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FDA okays new oral CGRP antagonist for migraine prevention
the manufacturer announced in a release.
The once-daily medication will be available in doses of 10 mg, 30 mg, and 60 mg.
“Qulipta provides a simple oral treatment option specifically developed to prevent migraine attacks and target CGRP, which is believed to be crucially involved in migraine in many patients,” coinvestigator Peter J. Goadsby, MD, PhD, DSc, neurologist and professor at the University of California, Los Angeles, and King’s College London, said in the release.
Approval was based partly on the findings from the phase 3 ADVANCE trial, in which patients with episodic migraine were randomly assigned to receive placebo or a 10-mg, 30-mg, or 60-mg daily dose of atogepant for 12 weeks.
As reported by this news organization, all three doses of atogepant reduced the number of mean monthly migraine days.
With this approval, neurologists will be able to choose from four monoclonal antibodies and two gepants for the preventive treatment of migraine.
“Having another gepant that can also be given preventively is a good idea, because one may be better than the other for a patient,” Alan M. Rapoport, MD, past president of the International Headache Society and founder and director emeritus of the New England Center for Headache, Stamford, Conn., told this news organization.
“Once we have a year or so of experience with atogepant, we’ll have a pretty good idea of which one works better preventively,” said Dr. Rapoport, who was not involved with the research.
Practice changing?
In the ADVANCE trial, there was a reduction of 3.69 migraine days with the 10-mg dose, 3.86 days with the 30-mg dose, and 4.2 days with the 60-mg dose. Placebo was associated with a reduction of 2.48 migraine days.
In addition, more than half of patients in each atogepant arm achieved a reduction in mean monthly migraine days of 50% or greater. This outcome occurred in 55.6% of the 10-mg atogepant group, 58.7% of the 30-mg group, and 60.8% of the 60-mg group. Approximately 29% patients who received placebo achieved this outcome.
The data indicated that atogepant has a favorable safety profile. The most common adverse events associated with treatment were constipation, nausea, and upper respiratory tract infection.
Dr. Rapoport, who is also a clinical professor of neurology at UCLA, noted that he was impressed with the efficacy.
“I’m not as impressed with the adverse events, but they’re not serious, and they don’t necessarily last,” he said.
Although being able to prescribe a single drug for acute and preventive treatment may be an advantage, it remains to be seen whether the tolerability and price of atogepant will be barriers for patients, Dr. Rapoport added.
How the approval will affect clinical practice is also unclear, he noted.
“If you’re going to start someone on a preventive, especially if it’s a woman of childbearing potential, you might just consider one of the two gepants. Doctors will decide once they see how they work,” said Dr. Rapoport.
Not a ‘breakthrough’ treatment
Also commenting ahead of the approval, Elizabeth W. Loder, MD, vice chair for academic affairs in the department of neurology at Brigham and Women’s Hospital, Boston, noted that the “safety of these CGRP medications in pregnancy is uncertain, and there are theoretical reasons to be concerned about it.”
Unlike injectable CGRP medications, atogepant is eliminated from the body relatively quickly after the patient stops taking it, said Dr. Loder, who is also professor of neurology at Harvard Medical School, Boston. However, atogepant may not otherwise differ greatly from other medications of its type.
“I don’t see a reason to think that one of these oral CGRP medicines is much more effective than another one,” said Dr. Loder.
“In my mind, as a clinician who will be prescribing these for patients, it will be cost and the ease of getting it covered that makes the difference,” she added.
These questions may raise concerns. “Those of us who treat patients who do not have private insurance find it very difficult to get these medications for them, even in situations where they have exhausted other alternatives,” said Dr. Loder.
Patients insured by Medicare or Medicaid “usually have no avenue to get some of these new, expensive treatments,” she said.
The approval of atogepant for acute and preventive treatment shows that the distinction between these indications may be artificial, Dr. Loder noted. The approval “will, I hope, help people think more flexibly about the way in which we use medications.”
It is a positive that atogepant has emerged as another option for preventive therapy, but the treatment cannot be considered a breakthrough, Dr. Loder added. The efficacy of atogepant, like that of other preventive treatments for migraine, is modest.
“It would be so nice if we could find things that were more effective than the treatments we currently have,” said Dr. Loder.
A version of this article first appeared on Medscape.com.
the manufacturer announced in a release.
The once-daily medication will be available in doses of 10 mg, 30 mg, and 60 mg.
“Qulipta provides a simple oral treatment option specifically developed to prevent migraine attacks and target CGRP, which is believed to be crucially involved in migraine in many patients,” coinvestigator Peter J. Goadsby, MD, PhD, DSc, neurologist and professor at the University of California, Los Angeles, and King’s College London, said in the release.
Approval was based partly on the findings from the phase 3 ADVANCE trial, in which patients with episodic migraine were randomly assigned to receive placebo or a 10-mg, 30-mg, or 60-mg daily dose of atogepant for 12 weeks.
As reported by this news organization, all three doses of atogepant reduced the number of mean monthly migraine days.
With this approval, neurologists will be able to choose from four monoclonal antibodies and two gepants for the preventive treatment of migraine.
“Having another gepant that can also be given preventively is a good idea, because one may be better than the other for a patient,” Alan M. Rapoport, MD, past president of the International Headache Society and founder and director emeritus of the New England Center for Headache, Stamford, Conn., told this news organization.
“Once we have a year or so of experience with atogepant, we’ll have a pretty good idea of which one works better preventively,” said Dr. Rapoport, who was not involved with the research.
Practice changing?
In the ADVANCE trial, there was a reduction of 3.69 migraine days with the 10-mg dose, 3.86 days with the 30-mg dose, and 4.2 days with the 60-mg dose. Placebo was associated with a reduction of 2.48 migraine days.
In addition, more than half of patients in each atogepant arm achieved a reduction in mean monthly migraine days of 50% or greater. This outcome occurred in 55.6% of the 10-mg atogepant group, 58.7% of the 30-mg group, and 60.8% of the 60-mg group. Approximately 29% patients who received placebo achieved this outcome.
