Migraine ICYMI

Key clinical point: Early wearing-off effect (WOE) is common in patients with chronic migraine (CM) receiving onabotulinumtoxinA (OnabotA) and more frequent after the first cycle of OnabotA, with depression and anxiety disorders being clinical predictors of the WOE.

Major finding: Early WOE was reported more frequently after the first vs second treatment cycle of OnabotA (35.6% vs 23.8% of patients), with depression and anxiety disorders being significant clinical predictors of WOE (odds ratio 3.4; 95% CI 1.22-10.84; P = .028).

Study details: Findings are from a prospective real-life study including 59 patients with CM and insufficient response, absence of tolerability, or contraindications to previous migraine therapies who initiated prophylactic treatment with OnabotA, 40.6% of whom reported a WOE.

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

Source: Rodríguez-Montolio J et al. Early wearing-off effect of OnabotulinumtoxinA in chronic migraine: A prospective real-life study. J Clin Med. 2023;12(16):5360 (Aug 17). doi: 10.3390/jcm12165360

Key clinical point: Early wearing-off effect (WOE) is common in patients with chronic migraine (CM) receiving onabotulinumtoxinA (OnabotA) and more frequent after the first cycle of OnabotA, with depression and anxiety disorders being clinical predictors of the WOE.

Major finding: Early WOE was reported more frequently after the first vs second treatment cycle of OnabotA (35.6% vs 23.8% of patients), with depression and anxiety disorders being significant clinical predictors of WOE (odds ratio 3.4; 95% CI 1.22-10.84; P = .028).

Study details: Findings are from a prospective real-life study including 59 patients with CM and insufficient response, absence of tolerability, or contraindications to previous migraine therapies who initiated prophylactic treatment with OnabotA, 40.6% of whom reported a WOE.

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

Source: Rodríguez-Montolio J et al. Early wearing-off effect of OnabotulinumtoxinA in chronic migraine: A prospective real-life study. J Clin Med. 2023;12(16):5360 (Aug 17). doi: 10.3390/jcm12165360

Key clinical point: Early wearing-off effect (WOE) is common in patients with chronic migraine (CM) receiving onabotulinumtoxinA (OnabotA) and more frequent after the first cycle of OnabotA, with depression and anxiety disorders being clinical predictors of the WOE.

Major finding: Early WOE was reported more frequently after the first vs second treatment cycle of OnabotA (35.6% vs 23.8% of patients), with depression and anxiety disorders being significant clinical predictors of WOE (odds ratio 3.4; 95% CI 1.22-10.84; P = .028).

Study details: Findings are from a prospective real-life study including 59 patients with CM and insufficient response, absence of tolerability, or contraindications to previous migraine therapies who initiated prophylactic treatment with OnabotA, 40.6% of whom reported a WOE.

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

Source: Rodríguez-Montolio J et al. Early wearing-off effect of OnabotulinumtoxinA in chronic migraine: A prospective real-life study. J Clin Med. 2023;12(16):5360 (Aug 17). doi: 10.3390/jcm12165360

Key clinical point: Ubrogepant shows similar efficacy and no new safety concerns for the treatment of perimenstrual migraine (pmM) and non-pmM attacks.

Major finding: At 2 hours post dose, pain freedom (P = .054) and pain relief (P = .683) were similar between pmM and non-pmM attacks treated with 50 mg ubrogepant. Absence of migraine-associated symptoms (photophobia and phonophobia) and functional disability was not significantly different between pmM and non-pmM attacks treated with 50 mg ubrogepant, with similar findings observed for 100 mg ubrogepant. Nausea and dizziness were reported in < 6% of participants overall in both the 50 mg and 100 mg ubrogepant groups.

Study details: This post hoc analysis of a long-term safety extension trial included 734 women with migraine, of whom 278 and 716 were treated with ubrogepant (50 mg or 100 mg) for ≥ 1 pmM and non-pmM attacks, respectively.

Disclosures: This study was funded by Allergan (prior to its acquisition by AbbVie). Four authors declared being employees of or holding stocks in AbbVie, and the other authors declared ties with various sources, including AbbVie.

Source: MacGregor EA et al. Safety and efficacy of ubrogepant for the acute treatment of perimenstrual migraine attacks: A post hoc analysis. Headache. 2023 (Sep 1). doi: 10.1111/head.14619

Key clinical point: Ubrogepant shows similar efficacy and no new safety concerns for the treatment of perimenstrual migraine (pmM) and non-pmM attacks.

Major finding: At 2 hours post dose, pain freedom (P = .054) and pain relief (P = .683) were similar between pmM and non-pmM attacks treated with 50 mg ubrogepant. Absence of migraine-associated symptoms (photophobia and phonophobia) and functional disability was not significantly different between pmM and non-pmM attacks treated with 50 mg ubrogepant, with similar findings observed for 100 mg ubrogepant. Nausea and dizziness were reported in < 6% of participants overall in both the 50 mg and 100 mg ubrogepant groups.

Study details: This post hoc analysis of a long-term safety extension trial included 734 women with migraine, of whom 278 and 716 were treated with ubrogepant (50 mg or 100 mg) for ≥ 1 pmM and non-pmM attacks, respectively.

Disclosures: This study was funded by Allergan (prior to its acquisition by AbbVie). Four authors declared being employees of or holding stocks in AbbVie, and the other authors declared ties with various sources, including AbbVie.

Source: MacGregor EA et al. Safety and efficacy of ubrogepant for the acute treatment of perimenstrual migraine attacks: A post hoc analysis. Headache. 2023 (Sep 1). doi: 10.1111/head.14619

Key clinical point: Ubrogepant shows similar efficacy and no new safety concerns for the treatment of perimenstrual migraine (pmM) and non-pmM attacks.

Major finding: At 2 hours post dose, pain freedom (P = .054) and pain relief (P = .683) were similar between pmM and non-pmM attacks treated with 50 mg ubrogepant. Absence of migraine-associated symptoms (photophobia and phonophobia) and functional disability was not significantly different between pmM and non-pmM attacks treated with 50 mg ubrogepant, with similar findings observed for 100 mg ubrogepant. Nausea and dizziness were reported in < 6% of participants overall in both the 50 mg and 100 mg ubrogepant groups.

Study details: This post hoc analysis of a long-term safety extension trial included 734 women with migraine, of whom 278 and 716 were treated with ubrogepant (50 mg or 100 mg) for ≥ 1 pmM and non-pmM attacks, respectively.

