Migraine ICYMI

Key clinical point: Triptans, including eletriptan, rizatriptan, sumatriptan, and zolmitriptan, were more efficacious than newer and more expensive medications, such as lasmiditan and rimegepant, for the acute treatment of migraine.

Major findings: All active interventions were superior to placebo in achieving freedom from pain at 2 hours (odds ratio [OR], 1.73) with naratriptan and (OR, 5.19) for eletriptan. Eletriptan was the most effective for pain relief at two hours (OR, 1.46-3.01), followed by rizatriptan (OR, 1.59-2.44), sumatriptan (OR, 1.35-2.04), and zolmitriptan (OR, 1.47-1.96). For sustained pain freedom, eletriptan and ibuprofen were the most effective.

Study details: This network meta-analysis of 137 randomized controlled trials included 89,445 adults with migraine who received one of 17 drugs, including antipyretics, ditans, gepants, nonsteroidal anti-inflammatory drugs, and triptans, or placebo.

Disclosures: This study was funded by the National Institute for Health and Care Research Oxford Health Biomedical Research Centre and the Lundbeck Foundation. Several authors reported having ties with various sources.

Source: Karlsson WK, Ostinelli EG, Zhuang ZA, et al. Comparative effects of drug interventions for the acute management of migraine episodes in adults: Systematic review and network meta-analysis. BMJ. 2024;386:e080107. Source

Key clinical point: Triptans, including eletriptan, rizatriptan, sumatriptan, and zolmitriptan, were more efficacious than newer and more expensive medications, such as lasmiditan and rimegepant, for the acute treatment of migraine.

Major findings: All active interventions were superior to placebo in achieving freedom from pain at 2 hours (odds ratio [OR], 1.73) with naratriptan and (OR, 5.19) for eletriptan. Eletriptan was the most effective for pain relief at two hours (OR, 1.46-3.01), followed by rizatriptan (OR, 1.59-2.44), sumatriptan (OR, 1.35-2.04), and zolmitriptan (OR, 1.47-1.96). For sustained pain freedom, eletriptan and ibuprofen were the most effective.

Study details: This network meta-analysis of 137 randomized controlled trials included 89,445 adults with migraine who received one of 17 drugs, including antipyretics, ditans, gepants, nonsteroidal anti-inflammatory drugs, and triptans, or placebo.

Disclosures: This study was funded by the National Institute for Health and Care Research Oxford Health Biomedical Research Centre and the Lundbeck Foundation. Several authors reported having ties with various sources.

Source: Karlsson WK, Ostinelli EG, Zhuang ZA, et al. Comparative effects of drug interventions for the acute management of migraine episodes in adults: Systematic review and network meta-analysis. BMJ. 2024;386:e080107. Source

Key clinical point: Triptans, including eletriptan, rizatriptan, sumatriptan, and zolmitriptan, were more efficacious than newer and more expensive medications, such as lasmiditan and rimegepant, for the acute treatment of migraine.

Major findings: All active interventions were superior to placebo in achieving freedom from pain at 2 hours (odds ratio [OR], 1.73) with naratriptan and (OR, 5.19) for eletriptan. Eletriptan was the most effective for pain relief at two hours (OR, 1.46-3.01), followed by rizatriptan (OR, 1.59-2.44), sumatriptan (OR, 1.35-2.04), and zolmitriptan (OR, 1.47-1.96). For sustained pain freedom, eletriptan and ibuprofen were the most effective.

Study details: This network meta-analysis of 137 randomized controlled trials included 89,445 adults with migraine who received one of 17 drugs, including antipyretics, ditans, gepants, nonsteroidal anti-inflammatory drugs, and triptans, or placebo.

Disclosures: This study was funded by the National Institute for Health and Care Research Oxford Health Biomedical Research Centre and the Lundbeck Foundation. Several authors reported having ties with various sources.

Source: Karlsson WK, Ostinelli EG, Zhuang ZA, et al. Comparative effects of drug interventions for the acute management of migraine episodes in adults: Systematic review and network meta-analysis. BMJ. 2024;386:e080107. Source

In a recent study of 6 monthly injections of 140 mg erenumab (Aimovig, Amgen), most patients with chronic migraine and nonopioid medication overuse headache (MOH) achieved remission. Published online in JAMA Neurology, the study is the first prospective, double-blind, randomized, placebo-controlled attempt to investigate patients with chronic migraine and MOH related to nonopioid medications, according to lead author Stewart J. Tepper, MD, and his coauthors.

Prior Studies Did Not Focus on MOH

Several prior phase 2 and 3 trials of calcitonin gene-related peptide (CGRP) ligand or receptor inhibitors that have been FDA-approved for migraine prevention have been performed. These drugs include erenumab, fremanezumab (Ajovy, Teva), galcanezumab (Emgality, Lilly), and eptinezumab (Vyepti, Lundbeck), for patients with and without medication overuse, said Alan M. Rapoport, MD, who was not involved with the new study. Dr. Rapoport is a clinical professor of neurology at the David Geffen School of Medicine of the University of California, in Los Angeles; past president of the International Headache Society; and founder and director emeritus of The New England Center for Headache in Stamford, Connecticut.

“But we could not call them patients with MOH because they weren’t studied prospectively, so that they had medication overuse according to International Classification of Headache Disorders (ICHD-3) criteria,” said Dr. Rapoport.

Phase 4, Randomized, Placebo-Controlled Trial

In the present clinical trial, investigators enrolled 584 patients with nonopioid MOH and history of failing at least one preventive treatment. After a 4-week baseline phase, researchers randomized patients 1:1:1 to 6 months’ treatment with erenumab 70 mg, erenumab 140 mg, or placebo.

Investigators defined remission as either of the following through months 4-6:

• < 10 mean monthly acute headache medication days per month (AHMD)
• < 14 mean monthly headache days (MHD)

In the primary analysis, 69.1% of patients in the 140 mg cohort achieved remission (P < .001) versus placebo. Remission rates in the 70 mg and the placebo cohorts were 60.3% (P < .13) and 52.6%, respectively. AHMD for the 140-mg, 70-mg, and placebo groups fell by 9.4, 7.8, and 6.6 days per month, respectively. Migraine Physical Function Impact Diary (non-EU sites) and Headache Impact Test-6 (EU sites) scores also showed greater improvement for patients treated with erenumab.

No new safety signals emerged, although erenumab-treated participants experienced 2-2.5 times as much COVID-19 disease.

Regarding the primary endpoint, said Dr. Rapoport, the 70-mg dose might also have yielded statistically significant improvement over placebo with a larger sample size. “I have seen that the higher dose of erenumab can be superior for efficacy than the lower in some of the double-blind trials,” he said. The 52.6% placebo response rate was rather high, he added, but not necessarily higher than in other migraine prevention trials.

“Placebo is a type of treatment,” Dr. Rapoport said. “It’s not as strong as the actual medication, which is specific for prevention, but it does work on the brain to some extent.”

He was more concerned, however, that authors did not counsel study patients about reducing or discontinuing their overused medications in a unified manner. Rather, it was left to individual investigators’ discretion, in different countries, as to whether to educate patients about the harms of medication overuse. “The fascinating aspect of this paper was that no patient was asked to detoxify from the overused medication,” said Dr. Rapoport, “and yet so many patients no longer had MOH at 6 months.”
 

Detox Versus No Detox

In a pioneering study of migraine medication overuse headache (then called rebound headache) published by Lee Kudrow, MD, in Advances in Neurology in 1982, patients who discontinued the overused medication fared much better than those who did not. Adding amitriptyline for migraine prevention further improved results, mostly in those who discontinued their overused medication.

Anticipating possible concerns, the authors wrote that their approach “may also be seen as a strength, as it represents a scenario closer to real life and avoids undue interference with the physician-patient relationship.” Indeed, said Dr. Rapoport, study results are perhaps more impressive because they were achieved through treatment with erenumab alone, without detoxification.
 

Managing Chronic Migraine and MOH

Until erenumab’s 2018 approval, migraine prevention options were limited to tricyclic antidepressants, beta blockers, and antiseizure medicines – though these medicines never seemed to work very well without detoxification, said Dr. Rapoport. Neurologists still use these categories for migraine prevention, he added, “because insurance companies insist that before we give the more expensive, newer medications like those that block CGRP, patients must fail 2 of those 3 categories of older medications which are not approved for chronic migraine.” Only onabotulinumtoxinA (Botox) is FDA-approved for chronic migraine. “There has been no head-to-head comparison of it and any of the monoclonal antibodies against CGRP,” he said.

In a March 2024 publication in Headache, the American Headache Society stated that requiring patients to fail older drugs is inappropriate, and that CGRP inhibitors, though costly, should be first-line for headache prevention. The key advantage of any drug that blocks CGRP in treating MOH is that unlike older drugs, CGRP inhibitors appear to work well even without detoxification, said Dr. Rapoport.

Additional study limitations included the possibility that the 24-week treatment period might not have allowed complete evaluation of long-term efficacy, the authors wrote. “These are usually pretty sick patients,” said Dr. Rapoport, who acknowledged the difficulty of keeping placebo patients off preventive medication altogether for 6 months. The study was extended to 12 months, and the results of an opiate overusers cohort also will be published.

Authors noted that according to a study published in Headache in 2022, most Americans with chronic migraine commonly go without preventive medications. Moreover, such medications do not always work. Accordingly, Dr. Rapoport said, the study duration was reasonable provided patients understood that they had a 33% chance of receiving no effective preventive medication over 6 months.

Extending the study’s month-long baseline period to 3 months before starting erenumab might have been helpful, he added, as that is the timeframe required to confirm MOH diagnosis according to ICHD-3. “However,” said Dr. Rapoport, “3 months with only usual medications, and then 1/3 of patients going 6-12 months with only placebo, would be tough for some patients.”

Dr. Rapoport reports no relevant financial conflicts.

In a recent study of 6 monthly injections of 140 mg erenumab (Aimovig, Amgen), most patients with chronic migraine and nonopioid medication overuse headache (MOH) achieved remission. Published online in JAMA Neurology, the study is the first prospective, double-blind, randomized, placebo-controlled attempt to investigate patients with chronic migraine and MOH related to nonopioid medications, according to lead author Stewart J. Tepper, MD, and his coauthors.

Prior Studies Did Not Focus on MOH

Several prior phase 2 and 3 trials of calcitonin gene-related peptide (CGRP) ligand or receptor inhibitors that have been FDA-approved for migraine prevention have been performed. These drugs include erenumab, fremanezumab (Ajovy, Teva), galcanezumab (Emgality, Lilly), and eptinezumab (Vyepti, Lundbeck), for patients with and without medication overuse, said Alan M. Rapoport, MD, who was not involved with the new study. Dr. Rapoport is a clinical professor of neurology at the David Geffen School of Medicine of the University of California, in Los Angeles; past president of the International Headache Society; and founder and director emeritus of The New England Center for Headache in Stamford, Connecticut.

“But we could not call them patients with MOH because they weren’t studied prospectively, so that they had medication overuse according to International Classification of Headache Disorders (ICHD-3) criteria,” said Dr. Rapoport.

Phase 4, Randomized, Placebo-Controlled Trial

In the present clinical trial, investigators enrolled 584 patients with nonopioid MOH and history of failing at least one preventive treatment. After a 4-week baseline phase, researchers randomized patients 1:1:1 to 6 months’ treatment with erenumab 70 mg, erenumab 140 mg, or placebo.

Investigators defined remission as either of the following through months 4-6:

• < 10 mean monthly acute headache medication days per month (AHMD)
• < 14 mean monthly headache days (MHD)

In the primary analysis, 69.1% of patients in the 140 mg cohort achieved remission (P < .001) versus placebo. Remission rates in the 70 mg and the placebo cohorts were 60.3% (P < .13) and 52.6%, respectively. AHMD for the 140-mg, 70-mg, and placebo groups fell by 9.4, 7.8, and 6.6 days per month, respectively. Migraine Physical Function Impact Diary (non-EU sites) and Headache Impact Test-6 (EU sites) scores also showed greater improvement for patients treated with erenumab.

No new safety signals emerged, although erenumab-treated participants experienced 2-2.5 times as much COVID-19 disease.