The data indicated that atogepant has a favorable safety profile. The most common adverse events associated with treatment were constipation, nausea, and upper respiratory tract infection.
Dr. Rapoport, who is also a clinical professor of neurology at UCLA, noted that he was impressed with the efficacy.
“I’m not as impressed with the adverse events, but they’re not serious, and they don’t necessarily last,” he said.
Although being able to prescribe a single drug for acute and preventive treatment may be an advantage, it remains to be seen whether the tolerability and price of atogepant will be barriers for patients, Dr. Rapoport added.
How the approval will affect clinical practice is also unclear, he noted.
“If you’re going to start someone on a preventive, especially if it’s a woman of childbearing potential, you might just consider one of the two gepants. Doctors will decide once they see how they work,” said Dr. Rapoport.
Not a ‘breakthrough’ treatment
Also commenting ahead of the approval, Elizabeth W. Loder, MD, vice chair for academic affairs in the department of neurology at Brigham and Women’s Hospital, Boston, noted that the “safety of these CGRP medications in pregnancy is uncertain, and there are theoretical reasons to be concerned about it.”
Unlike injectable CGRP medications, atogepant is eliminated from the body relatively quickly after the patient stops taking it, said Dr. Loder, who is also professor of neurology at Harvard Medical School, Boston. However, atogepant may not otherwise differ greatly from other medications of its type.
“I don’t see a reason to think that one of these oral CGRP medicines is much more effective than another one,” said Dr. Loder.
“In my mind, as a clinician who will be prescribing these for patients, it will be cost and the ease of getting it covered that makes the difference,” she added.
These questions may raise concerns. “Those of us who treat patients who do not have private insurance find it very difficult to get these medications for them, even in situations where they have exhausted other alternatives,” said Dr. Loder.
Patients insured by Medicare or Medicaid “usually have no avenue to get some of these new, expensive treatments,” she said.
The approval of atogepant for acute and preventive treatment shows that the distinction between these indications may be artificial, Dr. Loder noted. The approval “will, I hope, help people think more flexibly about the way in which we use medications.”
It is a positive that atogepant has emerged as another option for preventive therapy, but the treatment cannot be considered a breakthrough, Dr. Loder added. The efficacy of atogepant, like that of other preventive treatments for migraine, is modest.
“It would be so nice if we could find things that were more effective than the treatments we currently have,” said Dr. Loder.
A version of this article first appeared on Medscape.com.
the manufacturer announced in a release.
The once-daily medication will be available in doses of 10 mg, 30 mg, and 60 mg.
“Qulipta provides a simple oral treatment option specifically developed to prevent migraine attacks and target CGRP, which is believed to be crucially involved in migraine in many patients,” coinvestigator Peter J. Goadsby, MD, PhD, DSc, neurologist and professor at the University of California, Los Angeles, and King’s College London, said in the release.
Approval was based partly on the findings from the phase 3 ADVANCE trial, in which patients with episodic migraine were randomly assigned to receive placebo or a 10-mg, 30-mg, or 60-mg daily dose of atogepant for 12 weeks.
As reported by this news organization, all three doses of atogepant reduced the number of mean monthly migraine days.
With this approval, neurologists will be able to choose from four monoclonal antibodies and two gepants for the preventive treatment of migraine.
“Having another gepant that can also be given preventively is a good idea, because one may be better than the other for a patient,” Alan M. Rapoport, MD, past president of the International Headache Society and founder and director emeritus of the New England Center for Headache, Stamford, Conn., told this news organization.
“Once we have a year or so of experience with atogepant, we’ll have a pretty good idea of which one works better preventively,” said Dr. Rapoport, who was not involved with the research.
Practice changing?
In the ADVANCE trial, there was a reduction of 3.69 migraine days with the 10-mg dose, 3.86 days with the 30-mg dose, and 4.2 days with the 60-mg dose. Placebo was associated with a reduction of 2.48 migraine days.
In addition, more than half of patients in each atogepant arm achieved a reduction in mean monthly migraine days of 50% or greater. This outcome occurred in 55.6% of the 10-mg atogepant group, 58.7% of the 30-mg group, and 60.8% of the 60-mg group. Approximately 29% patients who received placebo achieved this outcome.
The data indicated that atogepant has a favorable safety profile. The most common adverse events associated with treatment were constipation, nausea, and upper respiratory tract infection.
Dr. Rapoport, who is also a clinical professor of neurology at UCLA, noted that he was impressed with the efficacy.
“I’m not as impressed with the adverse events, but they’re not serious, and they don’t necessarily last,” he said.
Although being able to prescribe a single drug for acute and preventive treatment may be an advantage, it remains to be seen whether the tolerability and price of atogepant will be barriers for patients, Dr. Rapoport added.
How the approval will affect clinical practice is also unclear, he noted.
“If you’re going to start someone on a preventive, especially if it’s a woman of childbearing potential, you might just consider one of the two gepants. Doctors will decide once they see how they work,” said Dr. Rapoport.
Not a ‘breakthrough’ treatment
Also commenting ahead of the approval, Elizabeth W. Loder, MD, vice chair for academic affairs in the department of neurology at Brigham and Women’s Hospital, Boston, noted that the “safety of these CGRP medications in pregnancy is uncertain, and there are theoretical reasons to be concerned about it.”
Unlike injectable CGRP medications, atogepant is eliminated from the body relatively quickly after the patient stops taking it, said Dr. Loder, who is also professor of neurology at Harvard Medical School, Boston. However, atogepant may not otherwise differ greatly from other medications of its type.
“I don’t see a reason to think that one of these oral CGRP medicines is much more effective than another one,” said Dr. Loder.
“In my mind, as a clinician who will be prescribing these for patients, it will be cost and the ease of getting it covered that makes the difference,” she added.
These questions may raise concerns. “Those of us who treat patients who do not have private insurance find it very difficult to get these medications for them, even in situations where they have exhausted other alternatives,” said Dr. Loder.