Disclosures: This study was funded by Allergan (prior to its acquisition by AbbVie). Four authors declared being employees of or holding stocks in AbbVie, and the other authors declared ties with various sources, including AbbVie.

Source: MacGregor EA et al. Safety and efficacy of ubrogepant for the acute treatment of perimenstrual migraine attacks: A post hoc analysis. Headache. 2023 (Sep 1). doi: 10.1111/head.14619

Key clinical point: In patients with migraine, COVID-19 vaccination worsened the overall migraine symptoms in the first month post-vaccination; however, COVID-19 infection solely increased the number of acute medication intake days in the first month following infection.

Major finding: COVID-19 vaccination led to a significant increase in the number of monthly migraine days (MMD), monthly headache days (MHD), and monthly acute medication days (MAMD) by 1.06, 1.52, and 0.72, respectively (all P < .001) in the first month post-vaccination. COVID-19 infection solely increased MAMD by 1.11 (P = .027) in the first month following infection, with no significant effects on MMD and MHD.

Study details: This longitudinal cohort study identified 547 patients with migraine, of whom 147 were included in the vaccine analysis and 59 in the infection analysis.

Disclosures: This study did not receive any funding. BWH van der Arend and GM Terwindt declared receiving independent support and consultancy or industry support from various sources. The other authors declared no conflicts of interest.

Source: van der Arend BWH et al. Effect of COVID vaccination on monthly migraine days: A longitudinal cohort study. Cephalalgia. 2023;43(9) (Sep 8). doi: 10.1177/03331024231198792

Key clinical point: In patients with migraine, COVID-19 vaccination worsened the overall migraine symptoms in the first month post-vaccination; however, COVID-19 infection solely increased the number of acute medication intake days in the first month following infection.

Major finding: COVID-19 vaccination led to a significant increase in the number of monthly migraine days (MMD), monthly headache days (MHD), and monthly acute medication days (MAMD) by 1.06, 1.52, and 0.72, respectively (all P < .001) in the first month post-vaccination. COVID-19 infection solely increased MAMD by 1.11 (P = .027) in the first month following infection, with no significant effects on MMD and MHD.

Study details: This longitudinal cohort study identified 547 patients with migraine, of whom 147 were included in the vaccine analysis and 59 in the infection analysis.

Disclosures: This study did not receive any funding. BWH van der Arend and GM Terwindt declared receiving independent support and consultancy or industry support from various sources. The other authors declared no conflicts of interest.

Source: van der Arend BWH et al. Effect of COVID vaccination on monthly migraine days: A longitudinal cohort study. Cephalalgia. 2023;43(9) (Sep 8). doi: 10.1177/03331024231198792

Key clinical point: In patients with migraine, COVID-19 vaccination worsened the overall migraine symptoms in the first month post-vaccination; however, COVID-19 infection solely increased the number of acute medication intake days in the first month following infection.

Major finding: COVID-19 vaccination led to a significant increase in the number of monthly migraine days (MMD), monthly headache days (MHD), and monthly acute medication days (MAMD) by 1.06, 1.52, and 0.72, respectively (all P < .001) in the first month post-vaccination. COVID-19 infection solely increased MAMD by 1.11 (P = .027) in the first month following infection, with no significant effects on MMD and MHD.

Study details: This longitudinal cohort study identified 547 patients with migraine, of whom 147 were included in the vaccine analysis and 59 in the infection analysis.

Disclosures: This study did not receive any funding. BWH van der Arend and GM Terwindt declared receiving independent support and consultancy or industry support from various sources. The other authors declared no conflicts of interest.

Source: van der Arend BWH et al. Effect of COVID vaccination on monthly migraine days: A longitudinal cohort study. Cephalalgia. 2023;43(9) (Sep 8). doi: 10.1177/03331024231198792

Key clinical point: Pain in the lower limbs of children and adolescents, often referred to as ‘growing pain’ (GP) by pediatricians and orthopedists, can be a precursor of or a comorbidity linked to migraine.

Major finding: Overall, 76% vs 22% of children and adolescents with vs without GP experienced a primary headache disorder fulfilling the International Classification of Headache Disorders-3 diagnostic criteria for migraine (P < .001). GP persisted in 14% of patients who initially had GP and appeared in 39% of patients who were previously asymptomatic (P = .026).

Study details: This cross-sectional, prospective study included 78 children and adolescents without any headache complaints who were aged between 5 and 10 years and were born to mothers with migraine, of whom 42 experienced GP and 36 patients did not experience GP.

Disclosures: This study did not disclose the funding source. The authors declared no conflict of interest.

Source: Silva-Néto RP et al. “Growing pains” in children and adolescents as an early symptom of migraine: A prospective study. Headache. 2023 (Sep 6). doi: 10.1111/head.14608

Key clinical point: Pain in the lower limbs of children and adolescents, often referred to as ‘growing pain’ (GP) by pediatricians and orthopedists, can be a precursor of or a comorbidity linked to migraine.

Major finding: Overall, 76% vs 22% of children and adolescents with vs without GP experienced a primary headache disorder fulfilling the International Classification of Headache Disorders-3 diagnostic criteria for migraine (P < .001). GP persisted in 14% of patients who initially had GP and appeared in 39% of patients who were previously asymptomatic (P = .026).

Study details: This cross-sectional, prospective study included 78 children and adolescents without any headache complaints who were aged between 5 and 10 years and were born to mothers with migraine, of whom 42 experienced GP and 36 patients did not experience GP.

Disclosures: This study did not disclose the funding source. The authors declared no conflict of interest.

Source: Silva-Néto RP et al. “Growing pains” in children and adolescents as an early symptom of migraine: A prospective study. Headache. 2023 (Sep 6). doi: 10.1111/head.14608

Key clinical point: Pain in the lower limbs of children and adolescents, often referred to as ‘growing pain’ (GP) by pediatricians and orthopedists, can be a precursor of or a comorbidity linked to migraine.

Major finding: Overall, 76% vs 22% of children and adolescents with vs without GP experienced a primary headache disorder fulfilling the International Classification of Headache Disorders-3 diagnostic criteria for migraine (P < .001). GP persisted in 14% of patients who initially had GP and appeared in 39% of patients who were previously asymptomatic (P = .026).

Study details: This cross-sectional, prospective study included 78 children and adolescents without any headache complaints who were aged between 5 and 10 years and were born to mothers with migraine, of whom 42 experienced GP and 36 patients did not experience GP.