Regarding the primary endpoint, said Dr. Rapoport, the 70-mg dose might also have yielded statistically significant improvement over placebo with a larger sample size. “I have seen that the higher dose of erenumab can be superior for efficacy than the lower in some of the double-blind trials,” he said. The 52.6% placebo response rate was rather high, he added, but not necessarily higher than in other migraine prevention trials.

“Placebo is a type of treatment,” Dr. Rapoport said. “It’s not as strong as the actual medication, which is specific for prevention, but it does work on the brain to some extent.”

He was more concerned, however, that authors did not counsel study patients about reducing or discontinuing their overused medications in a unified manner. Rather, it was left to individual investigators’ discretion, in different countries, as to whether to educate patients about the harms of medication overuse. “The fascinating aspect of this paper was that no patient was asked to detoxify from the overused medication,” said Dr. Rapoport, “and yet so many patients no longer had MOH at 6 months.”
 

Detox Versus No Detox

In a pioneering study of migraine medication overuse headache (then called rebound headache) published by Lee Kudrow, MD, in Advances in Neurology in 1982, patients who discontinued the overused medication fared much better than those who did not. Adding amitriptyline for migraine prevention further improved results, mostly in those who discontinued their overused medication.

Anticipating possible concerns, the authors wrote that their approach “may also be seen as a strength, as it represents a scenario closer to real life and avoids undue interference with the physician-patient relationship.” Indeed, said Dr. Rapoport, study results are perhaps more impressive because they were achieved through treatment with erenumab alone, without detoxification.
 

Managing Chronic Migraine and MOH

Until erenumab’s 2018 approval, migraine prevention options were limited to tricyclic antidepressants, beta blockers, and antiseizure medicines – though these medicines never seemed to work very well without detoxification, said Dr. Rapoport. Neurologists still use these categories for migraine prevention, he added, “because insurance companies insist that before we give the more expensive, newer medications like those that block CGRP, patients must fail 2 of those 3 categories of older medications which are not approved for chronic migraine.” Only onabotulinumtoxinA (Botox) is FDA-approved for chronic migraine. “There has been no head-to-head comparison of it and any of the monoclonal antibodies against CGRP,” he said.

In a March 2024 publication in Headache, the American Headache Society stated that requiring patients to fail older drugs is inappropriate, and that CGRP inhibitors, though costly, should be first-line for headache prevention. The key advantage of any drug that blocks CGRP in treating MOH is that unlike older drugs, CGRP inhibitors appear to work well even without detoxification, said Dr. Rapoport.

Additional study limitations included the possibility that the 24-week treatment period might not have allowed complete evaluation of long-term efficacy, the authors wrote. “These are usually pretty sick patients,” said Dr. Rapoport, who acknowledged the difficulty of keeping placebo patients off preventive medication altogether for 6 months. The study was extended to 12 months, and the results of an opiate overusers cohort also will be published.

Authors noted that according to a study published in Headache in 2022, most Americans with chronic migraine commonly go without preventive medications. Moreover, such medications do not always work. Accordingly, Dr. Rapoport said, the study duration was reasonable provided patients understood that they had a 33% chance of receiving no effective preventive medication over 6 months.

Extending the study’s month-long baseline period to 3 months before starting erenumab might have been helpful, he added, as that is the timeframe required to confirm MOH diagnosis according to ICHD-3. “However,” said Dr. Rapoport, “3 months with only usual medications, and then 1/3 of patients going 6-12 months with only placebo, would be tough for some patients.”

Dr. Rapoport reports no relevant financial conflicts.

In a recent study of 6 monthly injections of 140 mg erenumab (Aimovig, Amgen), most patients with chronic migraine and nonopioid medication overuse headache (MOH) achieved remission. Published online in JAMA Neurology, the study is the first prospective, double-blind, randomized, placebo-controlled attempt to investigate patients with chronic migraine and MOH related to nonopioid medications, according to lead author Stewart J. Tepper, MD, and his coauthors.

Prior Studies Did Not Focus on MOH

Several prior phase 2 and 3 trials of calcitonin gene-related peptide (CGRP) ligand or receptor inhibitors that have been FDA-approved for migraine prevention have been performed. These drugs include erenumab, fremanezumab (Ajovy, Teva), galcanezumab (Emgality, Lilly), and eptinezumab (Vyepti, Lundbeck), for patients with and without medication overuse, said Alan M. Rapoport, MD, who was not involved with the new study. Dr. Rapoport is a clinical professor of neurology at the David Geffen School of Medicine of the University of California, in Los Angeles; past president of the International Headache Society; and founder and director emeritus of The New England Center for Headache in Stamford, Connecticut.

“But we could not call them patients with MOH because they weren’t studied prospectively, so that they had medication overuse according to International Classification of Headache Disorders (ICHD-3) criteria,” said Dr. Rapoport.

Phase 4, Randomized, Placebo-Controlled Trial

In the present clinical trial, investigators enrolled 584 patients with nonopioid MOH and history of failing at least one preventive treatment. After a 4-week baseline phase, researchers randomized patients 1:1:1 to 6 months’ treatment with erenumab 70 mg, erenumab 140 mg, or placebo.

Investigators defined remission as either of the following through months 4-6:

• < 10 mean monthly acute headache medication days per month (AHMD)
• < 14 mean monthly headache days (MHD)

In the primary analysis, 69.1% of patients in the 140 mg cohort achieved remission (P < .001) versus placebo. Remission rates in the 70 mg and the placebo cohorts were 60.3% (P < .13) and 52.6%, respectively. AHMD for the 140-mg, 70-mg, and placebo groups fell by 9.4, 7.8, and 6.6 days per month, respectively. Migraine Physical Function Impact Diary (non-EU sites) and Headache Impact Test-6 (EU sites) scores also showed greater improvement for patients treated with erenumab.

No new safety signals emerged, although erenumab-treated participants experienced 2-2.5 times as much COVID-19 disease.

Regarding the primary endpoint, said Dr. Rapoport, the 70-mg dose might also have yielded statistically significant improvement over placebo with a larger sample size. “I have seen that the higher dose of erenumab can be superior for efficacy than the lower in some of the double-blind trials,” he said. The 52.6% placebo response rate was rather high, he added, but not necessarily higher than in other migraine prevention trials.

“Placebo is a type of treatment,” Dr. Rapoport said. “It’s not as strong as the actual medication, which is specific for prevention, but it does work on the brain to some extent.”

He was more concerned, however, that authors did not counsel study patients about reducing or discontinuing their overused medications in a unified manner. Rather, it was left to individual investigators’ discretion, in different countries, as to whether to educate patients about the harms of medication overuse. “The fascinating aspect of this paper was that no patient was asked to detoxify from the overused medication,” said Dr. Rapoport, “and yet so many patients no longer had MOH at 6 months.”
 

Detox Versus No Detox

In a pioneering study of migraine medication overuse headache (then called rebound headache) published by Lee Kudrow, MD, in Advances in Neurology in 1982, patients who discontinued the overused medication fared much better than those who did not. Adding amitriptyline for migraine prevention further improved results, mostly in those who discontinued their overused medication.

Anticipating possible concerns, the authors wrote that their approach “may also be seen as a strength, as it represents a scenario closer to real life and avoids undue interference with the physician-patient relationship.” Indeed, said Dr. Rapoport, study results are perhaps more impressive because they were achieved through treatment with erenumab alone, without detoxification.
 

Managing Chronic Migraine and MOH

Until erenumab’s 2018 approval, migraine prevention options were limited to tricyclic antidepressants, beta blockers, and antiseizure medicines – though these medicines never seemed to work very well without detoxification, said Dr. Rapoport. Neurologists still use these categories for migraine prevention, he added, “because insurance companies insist that before we give the more expensive, newer medications like those that block CGRP, patients must fail 2 of those 3 categories of older medications which are not approved for chronic migraine.” Only onabotulinumtoxinA (Botox) is FDA-approved for chronic migraine. “There has been no head-to-head comparison of it and any of the monoclonal antibodies against CGRP,” he said.

In a March 2024 publication in Headache, the American Headache Society stated that requiring patients to fail older drugs is inappropriate, and that CGRP inhibitors, though costly, should be first-line for headache prevention. The key advantage of any drug that blocks CGRP in treating MOH is that unlike older drugs, CGRP inhibitors appear to work well even without detoxification, said Dr. Rapoport.

Additional study limitations included the possibility that the 24-week treatment period might not have allowed complete evaluation of long-term efficacy, the authors wrote. “These are usually pretty sick patients,” said Dr. Rapoport, who acknowledged the difficulty of keeping placebo patients off preventive medication altogether for 6 months. The study was extended to 12 months, and the results of an opiate overusers cohort also will be published.

Authors noted that according to a study published in Headache in 2022, most Americans with chronic migraine commonly go without preventive medications. Moreover, such medications do not always work. Accordingly, Dr. Rapoport said, the study duration was reasonable provided patients understood that they had a 33% chance of receiving no effective preventive medication over 6 months.

Extending the study’s month-long baseline period to 3 months before starting erenumab might have been helpful, he added, as that is the timeframe required to confirm MOH diagnosis according to ICHD-3. “However,” said Dr. Rapoport, “3 months with only usual medications, and then 1/3 of patients going 6-12 months with only placebo, would be tough for some patients.”

Dr. Rapoport reports no relevant financial conflicts.

Neck pain is commonly associated with headaches, especially with migraine headaches. This is well recognized, and the symptom of neck pain occurring during headache episodes or even independently of headache episodes is at least partially related to pain sensitivity.¹ While neck pain is often considered a part of the migraine experience, it's not commonly thought of as a disabling symptom. However, neck pain can be a major aspect of migraine disability.

A systematic review published in August 2024 in the journal Cephalalgia described neck pain disability as a part of migraine. The authors used 33 clinic-based studies that utilized either the Neck Disability Index (NDI) or the Numeric Pain Rating Scale (NPRS) to define the severity of neck pain disability. They concluded that individuals with migraine had higher NDI and NPRS scores than patients with tension-type headaches and patients without headaches. According to the NDI scoring system, 0–4 points indicate no disability, 5–14 points indicate mild disability, 15–24 points indicate moderate disability, 25–34 points indicate severe disability, and ≥ 35 points indicate complete disability. The authors reported that the mean NDI score for patients with migraine was 16.2, which was approximately 12 points higher than for healthy headache-free control participants.² This brings to light an issue that can substantially affect patients' quality of life. Patients who have neck pain with migraine may need focused attention to that symptom, in addition to overall migraine therapy, and it is important to ask migraine patients about the degree to which neck pain affects their life. In fact, many patients might not even realize that their neck pain is associated with their migraines.

Cardiovascular disease is another comorbidity that has been inconsistently associated with migraine. A study published in Headache: The Journal of Headache and Face Pain in August 2024 used data from a Danish population-based cohort longitudinal study that included over 140,000 women. The authors reported that migraine was associated with a risk for major adverse cardiovascular and cerebrovascular events in women aged ≤ 60 years.³

This link has been noted previously, although the studies have been inconsistent regarding how strong the link is, any specific causality, and whether there is a link at all. Potential causes for the possible associations have been attributed to "endothelial dysfunction, hypercoagulability, platelet aggregation, vasospasm, cardiovascular risk factors, paradoxical embolism, spreading depolarization, shared genetic risk, use of non-steroidal anti-inflammatory drugs, and immobilization."⁴

Of note, there has also been documentation of a possible negative correlation between migraine and cardiovascular disease. Another article, from The Journal of Headache and Pain, published in August 2024, used data from 873,341 and 554,569 individuals, respectively, in two meta-analyses. The authors reported a potential protective effect of migraine on coronary artery disease and ischemic stroke, and a potential protective effect of coronary atherosclerosis and myocardial infarction on migraine.⁵

A possible explanation for the conflicting results could lie in heterogeneity of migraine. For example, vestibular migraine is associated with many comorbidities, including anxiety disorders or depressive disorders, sleep disorders, persistent postural-perceptual dizziness, and Meniere disease.⁶ Given the serious consequences of cardiovascular disease, screening for risk factors could be beneficial for preventing adverse health outcomes for migraine patients. Eventually, further research may reveal more specific correlations between comorbidities and migraine subtypes, rather than generalizing comorbidities to all migraine types.