Patients insured by Medicare or Medicaid “usually have no avenue to get some of these new, expensive treatments,” she said.
The approval of atogepant for acute and preventive treatment shows that the distinction between these indications may be artificial, Dr. Loder noted. The approval “will, I hope, help people think more flexibly about the way in which we use medications.”
It is a positive that atogepant has emerged as another option for preventive therapy, but the treatment cannot be considered a breakthrough, Dr. Loder added. The efficacy of atogepant, like that of other preventive treatments for migraine, is modest.
“It would be so nice if we could find things that were more effective than the treatments we currently have,” said Dr. Loder.
A version of this article first appeared on Medscape.com.
Assessing headache severity via migraine symptoms can help predict outcomes
according to an analysis of data from thousands of headache sufferers who recorded variables like pain and duration in a daily digital diary.
“Our hope is that this work serves as foundational basis for better understanding the complexity of headache as a symptom-based condition,” James S. McGinley, PhD, of Vector Psychometric Group in Chapel Hill, N.C., and coauthors wrote. The study was published in Cephalalgia.
To evaluate whether keeping track of daily headache features can produce a useful, predictive score, the researchers reviewed data from migraine patients that were collected via N1‑Headache, a commercial digital health platform. Ultimately, information from 4,380 adults with a self-reported migraine diagnosis was analyzed; the sample was 90% female and their mean age was 37 years. Study participants reported an average of 33 headaches per month over the last 3 months. Nine patient-reported variables were initially considered in calculating the Headache Day Severity (HDS) score: pain intensity, headache duration, aura, pulsating/throbbing pain, unilateral pain, pain aggravation by activity, nausea/vomiting, photophobia, and phonophobia.
After determining that unilateral pain was not a meaningful variable, the researchers’ model found that, for every 1 standard deviation increase in HDS, the patient’s odds of physician visit increased by 71% (odds ratio, 1.71; 95% confidence interval, 1.32-2.21) and the odds of an ED visit increased by 342% (OR, 4.42; 95% CI, 2.23-7.60). They also found that the likelihood of missed work or school increased by 190% (OR, 2.90; 95% CI, 2.56-3.29), the chances of missing household work increased by 237% (OR, 3.37; 95% CI, 3.06-3.72) and the odds of missing other leisure or social activity increased by 228% (OR, 3.28; 95% CI, 2.97-3.64).
Tracking multiple variables
“We encourage all of our patients to monitor their headaches; there are just too many variables to try to keep it in your head,” Robert Cowan, MD, professor of neurology and chief of the division of headache medicine at Stanford (Calif.) University, said in an interview. He referenced a previous study from the University of Washington where patients were asked to track their headaches; that data was then compared against their self-reported headaches at a quarterly physician visit.
“What they found was there was absolutely no correlation with reported frequency of headache at the visit and what was seen in the tracker,” he said. “If patients had a headache in the previous 3 days before their visit, they felt that their headaches were poorly controlled. If they hadn’t, they thought their headaches were under good control. So the value of tracking is pretty clear.”
He added that, while not every headache sufferer needs to track their daily routines and symptoms, once those symptoms interfere with your life on a day-to-day basis, it’s probably time to consider keeping tabs on yourself with a tool of some sort. And while this study’s calculated HDS score supports the idea of migraine’s complexity, it also leaves unanswered the question of how to treat patients with severe symptoms.
“Frequently,” he said, “we’ll see patients who say: ‘I can deal with the pain, but the nausea makes it impossible to work, or the light sensitivity makes it impossible to go outside.’ The big question within the headache community is, can you treat migraine and have it address the whole spectrum, from dizziness to light sensitivity to sound sensitivity to vertigo, or should you be going after individual symptoms? That’s a controversy that rages on; I think most of us go for a combination. We’re in a polypharmacy phase: ‘If nausea is a big problem, take this, but we also try to prevent the whole migraine complex, so take this as well.’ ”
The authors acknowledged their study’s limitations, including the inability to determine how many participants’ migraines were formally diagnosed by a trained medical professional and the lack of generalizability of data from a convenience sample, though they added that patients who independently track their own headaches “may be representative of those who would participate in a clinical trial.” In addition, as seven of the nine features were collected in N1‑Headache on a yes/no scale, they recognized that “increasing the number of response options for each item may improve our ability to measure HDS.”
The study was funded by Amgen through the Competitive Grant Program in Migraine Research. The authors declared several potential conflicts of interest, including receiving funding, research support, salary, and honoraria from various pharmaceutical companies.
according to an analysis of data from thousands of headache sufferers who recorded variables like pain and duration in a daily digital diary.
“Our hope is that this work serves as foundational basis for better understanding the complexity of headache as a symptom-based condition,” James S. McGinley, PhD, of Vector Psychometric Group in Chapel Hill, N.C., and coauthors wrote. The study was published in Cephalalgia.
To evaluate whether keeping track of daily headache features can produce a useful, predictive score, the researchers reviewed data from migraine patients that were collected via N1‑Headache, a commercial digital health platform. Ultimately, information from 4,380 adults with a self-reported migraine diagnosis was analyzed; the sample was 90% female and their mean age was 37 years. Study participants reported an average of 33 headaches per month over the last 3 months. Nine patient-reported variables were initially considered in calculating the Headache Day Severity (HDS) score: pain intensity, headache duration, aura, pulsating/throbbing pain, unilateral pain, pain aggravation by activity, nausea/vomiting, photophobia, and phonophobia.
After determining that unilateral pain was not a meaningful variable, the researchers’ model found that, for every 1 standard deviation increase in HDS, the patient’s odds of physician visit increased by 71% (odds ratio, 1.71; 95% confidence interval, 1.32-2.21) and the odds of an ED visit increased by 342% (OR, 4.42; 95% CI, 2.23-7.60). They also found that the likelihood of missed work or school increased by 190% (OR, 2.90; 95% CI, 2.56-3.29), the chances of missing household work increased by 237% (OR, 3.37; 95% CI, 3.06-3.72) and the odds of missing other leisure or social activity increased by 228% (OR, 3.28; 95% CI, 2.97-3.64).