Disclosures: This study did not disclose the funding source. The authors declared no conflict of interest.

Source: Silva-Néto RP et al. “Growing pains” in children and adolescents as an early symptom of migraine: A prospective study. Headache. 2023 (Sep 6). doi: 10.1111/head.14608

MDedge: What were the earliest acute care medications available for migraine?

Dr. Rapoport: In the 1940s, ergotamine tartrate tablets and sublingual tablets were introduced as therapy to treat migraine. They were not that well absorbed, caused nausea, and were not very effective—but they were the only treatment option. Then, beginning in the early 1990s, doctors began prescribing a class of medications called triptans to stop a migraine in progress. Patients are instructed to quickly take the triptan as soon as they know it is or will be a migraine headache; if they wait too long, it may not work as well—or at all. If they don’t have any improvement in 2 hours, they are encouraged to repeat the dosage, even though it often does not work well.

As I strongly recommend to my patients, triptans should not be used more than 2 days per week. An average of 3 days per week or more is too much, and triptan medications can cause medication overuse headache (MOH). If the patient develops MOH, they usually have more headaches rather than fewer—and the medication stops working well.

These medicines work in about 60% of patients and not so well in the other 40%. They do cause side effects in certain people, which may include some pain in their chest or neck muscles and  constriction of blood vessels. Some patients also feel a warm-to-hot feeling all over, tingling sensation, drowsiness, dizziness, and other side effects. Some will experience these side effects but continue to take these medications because they work; however, some patients can’t take them because they find the side effects to be too bothersome.

The first triptan to be marketed (in 1992) was a 6-mg, self-injected, subcutaneous injection of sumatriptan (Imitrex). Injection was the only available delivery method for a triptan until 1994, when the tablet form became available.

Typically, patients who hadn’t taken the sumatriptan injections preferred to start with the tablets, but the patients who had been taking the injection form were used to it and preferred to keep taking it. They knew that it worked well, and if they had mild side effects, they weren’t troubled by them. However, most new patients, when given a choice, asked for the tablet instead of the injection. In 1996, sumatriptan nasal spray was introduced, which is inconsistently absorbed, and patients report it does not taste or smell good. 

Within a few years, more triptan tablets became available: zolmitriptan (1997), rizatriptan (1998), naratriptan (1998), almotriptan and frovatriptan (2001), and eletriptan (2002). An oral film form of rizatriptan (RizaFilm) was FDA-approved in 2023. The zolmitriptan nasal spray was approved in 2003 and is easy to use, with few adverse effects and good efficacy. There is also a new type of sumatriptan nasal spray (approved in 2019) with a permeation enhancer that makes it adhere to the mucous membranes of the nose and allows it to work faster. It does not have the same disliked taste and smell that caused patients to avoid other similar medications. However, most patients still seem to prefer triptans in tablet form over the nasal spray or injection. 

Now there are a total of 2 triptan nasal sprays and 7 triptans in tablet form, 2 of which are orally disintegrating tablets (ODT), and there are several sumatriptan injections available that come in 3- 4- or 6-mg dosages. 

Do you prefer to prescribe a particular triptan medication to your patients, and if so, why?

Of the different forms of triptans (nasal sprays, tablets, and injections), my favorite is the nasal spray form of zolmitriptan 5 mg (it also comes in 2.5-mg doses, which I sometimes prescribe to pediatric patients). I prefer it because of how quickly it works to provide my patients relief from migraine. All tablets must go down the esophagus, into the stomach, then into the small intestine to the level of the jejunum, where it is absorbed. It then goes to the liver, where it is metabolized, and then (once it finally gets into the bloodstream), it starts working. By contrast, when medication is administered into the nasal cavity, it is quickly absorbed from the mucous membrane and enters the bloodstream there and begins working faster than the tablet does. Zolmitriptan also has fewer side effects than the tablet, and my patients appreciate that. If tablets of triptans do not work, I switch to zolmitriptan nasal spray and, in rare situations, the sumatriptan injection.

When would I switch a patient from a triptan any of the new classes of medicines? 

If a patient takes a triptan at the first sign of migraine and it doesn’t begin to work for 2 hours, that is taking too long. If the triptan relieves only 50% of the head pain, there is a good chance that the headache will linger and later return with a vengeance. That would make me consider switching a patient to one of the other types of migraine medications. Even if the patient repeats the triptan at 2 hours after the first one, it probably won’t be very effective at that point. I also want to know if a patient experiences any side effects from the triptan. If they say it works, but they get chest pain, drowsiness, or dizziness and can’t function, I may want to switch them to a newer medication.

Triptans can stimulate the serotonin 1B receptors on the nerves on the small blood vessels in various parts of the body. Because of that, they may constrict blood vessels, such as the coronary arteries in the heart or others in brain, which could possibly lead to a heart attack or stroke or hypertension in some patients. I might switch a medication from a triptan for a patient who is older (over 50), has high blood pressure or cholesterol, has obesity, does not regularly exercise, or has a family history of a heart attack or stroke at an early age. You really don’t want to constrict blood vessels in these patients and should consider a newer therapy.

Can you tell us more about the nasal sprays for acute care of migraine?

Other than the standard sumatriptan nasal spray, the half-dose of sumatriptan nasal spray with a permeation enhancer, and zolmitriptan nasal spray, there are 2 additional options on the market. They are both dihydroergotamine (DHE) mesylate, an ergot alkaloid liquid nasal spray. They are identical chemicals with different devices that produce the sprays. The older DHE nasal spray is called Migranal; it is used 1 time in each nostril, then 15 minutes later is repeated. I feel like it takes too long to get the medicine into the bloodstream because the nasal spray only emits a gentle spray that lays on the bottom of the nose. It doesn’t get to the top or back of the nasal cavity, where there are more blood vessels, which would result in better absorption and efficacy. The second nasal spray is called Trudhesa, which came out just a few years ago when another company took the same exact chemical entity and delivered it with a bigger sprayer that fires it up to the top and back of the nose, where it is better absorbed. That nasal spray seems to work better than the old nasal spray. We don’t have data showing how much better it works than the other, but patients tend to like it more. We may also see a fine DHE nasal powder soon, which may take slightly longer to work but with good efficacy that lasts longer.

Have any adverse events been reported with the DHE nasal sprays for migraine?

