subpopulation of late responders was noted to have higher body mass index (BMI), more frequent prior treatment failures, as well as other pain and psychiatric comorbidities. Allodynia and unilateral cranial autonomic symptoms were also noted to be significantly higher in this population.

This study helps better determine the length of a CGRP trial for prevention. Patients with more treatment failures and comorbidities should be given additional time for this class of medications to work, even beyond the initial 12 weeks.

The COVID-19 pandemic has changed the way of life for everyone, and this is especially true for people with chronic medical conditions. Hrytsenko and colleagues sought to quantify the effect that COVID-19 had on patients with a history of episodic or chronic migraine. They used a scale to determine "psycho-emotional state deterioration" in patients with migraine with and without a history of COVID-19.

The investigators included 133 participants with a prior diagnosis of migraine, either chronic or episodic. Of these, 95 had a positive polymerase chain reaction (PCR) test for COVID-19, indicating SARS-CoV-2 infection; 38 did not. The Hamilton Anxiety Rating Scale (HARS) was used to assess the severity of perceived anxiety symptoms and was used to determine psycho-emotional state. The Migraine Disability Assessment test (MIDAS) was used to determine their quality of life and degree of disability related to migraine. Patients with a history of COVID-19 had an increased usage of antimigraine medications, increased frequency of attacks, and higher HARS ratings. The average MIDAS score also increased significantly.

Many of our patients who were struggling prior to the COVID-19 pandemic unfortunately have done much worse after SARS-CoV-2 infection. A number of potential explanations exist for this, including worsening neuroinflammation in the context of COVID-19, which can specifically increase the propagation of inflammatory neurotransmitters, such as CGRP. Patients with a history of migraine respond to this with heightened frequency and severity of migraine.

There is a notable growing connection between certain neurologic conditions and vasomotor symptoms. Specifically, there appears to be an increased incidence of migraine and certain hypertensive or tachycardic conditions. Migraine is well known to be a vascular risk factor and migraine with aura even more so. Faubion and colleagues sought to quantify this in a specific menopausal population.

This was a large cross-sectional study, with an older median age compared with average migraine studies: 52.8 years. Nearly 60% of participants were postmenopausal and were recruited from a Mayo Clinic menopause registry. Participants were evaluated for a history of migraine based on The International Classification of Headache Disorders, third edition (ICHD3), criteria. They also had their symptoms measured on a menopause rating scale (the symptoms measured included hot flashes, sleep problems, physical and mental exhaustion, joint and muscular discomfort, and mood). Additional information was cross-referenced, including BMI, race, ethnicity, education, marital status, hypertension, and menopause status.

A diagnosis of migraine was associated with hypertension. There was no association between hypertension and hot flash severity, and there was a suggestion that hot flash severity and migraine history were not associated. The presence of other pain disorders also did not correlate with any other vasomotor symptoms.

This study does again link vasomotor issues with migraines. This connection remains well-founded and relevant. Antihypertensive medications have been some of the first preventive options ever offered to people with migraine. CGRP medications may actually lead to an increase in the risk for hypertension. Disconnection remains relevant and is something to discuss with patients with migraine, especially if they are at a higher risk.

The field of headache medicine has changed significantly since 2018 with the advent of calcitonin gene-related peptide (CGRP)–targeted medications. Although many patients improve after their first injection, and there is even a significant portion of "super responders" who can revert to nearly zero headache days per month, the majority of patients have a moderate response. Many patients who have not had a significant decrease in the frequency and severity of migraine attacks over 12 weeks wonder whether they will eventually achieve this on a CGRP medication. Barbanti and colleagues looked specifically at the subpopulation of late responders to CGRP treatments.

This was a multicenter, prospective study lasting 24 weeks, defining the differences in responders to CGRP treatments. Participants in this study had failed three or more prior preventive medications and had high-frequency, episodic, or chronic migraine. Their response rate was determined as follows: "responder" patients had a more than 50% reduction in baseline monthly migraine days between weeks 9 and 12, and "late responder" patients achieved that reduction after 12 weeks. All three injectable CGRP monoclonal antibodies were included in this trial.

Nearly 66% of patients treated with a CGRP monoclonal antibody had a 50% or greater response at 12 weeks. Of the study participants, 34% were considered nonresponders at 12 weeks, and 55% of those nonresponders did become responders between 13 and 24 weeks. This subpopulation of late responders was noted to have higher body mass index (BMI), more frequent prior treatment failures, as well as other pain and psychiatric comorbidities. Allodynia and unilateral cranial autonomic symptoms were also noted to be significantly higher in this population.