Sources

1. Al-Khazali HM, Krøll LS, Ashina H, et al. Neck pain and headache: Pathophysiology, treatments and future directions. Musculoskelet Sci Pract. 2023;66:102804. Source

2. Al-Khazali HM, Al-Sayegh Z, Younis S, et al. Systematic review and meta-analysis of Neck Disability Index and Numeric Pain Rating Scale in patients with migraine and tension-type headache. Cephalalgia. 2024;44:3331024241274266.  Source

3. Fuglsang CH, Pedersen L, Schmidt M, Vandenbroucke JP, Bøtker HE, Sørensen HT. The combined impact of migraine and gestational diabetes on long-term risk of premature myocardial infarction and stroke: A population-based cohort study. Headache. 2024 Aug 28.  Source

4. Agostoni EC, Longoni M. Migraine and cerebrovascular disease: still a dangerous connection? Neurol Sci. 2018;39(Suppl 1):33-37.  Source

5. Duan X, Du X, Zheng G, et al. Causality between migraine and cardiovascular disease: a bidirectional Mendelian randomization study. J Headache Pain. 2024;25:130. Source

6. Ma YM, Zhang DP, Zhang HL, et al. Why is vestibular migraine associated with many comorbidities? J Neurol. 2024 Sept 20. Source

Neck pain is commonly associated with headaches, especially with migraine headaches. This is well recognized, and the symptom of neck pain occurring during headache episodes or even independently of headache episodes is at least partially related to pain sensitivity.¹ While neck pain is often considered a part of the migraine experience, it's not commonly thought of as a disabling symptom. However, neck pain can be a major aspect of migraine disability.

A systematic review published in August 2024 in the journal Cephalalgia described neck pain disability as a part of migraine. The authors used 33 clinic-based studies that utilized either the Neck Disability Index (NDI) or the Numeric Pain Rating Scale (NPRS) to define the severity of neck pain disability. They concluded that individuals with migraine had higher NDI and NPRS scores than patients with tension-type headaches and patients without headaches. According to the NDI scoring system, 0–4 points indicate no disability, 5–14 points indicate mild disability, 15–24 points indicate moderate disability, 25–34 points indicate severe disability, and ≥ 35 points indicate complete disability. The authors reported that the mean NDI score for patients with migraine was 16.2, which was approximately 12 points higher than for healthy headache-free control participants.² This brings to light an issue that can substantially affect patients' quality of life. Patients who have neck pain with migraine may need focused attention to that symptom, in addition to overall migraine therapy, and it is important to ask migraine patients about the degree to which neck pain affects their life. In fact, many patients might not even realize that their neck pain is associated with their migraines.

Cardiovascular disease is another comorbidity that has been inconsistently associated with migraine. A study published in Headache: The Journal of Headache and Face Pain in August 2024 used data from a Danish population-based cohort longitudinal study that included over 140,000 women. The authors reported that migraine was associated with a risk for major adverse cardiovascular and cerebrovascular events in women aged ≤ 60 years.³

This link has been noted previously, although the studies have been inconsistent regarding how strong the link is, any specific causality, and whether there is a link at all. Potential causes for the possible associations have been attributed to "endothelial dysfunction, hypercoagulability, platelet aggregation, vasospasm, cardiovascular risk factors, paradoxical embolism, spreading depolarization, shared genetic risk, use of non-steroidal anti-inflammatory drugs, and immobilization."⁴

Of note, there has also been documentation of a possible negative correlation between migraine and cardiovascular disease. Another article, from The Journal of Headache and Pain, published in August 2024, used data from 873,341 and 554,569 individuals, respectively, in two meta-analyses. The authors reported a potential protective effect of migraine on coronary artery disease and ischemic stroke, and a potential protective effect of coronary atherosclerosis and myocardial infarction on migraine.⁵

A possible explanation for the conflicting results could lie in heterogeneity of migraine. For example, vestibular migraine is associated with many comorbidities, including anxiety disorders or depressive disorders, sleep disorders, persistent postural-perceptual dizziness, and Meniere disease.⁶ Given the serious consequences of cardiovascular disease, screening for risk factors could be beneficial for preventing adverse health outcomes for migraine patients. Eventually, further research may reveal more specific correlations between comorbidities and migraine subtypes, rather than generalizing comorbidities to all migraine types.

Sources

1. Al-Khazali HM, Krøll LS, Ashina H, et al. Neck pain and headache: Pathophysiology, treatments and future directions. Musculoskelet Sci Pract. 2023;66:102804. Source

2. Al-Khazali HM, Al-Sayegh Z, Younis S, et al. Systematic review and meta-analysis of Neck Disability Index and Numeric Pain Rating Scale in patients with migraine and tension-type headache. Cephalalgia. 2024;44:3331024241274266.  Source

3. Fuglsang CH, Pedersen L, Schmidt M, Vandenbroucke JP, Bøtker HE, Sørensen HT. The combined impact of migraine and gestational diabetes on long-term risk of premature myocardial infarction and stroke: A population-based cohort study. Headache. 2024 Aug 28.  Source

4. Agostoni EC, Longoni M. Migraine and cerebrovascular disease: still a dangerous connection? Neurol Sci. 2018;39(Suppl 1):33-37.  Source

5. Duan X, Du X, Zheng G, et al. Causality between migraine and cardiovascular disease: a bidirectional Mendelian randomization study. J Headache Pain. 2024;25:130. Source

6. Ma YM, Zhang DP, Zhang HL, et al. Why is vestibular migraine associated with many comorbidities? J Neurol. 2024 Sept 20. Source

Neck pain is commonly associated with headaches, especially with migraine headaches. This is well recognized, and the symptom of neck pain occurring during headache episodes or even independently of headache episodes is at least partially related to pain sensitivity.¹ While neck pain is often considered a part of the migraine experience, it's not commonly thought of as a disabling symptom. However, neck pain can be a major aspect of migraine disability.

A systematic review published in August 2024 in the journal Cephalalgia described neck pain disability as a part of migraine. The authors used 33 clinic-based studies that utilized either the Neck Disability Index (NDI) or the Numeric Pain Rating Scale (NPRS) to define the severity of neck pain disability. They concluded that individuals with migraine had higher NDI and NPRS scores than patients with tension-type headaches and patients without headaches. According to the NDI scoring system, 0–4 points indicate no disability, 5–14 points indicate mild disability, 15–24 points indicate moderate disability, 25–34 points indicate severe disability, and ≥ 35 points indicate complete disability. The authors reported that the mean NDI score for patients with migraine was 16.2, which was approximately 12 points higher than for healthy headache-free control participants.² This brings to light an issue that can substantially affect patients' quality of life. Patients who have neck pain with migraine may need focused attention to that symptom, in addition to overall migraine therapy, and it is important to ask migraine patients about the degree to which neck pain affects their life. In fact, many patients might not even realize that their neck pain is associated with their migraines.

Cardiovascular disease is another comorbidity that has been inconsistently associated with migraine. A study published in Headache: The Journal of Headache and Face Pain in August 2024 used data from a Danish population-based cohort longitudinal study that included over 140,000 women. The authors reported that migraine was associated with a risk for major adverse cardiovascular and cerebrovascular events in women aged ≤ 60 years.³

This link has been noted previously, although the studies have been inconsistent regarding how strong the link is, any specific causality, and whether there is a link at all. Potential causes for the possible associations have been attributed to "endothelial dysfunction, hypercoagulability, platelet aggregation, vasospasm, cardiovascular risk factors, paradoxical embolism, spreading depolarization, shared genetic risk, use of non-steroidal anti-inflammatory drugs, and immobilization."⁴

Of note, there has also been documentation of a possible negative correlation between migraine and cardiovascular disease. Another article, from The Journal of Headache and Pain, published in August 2024, used data from 873,341 and 554,569 individuals, respectively, in two meta-analyses. The authors reported a potential protective effect of migraine on coronary artery disease and ischemic stroke, and a potential protective effect of coronary atherosclerosis and myocardial infarction on migraine.⁵

A possible explanation for the conflicting results could lie in heterogeneity of migraine. For example, vestibular migraine is associated with many comorbidities, including anxiety disorders or depressive disorders, sleep disorders, persistent postural-perceptual dizziness, and Meniere disease.⁶ Given the serious consequences of cardiovascular disease, screening for risk factors could be beneficial for preventing adverse health outcomes for migraine patients. Eventually, further research may reveal more specific correlations between comorbidities and migraine subtypes, rather than generalizing comorbidities to all migraine types.

Sources

1. Al-Khazali HM, Krøll LS, Ashina H, et al. Neck pain and headache: Pathophysiology, treatments and future directions. Musculoskelet Sci Pract. 2023;66:102804. Source

2. Al-Khazali HM, Al-Sayegh Z, Younis S, et al. Systematic review and meta-analysis of Neck Disability Index and Numeric Pain Rating Scale in patients with migraine and tension-type headache. Cephalalgia. 2024;44:3331024241274266.  Source

3. Fuglsang CH, Pedersen L, Schmidt M, Vandenbroucke JP, Bøtker HE, Sørensen HT. The combined impact of migraine and gestational diabetes on long-term risk of premature myocardial infarction and stroke: A population-based cohort study. Headache. 2024 Aug 28.  Source

4. Agostoni EC, Longoni M. Migraine and cerebrovascular disease: still a dangerous connection? Neurol Sci. 2018;39(Suppl 1):33-37.  Source

5. Duan X, Du X, Zheng G, et al. Causality between migraine and cardiovascular disease: a bidirectional Mendelian randomization study. J Headache Pain. 2024;25:130. Source

6. Ma YM, Zhang DP, Zhang HL, et al. Why is vestibular migraine associated with many comorbidities? J Neurol. 2024 Sept 20. Source

As we move further into the 21st century, technology continues to revolutionize various facets of our lives. Healthcare is a prime example. Advances in technology have dramatically reshaped the way we develop medications, diagnose diseases, and enhance patient care. The rise of artificial intelligence (AI) and the widespread adoption of digital health technologies have marked a significant milestone in improving the quality of care. AI, with its ability to leverage algorithms, deep learning, and machine learning to process data, make decisions, and perform tasks autonomously, is becoming an integral part of modern society. It is embedded in various technologies that we rely on daily, from smartphones and smart home devices to content recommendations on streaming services and social media platforms.

In healthcare, AI has applications in numerous fields, such as radiology. AI streamlines processes such as organizing patient appointments, optimizing radiation protocols for safety and efficiency, and enhancing the documentation process through advanced image analysis. AI technology plays an integral role in imaging tasks like image enhancement, lesion detection, and precise measurement. In difficult-to-interpret radiologic studies, such as some mammography images, it can be a crucial aid to the radiologist. Additionally, the use of AI has significantly improved remote patient monitoring that enables healthcare professionals to monitor and assess patient conditions without needing in-person visits. Remote patient monitoring gained prominence during the COVID-19 pandemic and continues to be a valuable tool in post pandemic care. Study results have highlighted that AI-driven ambient dictation tools have increased provider engagement with patients during consultations while reducing the time spent documenting in electronic health records.

Like many other medical specialties, headache medicine also uses AI. Most prominently, AI has been used in models and engines in assisting with headache diagnoses. A noteworthy example of AI in headache medicine is the development of an online, computer-based diagnostic engine (CDE) by Rapoport et al, called BonTriage. This tool is designed to diagnose headaches by employing a rule set based on the International Classification of Headache Disorders-3 (ICHD-3) criteria for primary headache disorders while also evaluating secondary headaches and medication overuse headaches. By leveraging machine learning, the CDE has the potential to streamline the diagnostic process, reducing the number of questions needed to reach a diagnosis and making the experience more efficient. This information can then be printed as a PDF file and taken by the patient to a healthcare professional for further discussion, fostering a more accurate, fluid, and conversational consultation.

A study was conducted to evaluate the accuracy of the CDE. Participants were randomly assigned to 1 of 2 sequences: (1) using the CDE followed by a structured standard interview with a headache specialist using the same ICHD-3 criteria or (2) starting with the structured standard interview followed by the CDE. The results demonstrated nearly perfect agreement in diagnosing migraine and probable migraine between the CDE and structured standard interview (κ = 0.82, 95% CI: 0.74, 0.90). The CDE demonstrated a diagnostic accuracy of 91.6% (95% CI: 86.9%, 95.0%), a sensitivity rate of 89.0% (95% CI: 82.5%, 93.7%), and a specificity rate of 97.0% (95% CI: 89.5%, 99.6%).

