Migraine ICYMI

Key clinical point: Long-term treatment with galcanezumab led to three-quarters of patients with chronic migraine (CM) reverting to episodic migraine (EM), with more than half persistently reverting to episodic migraine (EM) under real-life conditions.

Major finding: Over 1 year, approximately ≥75% of patients reverted from CM to EM at each visit, with persistent reversion from CM to EM and medium-to-low frequency EM being reported by 52.3% and 20.6% of patients, respectively. Older age at onset (P  =  .01) and less frequent baseline monthly migraine days (P  =  .005) significantly increased the reversion frequency to EM.

Study details: Findings are from a 12-month observational, longitudinal cohort study, GARLIT, including 155 patients with CM who received galcanezumab.

Disclosures: This study did not receive any specific funding. Several authors reported receiving grants or honoraria from various sources.

Source: Altamura C et al for the GARLIT Study Group. Conversion from chronic to episodic migraine in patients treated with galcanezumab in real life in Italy: The 12-month observational, longitudinal, cohort multicenter GARLIT experience. J Neurol. 2022 (Jun 28). Doi: 10.1007/s00415-022-11226-4

Key clinical point: Long-term treatment with galcanezumab led to three-quarters of patients with chronic migraine (CM) reverting to episodic migraine (EM), with more than half persistently reverting to episodic migraine (EM) under real-life conditions.

Major finding: Over 1 year, approximately ≥75% of patients reverted from CM to EM at each visit, with persistent reversion from CM to EM and medium-to-low frequency EM being reported by 52.3% and 20.6% of patients, respectively. Older age at onset (P  =  .01) and less frequent baseline monthly migraine days (P  =  .005) significantly increased the reversion frequency to EM.

Study details: Findings are from a 12-month observational, longitudinal cohort study, GARLIT, including 155 patients with CM who received galcanezumab.

Disclosures: This study did not receive any specific funding. Several authors reported receiving grants or honoraria from various sources.

Source: Altamura C et al for the GARLIT Study Group. Conversion from chronic to episodic migraine in patients treated with galcanezumab in real life in Italy: The 12-month observational, longitudinal, cohort multicenter GARLIT experience. J Neurol. 2022 (Jun 28). Doi: 10.1007/s00415-022-11226-4

Key clinical point: Long-term treatment with galcanezumab led to three-quarters of patients with chronic migraine (CM) reverting to episodic migraine (EM), with more than half persistently reverting to episodic migraine (EM) under real-life conditions.

Major finding: Over 1 year, approximately ≥75% of patients reverted from CM to EM at each visit, with persistent reversion from CM to EM and medium-to-low frequency EM being reported by 52.3% and 20.6% of patients, respectively. Older age at onset (P  =  .01) and less frequent baseline monthly migraine days (P  =  .005) significantly increased the reversion frequency to EM.

Study details: Findings are from a 12-month observational, longitudinal cohort study, GARLIT, including 155 patients with CM who received galcanezumab.

Disclosures: This study did not receive any specific funding. Several authors reported receiving grants or honoraria from various sources.

Source: Altamura C et al for the GARLIT Study Group. Conversion from chronic to episodic migraine in patients treated with galcanezumab in real life in Italy: The 12-month observational, longitudinal, cohort multicenter GARLIT experience. J Neurol. 2022 (Jun 28). Doi: 10.1007/s00415-022-11226-4

Key clinical point: Eptinezumab (100 and 300 mg) was efficacious compared with placebo with an acceptable safety and tolerability profile in patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments.

Major finding: In 1-12 weeks, 100 and 300 mg eptinezumab vs placebo led to a significantly higher reduction in mean monthly migraine days (difference from placebo −2.7 and −3.2, respectively; both P < .0001) and higher odds of ≥75% migraine responder rates (odds ratio 9.2 and 11.4, respectively; both P < .0001), with comparable treatment-emergent adverse events.

Study details: Findings are from the phase 3b DELIVER trial including 892 patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments who were randomly assigned to receive eptinezumab (100 or 300 mg) or placebo.

Disclosures: This study was supported by H Lundbeck. Five authors reported being full-time employees or owning stock or stock options in H Lundbeck or its subsidiaries. Several authors reported ties with various sources and scientific journals.

Source: Ashina M et al. Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): A multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2022;21(7):597-607 (Jul 1). Doi: 10.1016/S1474-4422(22)00185-5

Key clinical point: Eptinezumab (100 and 300 mg) was efficacious compared with placebo with an acceptable safety and tolerability profile in patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments.

Major finding: In 1-12 weeks, 100 and 300 mg eptinezumab vs placebo led to a significantly higher reduction in mean monthly migraine days (difference from placebo −2.7 and −3.2, respectively; both P < .0001) and higher odds of ≥75% migraine responder rates (odds ratio 9.2 and 11.4, respectively; both P < .0001), with comparable treatment-emergent adverse events.

Study details: Findings are from the phase 3b DELIVER trial including 892 patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments who were randomly assigned to receive eptinezumab (100 or 300 mg) or placebo.

Disclosures: This study was supported by H Lundbeck. Five authors reported being full-time employees or owning stock or stock options in H Lundbeck or its subsidiaries. Several authors reported ties with various sources and scientific journals.

Source: Ashina M et al. Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): A multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2022;21(7):597-607 (Jul 1). Doi: 10.1016/S1474-4422(22)00185-5

Key clinical point: Eptinezumab (100 and 300 mg) was efficacious compared with placebo with an acceptable safety and tolerability profile in patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments.

Major finding: In 1-12 weeks, 100 and 300 mg eptinezumab vs placebo led to a significantly higher reduction in mean monthly migraine days (difference from placebo −2.7 and −3.2, respectively; both P < .0001) and higher odds of ≥75% migraine responder rates (odds ratio 9.2 and 11.4, respectively; both P < .0001), with comparable treatment-emergent adverse events.

Study details: Findings are from the phase 3b DELIVER trial including 892 patients with episodic and chronic migraine and 2-4 previous unsuccessful preventive treatments who were randomly assigned to receive eptinezumab (100 or 300 mg) or placebo.