Tracking multiple variables
“We encourage all of our patients to monitor their headaches; there are just too many variables to try to keep it in your head,” Robert Cowan, MD, professor of neurology and chief of the division of headache medicine at Stanford (Calif.) University, said in an interview. He referenced a previous study from the University of Washington where patients were asked to track their headaches; that data was then compared against their self-reported headaches at a quarterly physician visit.
“What they found was there was absolutely no correlation with reported frequency of headache at the visit and what was seen in the tracker,” he said. “If patients had a headache in the previous 3 days before their visit, they felt that their headaches were poorly controlled. If they hadn’t, they thought their headaches were under good control. So the value of tracking is pretty clear.”
He added that, while not every headache sufferer needs to track their daily routines and symptoms, once those symptoms interfere with your life on a day-to-day basis, it’s probably time to consider keeping tabs on yourself with a tool of some sort. And while this study’s calculated HDS score supports the idea of migraine’s complexity, it also leaves unanswered the question of how to treat patients with severe symptoms.
“Frequently,” he said, “we’ll see patients who say: ‘I can deal with the pain, but the nausea makes it impossible to work, or the light sensitivity makes it impossible to go outside.’ The big question within the headache community is, can you treat migraine and have it address the whole spectrum, from dizziness to light sensitivity to sound sensitivity to vertigo, or should you be going after individual symptoms? That’s a controversy that rages on; I think most of us go for a combination. We’re in a polypharmacy phase: ‘If nausea is a big problem, take this, but we also try to prevent the whole migraine complex, so take this as well.’ ”
The authors acknowledged their study’s limitations, including the inability to determine how many participants’ migraines were formally diagnosed by a trained medical professional and the lack of generalizability of data from a convenience sample, though they added that patients who independently track their own headaches “may be representative of those who would participate in a clinical trial.” In addition, as seven of the nine features were collected in N1‑Headache on a yes/no scale, they recognized that “increasing the number of response options for each item may improve our ability to measure HDS.”
The study was funded by Amgen through the Competitive Grant Program in Migraine Research. The authors declared several potential conflicts of interest, including receiving funding, research support, salary, and honoraria from various pharmaceutical companies.
according to an analysis of data from thousands of headache sufferers who recorded variables like pain and duration in a daily digital diary.
“Our hope is that this work serves as foundational basis for better understanding the complexity of headache as a symptom-based condition,” James S. McGinley, PhD, of Vector Psychometric Group in Chapel Hill, N.C., and coauthors wrote. The study was published in Cephalalgia.
To evaluate whether keeping track of daily headache features can produce a useful, predictive score, the researchers reviewed data from migraine patients that were collected via N1‑Headache, a commercial digital health platform. Ultimately, information from 4,380 adults with a self-reported migraine diagnosis was analyzed; the sample was 90% female and their mean age was 37 years. Study participants reported an average of 33 headaches per month over the last 3 months. Nine patient-reported variables were initially considered in calculating the Headache Day Severity (HDS) score: pain intensity, headache duration, aura, pulsating/throbbing pain, unilateral pain, pain aggravation by activity, nausea/vomiting, photophobia, and phonophobia.
After determining that unilateral pain was not a meaningful variable, the researchers’ model found that, for every 1 standard deviation increase in HDS, the patient’s odds of physician visit increased by 71% (odds ratio, 1.71; 95% confidence interval, 1.32-2.21) and the odds of an ED visit increased by 342% (OR, 4.42; 95% CI, 2.23-7.60). They also found that the likelihood of missed work or school increased by 190% (OR, 2.90; 95% CI, 2.56-3.29), the chances of missing household work increased by 237% (OR, 3.37; 95% CI, 3.06-3.72) and the odds of missing other leisure or social activity increased by 228% (OR, 3.28; 95% CI, 2.97-3.64).
Tracking multiple variables
“We encourage all of our patients to monitor their headaches; there are just too many variables to try to keep it in your head,” Robert Cowan, MD, professor of neurology and chief of the division of headache medicine at Stanford (Calif.) University, said in an interview. He referenced a previous study from the University of Washington where patients were asked to track their headaches; that data was then compared against their self-reported headaches at a quarterly physician visit.
“What they found was there was absolutely no correlation with reported frequency of headache at the visit and what was seen in the tracker,” he said. “If patients had a headache in the previous 3 days before their visit, they felt that their headaches were poorly controlled. If they hadn’t, they thought their headaches were under good control. So the value of tracking is pretty clear.”
He added that, while not every headache sufferer needs to track their daily routines and symptoms, once those symptoms interfere with your life on a day-to-day basis, it’s probably time to consider keeping tabs on yourself with a tool of some sort. And while this study’s calculated HDS score supports the idea of migraine’s complexity, it also leaves unanswered the question of how to treat patients with severe symptoms.
“Frequently,” he said, “we’ll see patients who say: ‘I can deal with the pain, but the nausea makes it impossible to work, or the light sensitivity makes it impossible to go outside.’ The big question within the headache community is, can you treat migraine and have it address the whole spectrum, from dizziness to light sensitivity to sound sensitivity to vertigo, or should you be going after individual symptoms? That’s a controversy that rages on; I think most of us go for a combination. We’re in a polypharmacy phase: ‘If nausea is a big problem, take this, but we also try to prevent the whole migraine complex, so take this as well.’ ”
The authors acknowledged their study’s limitations, including the inability to determine how many participants’ migraines were formally diagnosed by a trained medical professional and the lack of generalizability of data from a convenience sample, though they added that patients who independently track their own headaches “may be representative of those who would participate in a clinical trial.” In addition, as seven of the nine features were collected in N1‑Headache on a yes/no scale, they recognized that “increasing the number of response options for each item may improve our ability to measure HDS.”