This study helps better determine the length of a CGRP trial for prevention. Patients with more treatment failures and comorbidities should be given additional time for this class of medications to work, even beyond the initial 12 weeks.

The COVID-19 pandemic has changed the way of life for everyone, and this is especially true for people with chronic medical conditions. Hrytsenko and colleagues sought to quantify the effect that COVID-19 had on patients with a history of episodic or chronic migraine. They used a scale to determine "psycho-emotional state deterioration" in patients with migraine with and without a history of COVID-19.

The investigators included 133 participants with a prior diagnosis of migraine, either chronic or episodic. Of these, 95 had a positive polymerase chain reaction (PCR) test for COVID-19, indicating SARS-CoV-2 infection; 38 did not. The Hamilton Anxiety Rating Scale (HARS) was used to assess the severity of perceived anxiety symptoms and was used to determine psycho-emotional state. The Migraine Disability Assessment test (MIDAS) was used to determine their quality of life and degree of disability related to migraine. Patients with a history of COVID-19 had an increased usage of antimigraine medications, increased frequency of attacks, and higher HARS ratings. The average MIDAS score also increased significantly.

Many of our patients who were struggling prior to the COVID-19 pandemic unfortunately have done much worse after SARS-CoV-2 infection. A number of potential explanations exist for this, including worsening neuroinflammation in the context of COVID-19, which can specifically increase the propagation of inflammatory neurotransmitters, such as CGRP. Patients with a history of migraine respond to this with heightened frequency and severity of migraine.

There is a notable growing connection between certain neurologic conditions and vasomotor symptoms. Specifically, there appears to be an increased incidence of migraine and certain hypertensive or tachycardic conditions. Migraine is well known to be a vascular risk factor and migraine with aura even more so. Faubion and colleagues sought to quantify this in a specific menopausal population.

This was a large cross-sectional study, with an older median age compared with average migraine studies: 52.8 years. Nearly 60% of participants were postmenopausal and were recruited from a Mayo Clinic menopause registry. Participants were evaluated for a history of migraine based on The International Classification of Headache Disorders, third edition (ICHD3), criteria. They also had their symptoms measured on a menopause rating scale (the symptoms measured included hot flashes, sleep problems, physical and mental exhaustion, joint and muscular discomfort, and mood). Additional information was cross-referenced, including BMI, race, ethnicity, education, marital status, hypertension, and menopause status.

A diagnosis of migraine was associated with hypertension. There was no association between hypertension and hot flash severity, and there was a suggestion that hot flash severity and migraine history were not associated. The presence of other pain disorders also did not correlate with any other vasomotor symptoms.

This study does again link vasomotor issues with migraines. This connection remains well-founded and relevant. Antihypertensive medications have been some of the first preventive options ever offered to people with migraine. CGRP medications may actually lead to an increase in the risk for hypertension. Disconnection remains relevant and is something to discuss with patients with migraine, especially if they are at a higher risk.

The theme of this month's round-up is women's health, specifically as it relates to migraine. Three recent studies have highlighted the connection between estrogen and migraine, in terms of the potential increase in risk for certain conditions, such as gestational hypertension and endometriosis, and the use of potential therapies, such as calcitonin gene-related peptide (CGRP) antagonist medications to treat menstrual migraine.

Although most practitioners know that there is a deep connection between vascular risk and migraine, most are unfamiliar with the specific interplay between these two conditions. Antihypertensive medications are common preventive treatments for migraine, and migraine itself has been associated with an increased risk for specific vascular issues in pregnancy, most notably venous sinus thrombosis. Crowe and colleagues specifically looked at whether women with migraine experience a higher risk for hypertensive disorders of pregnancy.

This was a UK-based prospective cohort study using a large longitudinal database called the Clinical Practice Research Datalink. Over 1 million live-born or stillborn deliveries were analyzed from 1993 through 2020. The data were linked to diagnosis and prescription codes for migraine that were filled or documented before 20 weeks of gestation and compared with diagnosis codes for hypertensive disorders that occurred from week 20 through the pregnancy and delivery. Regression models were then used to estimate risk ratios and CI. Only single pregnancies were counted because multiple pregnancies already are associated with a higher risk for most other vascular conditions.