A patient may experience some pain or burning in the nose, have a funny taste in the mouth, or even experience a change in the way a food tastes for a while after taking the DHE nasal spray. It could also cause some chest discomfort because it stimulates the same receptors as the triptans, plus other receptors as well. 

Are there any newer acute care medications for migraine?

There are 2 newer groups of migraine medications that have come out within the past few years: gepants and a ditan. There are 2 gepants currently available. The first one to be FDA-approved for acute care of migraine (in 2019) was ubrogepant (Ubrelvy), and the second gepant, rimegepant (Nurtec), was approved in 2020. They both work approximately the same way, but they may cause different adverse events. They both sit on the calcitonin gene-related peptide (CGRP) receptors. These receptors are all over the body and the brain, but the place where researchers believe they work most effectively is on the first branch of the trigeminal nerve between the brainstem and the meninges. This is the trigeminovascular system. It works outside of the central nervous system and modulates what goes on inside the central nervous system.

Ubrogepant is a regular tablet that has 2 sizes, 50 and 100 mg. I might start a patient on a 50-mg tablet, and I will instruct them to take another dose (up to 200 mg a day) if they have not improved in 2 hours. Rimegepant comes only as a 75-mg ODT, or fast melt tablet which means a patient can put it on their tongue and they don’t need water with it. For example, if a patient is stuck on an interstate in a traffic jam at rush hour, is getting a terrible headache, and doesn’t happen to have water, they could just place the tablet it in their mouth, where it will dissolve in 5 to 10 seconds. A second dose doesn’t seem to be necessary; if the headache persists, I will switch to another type of medication that day.

The other category of acute migraine medicine that has been approved in the last few years is called a ditan. Only 1 ditan in the class is available right now, lasmiditan (Reyvow). It was FDA-approved in 2019 and works a little bit differently from the gepants, as it’s more like a triptan. Instead of stimulating the serotonin 1B and 1D receptors, it stimulates the serotonin 1F receptor. This is important because it doesn’t stimulate the 1B receptor and therefore doesn’t constrict blood vessels. The one good thing about this medication is it can be prescribed to an older patient or a patient that has any kind of coronary artery risk factors like smoking or obesity. It does enter the central nervous system to begin working, and when a drug does that, it’s more likely to have different side effects, such as dizziness or drowsiness—and this medication does cause both. The drug works well, but the side effects must be carefully observed. Patients are advised not to drive a car or operate machinery for 8 hours after taking this drug.

The advancements in the pharmacologic treatment options for the acute care of migraine offer a wide range of options for patients with migraine—allowing for more personalized and effective approaches for relief, with fewer adverse events than ever before.

MDedge: What were the earliest acute care medications available for migraine?

Dr. Rapoport: In the 1940s, ergotamine tartrate tablets and sublingual tablets were introduced as therapy to treat migraine. They were not that well absorbed, caused nausea, and were not very effective—but they were the only treatment option. Then, beginning in the early 1990s, doctors began prescribing a class of medications called triptans to stop a migraine in progress. Patients are instructed to quickly take the triptan as soon as they know it is or will be a migraine headache; if they wait too long, it may not work as well—or at all. If they don’t have any improvement in 2 hours, they are encouraged to repeat the dosage, even though it often does not work well.

As I strongly recommend to my patients, triptans should not be used more than 2 days per week. An average of 3 days per week or more is too much, and triptan medications can cause medication overuse headache (MOH). If the patient develops MOH, they usually have more headaches rather than fewer—and the medication stops working well.

These medicines work in about 60% of patients and not so well in the other 40%. They do cause side effects in certain people, which may include some pain in their chest or neck muscles and  constriction of blood vessels. Some patients also feel a warm-to-hot feeling all over, tingling sensation, drowsiness, dizziness, and other side effects. Some will experience these side effects but continue to take these medications because they work; however, some patients can’t take them because they find the side effects to be too bothersome.

The first triptan to be marketed (in 1992) was a 6-mg, self-injected, subcutaneous injection of sumatriptan (Imitrex). Injection was the only available delivery method for a triptan until 1994, when the tablet form became available.

Typically, patients who hadn’t taken the sumatriptan injections preferred to start with the tablets, but the patients who had been taking the injection form were used to it and preferred to keep taking it. They knew that it worked well, and if they had mild side effects, they weren’t troubled by them. However, most new patients, when given a choice, asked for the tablet instead of the injection. In 1996, sumatriptan nasal spray was introduced, which is inconsistently absorbed, and patients report it does not taste or smell good. 

Within a few years, more triptan tablets became available: zolmitriptan (1997), rizatriptan (1998), naratriptan (1998), almotriptan and frovatriptan (2001), and eletriptan (2002). An oral film form of rizatriptan (RizaFilm) was FDA-approved in 2023. The zolmitriptan nasal spray was approved in 2003 and is easy to use, with few adverse effects and good efficacy. There is also a new type of sumatriptan nasal spray (approved in 2019) with a permeation enhancer that makes it adhere to the mucous membranes of the nose and allows it to work faster. It does not have the same disliked taste and smell that caused patients to avoid other similar medications. However, most patients still seem to prefer triptans in tablet form over the nasal spray or injection. 

Now there are a total of 2 triptan nasal sprays and 7 triptans in tablet form, 2 of which are orally disintegrating tablets (ODT), and there are several sumatriptan injections available that come in 3- 4- or 6-mg dosages. 

Do you prefer to prescribe a particular triptan medication to your patients, and if so, why?

Of the different forms of triptans (nasal sprays, tablets, and injections), my favorite is the nasal spray form of zolmitriptan 5 mg (it also comes in 2.5-mg doses, which I sometimes prescribe to pediatric patients). I prefer it because of how quickly it works to provide my patients relief from migraine. All tablets must go down the esophagus, into the stomach, then into the small intestine to the level of the jejunum, where it is absorbed. It then goes to the liver, where it is metabolized, and then (once it finally gets into the bloodstream), it starts working. By contrast, when medication is administered into the nasal cavity, it is quickly absorbed from the mucous membrane and enters the bloodstream there and begins working faster than the tablet does. Zolmitriptan also has fewer side effects than the tablet, and my patients appreciate that. If tablets of triptans do not work, I switch to zolmitriptan nasal spray and, in rare situations, the sumatriptan injection.

When would I switch a patient from a triptan any of the new classes of medicines? 