The study was funded by Amgen through the Competitive Grant Program in Migraine Research. The authors declared several potential conflicts of interest, including receiving funding, research support, salary, and honoraria from various pharmaceutical companies.
FROM CEPHALALGIA
Atogepant reduces migraine days: ADVANCE trial results published
full results from a phase 3 trial suggest.
AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.
The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.
The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.
“Overall, this study showed us that atogepant was safe and surprisingly seems to be pretty effective regardless of the dose,” said lead author Jessica Ailani, MD, director of MedStar Georgetown Headache Center and associate professor of neurology at Georgetown University, Washington.
All doses effective
The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.
After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.
The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).
Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).
In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).
The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
Multidose flexibility
“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.
The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.
“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.
Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”
An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.
“You can easily identify patients who would do well on this medication,” she added.
In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
“Well-conducted study”
Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.
The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.
The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.
It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”
In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”
Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.
The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
full results from a phase 3 trial suggest.
AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.
The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.
The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.
“Overall, this study showed us that atogepant was safe and surprisingly seems to be pretty effective regardless of the dose,” said lead author Jessica Ailani, MD, director of MedStar Georgetown Headache Center and associate professor of neurology at Georgetown University, Washington.
All doses effective
The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.
After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.
The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).
Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).
In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).
The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
Multidose flexibility
“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.
The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.
“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.
Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”
An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.
“You can easily identify patients who would do well on this medication,” she added.
In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
“Well-conducted study”
Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.
The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.
The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.
It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”
In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”
Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.
The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
full results from a phase 3 trial suggest.
AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.
The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.
The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.
“Overall, this study showed us that atogepant was safe and surprisingly seems to be pretty effective regardless of the dose,” said lead author Jessica Ailani, MD, director of MedStar Georgetown Headache Center and associate professor of neurology at Georgetown University, Washington.
All doses effective
The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.
After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.
The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).
Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).
In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).
The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
Multidose flexibility
“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.
The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.
“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.
Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”
An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.
“You can easily identify patients who would do well on this medication,” she added.
In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
“Well-conducted study”
Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.
The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.
The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.
It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”
In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”
Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.
The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Headache seen affecting some pregnancy outcomes
, according to results from an observational study.
Migraine during pregnancy has been associated in previous studies with hypertensive pregnancy complications including preeclampsia; however, little is known about other headache types and their effects on pregnancy and birth outcomes.
For their research, published online July 20 in Cephalalgia, Isabella Neri, MD, PhD, and colleagues at Hospital Policlinico of Modena, Italy, looked at headache status for 515 consecutive pregnant women evaluated during their first trimester and followed through childbirth.
Altogether 224 women, or 43.5% of the cohort, were diagnosed with migraine without aura (n = 72), migraine with aura (n = 27), or tension-type headache (n = 125). The authors did not report on the severity or frequency of headaches.
Women with migraine with aura and tension-type headache saw higher rates of small-for-gestational-age infants (25.9% and 10.4% of births, respectively) compared with 5.5% for women without headache. Women presenting with tension-type headache saw elevated risk for small-for-gestational-age infants (odds ratio [OR] 4.19, P = .004) as did women with migraine with aura (OR 5.37, P = .02).
Admission to neonatal intensive care was significantly higher in all the headache groups. However, the authors found no statistically significant associations between headaches and any other perinatal outcome investigated in the study, including gestational diabetes, placental abruption, gestational hypertension, and preterm delivery.
A previous study conducted by the same research group had reported a relationship between migraine and gestational hypertension. The authors cited the small sample size of the migraine groups in the current study, “the diverse features of the population,” and the popularity of low-dose aspirin administration as potentially affecting that outcome.
Interpret findings with caution
Asked by this news organization to comment on the research, two headache neurologists praised Dr. Neri and colleagues’ research for focusing on an understudied topic – but also said that the results would not change their practice unless replicated in larger studies.
Elizabeth W. Loder, MD, MPH, chief emeritus of the division of headache at Brigham and Women’s Faulkner Hospital in Boston, urged caution in interpreting the findings, particularly with regard to tension-type headache. “This study adds to information suggesting that pregnancy complications probably are higher in women who have migraine with aura, and there’s biological plausibility for that,” Dr. Loder said. “Having aura means you may have some vascular abnormalities and things that logically might be associated with an increased risk of small-for-gestational age infants.” But the small size of the migraine-with-aura group in this study – 27 women – and the fact that other perinatal outcomes measured in the study did not reach significance, allows for the possibility that the small-for-gestational-age findings were due to chance, Dr. Loder noted.
With tension-type headache, a biological rationale for small-for-gestational-age risk is more elusive, Dr. Loder said. “I would want to see that association replicated in another study before I thought that I needed to warn women with tension-type headache about this potential outcome. There’s lot of uncertainty here about the magnitude of the risk.”
While Dr. Neri and colleagues described the instruments used in their study to diagnose migraine and migraine with aura, they did not explain how tension-type headache was diagnosed.
Tension-type headache, while common, is still not well characterized, Dr. Loder noted, and may represent a heterogeneous condition or the milder end of a biological continuum that includes migraine with aura. Also, the group in the study had a higher prevalence of smoking, and though the authors made statistical adjustments for smoking status, “smokers are systematically different than people who aren’t in other ways that could be associated with these outcomes,” Dr. Loder said.
While the authors of the study suggested that interventions might be indicated for women with tension-type headache in pregnancy, “showing an association doesn’t necessarily mean that intervening would make a difference” on pregnancy outcomes, Dr. Loder said.
Amaal J. Starling, MD, of the Mayo Clinic in Phoenix, Ariz., said in an interview that she, too, appreciated that this study looked at pregnancy outcomes in the setting of headache disorders. “Unfortunately even though headache disorders and especially migraine affect women so much, we still know very little about migraine in pregnancy,” she said.