Disclosures: This study was supported by H Lundbeck. Five authors reported being full-time employees or owning stock or stock options in H Lundbeck or its subsidiaries. Several authors reported ties with various sources and scientific journals.

Source: Ashina M et al. Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): A multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2022;21(7):597-607 (Jul 1). Doi: 10.1016/S1474-4422(22)00185-5

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The Health Terminology/Ontology Portal (HeTOP), on which the curious can discover information about off-label use, lists 645 medications prescribed for migraine worldwide. Treatments ranging from blood pressure medications to antidepressants, and anticonvulsants to antiepileptics, along with their doses and administrations, are all listed. The number of migraine-indicated medications is 114.  Dominated by triptans and topiramate, the list also includes erenumab, the calcitonin gene-related peptide CGRP agonist. The difference in figures between the predominately off label and migraine-approved lists is a good indicator of the struggle that health care providers have had through the years to help their patients.

 The idea now is to make that list even longer by finding biomarkers that lead to new therapies.

But first, a conversation about the trigeminal ganglia.

The trigeminal ganglia

The trigeminal ganglia sit on either side of the head, in front of the ears. Their primary role is to receive stimuli and convey it to the brain. The humantrigeminal ganglia contain 20,000 to 35,000 neurons and express an array of neuropeptides, including CGRP. Some neuropeptides, like CGRP and pituitary adenylate cyclase–activating peptide 38 (PACAP38) are vasodilators. Others, like substance P, are vasoconstrictors. Edvinsson and Goadsby discussed in 1994 how CGRP was released simultaneously in those with “spontaneous attacks of migraine.”

Over the past 30 years, researchers in our institution  and elsewhere have shown repeatedly that migraine develops in individuals who are exposed to certain signaling molecules, namely nitroglycerin, CGRP, cyclic guanosine monophosphate (cGMP), intracellular cyclic adenosine monophosphate (cAMP), potassium, and PACAP38, among others. Such exposure reinforces the notion that peripheral sensitization of trigeminal sensory neurons brings on headache. The attack could occur due to vasodilation, mast cell degranulation, involvement of the parasympathetic system, or activation of nerve fibers.

Some examples from the literature:

• In our research, results from a small study of patients under spontaneous migraine attack, who underwent a 3-Tesla MRI scan, showed that cortical thickness diminishes in the prefrontal and pericalcarine cortices. The analysis we performed involving individuals with migraine without aura revealed that these patients experience reduced cortical thickness and volume when migraine attacks come on, suggesting that cortical thickness and volume may serve as a potential biomarker.
• A comparison of 20 individuals with chronic migraine and 20 healthy controls by way of 3-Tesla magnetic resonance imaging scans revealed that those with headache appeared to have substantially increased neural connectivity between the hypothalamus and certain brain areas – yet there appeared to be no connectivity irregularities between the hypothalamus and brainstem, which as the authors noted, is the “migraine generator.”

In other words, vasodilation might be  a secondary symptom of migraine but likely isn’t its source.

Other migraine makers

Neurochemicals and nucleotides play a role in migraine formation, too:

• Nitric oxide. Can open blood vessels in the head and brain and has been shown to set migraine in motion. It leads to peak headache intensity 5.5 hours after infusion and causes migraine without aura.

• GRP. Gastrin-releasing peptide receptors cause delayed headache, including what qualifies as an induced migraine attack. Researchers also note that similar pathways trigger migraine with and without aura. 

• Intracellular cGMP and intracellular cAMP. These 2 cyclic nucleotides are found extensively in the trigeminovascular system and have a role in the pathogenesis of migraine.  Studies demonstrate that cGMP levels increase after nitroglycerin administration and cAMP increases after CGRP and PACAP38 exposure.

• Levcromakalim. This potassium channel opener is sensitive to ATP. In a trial published in 2019, researchers showed that modulating potassium channels could cause some headache pain, even in those without migraine. They infused 20 healthy volunteers with levcromakalim; over the next 5-plus hours, the middle meningeal artery of all 20 became and remained dilated. Later research showed that this dilation is linked to substance P. 

Identifying migraine types

Diagnosing migraine is 1 step; determining its type is another.

Consider that a person with a posttraumatic headache can have migraine-like symptoms. To find objective separate characteristics, researchers at Mayo Clinic designed a headache classification model using questionnaires, which were then paired with the patient’s MRI data. The questionnaires delved into headache characteristics, sensory hypersensitivities, cognitive functioning, and mood. The system worked well with primary migraine, with 97% accuracy. But with posttraumatic headache, the system was 65% accurate. What proved to differentiate persistent posttraumatic headache were questions regarding decision making and anxiety. These patients had severe symptoms of anxiety, depression, physical issues, and mild brain injury attributed to blasts.

All of which explains why we and others are actively looking for biomarkers.

The biomarkers

A look at clinicaltrials.gov shows that 15 trials are recruiting patients (including us) in the search for biomarkers. One wants to identify a computational algorithm using AI, based on 9 types of markers in hopes of identifying those predictive elements that will respond to CGRP-targeting monoclonal antibodies (mABs). The factors range from the clinical to epigenetic to structural and functional brain imaging. Another registered study is using ocular coherence tomography, among other technologies, to identify photophobia.

Our interests are in identifying CGRP as a definitive biomarker; finding structural and functional cerebral changes, using MRI, in study subjects before and after they are given erenumab. We also want to create a registry for migraine based on the structural and functional MRI findings.

Another significant reason for finding biomarkers is to identify the alteration that accompany progression from episodic to chronic migraine. Pozo-Rosich et al write that these imaging, neurophysiological, and biochemical changes that occur with this progression could be used “for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies.” And, ultimately, in practicing precision medicine to improve care of patients.

Significant barriers still exist in declaring a molecule is a biomarker. For example, a meta-analysis points to the replication challenge observed in neuroimaging research. Additionally, several genetic variants produce small effect sizes, which also might be impacted by environmental factors. This makes it difficult to map genetic biomarkers. Large prospective studies are needed to bring this area of research out of infancy to a place where treatment response can be clinically assessed. Additionally, while research evaluating provocation biomarkers has already contributed to the treatment landscape, large-scale registry studies may help uncover a predictive biomarker of treatment response. Blood biomarker research still needs a standardized protocol. Imaging-based biomarkers show much potential, but standardized imaging protocols and improved characterization and data integration are necessary going forward.