A diagnostic engine such as this can save time that clinicians spend on documentation and allow more time for discussion with the patient. For instance, a patient can take the printout received from the CDE to an appointment; the printout gives a detailed history plus information about social and psychological issues, a list of medications taken, and results of previous testing. The CDE system was originally designed to help patients see a specialist in the environment of a nationwide lack of headache specialists. There are currently 45 million patients with headaches who are seeking treatment with only around 550 certified headache specialists in the United States. The CDE printed information can help a patient obtain a consultation from a clinician quickly and start evaluation and treatment earlier. This expert online consultation is currently free of charge.

Kwon et al developed a machine learning–based model designed to automatically classify headache disorders using data from a questionnaire. Their model was able to predict diagnoses for conditions such as migraine, tension-type headaches, trigeminal autonomic cephalalgia, epicranial headache, and thunderclap headaches. The model was trained on data from 2162 patients, all diagnosed by headache specialists, and achieved an overall accuracy of 81%, with a sensitivity of 88% and a specificity of 95% for diagnosing migraines. However, the model’s performance was less robust when applied to other headache disorders.

Katsuki et al developed an AI model to help non specialists accurately diagnose headaches. This model analyzed 17 variables and was trained on data from 2800 patients, with additional testing and refinement using data from another 200 patients. To evaluate its effectiveness, 2 groups of non-headache specialists each assessed 50 patients: 1 group relied solely on their expertise, while the other used the AI model. The group without AI assistance achieved an overall accuracy of 46% (κ = 0.21), while the group using the AI model significantly improved, reaching an overall accuracy of 83.2% (κ = 0.68).

Building on their work with AI for diagnosing headaches, Katsuki et al conducted a study using a smartphone application that tracked user-reported headache events alongside local weather data. The AI model revealed that lower barometric pressure, higher humidity, and increased rainfall were linked to the onset of headache attacks. The application also identified triggers for headaches in specific weather patterns, such as a drop in barometric pressure noted 6 hours before headache onset. The application of AI in monitoring weather changes could be crucial, especially given concerns that the rising frequency of severe weather events due to climate change may be exacerbating the severity and burden of migraine. Additionally, recent post hoc analyses of fremanezumab clinical trials have provided further evidence that weather changes can trigger headaches.

Rapoport and colleagues have also developed an application called Migraine Mentor, which accurately tracks headaches, triggers, health data, and response to medication on a smartphone. The patient spends 3 minutes a day answering a few questions about their day and whether they had a headache or took any medication. At 1 or 2 months, Migraine Mentor can generate a detailed report with data and current trends that is sent to the patient, which the patient can then share with the clinician. The application also reminds patients when to document data and take medication.

However, although the use of AI in headache medicine appears promising, caution must be exercised to ensure proper results and information are disseminated. One rapidly expanding application of AI is the widely popular ChatGPT. ChatGPT, which stands for generative pretraining transformer, is a type of large language model (LLM). An LLM is a deep learning algorithm designed to recognize, translate, predict, summarize, and generate text responses based on a given prompt. This model is trained on an extensive dataset that includes a diverse array of books, articles, and websites, exposing it to various language structures and styles. This training enables ChatGPT to generate responses that closely mimic human communication. LLMs are being used more and more in medicine to assist with generating patient documentation and educational materials.

However, Dr Fred Cohen published a perspective piece detailing how LLMs (such as ChatGPT) can produce misleading and inaccurate answers. In his example, he tasked ChatGPT to describe the epidemiology of migraines in penguins; the AI model generated a well-written and highly believable manuscript titled, “Migraine Under the Ice: Understanding Headaches in Antarctica's Feathered Friends.” The manuscript highlights that migraines are more prevalent in male penguins compared to females, with the peak age of onset occurring between 4 and 5 years. Additionally, emperor and king penguins are identified as being more susceptible to developing migraines compared to other penguin species. The paper was fictitious (as no studies on migraine in penguins have been written to date), exemplifying that these models can produce nonfactual materials.

For years, technological advancements have been reshaping many aspects of life, and medicine is no exception. AI has been successfully applied to streamline medical documentation, develop new drug targets, and deepen our understanding of various diseases. The field of headache medicine now also uses AI. Recent developments show significant promise, with AI aiding in the diagnosis of migraine and other headache disorders. AI models have even been used in the identification of potential drug targets for migraine treatment. Although there are still limitations to overcome, the future of AI in headache medicine appears bright.

If you would like to read more about Dr. Cohen’s work on AI and migraine, please visit fredcohenmd.com or TikTok @fredcohenmd. 

As we move further into the 21st century, technology continues to revolutionize various facets of our lives. Healthcare is a prime example. Advances in technology have dramatically reshaped the way we develop medications, diagnose diseases, and enhance patient care. The rise of artificial intelligence (AI) and the widespread adoption of digital health technologies have marked a significant milestone in improving the quality of care. AI, with its ability to leverage algorithms, deep learning, and machine learning to process data, make decisions, and perform tasks autonomously, is becoming an integral part of modern society. It is embedded in various technologies that we rely on daily, from smartphones and smart home devices to content recommendations on streaming services and social media platforms.

In healthcare, AI has applications in numerous fields, such as radiology. AI streamlines processes such as organizing patient appointments, optimizing radiation protocols for safety and efficiency, and enhancing the documentation process through advanced image analysis. AI technology plays an integral role in imaging tasks like image enhancement, lesion detection, and precise measurement. In difficult-to-interpret radiologic studies, such as some mammography images, it can be a crucial aid to the radiologist. Additionally, the use of AI has significantly improved remote patient monitoring that enables healthcare professionals to monitor and assess patient conditions without needing in-person visits. Remote patient monitoring gained prominence during the COVID-19 pandemic and continues to be a valuable tool in post pandemic care. Study results have highlighted that AI-driven ambient dictation tools have increased provider engagement with patients during consultations while reducing the time spent documenting in electronic health records.

Like many other medical specialties, headache medicine also uses AI. Most prominently, AI has been used in models and engines in assisting with headache diagnoses. A noteworthy example of AI in headache medicine is the development of an online, computer-based diagnostic engine (CDE) by Rapoport et al, called BonTriage. This tool is designed to diagnose headaches by employing a rule set based on the International Classification of Headache Disorders-3 (ICHD-3) criteria for primary headache disorders while also evaluating secondary headaches and medication overuse headaches. By leveraging machine learning, the CDE has the potential to streamline the diagnostic process, reducing the number of questions needed to reach a diagnosis and making the experience more efficient. This information can then be printed as a PDF file and taken by the patient to a healthcare professional for further discussion, fostering a more accurate, fluid, and conversational consultation.

A study was conducted to evaluate the accuracy of the CDE. Participants were randomly assigned to 1 of 2 sequences: (1) using the CDE followed by a structured standard interview with a headache specialist using the same ICHD-3 criteria or (2) starting with the structured standard interview followed by the CDE. The results demonstrated nearly perfect agreement in diagnosing migraine and probable migraine between the CDE and structured standard interview (κ = 0.82, 95% CI: 0.74, 0.90). The CDE demonstrated a diagnostic accuracy of 91.6% (95% CI: 86.9%, 95.0%), a sensitivity rate of 89.0% (95% CI: 82.5%, 93.7%), and a specificity rate of 97.0% (95% CI: 89.5%, 99.6%).

A diagnostic engine such as this can save time that clinicians spend on documentation and allow more time for discussion with the patient. For instance, a patient can take the printout received from the CDE to an appointment; the printout gives a detailed history plus information about social and psychological issues, a list of medications taken, and results of previous testing. The CDE system was originally designed to help patients see a specialist in the environment of a nationwide lack of headache specialists. There are currently 45 million patients with headaches who are seeking treatment with only around 550 certified headache specialists in the United States. The CDE printed information can help a patient obtain a consultation from a clinician quickly and start evaluation and treatment earlier. This expert online consultation is currently free of charge.

Kwon et al developed a machine learning–based model designed to automatically classify headache disorders using data from a questionnaire. Their model was able to predict diagnoses for conditions such as migraine, tension-type headaches, trigeminal autonomic cephalalgia, epicranial headache, and thunderclap headaches. The model was trained on data from 2162 patients, all diagnosed by headache specialists, and achieved an overall accuracy of 81%, with a sensitivity of 88% and a specificity of 95% for diagnosing migraines. However, the model’s performance was less robust when applied to other headache disorders.

Katsuki et al developed an AI model to help non specialists accurately diagnose headaches. This model analyzed 17 variables and was trained on data from 2800 patients, with additional testing and refinement using data from another 200 patients. To evaluate its effectiveness, 2 groups of non-headache specialists each assessed 50 patients: 1 group relied solely on their expertise, while the other used the AI model. The group without AI assistance achieved an overall accuracy of 46% (κ = 0.21), while the group using the AI model significantly improved, reaching an overall accuracy of 83.2% (κ = 0.68).

Building on their work with AI for diagnosing headaches, Katsuki et al conducted a study using a smartphone application that tracked user-reported headache events alongside local weather data. The AI model revealed that lower barometric pressure, higher humidity, and increased rainfall were linked to the onset of headache attacks. The application also identified triggers for headaches in specific weather patterns, such as a drop in barometric pressure noted 6 hours before headache onset. The application of AI in monitoring weather changes could be crucial, especially given concerns that the rising frequency of severe weather events due to climate change may be exacerbating the severity and burden of migraine. Additionally, recent post hoc analyses of fremanezumab clinical trials have provided further evidence that weather changes can trigger headaches.

Rapoport and colleagues have also developed an application called Migraine Mentor, which accurately tracks headaches, triggers, health data, and response to medication on a smartphone. The patient spends 3 minutes a day answering a few questions about their day and whether they had a headache or took any medication. At 1 or 2 months, Migraine Mentor can generate a detailed report with data and current trends that is sent to the patient, which the patient can then share with the clinician. The application also reminds patients when to document data and take medication.

However, although the use of AI in headache medicine appears promising, caution must be exercised to ensure proper results and information are disseminated. One rapidly expanding application of AI is the widely popular ChatGPT. ChatGPT, which stands for generative pretraining transformer, is a type of large language model (LLM). An LLM is a deep learning algorithm designed to recognize, translate, predict, summarize, and generate text responses based on a given prompt. This model is trained on an extensive dataset that includes a diverse array of books, articles, and websites, exposing it to various language structures and styles. This training enables ChatGPT to generate responses that closely mimic human communication. LLMs are being used more and more in medicine to assist with generating patient documentation and educational materials.

However, Dr Fred Cohen published a perspective piece detailing how LLMs (such as ChatGPT) can produce misleading and inaccurate answers. In his example, he tasked ChatGPT to describe the epidemiology of migraines in penguins; the AI model generated a well-written and highly believable manuscript titled, “Migraine Under the Ice: Understanding Headaches in Antarctica's Feathered Friends.” The manuscript highlights that migraines are more prevalent in male penguins compared to females, with the peak age of onset occurring between 4 and 5 years. Additionally, emperor and king penguins are identified as being more susceptible to developing migraines compared to other penguin species. The paper was fictitious (as no studies on migraine in penguins have been written to date), exemplifying that these models can produce nonfactual materials.

For years, technological advancements have been reshaping many aspects of life, and medicine is no exception. AI has been successfully applied to streamline medical documentation, develop new drug targets, and deepen our understanding of various diseases. The field of headache medicine now also uses AI. Recent developments show significant promise, with AI aiding in the diagnosis of migraine and other headache disorders. AI models have even been used in the identification of potential drug targets for migraine treatment. Although there are still limitations to overcome, the future of AI in headache medicine appears bright.

If you would like to read more about Dr. Cohen’s work on AI and migraine, please visit fredcohenmd.com or TikTok @fredcohenmd. 

As we move further into the 21st century, technology continues to revolutionize various facets of our lives. Healthcare is a prime example. Advances in technology have dramatically reshaped the way we develop medications, diagnose diseases, and enhance patient care. The rise of artificial intelligence (AI) and the widespread adoption of digital health technologies have marked a significant milestone in improving the quality of care. AI, with its ability to leverage algorithms, deep learning, and machine learning to process data, make decisions, and perform tasks autonomously, is becoming an integral part of modern society. It is embedded in various technologies that we rely on daily, from smartphones and smart home devices to content recommendations on streaming services and social media platforms.