Dr. Starling noted that many women with migraine are discouraged by their health care providers from becoming pregnant, because of the false belief that migraine cannot be managed in pregnancy. In her own practice, she said, she treats many patients with severe headache who become pregnant and who require pharmacological intervention during pregnancy.
This does not mean she regards headache in pregnancy as innocent. “I want patients to be on high alert for changes in headache symptoms in pregnancy. If someone has worsening of headache or migraine or aura in the setting of pregnancy, we consider that a red flag,” potentially indicating complications such as high blood pressure, gestational hypertension, or a blood clot.
Like Dr. Loder, Dr. Starling said she was not surprised by Dr. Neri and colleagues’ finding that migraine with aura might impact pregnancy outcomes. “We know that migraine with aura has a lot of vascular abnormalities that underlie the pathogenesis,” she said.
Dr. Starling found the findings related to tension-type headache less convincing, not least because the diagnostic criteria for tension-type headache was not made clear in the study. “I view this as an exploratory study that says maybe there’s a signal here. A larger epidemiological study would need to be done to confirm or refute this data,” Dr. Starling said. Until the findings can be replicated, “this study would not affect my clinical practice in any way.”
Dr. Neri and colleagues described no outside funding for their research or financial conflicts of interest. Dr. Starling has received consulting fees from pharmaceutical manufacturers but reported no disclosures relevant to the study discussed. Dr. Loder reported no financial conflicts of interest.
, according to results from an observational study.
Migraine during pregnancy has been associated in previous studies with hypertensive pregnancy complications including preeclampsia; however, little is known about other headache types and their effects on pregnancy and birth outcomes.
For their research, published online July 20 in Cephalalgia, Isabella Neri, MD, PhD, and colleagues at Hospital Policlinico of Modena, Italy, looked at headache status for 515 consecutive pregnant women evaluated during their first trimester and followed through childbirth.
Altogether 224 women, or 43.5% of the cohort, were diagnosed with migraine without aura (n = 72), migraine with aura (n = 27), or tension-type headache (n = 125). The authors did not report on the severity or frequency of headaches.
Women with migraine with aura and tension-type headache saw higher rates of small-for-gestational-age infants (25.9% and 10.4% of births, respectively) compared with 5.5% for women without headache. Women presenting with tension-type headache saw elevated risk for small-for-gestational-age infants (odds ratio [OR] 4.19, P = .004) as did women with migraine with aura (OR 5.37, P = .02).
Admission to neonatal intensive care was significantly higher in all the headache groups. However, the authors found no statistically significant associations between headaches and any other perinatal outcome investigated in the study, including gestational diabetes, placental abruption, gestational hypertension, and preterm delivery.
A previous study conducted by the same research group had reported a relationship between migraine and gestational hypertension. The authors cited the small sample size of the migraine groups in the current study, “the diverse features of the population,” and the popularity of low-dose aspirin administration as potentially affecting that outcome.
Interpret findings with caution
Asked by this news organization to comment on the research, two headache neurologists praised Dr. Neri and colleagues’ research for focusing on an understudied topic – but also said that the results would not change their practice unless replicated in larger studies.
Elizabeth W. Loder, MD, MPH, chief emeritus of the division of headache at Brigham and Women’s Faulkner Hospital in Boston, urged caution in interpreting the findings, particularly with regard to tension-type headache. “This study adds to information suggesting that pregnancy complications probably are higher in women who have migraine with aura, and there’s biological plausibility for that,” Dr. Loder said. “Having aura means you may have some vascular abnormalities and things that logically might be associated with an increased risk of small-for-gestational age infants.” But the small size of the migraine-with-aura group in this study – 27 women – and the fact that other perinatal outcomes measured in the study did not reach significance, allows for the possibility that the small-for-gestational-age findings were due to chance, Dr. Loder noted.
With tension-type headache, a biological rationale for small-for-gestational-age risk is more elusive, Dr. Loder said. “I would want to see that association replicated in another study before I thought that I needed to warn women with tension-type headache about this potential outcome. There’s lot of uncertainty here about the magnitude of the risk.”
While Dr. Neri and colleagues described the instruments used in their study to diagnose migraine and migraine with aura, they did not explain how tension-type headache was diagnosed.
Tension-type headache, while common, is still not well characterized, Dr. Loder noted, and may represent a heterogeneous condition or the milder end of a biological continuum that includes migraine with aura. Also, the group in the study had a higher prevalence of smoking, and though the authors made statistical adjustments for smoking status, “smokers are systematically different than people who aren’t in other ways that could be associated with these outcomes,” Dr. Loder said.
While the authors of the study suggested that interventions might be indicated for women with tension-type headache in pregnancy, “showing an association doesn’t necessarily mean that intervening would make a difference” on pregnancy outcomes, Dr. Loder said.
Amaal J. Starling, MD, of the Mayo Clinic in Phoenix, Ariz., said in an interview that she, too, appreciated that this study looked at pregnancy outcomes in the setting of headache disorders. “Unfortunately even though headache disorders and especially migraine affect women so much, we still know very little about migraine in pregnancy,” she said.
Dr. Starling noted that many women with migraine are discouraged by their health care providers from becoming pregnant, because of the false belief that migraine cannot be managed in pregnancy. In her own practice, she said, she treats many patients with severe headache who become pregnant and who require pharmacological intervention during pregnancy.
This does not mean she regards headache in pregnancy as innocent. “I want patients to be on high alert for changes in headache symptoms in pregnancy. If someone has worsening of headache or migraine or aura in the setting of pregnancy, we consider that a red flag,” potentially indicating complications such as high blood pressure, gestational hypertension, or a blood clot.
Like Dr. Loder, Dr. Starling said she was not surprised by Dr. Neri and colleagues’ finding that migraine with aura might impact pregnancy outcomes. “We know that migraine with aura has a lot of vascular abnormalities that underlie the pathogenesis,” she said.
Dr. Starling found the findings related to tension-type headache less convincing, not least because the diagnostic criteria for tension-type headache was not made clear in the study. “I view this as an exploratory study that says maybe there’s a signal here. A larger epidemiological study would need to be done to confirm or refute this data,” Dr. Starling said. Until the findings can be replicated, “this study would not affect my clinical practice in any way.”