The patients

The discovery of the CGRPs couldn’t have been more timely.

Those of us who have been treating patients with migraine for years have seen the prevalence of this disease slowly rise. In 2018, the age-adjusted prevalence was 15.9% for all adults in the United States; in 2010, it was 13.2%. Worldwide, in 2019, it was 14%. In 2015, it was 11.6%.

In the past few years, journal articles have appeared regarding the connection between obesity, diabetes, hypertension, and migraine severity. Numerous other comorbidities affect our patients – not just the well-known psychiatric disorders – but also the respiratory, digestive, and central nervous system illnesses.

In other words, many of our patients come to us sicker than in years past.

Some cannot take one or more medications designed for acute migraine attacks due to comorbidities, including cardiovascular disease or related risk factors, and gastrointestinal bleeding.

A large survey of 15,133 people with migraine confirmed the findings on these numerous comorbidities; they reported that they have more insomnia, depression, and anxiety. As the authors point out, identifying these comorbidities can help with accurate diagnosis, treatment and its adherence, and prognosis. The authors also noted that as migraine days increase per month, so do the rates of comorbidities.

But the CGRPs are showing how beneficial they can be. One study assessing medication overuse showed how 60% of the enrolled patients no longer fit that description 6 months after receiving erenumab or galcanezumab. Some patients who contend with episodic migraine showed a complete response after receiving eptinezumab and galcanezumab. They also have helped patients with menstrual migraine and refractory migraine.

But they are not complete responses to these medications, which is an excellent reason to continue viewing, recording, and assessing the migraine brain, for all it can tell us.

The Health Terminology/Ontology Portal (HeTOP), on which the curious can discover information about off-label use, lists 645 medications prescribed for migraine worldwide. Treatments ranging from blood pressure medications to antidepressants, and anticonvulsants to antiepileptics, along with their doses and administrations, are all listed. The number of migraine-indicated medications is 114.  Dominated by triptans and topiramate, the list also includes erenumab, the calcitonin gene-related peptide CGRP agonist. The difference in figures between the predominately off label and migraine-approved lists is a good indicator of the struggle that health care providers have had through the years to help their patients.

 The idea now is to make that list even longer by finding biomarkers that lead to new therapies.

But first, a conversation about the trigeminal ganglia.

The trigeminal ganglia

The trigeminal ganglia sit on either side of the head, in front of the ears. Their primary role is to receive stimuli and convey it to the brain. The humantrigeminal ganglia contain 20,000 to 35,000 neurons and express an array of neuropeptides, including CGRP. Some neuropeptides, like CGRP and pituitary adenylate cyclase–activating peptide 38 (PACAP38) are vasodilators. Others, like substance P, are vasoconstrictors. Edvinsson and Goadsby discussed in 1994 how CGRP was released simultaneously in those with “spontaneous attacks of migraine.”

Over the past 30 years, researchers in our institution  and elsewhere have shown repeatedly that migraine develops in individuals who are exposed to certain signaling molecules, namely nitroglycerin, CGRP, cyclic guanosine monophosphate (cGMP), intracellular cyclic adenosine monophosphate (cAMP), potassium, and PACAP38, among others. Such exposure reinforces the notion that peripheral sensitization of trigeminal sensory neurons brings on headache. The attack could occur due to vasodilation, mast cell degranulation, involvement of the parasympathetic system, or activation of nerve fibers.

Some examples from the literature:

• In our research, results from a small study of patients under spontaneous migraine attack, who underwent a 3-Tesla MRI scan, showed that cortical thickness diminishes in the prefrontal and pericalcarine cortices. The analysis we performed involving individuals with migraine without aura revealed that these patients experience reduced cortical thickness and volume when migraine attacks come on, suggesting that cortical thickness and volume may serve as a potential biomarker.
• A comparison of 20 individuals with chronic migraine and 20 healthy controls by way of 3-Tesla magnetic resonance imaging scans revealed that those with headache appeared to have substantially increased neural connectivity between the hypothalamus and certain brain areas – yet there appeared to be no connectivity irregularities between the hypothalamus and brainstem, which as the authors noted, is the “migraine generator.”

In other words, vasodilation might be  a secondary symptom of migraine but likely isn’t its source.

Other migraine makers

Neurochemicals and nucleotides play a role in migraine formation, too:

• Nitric oxide. Can open blood vessels in the head and brain and has been shown to set migraine in motion. It leads to peak headache intensity 5.5 hours after infusion and causes migraine without aura.

• GRP. Gastrin-releasing peptide receptors cause delayed headache, including what qualifies as an induced migraine attack. Researchers also note that similar pathways trigger migraine with and without aura. 

• Intracellular cGMP and intracellular cAMP. These 2 cyclic nucleotides are found extensively in the trigeminovascular system and have a role in the pathogenesis of migraine.  Studies demonstrate that cGMP levels increase after nitroglycerin administration and cAMP increases after CGRP and PACAP38 exposure.

• Levcromakalim. This potassium channel opener is sensitive to ATP. In a trial published in 2019, researchers showed that modulating potassium channels could cause some headache pain, even in those without migraine. They infused 20 healthy volunteers with levcromakalim; over the next 5-plus hours, the middle meningeal artery of all 20 became and remained dilated. Later research showed that this dilation is linked to substance P. 

Identifying migraine types

Diagnosing migraine is 1 step; determining its type is another.

Consider that a person with a posttraumatic headache can have migraine-like symptoms. To find objective separate characteristics, researchers at Mayo Clinic designed a headache classification model using questionnaires, which were then paired with the patient’s MRI data. The questionnaires delved into headache characteristics, sensory hypersensitivities, cognitive functioning, and mood. The system worked well with primary migraine, with 97% accuracy. But with posttraumatic headache, the system was 65% accurate. What proved to differentiate persistent posttraumatic headache were questions regarding decision making and anxiety. These patients had severe symptoms of anxiety, depression, physical issues, and mild brain injury attributed to blasts.