If a patient takes a triptan at the first sign of migraine and it doesn’t begin to work for 2 hours, that is taking too long. If the triptan relieves only 50% of the head pain, there is a good chance that the headache will linger and later return with a vengeance. That would make me consider switching a patient to one of the other types of migraine medications. Even if the patient repeats the triptan at 2 hours after the first one, it probably won’t be very effective at that point. I also want to know if a patient experiences any side effects from the triptan. If they say it works, but they get chest pain, drowsiness, or dizziness and can’t function, I may want to switch them to a newer medication.

Triptans can stimulate the serotonin 1B receptors on the nerves on the small blood vessels in various parts of the body. Because of that, they may constrict blood vessels, such as the coronary arteries in the heart or others in brain, which could possibly lead to a heart attack or stroke or hypertension in some patients. I might switch a medication from a triptan for a patient who is older (over 50), has high blood pressure or cholesterol, has obesity, does not regularly exercise, or has a family history of a heart attack or stroke at an early age. You really don’t want to constrict blood vessels in these patients and should consider a newer therapy.

Can you tell us more about the nasal sprays for acute care of migraine?

Other than the standard sumatriptan nasal spray, the half-dose of sumatriptan nasal spray with a permeation enhancer, and zolmitriptan nasal spray, there are 2 additional options on the market. They are both dihydroergotamine (DHE) mesylate, an ergot alkaloid liquid nasal spray. They are identical chemicals with different devices that produce the sprays. The older DHE nasal spray is called Migranal; it is used 1 time in each nostril, then 15 minutes later is repeated. I feel like it takes too long to get the medicine into the bloodstream because the nasal spray only emits a gentle spray that lays on the bottom of the nose. It doesn’t get to the top or back of the nasal cavity, where there are more blood vessels, which would result in better absorption and efficacy. The second nasal spray is called Trudhesa, which came out just a few years ago when another company took the same exact chemical entity and delivered it with a bigger sprayer that fires it up to the top and back of the nose, where it is better absorbed. That nasal spray seems to work better than the old nasal spray. We don’t have data showing how much better it works than the other, but patients tend to like it more. We may also see a fine DHE nasal powder soon, which may take slightly longer to work but with good efficacy that lasts longer.

Have any adverse events been reported with the DHE nasal sprays for migraine?

A patient may experience some pain or burning in the nose, have a funny taste in the mouth, or even experience a change in the way a food tastes for a while after taking the DHE nasal spray. It could also cause some chest discomfort because it stimulates the same receptors as the triptans, plus other receptors as well. 

Are there any newer acute care medications for migraine?

There are 2 newer groups of migraine medications that have come out within the past few years: gepants and a ditan. There are 2 gepants currently available. The first one to be FDA-approved for acute care of migraine (in 2019) was ubrogepant (Ubrelvy), and the second gepant, rimegepant (Nurtec), was approved in 2020. They both work approximately the same way, but they may cause different adverse events. They both sit on the calcitonin gene-related peptide (CGRP) receptors. These receptors are all over the body and the brain, but the place where researchers believe they work most effectively is on the first branch of the trigeminal nerve between the brainstem and the meninges. This is the trigeminovascular system. It works outside of the central nervous system and modulates what goes on inside the central nervous system.

Ubrogepant is a regular tablet that has 2 sizes, 50 and 100 mg. I might start a patient on a 50-mg tablet, and I will instruct them to take another dose (up to 200 mg a day) if they have not improved in 2 hours. Rimegepant comes only as a 75-mg ODT, or fast melt tablet which means a patient can put it on their tongue and they don’t need water with it. For example, if a patient is stuck on an interstate in a traffic jam at rush hour, is getting a terrible headache, and doesn’t happen to have water, they could just place the tablet it in their mouth, where it will dissolve in 5 to 10 seconds. A second dose doesn’t seem to be necessary; if the headache persists, I will switch to another type of medication that day.

The other category of acute migraine medicine that has been approved in the last few years is called a ditan. Only 1 ditan in the class is available right now, lasmiditan (Reyvow). It was FDA-approved in 2019 and works a little bit differently from the gepants, as it’s more like a triptan. Instead of stimulating the serotonin 1B and 1D receptors, it stimulates the serotonin 1F receptor. This is important because it doesn’t stimulate the 1B receptor and therefore doesn’t constrict blood vessels. The one good thing about this medication is it can be prescribed to an older patient or a patient that has any kind of coronary artery risk factors like smoking or obesity. It does enter the central nervous system to begin working, and when a drug does that, it’s more likely to have different side effects, such as dizziness or drowsiness—and this medication does cause both. The drug works well, but the side effects must be carefully observed. Patients are advised not to drive a car or operate machinery for 8 hours after taking this drug.

The advancements in the pharmacologic treatment options for the acute care of migraine offer a wide range of options for patients with migraine—allowing for more personalized and effective approaches for relief, with fewer adverse events than ever before.

MDedge: What were the earliest acute care medications available for migraine?

Dr. Rapoport: In the 1940s, ergotamine tartrate tablets and sublingual tablets were introduced as therapy to treat migraine. They were not that well absorbed, caused nausea, and were not very effective—but they were the only treatment option. Then, beginning in the early 1990s, doctors began prescribing a class of medications called triptans to stop a migraine in progress. Patients are instructed to quickly take the triptan as soon as they know it is or will be a migraine headache; if they wait too long, it may not work as well—or at all. If they don’t have any improvement in 2 hours, they are encouraged to repeat the dosage, even though it often does not work well.

As I strongly recommend to my patients, triptans should not be used more than 2 days per week. An average of 3 days per week or more is too much, and triptan medications can cause medication overuse headache (MOH). If the patient develops MOH, they usually have more headaches rather than fewer—and the medication stops working well.

These medicines work in about 60% of patients and not so well in the other 40%. They do cause side effects in certain people, which may include some pain in their chest or neck muscles and  constriction of blood vessels. Some patients also feel a warm-to-hot feeling all over, tingling sensation, drowsiness, dizziness, and other side effects. Some will experience these side effects but continue to take these medications because they work; however, some patients can’t take them because they find the side effects to be too bothersome.

The first triptan to be marketed (in 1992) was a 6-mg, self-injected, subcutaneous injection of sumatriptan (Imitrex). Injection was the only available delivery method for a triptan until 1994, when the tablet form became available.

Typically, patients who hadn’t taken the sumatriptan injections preferred to start with the tablets, but the patients who had been taking the injection form were used to it and preferred to keep taking it. They knew that it worked well, and if they had mild side effects, they weren’t troubled by them. However, most new patients, when given a choice, asked for the tablet instead of the injection. In 1996, sumatriptan nasal spray was introduced, which is inconsistently absorbed, and patients report it does not taste or smell good. 