Any history of migraine prior to pregnancy was associated with an increased risk for gestational hypertension, eclampsia, and preeclampsia (relative risk 1.17). The greatest risk was higher frequency. Migraine that persisted into the first trimester led to a relative risk of 1.84. The use of migraine medications, especially vasoconstrictive-type medications, was also associated with a higher risk compared with women without migraine.

Women with migraine frequently present before family planning to discuss the potential risks and options of migraine treatment during pregnancy. In addition to discussing the most appropriate preventive and acute medications, it would be appropriate also to discuss any potential red flag symptoms that may occur during pregnancy. This discussion should include hypertensive disorders of pregnancy as per this study.

Since the advent of CGRP antagonist treatments for migraine, many practitioners and patients have been curious to know whether specific features of migraine are better treated with this class of medication. There are now both acute and preventive CGRP antagonists, both as small molecule agents and monoclonal antibodies (mAb). Menstrual migraines specifically can be a more difficult-to-treat subtype, and often when other triggers are negated, hormonal fluctuation can still be a significant problem for many patients. Verhagen and colleagues set out to determine whether CGRP mAb are more or less effective for menstrually associated migraine.

This analysis was post hoc, using data from a single-arm study investigating the efficacy of two of the CGRP mAb medications: erenumab and fremanezumab. Patients were included if they had a history of migraine with > 8 monthly migraine days and at least one antihypertensive or antiepileptic preventive treatment for migraine had previously failed. Any other prophylactic medications were tapered before starting this trial; patients were given a validated electronic diary, and adherence to this diary had to be > 80%. Women were also excluded if they did not have regular menses (for instance, if they were on continuous hormonal contraception) or they were postmenopausal. Logistic regression was used to compare the preventive effect of these medications on perimenstrual and non-perimenstrual migraine attacks.

A total of 45 women were included in this observation. The relative reduction in total monthly migraine days was 31.4%; 28% were noted during and around menses, 32% were during other times of the menstrual cycle. Sensitivity analysis showed no significant difference between these two periods of time, and the ratio remained statistically similar as well.

It appears that the relative reduction in monthly migraine days did not fluctuate when the patient was treated with a CGRP antagonist mAb. Although other classes of preventive medication, specifically onabotulinumtoxinA (Botox), may affect menstrually associated migraine less potently, it appears that the CGRP antagonist class may be just as effective regardless of the underlying migraine trigger. It would definitely be worth considering a CGRP antagonist trial, or the addition of a CGRP mAb, if menstrual migraine remains significant despite otherwise effective preventive treatment.

Migraine is strongly affected by fluctuations in estrogen, and women with endometriosis often experience headaches associated with their severe attacks. Pasquini and colleagues specifically looked to see if the headache associated with endometriosis could be better diagnosed. Specifically, were these women experiencing migraine or another headache disorder?

This was a consecutive case-control series of 131 women admitted to a specialty endometriosis clinic. They were given a validated headache questionnaire that was reviewed by a neurologist to determine a diagnosis of migraine vs a diagnosis of another headache disorder. The case group included women with a history of endometriosis who were previously diagnosed with migraine, while the control group consisted of women with endometriosis only who did not have a history of headache.

Diagnosis of migraine was made in 53.4% of all patients: 18.6% of those experienced pure menstrual migraine (defined as migraine only occurring perimenstrually), 46% had some menstrually associated migraine symptoms, and 36% had purely non-menstrual migraine. Painful periods and dysuria were more frequent in patients with endometriosis and migraine compared with those without migraine. Other menstrually related conditions, including the duration of endometriosis, the phenotype of endometriosis, the presence of other systemic comorbidities, or heavy menstrual bleeding did not seem to differ significantly between the migraine and non-migraine groups.

Women of reproductive age consistently are seen most often for migraine and other headache conditions. Much of this is related to menstrual migraine and the effect that hormonal fluctuation has on migraine frequency and severity. Most practitioners work closely with their patient's gynecologist to determine which hormonal treatments and migraine treatments are most appropriate and safe for each individual situation. This study in particular sheds light on the particular phenotypes of headache pain and the specific headache diagnosis that most women with endometriosis experience.

The theme of this month's round-up is women's health, specifically as it relates to migraine. Three recent studies have highlighted the connection between estrogen and migraine, in terms of the potential increase in risk for certain conditions, such as gestational hypertension and endometriosis, and the use of potential therapies, such as calcitonin gene-related peptide (CGRP) antagonist medications to treat menstrual migraine.