In healthcare, AI has applications in numerous fields, such as radiology. AI streamlines processes such as organizing patient appointments, optimizing radiation protocols for safety and efficiency, and enhancing the documentation process through advanced image analysis. AI technology plays an integral role in imaging tasks like image enhancement, lesion detection, and precise measurement. In difficult-to-interpret radiologic studies, such as some mammography images, it can be a crucial aid to the radiologist. Additionally, the use of AI has significantly improved remote patient monitoring that enables healthcare professionals to monitor and assess patient conditions without needing in-person visits. Remote patient monitoring gained prominence during the COVID-19 pandemic and continues to be a valuable tool in post pandemic care. Study results have highlighted that AI-driven ambient dictation tools have increased provider engagement with patients during consultations while reducing the time spent documenting in electronic health records.

Like many other medical specialties, headache medicine also uses AI. Most prominently, AI has been used in models and engines in assisting with headache diagnoses. A noteworthy example of AI in headache medicine is the development of an online, computer-based diagnostic engine (CDE) by Rapoport et al, called BonTriage. This tool is designed to diagnose headaches by employing a rule set based on the International Classification of Headache Disorders-3 (ICHD-3) criteria for primary headache disorders while also evaluating secondary headaches and medication overuse headaches. By leveraging machine learning, the CDE has the potential to streamline the diagnostic process, reducing the number of questions needed to reach a diagnosis and making the experience more efficient. This information can then be printed as a PDF file and taken by the patient to a healthcare professional for further discussion, fostering a more accurate, fluid, and conversational consultation.

A study was conducted to evaluate the accuracy of the CDE. Participants were randomly assigned to 1 of 2 sequences: (1) using the CDE followed by a structured standard interview with a headache specialist using the same ICHD-3 criteria or (2) starting with the structured standard interview followed by the CDE. The results demonstrated nearly perfect agreement in diagnosing migraine and probable migraine between the CDE and structured standard interview (κ = 0.82, 95% CI: 0.74, 0.90). The CDE demonstrated a diagnostic accuracy of 91.6% (95% CI: 86.9%, 95.0%), a sensitivity rate of 89.0% (95% CI: 82.5%, 93.7%), and a specificity rate of 97.0% (95% CI: 89.5%, 99.6%).

A diagnostic engine such as this can save time that clinicians spend on documentation and allow more time for discussion with the patient. For instance, a patient can take the printout received from the CDE to an appointment; the printout gives a detailed history plus information about social and psychological issues, a list of medications taken, and results of previous testing. The CDE system was originally designed to help patients see a specialist in the environment of a nationwide lack of headache specialists. There are currently 45 million patients with headaches who are seeking treatment with only around 550 certified headache specialists in the United States. The CDE printed information can help a patient obtain a consultation from a clinician quickly and start evaluation and treatment earlier. This expert online consultation is currently free of charge.

Kwon et al developed a machine learning–based model designed to automatically classify headache disorders using data from a questionnaire. Their model was able to predict diagnoses for conditions such as migraine, tension-type headaches, trigeminal autonomic cephalalgia, epicranial headache, and thunderclap headaches. The model was trained on data from 2162 patients, all diagnosed by headache specialists, and achieved an overall accuracy of 81%, with a sensitivity of 88% and a specificity of 95% for diagnosing migraines. However, the model’s performance was less robust when applied to other headache disorders.

Katsuki et al developed an AI model to help non specialists accurately diagnose headaches. This model analyzed 17 variables and was trained on data from 2800 patients, with additional testing and refinement using data from another 200 patients. To evaluate its effectiveness, 2 groups of non-headache specialists each assessed 50 patients: 1 group relied solely on their expertise, while the other used the AI model. The group without AI assistance achieved an overall accuracy of 46% (κ = 0.21), while the group using the AI model significantly improved, reaching an overall accuracy of 83.2% (κ = 0.68).

Building on their work with AI for diagnosing headaches, Katsuki et al conducted a study using a smartphone application that tracked user-reported headache events alongside local weather data. The AI model revealed that lower barometric pressure, higher humidity, and increased rainfall were linked to the onset of headache attacks. The application also identified triggers for headaches in specific weather patterns, such as a drop in barometric pressure noted 6 hours before headache onset. The application of AI in monitoring weather changes could be crucial, especially given concerns that the rising frequency of severe weather events due to climate change may be exacerbating the severity and burden of migraine. Additionally, recent post hoc analyses of fremanezumab clinical trials have provided further evidence that weather changes can trigger headaches.

Rapoport and colleagues have also developed an application called Migraine Mentor, which accurately tracks headaches, triggers, health data, and response to medication on a smartphone. The patient spends 3 minutes a day answering a few questions about their day and whether they had a headache or took any medication. At 1 or 2 months, Migraine Mentor can generate a detailed report with data and current trends that is sent to the patient, which the patient can then share with the clinician. The application also reminds patients when to document data and take medication.

However, although the use of AI in headache medicine appears promising, caution must be exercised to ensure proper results and information are disseminated. One rapidly expanding application of AI is the widely popular ChatGPT. ChatGPT, which stands for generative pretraining transformer, is a type of large language model (LLM). An LLM is a deep learning algorithm designed to recognize, translate, predict, summarize, and generate text responses based on a given prompt. This model is trained on an extensive dataset that includes a diverse array of books, articles, and websites, exposing it to various language structures and styles. This training enables ChatGPT to generate responses that closely mimic human communication. LLMs are being used more and more in medicine to assist with generating patient documentation and educational materials.

However, Dr Fred Cohen published a perspective piece detailing how LLMs (such as ChatGPT) can produce misleading and inaccurate answers. In his example, he tasked ChatGPT to describe the epidemiology of migraines in penguins; the AI model generated a well-written and highly believable manuscript titled, “Migraine Under the Ice: Understanding Headaches in Antarctica's Feathered Friends.” The manuscript highlights that migraines are more prevalent in male penguins compared to females, with the peak age of onset occurring between 4 and 5 years. Additionally, emperor and king penguins are identified as being more susceptible to developing migraines compared to other penguin species. The paper was fictitious (as no studies on migraine in penguins have been written to date), exemplifying that these models can produce nonfactual materials.

For years, technological advancements have been reshaping many aspects of life, and medicine is no exception. AI has been successfully applied to streamline medical documentation, develop new drug targets, and deepen our understanding of various diseases. The field of headache medicine now also uses AI. Recent developments show significant promise, with AI aiding in the diagnosis of migraine and other headache disorders. AI models have even been used in the identification of potential drug targets for migraine treatment. Although there are still limitations to overcome, the future of AI in headache medicine appears bright.

If you would like to read more about Dr. Cohen’s work on AI and migraine, please visit fredcohenmd.com or TikTok @fredcohenmd. 

Four triptans are more effective for acute migraine than newer, more expensive medications for this headache type, new research suggested.

Results of a large systematic review and meta-analysis showed that eletriptan, rizatriptan, sumatriptan, and zolmitriptan were more effective than lasmiditan, rimegepant, and ubrogepant, which investigators found were as effective as nonsteroidal anti-inflammatory drugs (NSAIDs).

International guidelines generally endorse NSAIDs as the first-line treatment for migraine and recommend triptans for moderate to severe episodes or when the response to NSAIDs is insufficient.

However, based on the study’s findings, these four triptans should be considered the treatment of choice for migraine, study investigator Andrea Cipriani, MD, PhD, professor of psychiatry at the University of Oxford in England and director of the Oxford Health Clinical Research Facility, told a press briefing.

The investigators added that these particular triptans should be “included in the WHO [World Health Organization] List of Essential Medicines to promote global accessibility and uniform standards of care.”

The study was published online in The BMJ.
 

Filling the Knowledge Gap

To date, almost all migraine studies have compared migraine drugs with placebo, so there’s a knowledge gap, said Dr. Cipriani. As a result, “there’s no clear consensus among experts and guidelines about which specific drug classes should be prescribed initially, and this is a clinical problem.”

The researchers pointed out that, in recent years, lasmiditan and gepants have been introduced as further treatment options, especially for patients in whom triptans are contraindicated because of their potential vasoconstrictive effects and higher risk for ischemic events.

The analysis included 137 double-blind, randomized, controlled trials that were primarily sponsored by the pharmaceutical industry. It included 89,445 adult outpatients with migraine (mean age, 40.3 years; 85.6% women).

Only drugs licensed for migraine or headache that are recommended in at least one country were included. Researchers divided these 17 drugs into five categories: Antipyretics (paracetamol), ditans (lasmiditan), gepants (rimegepant and ubrogepant), NSAIDs (acetylsalicylic acid, celecoxib, diclofenac potassium, ibuprofen, naproxen sodium, and phenazone), and triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan).

The study’s primary outcomes were freedom from pain at 2 hours and at 2-24 hours, without the use of rescue drugs.

Investigators used sumatriptan as the reference intervention because it is the most commonly prescribed migraine drug and is included in the WHO Model Lists of Essential Medicines.

The study showed all active interventions were better than placebo for pain freedom at 2 hours; with the exception of paracetamol and naratriptan, all were better for sustained pain freedom from 2 to 24 hours.

When the active interventions were compared with each other, eletriptan outperformed other drugs for achieving pain freedom at 2 hours. It was followed by rizatriptan, sumatriptan, and zolmitriptan (odds ratio [OR], 1.35-3.01). For sustained pain freedom up to 24 hours, the most efficacious interventions were eletriptan (OR, 1.41-2.73) and ibuprofen (OR, 3.16-4.82).

As for secondary efficacy outcomes, in head-to-head comparisons, eletriptan was superior to nearly all other active interventions for pain relief at 2 hours and for the use of rescue drugs.

As for adverse events, dizziness was more commonly associated with lasmiditan, eletriptan, sumatriptan, and zolmitriptan, while fatigue and sedation occurred more frequently with eletriptan and lasmiditan. Nausea was more often associated with lasmiditan, sumatriptan, zolmitriptan, and ubrogepant. Eletriptan was the only intervention most frequently associated with chest pain or discomfort.
 

Need to Update Guidelines?

Considering the new results, Dr. Cipriani and study coauthor Messoud Ashina, MD, PhD, professor of neurology, University of Copenhagen in Denmark, said clinical guidelines for acute migraine management should be updated.

While triptans are contraindicated in patients with vascular disease, the researchers noted that “cerebrovascular events may present primarily as migraine-like headaches, and misdiagnosis of transient ischemic attack and minor stroke as migraine is not rare.”

Recently, lasmiditan, rimegepant, and ubrogepant — which are not associated with vasoconstrictive effects — have been promoted as alternatives in patients for whom triptans are contraindicated or not tolerated. But the high costs of these drugs put them out of reach for some patients, the investigators noted.

Triptans are widely underutilized, Dr. Ashina noted during the press briefing. Current use ranges from 17% to 22% in the United States and from 3% to 22.5% in Europe.

The investigators said that triptans have been shown to be superior and should be promoted globally, adding that the limited access and substantial underutilization of these medications are “missed opportunities to offer more effective treatments.”

The new results underscore the importance of head-to-head trials, which is the gold standard, said Dr. Cipriani.

The investigators noted that the study’s main limitation was the quality of the data, which was deemed to be low, or very low, for most comparisons. Other potential limitations included lack of individual patient data; exclusion of combination drugs; inclusion of only oral treatments; and not considering type of oral formulation, consistency in response across migraine episodes, or cost-effectiveness.

The study also did not cover important clinical issues that might inform treatment decision-making, including drug overuse headache or potential withdrawal symptoms. And the authors were unable to quantify some outcomes, such as global functioning.
 

‘Best Profile’?

Reached for comment, Neurologist Nina Riggins, MD, PhD, Headache Center of Excellence, Palo Alto VA Medical Center in California, praised the authors for a “great job” of bringing attention to the topic.

However, she noted that the investigators’ characterization of the four triptans as having the “best profile” for acute migraine gave her pause.

“Calling triptans the medication with the ‘best profile’ might be not applicable in many cases,” she said. For example, those who need acute medication more than two to three times a week in addition to those with cardiovascular contraindications to triptans may fall outside of that category.

Dr. Riggins said that “it makes sense” that longer-acting triptans like frovatriptan and naratriptan may not rank highly for efficacy within the first 2 hours. However, these agents likely offer a superior therapeutic profile in specific contexts, such as menstrual-related migraine.