Within a few years, more triptan tablets became available: zolmitriptan (1997), rizatriptan (1998), naratriptan (1998), almotriptan and frovatriptan (2001), and eletriptan (2002). An oral film form of rizatriptan (RizaFilm) was FDA-approved in 2023. The zolmitriptan nasal spray was approved in 2003 and is easy to use, with few adverse effects and good efficacy. There is also a new type of sumatriptan nasal spray (approved in 2019) with a permeation enhancer that makes it adhere to the mucous membranes of the nose and allows it to work faster. It does not have the same disliked taste and smell that caused patients to avoid other similar medications. However, most patients still seem to prefer triptans in tablet form over the nasal spray or injection. 

Now there are a total of 2 triptan nasal sprays and 7 triptans in tablet form, 2 of which are orally disintegrating tablets (ODT), and there are several sumatriptan injections available that come in 3- 4- or 6-mg dosages. 

Do you prefer to prescribe a particular triptan medication to your patients, and if so, why?

Of the different forms of triptans (nasal sprays, tablets, and injections), my favorite is the nasal spray form of zolmitriptan 5 mg (it also comes in 2.5-mg doses, which I sometimes prescribe to pediatric patients). I prefer it because of how quickly it works to provide my patients relief from migraine. All tablets must go down the esophagus, into the stomach, then into the small intestine to the level of the jejunum, where it is absorbed. It then goes to the liver, where it is metabolized, and then (once it finally gets into the bloodstream), it starts working. By contrast, when medication is administered into the nasal cavity, it is quickly absorbed from the mucous membrane and enters the bloodstream there and begins working faster than the tablet does. Zolmitriptan also has fewer side effects than the tablet, and my patients appreciate that. If tablets of triptans do not work, I switch to zolmitriptan nasal spray and, in rare situations, the sumatriptan injection.

When would I switch a patient from a triptan any of the new classes of medicines? 

If a patient takes a triptan at the first sign of migraine and it doesn’t begin to work for 2 hours, that is taking too long. If the triptan relieves only 50% of the head pain, there is a good chance that the headache will linger and later return with a vengeance. That would make me consider switching a patient to one of the other types of migraine medications. Even if the patient repeats the triptan at 2 hours after the first one, it probably won’t be very effective at that point. I also want to know if a patient experiences any side effects from the triptan. If they say it works, but they get chest pain, drowsiness, or dizziness and can’t function, I may want to switch them to a newer medication.

Triptans can stimulate the serotonin 1B receptors on the nerves on the small blood vessels in various parts of the body. Because of that, they may constrict blood vessels, such as the coronary arteries in the heart or others in brain, which could possibly lead to a heart attack or stroke or hypertension in some patients. I might switch a medication from a triptan for a patient who is older (over 50), has high blood pressure or cholesterol, has obesity, does not regularly exercise, or has a family history of a heart attack or stroke at an early age. You really don’t want to constrict blood vessels in these patients and should consider a newer therapy.

Can you tell us more about the nasal sprays for acute care of migraine?

Other than the standard sumatriptan nasal spray, the half-dose of sumatriptan nasal spray with a permeation enhancer, and zolmitriptan nasal spray, there are 2 additional options on the market. They are both dihydroergotamine (DHE) mesylate, an ergot alkaloid liquid nasal spray. They are identical chemicals with different devices that produce the sprays. The older DHE nasal spray is called Migranal; it is used 1 time in each nostril, then 15 minutes later is repeated. I feel like it takes too long to get the medicine into the bloodstream because the nasal spray only emits a gentle spray that lays on the bottom of the nose. It doesn’t get to the top or back of the nasal cavity, where there are more blood vessels, which would result in better absorption and efficacy. The second nasal spray is called Trudhesa, which came out just a few years ago when another company took the same exact chemical entity and delivered it with a bigger sprayer that fires it up to the top and back of the nose, where it is better absorbed. That nasal spray seems to work better than the old nasal spray. We don’t have data showing how much better it works than the other, but patients tend to like it more. We may also see a fine DHE nasal powder soon, which may take slightly longer to work but with good efficacy that lasts longer.

Have any adverse events been reported with the DHE nasal sprays for migraine?

A patient may experience some pain or burning in the nose, have a funny taste in the mouth, or even experience a change in the way a food tastes for a while after taking the DHE nasal spray. It could also cause some chest discomfort because it stimulates the same receptors as the triptans, plus other receptors as well. 

Are there any newer acute care medications for migraine?

There are 2 newer groups of migraine medications that have come out within the past few years: gepants and a ditan. There are 2 gepants currently available. The first one to be FDA-approved for acute care of migraine (in 2019) was ubrogepant (Ubrelvy), and the second gepant, rimegepant (Nurtec), was approved in 2020. They both work approximately the same way, but they may cause different adverse events. They both sit on the calcitonin gene-related peptide (CGRP) receptors. These receptors are all over the body and the brain, but the place where researchers believe they work most effectively is on the first branch of the trigeminal nerve between the brainstem and the meninges. This is the trigeminovascular system. It works outside of the central nervous system and modulates what goes on inside the central nervous system.

Ubrogepant is a regular tablet that has 2 sizes, 50 and 100 mg. I might start a patient on a 50-mg tablet, and I will instruct them to take another dose (up to 200 mg a day) if they have not improved in 2 hours. Rimegepant comes only as a 75-mg ODT, or fast melt tablet which means a patient can put it on their tongue and they don’t need water with it. For example, if a patient is stuck on an interstate in a traffic jam at rush hour, is getting a terrible headache, and doesn’t happen to have water, they could just place the tablet it in their mouth, where it will dissolve in 5 to 10 seconds. A second dose doesn’t seem to be necessary; if the headache persists, I will switch to another type of medication that day.

The other category of acute migraine medicine that has been approved in the last few years is called a ditan. Only 1 ditan in the class is available right now, lasmiditan (Reyvow). It was FDA-approved in 2019 and works a little bit differently from the gepants, as it’s more like a triptan. Instead of stimulating the serotonin 1B and 1D receptors, it stimulates the serotonin 1F receptor. This is important because it doesn’t stimulate the 1B receptor and therefore doesn’t constrict blood vessels. The one good thing about this medication is it can be prescribed to an older patient or a patient that has any kind of coronary artery risk factors like smoking or obesity. It does enter the central nervous system to begin working, and when a drug does that, it’s more likely to have different side effects, such as dizziness or drowsiness—and this medication does cause both. The drug works well, but the side effects must be carefully observed. Patients are advised not to drive a car or operate machinery for 8 hours after taking this drug.