All of which explains why we and others are actively looking for biomarkers.

The biomarkers

A look at clinicaltrials.gov shows that 15 trials are recruiting patients (including us) in the search for biomarkers. One wants to identify a computational algorithm using AI, based on 9 types of markers in hopes of identifying those predictive elements that will respond to CGRP-targeting monoclonal antibodies (mABs). The factors range from the clinical to epigenetic to structural and functional brain imaging. Another registered study is using ocular coherence tomography, among other technologies, to identify photophobia.

Our interests are in identifying CGRP as a definitive biomarker; finding structural and functional cerebral changes, using MRI, in study subjects before and after they are given erenumab. We also want to create a registry for migraine based on the structural and functional MRI findings.

Another significant reason for finding biomarkers is to identify the alteration that accompany progression from episodic to chronic migraine. Pozo-Rosich et al write that these imaging, neurophysiological, and biochemical changes that occur with this progression could be used “for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies.” And, ultimately, in practicing precision medicine to improve care of patients.

Significant barriers still exist in declaring a molecule is a biomarker. For example, a meta-analysis points to the replication challenge observed in neuroimaging research. Additionally, several genetic variants produce small effect sizes, which also might be impacted by environmental factors. This makes it difficult to map genetic biomarkers. Large prospective studies are needed to bring this area of research out of infancy to a place where treatment response can be clinically assessed. Additionally, while research evaluating provocation biomarkers has already contributed to the treatment landscape, large-scale registry studies may help uncover a predictive biomarker of treatment response. Blood biomarker research still needs a standardized protocol. Imaging-based biomarkers show much potential, but standardized imaging protocols and improved characterization and data integration are necessary going forward.

The patients

The discovery of the CGRPs couldn’t have been more timely.

Those of us who have been treating patients with migraine for years have seen the prevalence of this disease slowly rise. In 2018, the age-adjusted prevalence was 15.9% for all adults in the United States; in 2010, it was 13.2%. Worldwide, in 2019, it was 14%. In 2015, it was 11.6%.

In the past few years, journal articles have appeared regarding the connection between obesity, diabetes, hypertension, and migraine severity. Numerous other comorbidities affect our patients – not just the well-known psychiatric disorders – but also the respiratory, digestive, and central nervous system illnesses.

In other words, many of our patients come to us sicker than in years past.

Some cannot take one or more medications designed for acute migraine attacks due to comorbidities, including cardiovascular disease or related risk factors, and gastrointestinal bleeding.

A large survey of 15,133 people with migraine confirmed the findings on these numerous comorbidities; they reported that they have more insomnia, depression, and anxiety. As the authors point out, identifying these comorbidities can help with accurate diagnosis, treatment and its adherence, and prognosis. The authors also noted that as migraine days increase per month, so do the rates of comorbidities.

But the CGRPs are showing how beneficial they can be. One study assessing medication overuse showed how 60% of the enrolled patients no longer fit that description 6 months after receiving erenumab or galcanezumab. Some patients who contend with episodic migraine showed a complete response after receiving eptinezumab and galcanezumab. They also have helped patients with menstrual migraine and refractory migraine.

But they are not complete responses to these medications, which is an excellent reason to continue viewing, recording, and assessing the migraine brain, for all it can tell us.

The Health Terminology/Ontology Portal (HeTOP), on which the curious can discover information about off-label use, lists 645 medications prescribed for migraine worldwide. Treatments ranging from blood pressure medications to antidepressants, and anticonvulsants to antiepileptics, along with their doses and administrations, are all listed. The number of migraine-indicated medications is 114.  Dominated by triptans and topiramate, the list also includes erenumab, the calcitonin gene-related peptide CGRP agonist. The difference in figures between the predominately off label and migraine-approved lists is a good indicator of the struggle that health care providers have had through the years to help their patients.

 The idea now is to make that list even longer by finding biomarkers that lead to new therapies.

But first, a conversation about the trigeminal ganglia.

The trigeminal ganglia

The trigeminal ganglia sit on either side of the head, in front of the ears. Their primary role is to receive stimuli and convey it to the brain. The humantrigeminal ganglia contain 20,000 to 35,000 neurons and express an array of neuropeptides, including CGRP. Some neuropeptides, like CGRP and pituitary adenylate cyclase–activating peptide 38 (PACAP38) are vasodilators. Others, like substance P, are vasoconstrictors. Edvinsson and Goadsby discussed in 1994 how CGRP was released simultaneously in those with “spontaneous attacks of migraine.”

Over the past 30 years, researchers in our institution  and elsewhere have shown repeatedly that migraine develops in individuals who are exposed to certain signaling molecules, namely nitroglycerin, CGRP, cyclic guanosine monophosphate (cGMP), intracellular cyclic adenosine monophosphate (cAMP), potassium, and PACAP38, among others. Such exposure reinforces the notion that peripheral sensitization of trigeminal sensory neurons brings on headache. The attack could occur due to vasodilation, mast cell degranulation, involvement of the parasympathetic system, or activation of nerve fibers.

Some examples from the literature:

• In our research, results from a small study of patients under spontaneous migraine attack, who underwent a 3-Tesla MRI scan, showed that cortical thickness diminishes in the prefrontal and pericalcarine cortices. The analysis we performed involving individuals with migraine without aura revealed that these patients experience reduced cortical thickness and volume when migraine attacks come on, suggesting that cortical thickness and volume may serve as a potential biomarker.
• A comparison of 20 individuals with chronic migraine and 20 healthy controls by way of 3-Tesla magnetic resonance imaging scans revealed that those with headache appeared to have substantially increased neural connectivity between the hypothalamus and certain brain areas – yet there appeared to be no connectivity irregularities between the hypothalamus and brainstem, which as the authors noted, is the “migraine generator.”

In other words, vasodilation might be  a secondary symptom of migraine but likely isn’t its source.

Other migraine makers

Neurochemicals and nucleotides play a role in migraine formation, too:

• Nitric oxide. Can open blood vessels in the head and brain and has been shown to set migraine in motion. It leads to peak headache intensity 5.5 hours after infusion and causes migraine without aura.