In addition, while triptans are known to cause medication overuse headache, this may not be the case with gepants, she noted.

In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Eloísa Rubio-Beltrán, PhD, research associate with The Migraine Trust at the Wolfson Sensory, Pain and Regeneration Centre, King’s College London in England, said the findings should affect migraine treatment guidelines.

“As the study highlights, due to their high efficacy and low cost, triptans should be the first-line treatment option for the acute treatment of migraine. These results should inform treatment guidelines and support the inclusion of the best performing triptans into the List of Essential Medicines, to optimize treatment, allowing patients to access more efficacious options,” said Dr. Rubio-Beltrán.

It is also important to note that gepants and ditans were developed to offer alternatives for patients who show no improvement from triptans, she added.

She pointed out that these medications were not developed as a substitute for triptans, but rather to expand the number of treatment options for migraine.

“Nonetheless,” she added, “this study highlights the need for further research on the pathophysiology of migraine, which will allow the discovery of novel targets, and thus, novel treatments options that will benefit all patient populations.”

The study was funded by the NIHR Oxford Health Biomedical Research Centre and the Lundbeck Foundation. Dr. Cipriani reported receiving research, educational, and consultancy fees from Italian Network for Pediatric Clinical Trials, Fondazione Cariplo, Lundbeck, and Angelini Pharma. Dr. Ashina is a consultant, speaker, or scientific adviser for AbbVie, Amgen, AstraZeneca, Eli Lilly, GSK, Lundbeck, Novartis, Pfizer, and Teva; is the past president of the International Headache Society; and an associate editor of The Journal of Headache and Pain and Brain. Dr. Riggins has consulted for Gerson Lehrman Group; participated in compensated work with AcademicCME and Association of Migraine Disorders; was a principal investigator on research with electroCore, Theranica, and Eli Lilly; serves on advisory boards for Theranica, Teva, Lundbeck, Amneal Pharmaceuticals, NeurologyLive, and Miles for Migraine; and is a project advisor for Clinical Awareness Initiative with Clinical Neurological Society of America. Dr. Rubio-Beltrán reported serving as a junior editorial board member of The Journal of Headache and Pain and a junior representative of the International Headache Society; receiving research support from The Migraine Trust, Eli Lilly, CoLucid Pharmaceuticals, Amgen, Novartis, and Kallyope; and receiving travel support from CoLucid Pharmaceuticals, Allergan, and Novartis.

A version of this article first appeared on Medscape.com.

Four triptans are more effective for acute migraine than newer, more expensive medications for this headache type, new research suggested.

Results of a large systematic review and meta-analysis showed that eletriptan, rizatriptan, sumatriptan, and zolmitriptan were more effective than lasmiditan, rimegepant, and ubrogepant, which investigators found were as effective as nonsteroidal anti-inflammatory drugs (NSAIDs).

International guidelines generally endorse NSAIDs as the first-line treatment for migraine and recommend triptans for moderate to severe episodes or when the response to NSAIDs is insufficient.

However, based on the study’s findings, these four triptans should be considered the treatment of choice for migraine, study investigator Andrea Cipriani, MD, PhD, professor of psychiatry at the University of Oxford in England and director of the Oxford Health Clinical Research Facility, told a press briefing.

The investigators added that these particular triptans should be “included in the WHO [World Health Organization] List of Essential Medicines to promote global accessibility and uniform standards of care.”

The study was published online in The BMJ.
 

Filling the Knowledge Gap

To date, almost all migraine studies have compared migraine drugs with placebo, so there’s a knowledge gap, said Dr. Cipriani. As a result, “there’s no clear consensus among experts and guidelines about which specific drug classes should be prescribed initially, and this is a clinical problem.”

The researchers pointed out that, in recent years, lasmiditan and gepants have been introduced as further treatment options, especially for patients in whom triptans are contraindicated because of their potential vasoconstrictive effects and higher risk for ischemic events.

The analysis included 137 double-blind, randomized, controlled trials that were primarily sponsored by the pharmaceutical industry. It included 89,445 adult outpatients with migraine (mean age, 40.3 years; 85.6% women).

Only drugs licensed for migraine or headache that are recommended in at least one country were included. Researchers divided these 17 drugs into five categories: Antipyretics (paracetamol), ditans (lasmiditan), gepants (rimegepant and ubrogepant), NSAIDs (acetylsalicylic acid, celecoxib, diclofenac potassium, ibuprofen, naproxen sodium, and phenazone), and triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan).

The study’s primary outcomes were freedom from pain at 2 hours and at 2-24 hours, without the use of rescue drugs.

Investigators used sumatriptan as the reference intervention because it is the most commonly prescribed migraine drug and is included in the WHO Model Lists of Essential Medicines.

The study showed all active interventions were better than placebo for pain freedom at 2 hours; with the exception of paracetamol and naratriptan, all were better for sustained pain freedom from 2 to 24 hours.

When the active interventions were compared with each other, eletriptan outperformed other drugs for achieving pain freedom at 2 hours. It was followed by rizatriptan, sumatriptan, and zolmitriptan (odds ratio [OR], 1.35-3.01). For sustained pain freedom up to 24 hours, the most efficacious interventions were eletriptan (OR, 1.41-2.73) and ibuprofen (OR, 3.16-4.82).

As for secondary efficacy outcomes, in head-to-head comparisons, eletriptan was superior to nearly all other active interventions for pain relief at 2 hours and for the use of rescue drugs.

As for adverse events, dizziness was more commonly associated with lasmiditan, eletriptan, sumatriptan, and zolmitriptan, while fatigue and sedation occurred more frequently with eletriptan and lasmiditan. Nausea was more often associated with lasmiditan, sumatriptan, zolmitriptan, and ubrogepant. Eletriptan was the only intervention most frequently associated with chest pain or discomfort.
 

Need to Update Guidelines?

Considering the new results, Dr. Cipriani and study coauthor Messoud Ashina, MD, PhD, professor of neurology, University of Copenhagen in Denmark, said clinical guidelines for acute migraine management should be updated.

While triptans are contraindicated in patients with vascular disease, the researchers noted that “cerebrovascular events may present primarily as migraine-like headaches, and misdiagnosis of transient ischemic attack and minor stroke as migraine is not rare.”

Recently, lasmiditan, rimegepant, and ubrogepant — which are not associated with vasoconstrictive effects — have been promoted as alternatives in patients for whom triptans are contraindicated or not tolerated. But the high costs of these drugs put them out of reach for some patients, the investigators noted.

Triptans are widely underutilized, Dr. Ashina noted during the press briefing. Current use ranges from 17% to 22% in the United States and from 3% to 22.5% in Europe.

The investigators said that triptans have been shown to be superior and should be promoted globally, adding that the limited access and substantial underutilization of these medications are “missed opportunities to offer more effective treatments.”

The new results underscore the importance of head-to-head trials, which is the gold standard, said Dr. Cipriani.

The investigators noted that the study’s main limitation was the quality of the data, which was deemed to be low, or very low, for most comparisons. Other potential limitations included lack of individual patient data; exclusion of combination drugs; inclusion of only oral treatments; and not considering type of oral formulation, consistency in response across migraine episodes, or cost-effectiveness.

The study also did not cover important clinical issues that might inform treatment decision-making, including drug overuse headache or potential withdrawal symptoms. And the authors were unable to quantify some outcomes, such as global functioning.
 

‘Best Profile’?

Reached for comment, Neurologist Nina Riggins, MD, PhD, Headache Center of Excellence, Palo Alto VA Medical Center in California, praised the authors for a “great job” of bringing attention to the topic.

However, she noted that the investigators’ characterization of the four triptans as having the “best profile” for acute migraine gave her pause.

“Calling triptans the medication with the ‘best profile’ might be not applicable in many cases,” she said. For example, those who need acute medication more than two to three times a week in addition to those with cardiovascular contraindications to triptans may fall outside of that category.

Dr. Riggins said that “it makes sense” that longer-acting triptans like frovatriptan and naratriptan may not rank highly for efficacy within the first 2 hours. However, these agents likely offer a superior therapeutic profile in specific contexts, such as menstrual-related migraine.

In addition, while triptans are known to cause medication overuse headache, this may not be the case with gepants, she noted.

In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Eloísa Rubio-Beltrán, PhD, research associate with The Migraine Trust at the Wolfson Sensory, Pain and Regeneration Centre, King’s College London in England, said the findings should affect migraine treatment guidelines.

“As the study highlights, due to their high efficacy and low cost, triptans should be the first-line treatment option for the acute treatment of migraine. These results should inform treatment guidelines and support the inclusion of the best performing triptans into the List of Essential Medicines, to optimize treatment, allowing patients to access more efficacious options,” said Dr. Rubio-Beltrán.

It is also important to note that gepants and ditans were developed to offer alternatives for patients who show no improvement from triptans, she added.

She pointed out that these medications were not developed as a substitute for triptans, but rather to expand the number of treatment options for migraine.

“Nonetheless,” she added, “this study highlights the need for further research on the pathophysiology of migraine, which will allow the discovery of novel targets, and thus, novel treatments options that will benefit all patient populations.”

The study was funded by the NIHR Oxford Health Biomedical Research Centre and the Lundbeck Foundation. Dr. Cipriani reported receiving research, educational, and consultancy fees from Italian Network for Pediatric Clinical Trials, Fondazione Cariplo, Lundbeck, and Angelini Pharma. Dr. Ashina is a consultant, speaker, or scientific adviser for AbbVie, Amgen, AstraZeneca, Eli Lilly, GSK, Lundbeck, Novartis, Pfizer, and Teva; is the past president of the International Headache Society; and an associate editor of The Journal of Headache and Pain and Brain. Dr. Riggins has consulted for Gerson Lehrman Group; participated in compensated work with AcademicCME and Association of Migraine Disorders; was a principal investigator on research with electroCore, Theranica, and Eli Lilly; serves on advisory boards for Theranica, Teva, Lundbeck, Amneal Pharmaceuticals, NeurologyLive, and Miles for Migraine; and is a project advisor for Clinical Awareness Initiative with Clinical Neurological Society of America. Dr. Rubio-Beltrán reported serving as a junior editorial board member of The Journal of Headache and Pain and a junior representative of the International Headache Society; receiving research support from The Migraine Trust, Eli Lilly, CoLucid Pharmaceuticals, Amgen, Novartis, and Kallyope; and receiving travel support from CoLucid Pharmaceuticals, Allergan, and Novartis.

A version of this article first appeared on Medscape.com.

Four triptans are more effective for acute migraine than newer, more expensive medications for this headache type, new research suggested.

Results of a large systematic review and meta-analysis showed that eletriptan, rizatriptan, sumatriptan, and zolmitriptan were more effective than lasmiditan, rimegepant, and ubrogepant, which investigators found were as effective as nonsteroidal anti-inflammatory drugs (NSAIDs).

International guidelines generally endorse NSAIDs as the first-line treatment for migraine and recommend triptans for moderate to severe episodes or when the response to NSAIDs is insufficient.

However, based on the study’s findings, these four triptans should be considered the treatment of choice for migraine, study investigator Andrea Cipriani, MD, PhD, professor of psychiatry at the University of Oxford in England and director of the Oxford Health Clinical Research Facility, told a press briefing.

The investigators added that these particular triptans should be “included in the WHO [World Health Organization] List of Essential Medicines to promote global accessibility and uniform standards of care.”

The study was published online in The BMJ.
 

Filling the Knowledge Gap

To date, almost all migraine studies have compared migraine drugs with placebo, so there’s a knowledge gap, said Dr. Cipriani. As a result, “there’s no clear consensus among experts and guidelines about which specific drug classes should be prescribed initially, and this is a clinical problem.”

The researchers pointed out that, in recent years, lasmiditan and gepants have been introduced as further treatment options, especially for patients in whom triptans are contraindicated because of their potential vasoconstrictive effects and higher risk for ischemic events.

The analysis included 137 double-blind, randomized, controlled trials that were primarily sponsored by the pharmaceutical industry. It included 89,445 adult outpatients with migraine (mean age, 40.3 years; 85.6% women).

Only drugs licensed for migraine or headache that are recommended in at least one country were included. Researchers divided these 17 drugs into five categories: Antipyretics (paracetamol), ditans (lasmiditan), gepants (rimegepant and ubrogepant), NSAIDs (acetylsalicylic acid, celecoxib, diclofenac potassium, ibuprofen, naproxen sodium, and phenazone), and triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan).