Although most practitioners know that there is a deep connection between vascular risk and migraine, most are unfamiliar with the specific interplay between these two conditions. Antihypertensive medications are common preventive treatments for migraine, and migraine itself has been associated with an increased risk for specific vascular issues in pregnancy, most notably venous sinus thrombosis. Crowe and colleagues specifically looked at whether women with migraine experience a higher risk for hypertensive disorders of pregnancy.

This was a UK-based prospective cohort study using a large longitudinal database called the Clinical Practice Research Datalink. Over 1 million live-born or stillborn deliveries were analyzed from 1993 through 2020. The data were linked to diagnosis and prescription codes for migraine that were filled or documented before 20 weeks of gestation and compared with diagnosis codes for hypertensive disorders that occurred from week 20 through the pregnancy and delivery. Regression models were then used to estimate risk ratios and CI. Only single pregnancies were counted because multiple pregnancies already are associated with a higher risk for most other vascular conditions.

Any history of migraine prior to pregnancy was associated with an increased risk for gestational hypertension, eclampsia, and preeclampsia (relative risk 1.17). The greatest risk was higher frequency. Migraine that persisted into the first trimester led to a relative risk of 1.84. The use of migraine medications, especially vasoconstrictive-type medications, was also associated with a higher risk compared with women without migraine.

Women with migraine frequently present before family planning to discuss the potential risks and options of migraine treatment during pregnancy. In addition to discussing the most appropriate preventive and acute medications, it would be appropriate also to discuss any potential red flag symptoms that may occur during pregnancy. This discussion should include hypertensive disorders of pregnancy as per this study.

Since the advent of CGRP antagonist treatments for migraine, many practitioners and patients have been curious to know whether specific features of migraine are better treated with this class of medication. There are now both acute and preventive CGRP antagonists, both as small molecule agents and monoclonal antibodies (mAb). Menstrual migraines specifically can be a more difficult-to-treat subtype, and often when other triggers are negated, hormonal fluctuation can still be a significant problem for many patients. Verhagen and colleagues set out to determine whether CGRP mAb are more or less effective for menstrually associated migraine.

This analysis was post hoc, using data from a single-arm study investigating the efficacy of two of the CGRP mAb medications: erenumab and fremanezumab. Patients were included if they had a history of migraine with > 8 monthly migraine days and at least one antihypertensive or antiepileptic preventive treatment for migraine had previously failed. Any other prophylactic medications were tapered before starting this trial; patients were given a validated electronic diary, and adherence to this diary had to be > 80%. Women were also excluded if they did not have regular menses (for instance, if they were on continuous hormonal contraception) or they were postmenopausal. Logistic regression was used to compare the preventive effect of these medications on perimenstrual and non-perimenstrual migraine attacks.

A total of 45 women were included in this observation. The relative reduction in total monthly migraine days was 31.4%; 28% were noted during and around menses, 32% were during other times of the menstrual cycle. Sensitivity analysis showed no significant difference between these two periods of time, and the ratio remained statistically similar as well.

It appears that the relative reduction in monthly migraine days did not fluctuate when the patient was treated with a CGRP antagonist mAb. Although other classes of preventive medication, specifically onabotulinumtoxinA (Botox), may affect menstrually associated migraine less potently, it appears that the CGRP antagonist class may be just as effective regardless of the underlying migraine trigger. It would definitely be worth considering a CGRP antagonist trial, or the addition of a CGRP mAb, if menstrual migraine remains significant despite otherwise effective preventive treatment.

Migraine is strongly affected by fluctuations in estrogen, and women with endometriosis often experience headaches associated with their severe attacks. Pasquini and colleagues specifically looked to see if the headache associated with endometriosis could be better diagnosed. Specifically, were these women experiencing migraine or another headache disorder?

This was a consecutive case-control series of 131 women admitted to a specialty endometriosis clinic. They were given a validated headache questionnaire that was reviewed by a neurologist to determine a diagnosis of migraine vs a diagnosis of another headache disorder. The case group included women with a history of endometriosis who were previously diagnosed with migraine, while the control group consisted of women with endometriosis only who did not have a history of headache.

Diagnosis of migraine was made in 53.4% of all patients: 18.6% of those experienced pure menstrual migraine (defined as migraine only occurring perimenstrually), 46% had some menstrually associated migraine symptoms, and 36% had purely non-menstrual migraine. Painful periods and dysuria were more frequent in patients with endometriosis and migraine compared with those without migraine. Other menstrually related conditions, including the duration of endometriosis, the phenotype of endometriosis, the presence of other systemic comorbidities, or heavy menstrual bleeding did not seem to differ significantly between the migraine and non-migraine groups.