• GRP. Gastrin-releasing peptide receptors cause delayed headache, including what qualifies as an induced migraine attack. Researchers also note that similar pathways trigger migraine with and without aura. 

• Intracellular cGMP and intracellular cAMP. These 2 cyclic nucleotides are found extensively in the trigeminovascular system and have a role in the pathogenesis of migraine.  Studies demonstrate that cGMP levels increase after nitroglycerin administration and cAMP increases after CGRP and PACAP38 exposure.

• Levcromakalim. This potassium channel opener is sensitive to ATP. In a trial published in 2019, researchers showed that modulating potassium channels could cause some headache pain, even in those without migraine. They infused 20 healthy volunteers with levcromakalim; over the next 5-plus hours, the middle meningeal artery of all 20 became and remained dilated. Later research showed that this dilation is linked to substance P. 

Identifying migraine types

Diagnosing migraine is 1 step; determining its type is another.

Consider that a person with a posttraumatic headache can have migraine-like symptoms. To find objective separate characteristics, researchers at Mayo Clinic designed a headache classification model using questionnaires, which were then paired with the patient’s MRI data. The questionnaires delved into headache characteristics, sensory hypersensitivities, cognitive functioning, and mood. The system worked well with primary migraine, with 97% accuracy. But with posttraumatic headache, the system was 65% accurate. What proved to differentiate persistent posttraumatic headache were questions regarding decision making and anxiety. These patients had severe symptoms of anxiety, depression, physical issues, and mild brain injury attributed to blasts.

All of which explains why we and others are actively looking for biomarkers.

The biomarkers

A look at clinicaltrials.gov shows that 15 trials are recruiting patients (including us) in the search for biomarkers. One wants to identify a computational algorithm using AI, based on 9 types of markers in hopes of identifying those predictive elements that will respond to CGRP-targeting monoclonal antibodies (mABs). The factors range from the clinical to epigenetic to structural and functional brain imaging. Another registered study is using ocular coherence tomography, among other technologies, to identify photophobia.

Our interests are in identifying CGRP as a definitive biomarker; finding structural and functional cerebral changes, using MRI, in study subjects before and after they are given erenumab. We also want to create a registry for migraine based on the structural and functional MRI findings.

Another significant reason for finding biomarkers is to identify the alteration that accompany progression from episodic to chronic migraine. Pozo-Rosich et al write that these imaging, neurophysiological, and biochemical changes that occur with this progression could be used “for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies.” And, ultimately, in practicing precision medicine to improve care of patients.

Significant barriers still exist in declaring a molecule is a biomarker. For example, a meta-analysis points to the replication challenge observed in neuroimaging research. Additionally, several genetic variants produce small effect sizes, which also might be impacted by environmental factors. This makes it difficult to map genetic biomarkers. Large prospective studies are needed to bring this area of research out of infancy to a place where treatment response can be clinically assessed. Additionally, while research evaluating provocation biomarkers has already contributed to the treatment landscape, large-scale registry studies may help uncover a predictive biomarker of treatment response. Blood biomarker research still needs a standardized protocol. Imaging-based biomarkers show much potential, but standardized imaging protocols and improved characterization and data integration are necessary going forward.

The patients

The discovery of the CGRPs couldn’t have been more timely.

Those of us who have been treating patients with migraine for years have seen the prevalence of this disease slowly rise. In 2018, the age-adjusted prevalence was 15.9% for all adults in the United States; in 2010, it was 13.2%. Worldwide, in 2019, it was 14%. In 2015, it was 11.6%.

In the past few years, journal articles have appeared regarding the connection between obesity, diabetes, hypertension, and migraine severity. Numerous other comorbidities affect our patients – not just the well-known psychiatric disorders – but also the respiratory, digestive, and central nervous system illnesses.

In other words, many of our patients come to us sicker than in years past.

Some cannot take one or more medications designed for acute migraine attacks due to comorbidities, including cardiovascular disease or related risk factors, and gastrointestinal bleeding.

A large survey of 15,133 people with migraine confirmed the findings on these numerous comorbidities; they reported that they have more insomnia, depression, and anxiety. As the authors point out, identifying these comorbidities can help with accurate diagnosis, treatment and its adherence, and prognosis. The authors also noted that as migraine days increase per month, so do the rates of comorbidities.

But the CGRPs are showing how beneficial they can be. One study assessing medication overuse showed how 60% of the enrolled patients no longer fit that description 6 months after receiving erenumab or galcanezumab. Some patients who contend with episodic migraine showed a complete response after receiving eptinezumab and galcanezumab. They also have helped patients with menstrual migraine and refractory migraine.

But they are not complete responses to these medications, which is an excellent reason to continue viewing, recording, and assessing the migraine brain, for all it can tell us.

Key clinical point: Erenumab is effective and well tolerated in patients with chronic migraine who did not respond to previous migraine treatments.

Major finding: Overall, 71.4% of patients treated with erenumab achieved ≥30% reduction in monthly migraine days from baseline to 9-12 weeks and 34.0% of patients at all assessment periods through 52 weeks. Constipation was the most common adverse event and 13.7% of patients discontinued treatment because of a lack of tolerability.

Study details: The data come from a 52-week, prospective, observational study including 300 patients with chronic migraine who received ≥1 dose of erenumab, of which 273 and 119 patients completed 12 and 52 weeks of treatment, respectively.

Disclosures: This study was funded by and conducted in collaboration with Novartis Pharma AG, Basel, Switzerland. Some authors reported being consultants, speakers, or scientific advisors for or receiving personal fees from various sources, including Novartis. Two authors declared being employees of and holding stocks in Novartis.

Source: Cullum CK et al. Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: A 52-week, single-center, prospective, observational study. J Headache Pain. 2022;23(1):61 Jun 2). Doi:10.1186/s10194-022-01433-9

Key clinical point: Erenumab is effective and well tolerated in patients with chronic migraine who did not respond to previous migraine treatments.

Major finding: Overall, 71.4% of patients treated with erenumab achieved ≥30% reduction in monthly migraine days from baseline to 9-12 weeks and 34.0% of patients at all assessment periods through 52 weeks. Constipation was the most common adverse event and 13.7% of patients discontinued treatment because of a lack of tolerability.