The study’s primary outcomes were freedom from pain at 2 hours and at 2-24 hours, without the use of rescue drugs.

Investigators used sumatriptan as the reference intervention because it is the most commonly prescribed migraine drug and is included in the WHO Model Lists of Essential Medicines.

The study showed all active interventions were better than placebo for pain freedom at 2 hours; with the exception of paracetamol and naratriptan, all were better for sustained pain freedom from 2 to 24 hours.

When the active interventions were compared with each other, eletriptan outperformed other drugs for achieving pain freedom at 2 hours. It was followed by rizatriptan, sumatriptan, and zolmitriptan (odds ratio [OR], 1.35-3.01). For sustained pain freedom up to 24 hours, the most efficacious interventions were eletriptan (OR, 1.41-2.73) and ibuprofen (OR, 3.16-4.82).

As for secondary efficacy outcomes, in head-to-head comparisons, eletriptan was superior to nearly all other active interventions for pain relief at 2 hours and for the use of rescue drugs.

As for adverse events, dizziness was more commonly associated with lasmiditan, eletriptan, sumatriptan, and zolmitriptan, while fatigue and sedation occurred more frequently with eletriptan and lasmiditan. Nausea was more often associated with lasmiditan, sumatriptan, zolmitriptan, and ubrogepant. Eletriptan was the only intervention most frequently associated with chest pain or discomfort.
 

Need to Update Guidelines?

Considering the new results, Dr. Cipriani and study coauthor Messoud Ashina, MD, PhD, professor of neurology, University of Copenhagen in Denmark, said clinical guidelines for acute migraine management should be updated.

While triptans are contraindicated in patients with vascular disease, the researchers noted that “cerebrovascular events may present primarily as migraine-like headaches, and misdiagnosis of transient ischemic attack and minor stroke as migraine is not rare.”

Recently, lasmiditan, rimegepant, and ubrogepant — which are not associated with vasoconstrictive effects — have been promoted as alternatives in patients for whom triptans are contraindicated or not tolerated. But the high costs of these drugs put them out of reach for some patients, the investigators noted.

Triptans are widely underutilized, Dr. Ashina noted during the press briefing. Current use ranges from 17% to 22% in the United States and from 3% to 22.5% in Europe.

The investigators said that triptans have been shown to be superior and should be promoted globally, adding that the limited access and substantial underutilization of these medications are “missed opportunities to offer more effective treatments.”

The new results underscore the importance of head-to-head trials, which is the gold standard, said Dr. Cipriani.

The investigators noted that the study’s main limitation was the quality of the data, which was deemed to be low, or very low, for most comparisons. Other potential limitations included lack of individual patient data; exclusion of combination drugs; inclusion of only oral treatments; and not considering type of oral formulation, consistency in response across migraine episodes, or cost-effectiveness.

The study also did not cover important clinical issues that might inform treatment decision-making, including drug overuse headache or potential withdrawal symptoms. And the authors were unable to quantify some outcomes, such as global functioning.
 

‘Best Profile’?

Reached for comment, Neurologist Nina Riggins, MD, PhD, Headache Center of Excellence, Palo Alto VA Medical Center in California, praised the authors for a “great job” of bringing attention to the topic.

However, she noted that the investigators’ characterization of the four triptans as having the “best profile” for acute migraine gave her pause.

“Calling triptans the medication with the ‘best profile’ might be not applicable in many cases,” she said. For example, those who need acute medication more than two to three times a week in addition to those with cardiovascular contraindications to triptans may fall outside of that category.

Dr. Riggins said that “it makes sense” that longer-acting triptans like frovatriptan and naratriptan may not rank highly for efficacy within the first 2 hours. However, these agents likely offer a superior therapeutic profile in specific contexts, such as menstrual-related migraine.

In addition, while triptans are known to cause medication overuse headache, this may not be the case with gepants, she noted.

In a release from the Science Media Center, a nonprofit organization promoting voices and views of the scientific community, Eloísa Rubio-Beltrán, PhD, research associate with The Migraine Trust at the Wolfson Sensory, Pain and Regeneration Centre, King’s College London in England, said the findings should affect migraine treatment guidelines.

“As the study highlights, due to their high efficacy and low cost, triptans should be the first-line treatment option for the acute treatment of migraine. These results should inform treatment guidelines and support the inclusion of the best performing triptans into the List of Essential Medicines, to optimize treatment, allowing patients to access more efficacious options,” said Dr. Rubio-Beltrán.

It is also important to note that gepants and ditans were developed to offer alternatives for patients who show no improvement from triptans, she added.

She pointed out that these medications were not developed as a substitute for triptans, but rather to expand the number of treatment options for migraine.

“Nonetheless,” she added, “this study highlights the need for further research on the pathophysiology of migraine, which will allow the discovery of novel targets, and thus, novel treatments options that will benefit all patient populations.”

The study was funded by the NIHR Oxford Health Biomedical Research Centre and the Lundbeck Foundation. Dr. Cipriani reported receiving research, educational, and consultancy fees from Italian Network for Pediatric Clinical Trials, Fondazione Cariplo, Lundbeck, and Angelini Pharma. Dr. Ashina is a consultant, speaker, or scientific adviser for AbbVie, Amgen, AstraZeneca, Eli Lilly, GSK, Lundbeck, Novartis, Pfizer, and Teva; is the past president of the International Headache Society; and an associate editor of The Journal of Headache and Pain and Brain. Dr. Riggins has consulted for Gerson Lehrman Group; participated in compensated work with AcademicCME and Association of Migraine Disorders; was a principal investigator on research with electroCore, Theranica, and Eli Lilly; serves on advisory boards for Theranica, Teva, Lundbeck, Amneal Pharmaceuticals, NeurologyLive, and Miles for Migraine; and is a project advisor for Clinical Awareness Initiative with Clinical Neurological Society of America. Dr. Rubio-Beltrán reported serving as a junior editorial board member of The Journal of Headache and Pain and a junior representative of the International Headache Society; receiving research support from The Migraine Trust, Eli Lilly, CoLucid Pharmaceuticals, Amgen, Novartis, and Kallyope; and receiving travel support from CoLucid Pharmaceuticals, Allergan, and Novartis.

A version of this article first appeared on Medscape.com.

Key clinical point: Although valsartan is not typically used for migraine treatment, it was found to reduce migraine frequency and severity as effectively as propranolol, and in some instances, more effectively.

Major findings: Valsartan vs propranolol significantly reduced the mean score of migraine frequency and severity (1.82 vs 2.39; P = .042), and a lower rate of grade 3 headaches (0% vs 7.14%; P = .029) and a lower Headache Index score (1.41 vs 3.22; P = .048) in patients with migraine. Conversely, propranolol was more effective than valsartan in lowering the Headache Unit Index score (0.06 vs 0.13; P = .025).

Study details: This double-blind trial included 56 adult patients with migraine who were randomly assigned to receive propranolol (20 mg twice daily) or valsartan (40 mg once daily) for 12 weeks.

Disclosure: This study was supported by a grant from Urmia University of Medical Sciences. The authors declared no conflicts of interest.

Source: Mosarrezaii A, Tahazadeh D, Soleimantabar H, Panahi P. Comparison of the efficacy of propranolol versus valsartan in the prevention of migraine: A randomized controlled trial. Pain Manag Nurs. 2024 (Aug 13). doi: 10.1016/j.pmn.2024.07.001 Source

Key clinical point: Although valsartan is not typically used for migraine treatment, it was found to reduce migraine frequency and severity as effectively as propranolol, and in some instances, more effectively.

Major findings: Valsartan vs propranolol significantly reduced the mean score of migraine frequency and severity (1.82 vs 2.39; P = .042), and a lower rate of grade 3 headaches (0% vs 7.14%; P = .029) and a lower Headache Index score (1.41 vs 3.22; P = .048) in patients with migraine. Conversely, propranolol was more effective than valsartan in lowering the Headache Unit Index score (0.06 vs 0.13; P = .025).

Study details: This double-blind trial included 56 adult patients with migraine who were randomly assigned to receive propranolol (20 mg twice daily) or valsartan (40 mg once daily) for 12 weeks.

Disclosure: This study was supported by a grant from Urmia University of Medical Sciences. The authors declared no conflicts of interest.

Source: Mosarrezaii A, Tahazadeh D, Soleimantabar H, Panahi P. Comparison of the efficacy of propranolol versus valsartan in the prevention of migraine: A randomized controlled trial. Pain Manag Nurs. 2024 (Aug 13). doi: 10.1016/j.pmn.2024.07.001 Source

Key clinical point: Although valsartan is not typically used for migraine treatment, it was found to reduce migraine frequency and severity as effectively as propranolol, and in some instances, more effectively.

Major findings: Valsartan vs propranolol significantly reduced the mean score of migraine frequency and severity (1.82 vs 2.39; P = .042), and a lower rate of grade 3 headaches (0% vs 7.14%; P = .029) and a lower Headache Index score (1.41 vs 3.22; P = .048) in patients with migraine. Conversely, propranolol was more effective than valsartan in lowering the Headache Unit Index score (0.06 vs 0.13; P = .025).

Study details: This double-blind trial included 56 adult patients with migraine who were randomly assigned to receive propranolol (20 mg twice daily) or valsartan (40 mg once daily) for 12 weeks.

Disclosure: This study was supported by a grant from Urmia University of Medical Sciences. The authors declared no conflicts of interest.

Source: Mosarrezaii A, Tahazadeh D, Soleimantabar H, Panahi P. Comparison of the efficacy of propranolol versus valsartan in the prevention of migraine: A randomized controlled trial. Pain Manag Nurs. 2024 (Aug 13). doi: 10.1016/j.pmn.2024.07.001 Source

Key clinical point: Migraine may have a protective effect against some cardiovascular diseases, such as coronary artery disease (CAD) and ischemic stroke, in this Mendelian randomization (MR) analysis, with coronary atherosclerosis (CA) and myocardial infarction (MI), reducing the risk for migraine in reverse MR analysis.

Major findings: Genetically predicted risk of migraine was associated with a lower risk for CAD (odds ratio [OR] 0.881; P = .023) and ischemic stroke (OR 0.912; P = .006). Reciprocally, CA (OR 0.865; P = .001) and MI (OR 0.798; P = .012) were associated with a lower risk for migraine.

Study details: This bidirectional MR study analyzed the causal effect of migraine on CVD using data from 873,341 and 554,569 individuals, and the causal effect of CVD on migraine using data from 484,598 and 463,010 individuals, using large-scale Genome-Wide Association Study databases.

Disclosure: The study was supported by the National Natural Science Foundation of China, and others. The authors reported no conflicts of interest.

Source: Duan X, Du X, Zheng G, et al. Causality between migraine and cardiovascular disease: A bidirectional Mendelian randomization study. J Headache Pain. 2024;25:130 (Aug 13). doi: 10.1186/s10194-024-01836-w Source

Key clinical point: Migraine may have a protective effect against some cardiovascular diseases, such as coronary artery disease (CAD) and ischemic stroke, in this Mendelian randomization (MR) analysis, with coronary atherosclerosis (CA) and myocardial infarction (MI), reducing the risk for migraine in reverse MR analysis.

Major findings: Genetically predicted risk of migraine was associated with a lower risk for CAD (odds ratio [OR] 0.881; P = .023) and ischemic stroke (OR 0.912; P = .006). Reciprocally, CA (OR 0.865; P = .001) and MI (OR 0.798; P = .012) were associated with a lower risk for migraine.

Study details: This bidirectional MR study analyzed the causal effect of migraine on CVD using data from 873,341 and 554,569 individuals, and the causal effect of CVD on migraine using data from 484,598 and 463,010 individuals, using large-scale Genome-Wide Association Study databases.

Disclosure: The study was supported by the National Natural Science Foundation of China, and others. The authors reported no conflicts of interest.

Source: Duan X, Du X, Zheng G, et al. Causality between migraine and cardiovascular disease: A bidirectional Mendelian randomization study. J Headache Pain. 2024;25:130 (Aug 13). doi: 10.1186/s10194-024-01836-w Source

Key clinical point: Migraine may have a protective effect against some cardiovascular diseases, such as coronary artery disease (CAD) and ischemic stroke, in this Mendelian randomization (MR) analysis, with coronary atherosclerosis (CA) and myocardial infarction (MI), reducing the risk for migraine in reverse MR analysis.