The advancements in the pharmacologic treatment options for the acute care of migraine offer a wide range of options for patients with migraine—allowing for more personalized and effective approaches for relief, with fewer adverse events than ever before.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Key clinical point: Severe obesity (body mass index [BMI] > 40 kg/m²) and postmenopausal status were associated with a significantly higher migraine frequency, with severe obesity also being associated with higher migraine severity.

Major finding: Migraine headache index scores (165.5 vs 105.5; P  =  .01) and the number of migraine headaches per month (P  =  .007) were significantly higher in patients with severe obesity vs those with healthy weight (BMI 18.5-24.9 kg/m²), with the number of migraine headaches per month being significantly higher among postmenopausal vs premenopausal women (mean 23 vs 19 days; P  =  .02).

Study details: Findings are from a retrospective cohort study including 223 patients with refractory migraine.

Disclosures: This study did not receive any specific funding. The authors declared no competing interests.

Source: Saffari TM et al. Severe obesity is associated with increased migraine severity and frequency: A retrospective cohort study. J Clin Neurosci. 2023;115:8-13 (Jul 14). doi: 10.1016/j.jocn.2023.07.007

Key clinical point: Severe obesity (body mass index [BMI] > 40 kg/m²) and postmenopausal status were associated with a significantly higher migraine frequency, with severe obesity also being associated with higher migraine severity.

Major finding: Migraine headache index scores (165.5 vs 105.5; P  =  .01) and the number of migraine headaches per month (P  =  .007) were significantly higher in patients with severe obesity vs those with healthy weight (BMI 18.5-24.9 kg/m²), with the number of migraine headaches per month being significantly higher among postmenopausal vs premenopausal women (mean 23 vs 19 days; P  =  .02).

Study details: Findings are from a retrospective cohort study including 223 patients with refractory migraine.

Disclosures: This study did not receive any specific funding. The authors declared no competing interests.

Source: Saffari TM et al. Severe obesity is associated with increased migraine severity and frequency: A retrospective cohort study. J Clin Neurosci. 2023;115:8-13 (Jul 14). doi: 10.1016/j.jocn.2023.07.007

Key clinical point: Severe obesity (body mass index [BMI] > 40 kg/m²) and postmenopausal status were associated with a significantly higher migraine frequency, with severe obesity also being associated with higher migraine severity.

Major finding: Migraine headache index scores (165.5 vs 105.5; P  =  .01) and the number of migraine headaches per month (P  =  .007) were significantly higher in patients with severe obesity vs those with healthy weight (BMI 18.5-24.9 kg/m²), with the number of migraine headaches per month being significantly higher among postmenopausal vs premenopausal women (mean 23 vs 19 days; P  =  .02).

Study details: Findings are from a retrospective cohort study including 223 patients with refractory migraine.

Disclosures: This study did not receive any specific funding. The authors declared no competing interests.

Source: Saffari TM et al. Severe obesity is associated with increased migraine severity and frequency: A retrospective cohort study. J Clin Neurosci. 2023;115:8-13 (Jul 14). doi: 10.1016/j.jocn.2023.07.007

Key clinical point: Higher dietary intake of zinc was negatively associated with the risk for migraine in adults, with the association being more prominent among those age 20-50 years.

Major finding: Compared with participants in the lowest quintile of dietary zinc consumption (≤ 5.93 mg/day), the risk for migraine was lower among those in the higher quintiles of dietary zinc consumption (5.94-8.38 mg/day: adjusted odds ratio [aOR] 0.73; P  =  .004; 8.39-11.26 mg/day: aOR 0.72; P  =  .02; and 11.27-15.75 mg/day: aOR 0.76; P  =  .04), with a non-linear association observed between zinc intake and migraine in the age 20-50 years group (P < .001).

Study details: This cross-sectional study included 9849 adult participants (age ≥ 20 years), of whom 1963 (19.93%) had migraine.

Disclosures: This study was supported by the National Natural Science Foundation of China, Natural Science Foundation of Jiangxi Province, and Jiangxi Provincial Department of Education Science and Technology Program Project. No potential conflicts of interest were declared.

Source: Zheng H et al. Dietary zinc intake in relation to migraine among adults: A cross sectional study of NHANES 1999-2004. Nutr Neurosci. 2023 (Aug 4). doi: 10.1080/1028415X.2023.2243678

Key clinical point: Higher dietary intake of zinc was negatively associated with the risk for migraine in adults, with the association being more prominent among those age 20-50 years.

Major finding: Compared with participants in the lowest quintile of dietary zinc consumption (≤ 5.93 mg/day), the risk for migraine was lower among those in the higher quintiles of dietary zinc consumption (5.94-8.38 mg/day: adjusted odds ratio [aOR] 0.73; P  =  .004; 8.39-11.26 mg/day: aOR 0.72; P  =  .02; and 11.27-15.75 mg/day: aOR 0.76; P  =  .04), with a non-linear association observed between zinc intake and migraine in the age 20-50 years group (P < .001).

Study details: This cross-sectional study included 9849 adult participants (age ≥ 20 years), of whom 1963 (19.93%) had migraine.

Disclosures: This study was supported by the National Natural Science Foundation of China, Natural Science Foundation of Jiangxi Province, and Jiangxi Provincial Department of Education Science and Technology Program Project. No potential conflicts of interest were declared.

Source: Zheng H et al. Dietary zinc intake in relation to migraine among adults: A cross sectional study of NHANES 1999-2004. Nutr Neurosci. 2023 (Aug 4). doi: 10.1080/1028415X.2023.2243678

Key clinical point: Higher dietary intake of zinc was negatively associated with the risk for migraine in adults, with the association being more prominent among those age 20-50 years.

Major finding: Compared with participants in the lowest quintile of dietary zinc consumption (≤ 5.93 mg/day), the risk for migraine was lower among those in the higher quintiles of dietary zinc consumption (5.94-8.38 mg/day: adjusted odds ratio [aOR] 0.73; P  =  .004; 8.39-11.26 mg/day: aOR 0.72; P  =  .02; and 11.27-15.75 mg/day: aOR 0.76; P  =  .04), with a non-linear association observed between zinc intake and migraine in the age 20-50 years group (P < .001).