Study details: The data come from a 52-week, prospective, observational study including 300 patients with chronic migraine who received ≥1 dose of erenumab, of which 273 and 119 patients completed 12 and 52 weeks of treatment, respectively.

Disclosures: This study was funded by and conducted in collaboration with Novartis Pharma AG, Basel, Switzerland. Some authors reported being consultants, speakers, or scientific advisors for or receiving personal fees from various sources, including Novartis. Two authors declared being employees of and holding stocks in Novartis.

Source: Cullum CK et al. Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: A 52-week, single-center, prospective, observational study. J Headache Pain. 2022;23(1):61 Jun 2). Doi:10.1186/s10194-022-01433-9

Key clinical point: Erenumab is effective and well tolerated in patients with chronic migraine who did not respond to previous migraine treatments.

Major finding: Overall, 71.4% of patients treated with erenumab achieved ≥30% reduction in monthly migraine days from baseline to 9-12 weeks and 34.0% of patients at all assessment periods through 52 weeks. Constipation was the most common adverse event and 13.7% of patients discontinued treatment because of a lack of tolerability.

Study details: The data come from a 52-week, prospective, observational study including 300 patients with chronic migraine who received ≥1 dose of erenumab, of which 273 and 119 patients completed 12 and 52 weeks of treatment, respectively.

Disclosures: This study was funded by and conducted in collaboration with Novartis Pharma AG, Basel, Switzerland. Some authors reported being consultants, speakers, or scientific advisors for or receiving personal fees from various sources, including Novartis. Two authors declared being employees of and holding stocks in Novartis.

Source: Cullum CK et al. Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: A 52-week, single-center, prospective, observational study. J Headache Pain. 2022;23(1):61 Jun 2). Doi:10.1186/s10194-022-01433-9

Key clinical point: Severe migraine without aura increased the long-term risk for atrial fibrillation (AF) by 16%-21% in both men and women. The risk for future AF was highest in women with severe migraine with aura but not significant in male counterparts.

Major finding: Men (adjusted hazard ratio [aHR] 1.21; 95% CI 1.12-1.31) and women (aHR 1.16; 95% CI 1.09-1.22) with severe migraine without aura had a modest but significantly higher risk for AF. The risk was most prominent in women with severe migraine with aura (aHR 1.48; 95% CI 1.18-1.85), but was not significant in men.

Study details: Findings are from a large-scale population-based study including 4,020,488 participants without AF, of which 4986 and 105,029 had migraine with and without aura, respectively.

Disclosures: This study was supported by a Korea Medical Device Development Fund grant funded by the Korea Government. E-K Choi and GYH Lip reported receiving research grants or speaking fees or serving as consultants or speakers for various sources.

Source: Rhee T-M et al. Type and severity of migraine determines risk of atrial fibrillation in women.Front Cardiovasc Med. 2022;9:910225(May 31). Doi:10.3389/fcvm.2022.910225

Key clinical point: Severe migraine without aura increased the long-term risk for atrial fibrillation (AF) by 16%-21% in both men and women. The risk for future AF was highest in women with severe migraine with aura but not significant in male counterparts.

Major finding: Men (adjusted hazard ratio [aHR] 1.21; 95% CI 1.12-1.31) and women (aHR 1.16; 95% CI 1.09-1.22) with severe migraine without aura had a modest but significantly higher risk for AF. The risk was most prominent in women with severe migraine with aura (aHR 1.48; 95% CI 1.18-1.85), but was not significant in men.

Study details: Findings are from a large-scale population-based study including 4,020,488 participants without AF, of which 4986 and 105,029 had migraine with and without aura, respectively.

Disclosures: This study was supported by a Korea Medical Device Development Fund grant funded by the Korea Government. E-K Choi and GYH Lip reported receiving research grants or speaking fees or serving as consultants or speakers for various sources.

Source: Rhee T-M et al. Type and severity of migraine determines risk of atrial fibrillation in women.Front Cardiovasc Med. 2022;9:910225(May 31). Doi:10.3389/fcvm.2022.910225

Key clinical point: Severe migraine without aura increased the long-term risk for atrial fibrillation (AF) by 16%-21% in both men and women. The risk for future AF was highest in women with severe migraine with aura but not significant in male counterparts.

Major finding: Men (adjusted hazard ratio [aHR] 1.21; 95% CI 1.12-1.31) and women (aHR 1.16; 95% CI 1.09-1.22) with severe migraine without aura had a modest but significantly higher risk for AF. The risk was most prominent in women with severe migraine with aura (aHR 1.48; 95% CI 1.18-1.85), but was not significant in men.

Study details: Findings are from a large-scale population-based study including 4,020,488 participants without AF, of which 4986 and 105,029 had migraine with and without aura, respectively.

Disclosures: This study was supported by a Korea Medical Device Development Fund grant funded by the Korea Government. E-K Choi and GYH Lip reported receiving research grants or speaking fees or serving as consultants or speakers for various sources.

Source: Rhee T-M et al. Type and severity of migraine determines risk of atrial fibrillation in women.Front Cardiovasc Med. 2022;9:910225(May 31). Doi:10.3389/fcvm.2022.910225

Key clinical point: A higher proportion of patients with migraine treated with atogepant vs. placebo showed a significant reduction in the monthly migraine days (MMD) during the 12 weeks of treatment.

Major finding: At 12 weeks, ≥50% reduction in the mean MMD was achieved by a significantly higher proportion of patients receiving 10 mg (55.6%), 30 mg (58.7%), or 60 mg (60.8%) atogepantcompared with placebo (29.0%; all P < .001), with findings being similar for ≥25%, ≥75%, and 100% reduction in mean MMD. The incidence of treatment-emergent adverse events was similar among the treatment groups.

Study details: This was a secondary analysis of the ADVANCE trial including 873 patients with a ≥1-year history of migraine with or without aura who were randomly assigned to receive atogepant (10, 30, or 60 mg; n=659) or placebo (n=214).

Disclosures: This study was sponsored by Allergan. Some authors declared receiving speaking fees, consulting fees, personal fees, research grants, or royalties or owing stocks or stock options in various sources, including Allergan/AbbVie.