Women of reproductive age consistently are seen most often for migraine and other headache conditions. Much of this is related to menstrual migraine and the effect that hormonal fluctuation has on migraine frequency and severity. Most practitioners work closely with their patient's gynecologist to determine which hormonal treatments and migraine treatments are most appropriate and safe for each individual situation. This study in particular sheds light on the particular phenotypes of headache pain and the specific headache diagnosis that most women with endometriosis experience.

The theme of this month's round-up is women's health, specifically as it relates to migraine. Three recent studies have highlighted the connection between estrogen and migraine, in terms of the potential increase in risk for certain conditions, such as gestational hypertension and endometriosis, and the use of potential therapies, such as calcitonin gene-related peptide (CGRP) antagonist medications to treat menstrual migraine.

Although most practitioners know that there is a deep connection between vascular risk and migraine, most are unfamiliar with the specific interplay between these two conditions. Antihypertensive medications are common preventive treatments for migraine, and migraine itself has been associated with an increased risk for specific vascular issues in pregnancy, most notably venous sinus thrombosis. Crowe and colleagues specifically looked at whether women with migraine experience a higher risk for hypertensive disorders of pregnancy.

This was a UK-based prospective cohort study using a large longitudinal database called the Clinical Practice Research Datalink. Over 1 million live-born or stillborn deliveries were analyzed from 1993 through 2020. The data were linked to diagnosis and prescription codes for migraine that were filled or documented before 20 weeks of gestation and compared with diagnosis codes for hypertensive disorders that occurred from week 20 through the pregnancy and delivery. Regression models were then used to estimate risk ratios and CI. Only single pregnancies were counted because multiple pregnancies already are associated with a higher risk for most other vascular conditions.

Any history of migraine prior to pregnancy was associated with an increased risk for gestational hypertension, eclampsia, and preeclampsia (relative risk 1.17). The greatest risk was higher frequency. Migraine that persisted into the first trimester led to a relative risk of 1.84. The use of migraine medications, especially vasoconstrictive-type medications, was also associated with a higher risk compared with women without migraine.

Women with migraine frequently present before family planning to discuss the potential risks and options of migraine treatment during pregnancy. In addition to discussing the most appropriate preventive and acute medications, it would be appropriate also to discuss any potential red flag symptoms that may occur during pregnancy. This discussion should include hypertensive disorders of pregnancy as per this study.

Since the advent of CGRP antagonist treatments for migraine, many practitioners and patients have been curious to know whether specific features of migraine are better treated with this class of medication. There are now both acute and preventive CGRP antagonists, both as small molecule agents and monoclonal antibodies (mAb). Menstrual migraines specifically can be a more difficult-to-treat subtype, and often when other triggers are negated, hormonal fluctuation can still be a significant problem for many patients. Verhagen and colleagues set out to determine whether CGRP mAb are more or less effective for menstrually associated migraine.

This analysis was post hoc, using data from a single-arm study investigating the efficacy of two of the CGRP mAb medications: erenumab and fremanezumab. Patients were included if they had a history of migraine with > 8 monthly migraine days and at least one antihypertensive or antiepileptic preventive treatment for migraine had previously failed. Any other prophylactic medications were tapered before starting this trial; patients were given a validated electronic diary, and adherence to this diary had to be > 80%. Women were also excluded if they did not have regular menses (for instance, if they were on continuous hormonal contraception) or they were postmenopausal. Logistic regression was used to compare the preventive effect of these medications on perimenstrual and non-perimenstrual migraine attacks.

A total of 45 women were included in this observation. The relative reduction in total monthly migraine days was 31.4%; 28% were noted during and around menses, 32% were during other times of the menstrual cycle. Sensitivity analysis showed no significant difference between these two periods of time, and the ratio remained statistically similar as well.

It appears that the relative reduction in monthly migraine days did not fluctuate when the patient was treated with a CGRP antagonist mAb. Although other classes of preventive medication, specifically onabotulinumtoxinA (Botox), may affect menstrually associated migraine less potently, it appears that the CGRP antagonist class may be just as effective regardless of the underlying migraine trigger. It would definitely be worth considering a CGRP antagonist trial, or the addition of a CGRP mAb, if menstrual migraine remains significant despite otherwise effective preventive treatment.

Migraine is strongly affected by fluctuations in estrogen, and women with endometriosis often experience headaches associated with their severe attacks. Pasquini and colleagues specifically looked to see if the headache associated with endometriosis could be better diagnosed. Specifically, were these women experiencing migraine or another headache disorder?