Study details: This cross-sectional study included 9849 adult participants (age ≥ 20 years), of whom 1963 (19.93%) had migraine.

Disclosures: This study was supported by the National Natural Science Foundation of China, Natural Science Foundation of Jiangxi Province, and Jiangxi Provincial Department of Education Science and Technology Program Project. No potential conflicts of interest were declared.

Source: Zheng H et al. Dietary zinc intake in relation to migraine among adults: A cross sectional study of NHANES 1999-2004. Nutr Neurosci. 2023 (Aug 4). doi: 10.1080/1028415X.2023.2243678

Key clinical point: Patients with migraine are at a greater risk of experiencing rheumatoid arthritis (RA) attacks, with the risk being prominently higher among those having migraine without aura.

Major finding: The risk for RA was 1.94 times higher in patients with migraine vs control individuals (adjusted odds ratio [aOR] 1.94; 95% CI 1.74-2.17), with the risk being prominent in those with migraine without aura (aOR 1.49; 95% CI 1.35-1.64).

Study details: The data come from a meta-analysis of five studies including 321,877 participants.

Disclosures: This study did not disclose the funding source. The authors declared no competing interests.

Source: Tian D et al. Migraine and risk of rheumatoid arthritis: A systematic review and meta-analysis of observational studies. Heliyon. 2023;9(8):e18430 (Jul 18). doi: 10.1016/j.heliyon.2023.e18430

Key clinical point: Patients with migraine are at a greater risk of experiencing rheumatoid arthritis (RA) attacks, with the risk being prominently higher among those having migraine without aura.

Major finding: The risk for RA was 1.94 times higher in patients with migraine vs control individuals (adjusted odds ratio [aOR] 1.94; 95% CI 1.74-2.17), with the risk being prominent in those with migraine without aura (aOR 1.49; 95% CI 1.35-1.64).

Study details: The data come from a meta-analysis of five studies including 321,877 participants.

Disclosures: This study did not disclose the funding source. The authors declared no competing interests.

Source: Tian D et al. Migraine and risk of rheumatoid arthritis: A systematic review and meta-analysis of observational studies. Heliyon. 2023;9(8):e18430 (Jul 18). doi: 10.1016/j.heliyon.2023.e18430

Key clinical point: Patients with migraine are at a greater risk of experiencing rheumatoid arthritis (RA) attacks, with the risk being prominently higher among those having migraine without aura.

Major finding: The risk for RA was 1.94 times higher in patients with migraine vs control individuals (adjusted odds ratio [aOR] 1.94; 95% CI 1.74-2.17), with the risk being prominent in those with migraine without aura (aOR 1.49; 95% CI 1.35-1.64).

Study details: The data come from a meta-analysis of five studies including 321,877 participants.

Disclosures: This study did not disclose the funding source. The authors declared no competing interests.

Source: Tian D et al. Migraine and risk of rheumatoid arthritis: A systematic review and meta-analysis of observational studies. Heliyon. 2023;9(8):e18430 (Jul 18). doi: 10.1016/j.heliyon.2023.e18430

Key clinical point: Ubrogepant in combination with onabotulinumtoxinA led to meaningful pain relief and return to normal function at 2 and 4 hours post-dose in patients with self-identified migraine.

Major finding: Overall, 53.3% and 76.2% of patients achieved meaningful pain relief and 25.4% and 45.9% of patients achieved returned to normal function at 2 and 4 hours post-dose after the first treated attack, respectively.

Study details: The data come from a prospective real-world study including 122 patients with migraine (age ≥ 18 years) who received ubrogepant in combination with onabotulinumtoxinA.

Disclosures: This study was funded by Allergan (prior to its acquisition by AbbVie). Some authors declared receiving research support, royalties, or honoraria from, and serving as consultants and advisory board members for various sources, including AbbVie. Three authors declared being employees of or holding stocks in AbbVie.

Source: Manack Adams A et al. Real-world effectiveness, satisfaction, and optimization of ubrogepant for the acute treatment of migraine in combination with onabotulinumtoxinA: Results from the COURAGE Study. J Headache Pain. 2023;24:102 (Aug 3). doi: 10.1186/s10194-023-01622-0

Key clinical point: Ubrogepant in combination with onabotulinumtoxinA led to meaningful pain relief and return to normal function at 2 and 4 hours post-dose in patients with self-identified migraine.

Major finding: Overall, 53.3% and 76.2% of patients achieved meaningful pain relief and 25.4% and 45.9% of patients achieved returned to normal function at 2 and 4 hours post-dose after the first treated attack, respectively.

Study details: The data come from a prospective real-world study including 122 patients with migraine (age ≥ 18 years) who received ubrogepant in combination with onabotulinumtoxinA.

Disclosures: This study was funded by Allergan (prior to its acquisition by AbbVie). Some authors declared receiving research support, royalties, or honoraria from, and serving as consultants and advisory board members for various sources, including AbbVie. Three authors declared being employees of or holding stocks in AbbVie.

Source: Manack Adams A et al. Real-world effectiveness, satisfaction, and optimization of ubrogepant for the acute treatment of migraine in combination with onabotulinumtoxinA: Results from the COURAGE Study. J Headache Pain. 2023;24:102 (Aug 3). doi: 10.1186/s10194-023-01622-0

Key clinical point: Ubrogepant in combination with onabotulinumtoxinA led to meaningful pain relief and return to normal function at 2 and 4 hours post-dose in patients with self-identified migraine.

Major finding: Overall, 53.3% and 76.2% of patients achieved meaningful pain relief and 25.4% and 45.9% of patients achieved returned to normal function at 2 and 4 hours post-dose after the first treated attack, respectively.

Study details: The data come from a prospective real-world study including 122 patients with migraine (age ≥ 18 years) who received ubrogepant in combination with onabotulinumtoxinA.

Disclosures: This study was funded by Allergan (prior to its acquisition by AbbVie). Some authors declared receiving research support, royalties, or honoraria from, and serving as consultants and advisory board members for various sources, including AbbVie. Three authors declared being employees of or holding stocks in AbbVie.

Source: Manack Adams A et al. Real-world effectiveness, satisfaction, and optimization of ubrogepant for the acute treatment of migraine in combination with onabotulinumtoxinA: Results from the COURAGE Study. J Headache Pain. 2023;24:102 (Aug 3). doi: 10.1186/s10194-023-01622-0