Dr. Neri and colleagues described no outside funding for their research or financial conflicts of interest. Dr. Starling has received consulting fees from pharmaceutical manufacturers but reported no disclosures relevant to the study discussed. Dr. Loder reported no financial conflicts of interest.
, according to results from an observational study.
Migraine during pregnancy has been associated in previous studies with hypertensive pregnancy complications including preeclampsia; however, little is known about other headache types and their effects on pregnancy and birth outcomes.
For their research, published online July 20 in Cephalalgia, Isabella Neri, MD, PhD, and colleagues at Hospital Policlinico of Modena, Italy, looked at headache status for 515 consecutive pregnant women evaluated during their first trimester and followed through childbirth.
Altogether 224 women, or 43.5% of the cohort, were diagnosed with migraine without aura (n = 72), migraine with aura (n = 27), or tension-type headache (n = 125). The authors did not report on the severity or frequency of headaches.
Women with migraine with aura and tension-type headache saw higher rates of small-for-gestational-age infants (25.9% and 10.4% of births, respectively) compared with 5.5% for women without headache. Women presenting with tension-type headache saw elevated risk for small-for-gestational-age infants (odds ratio [OR] 4.19, P = .004) as did women with migraine with aura (OR 5.37, P = .02).
Admission to neonatal intensive care was significantly higher in all the headache groups. However, the authors found no statistically significant associations between headaches and any other perinatal outcome investigated in the study, including gestational diabetes, placental abruption, gestational hypertension, and preterm delivery.
A previous study conducted by the same research group had reported a relationship between migraine and gestational hypertension. The authors cited the small sample size of the migraine groups in the current study, “the diverse features of the population,” and the popularity of low-dose aspirin administration as potentially affecting that outcome.
Interpret findings with caution
Asked by this news organization to comment on the research, two headache neurologists praised Dr. Neri and colleagues’ research for focusing on an understudied topic – but also said that the results would not change their practice unless replicated in larger studies.
Elizabeth W. Loder, MD, MPH, chief emeritus of the division of headache at Brigham and Women’s Faulkner Hospital in Boston, urged caution in interpreting the findings, particularly with regard to tension-type headache. “This study adds to information suggesting that pregnancy complications probably are higher in women who have migraine with aura, and there’s biological plausibility for that,” Dr. Loder said. “Having aura means you may have some vascular abnormalities and things that logically might be associated with an increased risk of small-for-gestational age infants.” But the small size of the migraine-with-aura group in this study – 27 women – and the fact that other perinatal outcomes measured in the study did not reach significance, allows for the possibility that the small-for-gestational-age findings were due to chance, Dr. Loder noted.
With tension-type headache, a biological rationale for small-for-gestational-age risk is more elusive, Dr. Loder said. “I would want to see that association replicated in another study before I thought that I needed to warn women with tension-type headache about this potential outcome. There’s lot of uncertainty here about the magnitude of the risk.”
While Dr. Neri and colleagues described the instruments used in their study to diagnose migraine and migraine with aura, they did not explain how tension-type headache was diagnosed.
Tension-type headache, while common, is still not well characterized, Dr. Loder noted, and may represent a heterogeneous condition or the milder end of a biological continuum that includes migraine with aura. Also, the group in the study had a higher prevalence of smoking, and though the authors made statistical adjustments for smoking status, “smokers are systematically different than people who aren’t in other ways that could be associated with these outcomes,” Dr. Loder said.
While the authors of the study suggested that interventions might be indicated for women with tension-type headache in pregnancy, “showing an association doesn’t necessarily mean that intervening would make a difference” on pregnancy outcomes, Dr. Loder said.
Amaal J. Starling, MD, of the Mayo Clinic in Phoenix, Ariz., said in an interview that she, too, appreciated that this study looked at pregnancy outcomes in the setting of headache disorders. “Unfortunately even though headache disorders and especially migraine affect women so much, we still know very little about migraine in pregnancy,” she said.
Dr. Starling noted that many women with migraine are discouraged by their health care providers from becoming pregnant, because of the false belief that migraine cannot be managed in pregnancy. In her own practice, she said, she treats many patients with severe headache who become pregnant and who require pharmacological intervention during pregnancy.
This does not mean she regards headache in pregnancy as innocent. “I want patients to be on high alert for changes in headache symptoms in pregnancy. If someone has worsening of headache or migraine or aura in the setting of pregnancy, we consider that a red flag,” potentially indicating complications such as high blood pressure, gestational hypertension, or a blood clot.
Like Dr. Loder, Dr. Starling said she was not surprised by Dr. Neri and colleagues’ finding that migraine with aura might impact pregnancy outcomes. “We know that migraine with aura has a lot of vascular abnormalities that underlie the pathogenesis,” she said.
Dr. Starling found the findings related to tension-type headache less convincing, not least because the diagnostic criteria for tension-type headache was not made clear in the study. “I view this as an exploratory study that says maybe there’s a signal here. A larger epidemiological study would need to be done to confirm or refute this data,” Dr. Starling said. Until the findings can be replicated, “this study would not affect my clinical practice in any way.”
Dr. Neri and colleagues described no outside funding for their research or financial conflicts of interest. Dr. Starling has received consulting fees from pharmaceutical manufacturers but reported no disclosures relevant to the study discussed. Dr. Loder reported no financial conflicts of interest.
FROM CEPHALALGIA
Devices for the treatment of migraine
Remote upper arm neuromodulation and combined occipital and trigeminal neuromodulation lead the way as the newest entries to the field, followed by 8 other devices that are now available or are expected to be soon.
The increasing array of prescription medications for the treatment of migraine are welcome additions for patients who suffer from this life-altering condition and the clinicians who treat it; but not all individuals tolerate oral and injectable therapies, and others face the risk of adverse events and medication overuse headache.1 Fortunately, there are a number of devices available to consider, and still others are awaiting approval from the US Food and Drug Administration (FDA).