This was a consecutive case-control series of 131 women admitted to a specialty endometriosis clinic. They were given a validated headache questionnaire that was reviewed by a neurologist to determine a diagnosis of migraine vs a diagnosis of another headache disorder. The case group included women with a history of endometriosis who were previously diagnosed with migraine, while the control group consisted of women with endometriosis only who did not have a history of headache.

Diagnosis of migraine was made in 53.4% of all patients: 18.6% of those experienced pure menstrual migraine (defined as migraine only occurring perimenstrually), 46% had some menstrually associated migraine symptoms, and 36% had purely non-menstrual migraine. Painful periods and dysuria were more frequent in patients with endometriosis and migraine compared with those without migraine. Other menstrually related conditions, including the duration of endometriosis, the phenotype of endometriosis, the presence of other systemic comorbidities, or heavy menstrual bleeding did not seem to differ significantly between the migraine and non-migraine groups.

Women of reproductive age consistently are seen most often for migraine and other headache conditions. Much of this is related to menstrual migraine and the effect that hormonal fluctuation has on migraine frequency and severity. Most practitioners work closely with their patient's gynecologist to determine which hormonal treatments and migraine treatments are most appropriate and safe for each individual situation. This study in particular sheds light on the particular phenotypes of headache pain and the specific headache diagnosis that most women with endometriosis experience.

Key clinical point: Women with endometriosis seemed prone to migraine, with menstrual-related migraine being the most common type and dysmenorrhea and dysuria being more frequent when endometriosis and migraine coexisted.

Major finding: Overall, 53.4% of women had migraine, of which 64.3% had migraine related to menstruation and 35.7% had non-menstrual migraine. Typical endometriosis-related pain symptoms such as dysmenorrhea (94.3% vs 82.0%; P  =  .03) and dysuria (27.1% vs 9.8%; P < .01) occurred significantly more frequently in patients with vs without migraine.

Study details: This was a prospective, nested case-control study including 131 women with endometriosis with or without migraine.

Disclosures: This study was supported by a grant from Ministero della Salute, Italy. The authors declared no conflicts of interest.

Source: Pasquini B, Seravalli V, et al. Endometriosis and the diagnosis of different forms of migraine: an association with dysmenorrhea. Reprod Biomed Online. 2023 (Apr 6). Doi: 10.1016/j.rbmo.2023.03.020

Key clinical point: Women with endometriosis seemed prone to migraine, with menstrual-related migraine being the most common type and dysmenorrhea and dysuria being more frequent when endometriosis and migraine coexisted.

Major finding: Overall, 53.4% of women had migraine, of which 64.3% had migraine related to menstruation and 35.7% had non-menstrual migraine. Typical endometriosis-related pain symptoms such as dysmenorrhea (94.3% vs 82.0%; P  =  .03) and dysuria (27.1% vs 9.8%; P < .01) occurred significantly more frequently in patients with vs without migraine.

Study details: This was a prospective, nested case-control study including 131 women with endometriosis with or without migraine.

Disclosures: This study was supported by a grant from Ministero della Salute, Italy. The authors declared no conflicts of interest.

Source: Pasquini B, Seravalli V, et al. Endometriosis and the diagnosis of different forms of migraine: an association with dysmenorrhea. Reprod Biomed Online. 2023 (Apr 6). Doi: 10.1016/j.rbmo.2023.03.020

Key clinical point: Women with endometriosis seemed prone to migraine, with menstrual-related migraine being the most common type and dysmenorrhea and dysuria being more frequent when endometriosis and migraine coexisted.

Major finding: Overall, 53.4% of women had migraine, of which 64.3% had migraine related to menstruation and 35.7% had non-menstrual migraine. Typical endometriosis-related pain symptoms such as dysmenorrhea (94.3% vs 82.0%; P  =  .03) and dysuria (27.1% vs 9.8%; P < .01) occurred significantly more frequently in patients with vs without migraine.

Study details: This was a prospective, nested case-control study including 131 women with endometriosis with or without migraine.

Disclosures: This study was supported by a grant from Ministero della Salute, Italy. The authors declared no conflicts of interest.

Source: Pasquini B, Seravalli V, et al. Endometriosis and the diagnosis of different forms of migraine: an association with dysmenorrhea. Reprod Biomed Online. 2023 (Apr 6). Doi: 10.1016/j.rbmo.2023.03.020