Major findings: Genetically predicted risk of migraine was associated with a lower risk for CAD (odds ratio [OR] 0.881; P = .023) and ischemic stroke (OR 0.912; P = .006). Reciprocally, CA (OR 0.865; P = .001) and MI (OR 0.798; P = .012) were associated with a lower risk for migraine.

Study details: This bidirectional MR study analyzed the causal effect of migraine on CVD using data from 873,341 and 554,569 individuals, and the causal effect of CVD on migraine using data from 484,598 and 463,010 individuals, using large-scale Genome-Wide Association Study databases.

Disclosure: The study was supported by the National Natural Science Foundation of China, and others. The authors reported no conflicts of interest.

Source: Duan X, Du X, Zheng G, et al. Causality between migraine and cardiovascular disease: A bidirectional Mendelian randomization study. J Headache Pain. 2024;25:130 (Aug 13). doi: 10.1186/s10194-024-01836-w Source

Key clinical point: Administration of monthly or quarterly fremanezumab reduced acute medication use and alleviated migraine-associated symptoms in patients with episodic migraine (EM).

Major findings: Fremanezumab, administered monthly vs placebo significantly reduced the acute medication use for headaches (–2.98 vs –0.01; P < .001) and number of days with nausea or vomiting (–1.59 vs –0.66; P = .023) in the first month after initial dosage, with continued benefits till months 2 and 3. Fremanezumab, administered quarterly, also yielded promising outcomes.

Study details: Findings are from an exploratory endpoint analysis of a phase 2b/3 randomized trial including patients with EM who were randomly assigned to receive either monthly fremanezumab (n =  121), quarterly fremanezumab (n =  119), or placebo (n =  117) in monthly intervals.

Disclosures: This study was funded by Otsuka Pharmaceutical Co., Ltd. Five authors declared being full-time employees of Otsuka Pharmaceutical Co., Ltd. Other authors declared having other ties with various sources, including Otsuka Pharmaceutical Co., Ltd.

Source: Tatsumoto M, Ishida M, Iba K, et al. Effects of fremanezumab on migraine-associated symptoms and medication use in Japanese and Korean patients with episodic migraine: Exploratory endpoint analysis of a multicenter, randomized, double-blind, placebo-controlled trial. Headache. 2024 (Sept 2). doi: 10.1111/head.14810 Source

Key clinical point: Administration of monthly or quarterly fremanezumab reduced acute medication use and alleviated migraine-associated symptoms in patients with episodic migraine (EM).

Major findings: Fremanezumab, administered monthly vs placebo significantly reduced the acute medication use for headaches (–2.98 vs –0.01; P < .001) and number of days with nausea or vomiting (–1.59 vs –0.66; P = .023) in the first month after initial dosage, with continued benefits till months 2 and 3. Fremanezumab, administered quarterly, also yielded promising outcomes.

Study details: Findings are from an exploratory endpoint analysis of a phase 2b/3 randomized trial including patients with EM who were randomly assigned to receive either monthly fremanezumab (n =  121), quarterly fremanezumab (n =  119), or placebo (n =  117) in monthly intervals.

Disclosures: This study was funded by Otsuka Pharmaceutical Co., Ltd. Five authors declared being full-time employees of Otsuka Pharmaceutical Co., Ltd. Other authors declared having other ties with various sources, including Otsuka Pharmaceutical Co., Ltd.

Source: Tatsumoto M, Ishida M, Iba K, et al. Effects of fremanezumab on migraine-associated symptoms and medication use in Japanese and Korean patients with episodic migraine: Exploratory endpoint analysis of a multicenter, randomized, double-blind, placebo-controlled trial. Headache. 2024 (Sept 2). doi: 10.1111/head.14810 Source

Key clinical point: Administration of monthly or quarterly fremanezumab reduced acute medication use and alleviated migraine-associated symptoms in patients with episodic migraine (EM).

Major findings: Fremanezumab, administered monthly vs placebo significantly reduced the acute medication use for headaches (–2.98 vs –0.01; P < .001) and number of days with nausea or vomiting (–1.59 vs –0.66; P = .023) in the first month after initial dosage, with continued benefits till months 2 and 3. Fremanezumab, administered quarterly, also yielded promising outcomes.

Study details: Findings are from an exploratory endpoint analysis of a phase 2b/3 randomized trial including patients with EM who were randomly assigned to receive either monthly fremanezumab (n =  121), quarterly fremanezumab (n =  119), or placebo (n =  117) in monthly intervals.

Disclosures: This study was funded by Otsuka Pharmaceutical Co., Ltd. Five authors declared being full-time employees of Otsuka Pharmaceutical Co., Ltd. Other authors declared having other ties with various sources, including Otsuka Pharmaceutical Co., Ltd.

Source: Tatsumoto M, Ishida M, Iba K, et al. Effects of fremanezumab on migraine-associated symptoms and medication use in Japanese and Korean patients with episodic migraine: Exploratory endpoint analysis of a multicenter, randomized, double-blind, placebo-controlled trial. Headache. 2024 (Sept 2). doi: 10.1111/head.14810 Source

Key clinical point: Eicosapentaenoic acid (EPA), used with standard prophylactic pharmacotherapy, significantly reduced migraine headache days (MHD) and migraine attacks in patients with chronic migraine (CM).

Major findings: The score relating to headache impact was significantly lower in the EPA vs placebo group at weeks 4 (P = .017) and 8 (P = .042). At 8 weeks, EPA treatment led to a greater reduction in mean MHD (−9.76 vs −4.60; P < .001) and mean number of attacks per month (3 vs 4; P = .012) than placebo. In the EPA group, only three patients experienced nausea and gastrointestinal upset.

Study details: This randomized controlled trial included 60 adult patients with CM who received 1000 mg EPA or placebo twice daily for 8 weeks and continued their first-line preventive pharmacotherapy throughout the trial.

Disclosure: The study was supported by the research committee of Shahid Beheshti University of Medical Sciences, Iran. The authors declared no conflicts of interest.

Source: Mohammadnezhad G, Assarzadegan F, Koosha M, Esmaily H. Eicosapentaenoic acid versus placebo as adjunctive therapy in chronic migraine: A randomized controlled trial. Headache. 2024 (Sept 2). doi: 10.1111/head.14808  Source

Key clinical point: Eicosapentaenoic acid (EPA), used with standard prophylactic pharmacotherapy, significantly reduced migraine headache days (MHD) and migraine attacks in patients with chronic migraine (CM).

Major findings: The score relating to headache impact was significantly lower in the EPA vs placebo group at weeks 4 (P = .017) and 8 (P = .042). At 8 weeks, EPA treatment led to a greater reduction in mean MHD (−9.76 vs −4.60; P < .001) and mean number of attacks per month (3 vs 4; P = .012) than placebo. In the EPA group, only three patients experienced nausea and gastrointestinal upset.

Study details: This randomized controlled trial included 60 adult patients with CM who received 1000 mg EPA or placebo twice daily for 8 weeks and continued their first-line preventive pharmacotherapy throughout the trial.

Disclosure: The study was supported by the research committee of Shahid Beheshti University of Medical Sciences, Iran. The authors declared no conflicts of interest.

Source: Mohammadnezhad G, Assarzadegan F, Koosha M, Esmaily H. Eicosapentaenoic acid versus placebo as adjunctive therapy in chronic migraine: A randomized controlled trial. Headache. 2024 (Sept 2). doi: 10.1111/head.14808  Source

Key clinical point: Eicosapentaenoic acid (EPA), used with standard prophylactic pharmacotherapy, significantly reduced migraine headache days (MHD) and migraine attacks in patients with chronic migraine (CM).

Major findings: The score relating to headache impact was significantly lower in the EPA vs placebo group at weeks 4 (P = .017) and 8 (P = .042). At 8 weeks, EPA treatment led to a greater reduction in mean MHD (−9.76 vs −4.60; P < .001) and mean number of attacks per month (3 vs 4; P = .012) than placebo. In the EPA group, only three patients experienced nausea and gastrointestinal upset.

Study details: This randomized controlled trial included 60 adult patients with CM who received 1000 mg EPA or placebo twice daily for 8 weeks and continued their first-line preventive pharmacotherapy throughout the trial.

Disclosure: The study was supported by the research committee of Shahid Beheshti University of Medical Sciences, Iran. The authors declared no conflicts of interest.

Source: Mohammadnezhad G, Assarzadegan F, Koosha M, Esmaily H. Eicosapentaenoic acid versus placebo as adjunctive therapy in chronic migraine: A randomized controlled trial. Headache. 2024 (Sept 2). doi: 10.1111/head.14808  Source

Key clinical point: Zavegepant nasal spray, administered as needed for up to eight doses per month, demonstrated long-term safety in the acute treatment of migraine over 1 year.

Major finding: The most common adverse events (AE), reported in ≥5% patients receiving zavegepant, were dysgeusia, nasal discomfort, COVID-19, nausea, nasal congestion, throat irritation, and back pain. In the 1-year period, only 6.8% patients discontinued treatment due to AE; dysgeusia was the most common cause, accounting for 1.5% of discontinuations. No deaths were reported.

Study details: This phase 2/3, open-label safety study included 603 adults with moderate to severe migraine who had a history of 2 to 8 moderate to severe attacks per month and were treated with intranasal 10 mg zavegepant daily for 1 year.

Disclosures: This study was funded by Biohaven Pharmaceuticals. Some authors declared being employees of or holding stocks of or stock options in Biohaven Pharmaceuticals. Some others declared having ties with various sources, including Biohaven Pharmaceuticals.

Source: Mullin K, Croop R, Mosher L, et al. Long-term safety of zavegepant nasal spray for acute treatment of migraine: A phase 2/3 open-label study. Cephalalgia. 2024 (Aug 30). doi: 10.1177/033310242412594 Source

Key clinical point: Zavegepant nasal spray, administered as needed for up to eight doses per month, demonstrated long-term safety in the acute treatment of migraine over 1 year.

Major finding: The most common adverse events (AE), reported in ≥5% patients receiving zavegepant, were dysgeusia, nasal discomfort, COVID-19, nausea, nasal congestion, throat irritation, and back pain. In the 1-year period, only 6.8% patients discontinued treatment due to AE; dysgeusia was the most common cause, accounting for 1.5% of discontinuations. No deaths were reported.

Study details: This phase 2/3, open-label safety study included 603 adults with moderate to severe migraine who had a history of 2 to 8 moderate to severe attacks per month and were treated with intranasal 10 mg zavegepant daily for 1 year.

Disclosures: This study was funded by Biohaven Pharmaceuticals. Some authors declared being employees of or holding stocks of or stock options in Biohaven Pharmaceuticals. Some others declared having ties with various sources, including Biohaven Pharmaceuticals.

Source: Mullin K, Croop R, Mosher L, et al. Long-term safety of zavegepant nasal spray for acute treatment of migraine: A phase 2/3 open-label study. Cephalalgia. 2024 (Aug 30). doi: 10.1177/033310242412594 Source

Key clinical point: Zavegepant nasal spray, administered as needed for up to eight doses per month, demonstrated long-term safety in the acute treatment of migraine over 1 year.

Major finding: The most common adverse events (AE), reported in ≥5% patients receiving zavegepant, were dysgeusia, nasal discomfort, COVID-19, nausea, nasal congestion, throat irritation, and back pain. In the 1-year period, only 6.8% patients discontinued treatment due to AE; dysgeusia was the most common cause, accounting for 1.5% of discontinuations. No deaths were reported.

Study details: This phase 2/3, open-label safety study included 603 adults with moderate to severe migraine who had a history of 2 to 8 moderate to severe attacks per month and were treated with intranasal 10 mg zavegepant daily for 1 year.

Disclosures: This study was funded by Biohaven Pharmaceuticals. Some authors declared being employees of or holding stocks of or stock options in Biohaven Pharmaceuticals. Some others declared having ties with various sources, including Biohaven Pharmaceuticals.

Source: Mullin K, Croop R, Mosher L, et al. Long-term safety of zavegepant nasal spray for acute treatment of migraine: A phase 2/3 open-label study. Cephalalgia. 2024 (Aug 30). doi: 10.1177/033310242412594 Source