Source: Lipton RB et al.Rates of response to atogepant for migraine prophylaxis among adults:

A secondary analysis of a randomized clinical trial.JAMA Netw Open. 2022;5(6):e2215499 Jun 8). Doi: 10.1001/jamanetworkopen.2022.15499

Key clinical point: A higher proportion of patients with migraine treated with atogepant vs. placebo showed a significant reduction in the monthly migraine days (MMD) during the 12 weeks of treatment.

Major finding: At 12 weeks, ≥50% reduction in the mean MMD was achieved by a significantly higher proportion of patients receiving 10 mg (55.6%), 30 mg (58.7%), or 60 mg (60.8%) atogepantcompared with placebo (29.0%; all P < .001), with findings being similar for ≥25%, ≥75%, and 100% reduction in mean MMD. The incidence of treatment-emergent adverse events was similar among the treatment groups.

Study details: This was a secondary analysis of the ADVANCE trial including 873 patients with a ≥1-year history of migraine with or without aura who were randomly assigned to receive atogepant (10, 30, or 60 mg; n=659) or placebo (n=214).

Disclosures: This study was sponsored by Allergan. Some authors declared receiving speaking fees, consulting fees, personal fees, research grants, or royalties or owing stocks or stock options in various sources, including Allergan/AbbVie.

Source: Lipton RB et al.Rates of response to atogepant for migraine prophylaxis among adults:

A secondary analysis of a randomized clinical trial.JAMA Netw Open. 2022;5(6):e2215499 Jun 8). Doi: 10.1001/jamanetworkopen.2022.15499

Key clinical point: A higher proportion of patients with migraine treated with atogepant vs. placebo showed a significant reduction in the monthly migraine days (MMD) during the 12 weeks of treatment.

Major finding: At 12 weeks, ≥50% reduction in the mean MMD was achieved by a significantly higher proportion of patients receiving 10 mg (55.6%), 30 mg (58.7%), or 60 mg (60.8%) atogepantcompared with placebo (29.0%; all P < .001), with findings being similar for ≥25%, ≥75%, and 100% reduction in mean MMD. The incidence of treatment-emergent adverse events was similar among the treatment groups.

Study details: This was a secondary analysis of the ADVANCE trial including 873 patients with a ≥1-year history of migraine with or without aura who were randomly assigned to receive atogepant (10, 30, or 60 mg; n=659) or placebo (n=214).

Disclosures: This study was sponsored by Allergan. Some authors declared receiving speaking fees, consulting fees, personal fees, research grants, or royalties or owing stocks or stock options in various sources, including Allergan/AbbVie.

Source: Lipton RB et al.Rates of response to atogepant for migraine prophylaxis among adults:

A secondary analysis of a randomized clinical trial.JAMA Netw Open. 2022;5(6):e2215499 Jun 8). Doi: 10.1001/jamanetworkopen.2022.15499

Key clinical point: Migraine was significantly associated with fetal-type posterior cerebral artery (PCA) status in patients with ischemic stroke.

Major finding: Fetal-type PCA status was independently associated with migraine (adjusted odds ratio [aOR] 2.06; P = .005). The other factors independently associated with migraine were hypertension (aOR 1.97; P = .011), female gender (aOR 2.03; P = .017) and National Institutes of Health Stroke Scale score at admission (aOR 1.08; P = .018).

Study details: This cross-sectional study included 750 patients aged ≥18 yearswith ischemic stroke, of which 11.3% had migraine history.

Disclosures: This study received no specific funding. The authors declared no conflicts of interest.

Source: Zhang Y et al. The association between migraine and fetal-type posterior cerebral artery in patients with ischemic stroke. Cerebrovasc Dis. 2022 (May 13). Doi:10.1159/000524616

Key clinical point: Migraine was significantly associated with fetal-type posterior cerebral artery (PCA) status in patients with ischemic stroke.

Major finding: Fetal-type PCA status was independently associated with migraine (adjusted odds ratio [aOR] 2.06; P = .005). The other factors independently associated with migraine were hypertension (aOR 1.97; P = .011), female gender (aOR 2.03; P = .017) and National Institutes of Health Stroke Scale score at admission (aOR 1.08; P = .018).

Study details: This cross-sectional study included 750 patients aged ≥18 yearswith ischemic stroke, of which 11.3% had migraine history.

Disclosures: This study received no specific funding. The authors declared no conflicts of interest.

Source: Zhang Y et al. The association between migraine and fetal-type posterior cerebral artery in patients with ischemic stroke. Cerebrovasc Dis. 2022 (May 13). Doi:10.1159/000524616

Key clinical point: Migraine was significantly associated with fetal-type posterior cerebral artery (PCA) status in patients with ischemic stroke.

Major finding: Fetal-type PCA status was independently associated with migraine (adjusted odds ratio [aOR] 2.06; P = .005). The other factors independently associated with migraine were hypertension (aOR 1.97; P = .011), female gender (aOR 2.03; P = .017) and National Institutes of Health Stroke Scale score at admission (aOR 1.08; P = .018).

Study details: This cross-sectional study included 750 patients aged ≥18 yearswith ischemic stroke, of which 11.3% had migraine history.

Disclosures: This study received no specific funding. The authors declared no conflicts of interest.

Source: Zhang Y et al. The association between migraine and fetal-type posterior cerebral artery in patients with ischemic stroke. Cerebrovasc Dis. 2022 (May 13). Doi:10.1159/000524616

Key clinical point: Erenumab is effective and welltolerated in patients with chronic migraine who did not respond to previous migraine treatments.

Major finding: Overall,71.4% of patients treated with erenumabachieved ≥30% reduction in monthly migraine days from baseline to 9-12 weeks and 34.0% of patients at all assessment periods through 52weeks. Constipation was the most common adverse event and 13.7% of patients discontinued treatment because of a lack of tolerability.

Study details: The data come from a 52-week, prospective, observational study including 300 patients with chronic migraine who received ≥1 dose of erenumab, of which 273 and 119 patients completed 12 and 52 weeks of treatment, respectively.

Disclosures: This study was funded by and conducted in collaboration with Novartis Pharma AG, Basel, Switzerland. Some authors reported being consultants, speakers, or scientific advisorsfor or receiving personal fees from various sources, including Novartis. Two authors declared being employees of and holding stocks in Novartis.

Source: Cullum CK et al.Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: A 52-week, single-center, prospective, observational study. J Headache Pain. 2022;23(1):61 Jun 2). Doi:10.1186/s10194-022-01433-9

Key clinical point: Erenumab is effective and welltolerated in patients with chronic migraine who did not respond to previous migraine treatments.

Major finding: Overall,71.4% of patients treated with erenumabachieved ≥30% reduction in monthly migraine days from baseline to 9-12 weeks and 34.0% of patients at all assessment periods through 52weeks. Constipation was the most common adverse event and 13.7% of patients discontinued treatment because of a lack of tolerability.

Study details: The data come from a 52-week, prospective, observational study including 300 patients with chronic migraine who received ≥1 dose of erenumab, of which 273 and 119 patients completed 12 and 52 weeks of treatment, respectively.

Disclosures: This study was funded by and conducted in collaboration with Novartis Pharma AG, Basel, Switzerland. Some authors reported being consultants, speakers, or scientific advisorsfor or receiving personal fees from various sources, including Novartis. Two authors declared being employees of and holding stocks in Novartis.

Source: Cullum CK et al.Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: A 52-week, single-center, prospective, observational study. J Headache Pain. 2022;23(1):61 Jun 2). Doi:10.1186/s10194-022-01433-9

Key clinical point: Erenumab is effective and welltolerated in patients with chronic migraine who did not respond to previous migraine treatments.

Major finding: Overall,71.4% of patients treated with erenumabachieved ≥30% reduction in monthly migraine days from baseline to 9-12 weeks and 34.0% of patients at all assessment periods through 52weeks. Constipation was the most common adverse event and 13.7% of patients discontinued treatment because of a lack of tolerability.

Study details: The data come from a 52-week, prospective, observational study including 300 patients with chronic migraine who received ≥1 dose of erenumab, of which 273 and 119 patients completed 12 and 52 weeks of treatment, respectively.

Disclosures: This study was funded by and conducted in collaboration with Novartis Pharma AG, Basel, Switzerland. Some authors reported being consultants, speakers, or scientific advisorsfor or receiving personal fees from various sources, including Novartis. Two authors declared being employees of and holding stocks in Novartis.

Source: Cullum CK et al.Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: A 52-week, single-center, prospective, observational study. J Headache Pain. 2022;23(1):61 Jun 2). Doi:10.1186/s10194-022-01433-9

Key clinical point: Intravenous (IV) ketorolac plus metoclopramide failed to improve pain intensity in children presenting to the emergency department (ED) for the acute treatment of migraine compared with metoclopramide monotherapy.

Major finding: The mean change in pain intensity as assessed by a 100 mm Visual Analog Scale at 120 minutes was −44 mm (95% CI 32-57 mm) in the monotherapy group and −36 mm (95% CI 23-49 mm) in the ketorolac group, corresponding to a mean difference of 8 mm between the groups (P = .355),with no significant between-group difference in headache recurrence and adverse events.

Study details: Findings arefrom a double-blind, randomized placebo-controlled trialincluding 53children aged 6-17 years presenting to the ED for the acute treatment of migraine. They were randomly assigned to receive IV ketorolac plus metoclopramide (n=26) or IV metoclopramide plus placebo (n=27).

Disclosures: This study was funded by the Canadian Institutes of Health Research through a Drug Safety and Effectiveness Network grant. The authors declared no conflicts of interest.

Source: Richer LP et al.A randomized trial of ketorolac and metoclopramide for migraine in the emergency department.Headache. 2022; 62: 681-689(Jun 7). Doi:10.1111/head.14307

Key clinical point: Intravenous (IV) ketorolac plus metoclopramide failed to improve pain intensity in children presenting to the emergency department (ED) for the acute treatment of migraine compared with metoclopramide monotherapy.

Major finding: The mean change in pain intensity as assessed by a 100 mm Visual Analog Scale at 120 minutes was −44 mm (95% CI 32-57 mm) in the monotherapy group and −36 mm (95% CI 23-49 mm) in the ketorolac group, corresponding to a mean difference of 8 mm between the groups (P = .355),with no significant between-group difference in headache recurrence and adverse events.

Study details: Findings arefrom a double-blind, randomized placebo-controlled trialincluding 53children aged 6-17 years presenting to the ED for the acute treatment of migraine. They were randomly assigned to receive IV ketorolac plus metoclopramide (n=26) or IV metoclopramide plus placebo (n=27).

Disclosures: This study was funded by the Canadian Institutes of Health Research through a Drug Safety and Effectiveness Network grant. The authors declared no conflicts of interest.

Source: Richer LP et al.A randomized trial of ketorolac and metoclopramide for migraine in the emergency department.Headache. 2022; 62: 681-689(Jun 7). Doi:10.1111/head.14307

Key clinical point: Intravenous (IV) ketorolac plus metoclopramide failed to improve pain intensity in children presenting to the emergency department (ED) for the acute treatment of migraine compared with metoclopramide monotherapy.

Major finding: The mean change in pain intensity as assessed by a 100 mm Visual Analog Scale at 120 minutes was −44 mm (95% CI 32-57 mm) in the monotherapy group and −36 mm (95% CI 23-49 mm) in the ketorolac group, corresponding to a mean difference of 8 mm between the groups (P = .355),with no significant between-group difference in headache recurrence and adverse events.

Study details: Findings arefrom a double-blind, randomized placebo-controlled trialincluding 53children aged 6-17 years presenting to the ED for the acute treatment of migraine. They were randomly assigned to receive IV ketorolac plus metoclopramide (n=26) or IV metoclopramide plus placebo (n=27).

Disclosures: This study was funded by the Canadian Institutes of Health Research through a Drug Safety and Effectiveness Network grant. The authors declared no conflicts of interest.

Source: Richer LP et al.A randomized trial of ketorolac and metoclopramide for migraine in the emergency department.Headache. 2022; 62: 681-689(Jun 7). Doi:10.1111/head.14307