Two of the most promising devices are remote upper arm neuromodulation (REN) and combined occipital and trigeminal neuromodulation. Here we highlight data from pivotal trials evaluating these 2 treatment options and provide information about other devices worth consideration.
Remote Upper Arm Neuromodulation (REN)
Nerivio was initially authorized by the FDA for the acute treatment of episodic migraine. Available by prescription, the device is administered by the patient at home.2 It stimulates upper arm peripheral nerves, which induces conditioned pain modulation (CPM) that inhibits pain in remote parts of the body. In other words, a descending, endogenous analgesic “pain inhibits pain” mechanism is used.
The initial authorization was based on the results of a randomized, double-blind, sham-controlled, multicenter study involving 252 individuals who were experiencing 2 to 8 migraine headaches per month. Participants were assigned to either a treatment group (n=126), where the device was applied for 30 to 45 minutes within an hour of a migraine attack, or to a sham treatment group (n=126). Investigators looked at migraine pain levels at baseline and at 2 and 48 hours post-treatment, as well as patient-reported most bothersome symptoms. They found that REN provided superior, clinically meaningful relief from migraine pain and the most bothersome symptoms, as follows3:
- 67% of patients in the active treatment group achieved a response at 2 hours vs 39% of individuals in the sham-treatment group
- Pain-free rates at 2 hours in each group were 37% and 18%, respectively
- Most bothersome symptom relief rates at 2 hours were 46% and 22%, respectively
Additionally, pain relief and pain-free responses were sustained at 48 hours. Nearly 40% of active treatment participants still reported pain relief at 48 hours, with pain-free rates at 48 hours in each group of 21% and 8%, respectively. The adverse event rate was low. The most commonly reported adverse event in the active-treatment group was a sensation of warmth (2.4%). Arm pain (1.6%), redness (1.6%), and numbness (0.8%) were also reported in those receiving active treatment.3
In 2020, REN received authorization for the acute treatment of chronic migraine in adults, and the following year authorization was expanded to include adolescent migraine. This development offered a nonpharmacologic treatment approach for migraine sufferers who experience 15 or more headache days per month, which is significant because it reduces the likelihood of medication overuse headache.
Approval for chronic migraine was based on results of an open-label, single-arm, dual-center study involving 38 individuals with chronic migraine. Participants used the device over 4 weeks within 1 hour of a migraine attack. Investigators assessed pain levels at 2 and 24 hours after use; they defined consistency of response as response to at least half of the treatments. The study demonstrated the following4:
- 74% of patients attained pain relief at 2 hours
- 26% were pain free at 2 hours
- 84% achieved sustained pain relief at 24 hours
- 45% achieved sustained pain relief at 24 hours in at least half of their treated attacks
- <2% of participants experienced device-related adverse events
The authors concluded that REN could be used for a series of migraine attacks and is a safe and effective nonpharmacologic approach for individuals who suffer from chronic migraine.4
The findings from these trials are supported by a subsequent trial published earlier this year. This open-label, single-arm study evaluated 91 individuals with chronic migraine who were treated with REN for 4 weeks. Investigators assessed pain levels, associated pain symptoms, and functional disability at baseline as well as at 2 and 24 hours post-treatment. Of the patients in this study5:
- At 2 hours, 59% achieved pain relief, and 21% reported that their pain disappeared
- 73% noted sustained pain relief at 24 hours
- REN was shown to impact nausea, photophobia, and phonophobia favorably, and patients’ functional ability also improved after use
Results from 2 additional trials were also recently released. One study involving 35 adolescents treated with either REN or standard-of-care medications showed REN to be superior with regard to pain freedom (37% vs 9%), consistency of pain freedom (40% vs 9%), pain relief (71% vs 57%), and consistency of pain relief (80% vs 57%).6 The other study included 91 women with a history of menstrual migraine and at least 4 REN treatments. Nearly 75% of patients reported Nerivio to be at least moderately effective, 45% said they were satisfied with the treatment, and all participants noted that it was at least moderately tolerable.7
Combined Occipital and Trigeminal Neuromodulation
In March 2021, the FDA authorized combined occipital and trigeminal neuromodulation (Relivion) for self-treatment of acute migraine.8 It is not yet commercially available, but it will require a prescription. The headset-like device stimulates the occipital and trigeminal nerves by delivering precise modulated pulses simultaneously to 6 branches of the occipital and trigeminal nerves via 3 adaptive output channels. The occipital and trigeminal nerves conduct the signals directly to the brainstem, which maximizes the synergistic effect.9
The results of 2 clinical trials led to FDA approval. These studies have not yet been published in a peer-reviewed journal. The first study, presented at the 61st Annual Scientific Meeting of the American Headache Society in 2019, was a prospective, randomized, double-blind, parallel-group, sham-controlled clinical study involving 55 individuals with chronic or episodic migraine. Participants administered the device for 1 hour soon after migraine onset or administered a sham treatment. Researchers looked at pain score change from baseline to 1 hour post-treatment, as well as pain intensity at baseline and at 1, 2, and 24 hours post-treatment. The study showed that 76% of participants in the active-treatment group experienced headache relief at 2 hours vs 32% in the sham-treatment contingent. No serious adverse events were reported.10 The investigators hypothesized that the positive results observed were a result of the synergistic neuromodulatory effect elicited by concurrent activation of the occipital and trigeminal neural pathways.
Following this study, there was a multi-center, prospective, randomized, double-blind, placebo-controlled clinical trial involving 131 individuals with migraine with or without aura. Participants were assigned to either active treatment or placebo. Investigators assessed reported migraine pain reduction at 2 hours, as well as improvement in most bothersome symptoms after 2 hours, reported pain reduction at 1 hour, and being pain-free at 2 hours. At 2 hours post-treatment11:
- 46% of individuals who were actively treated reached complete freedom from pain vs 12% in the control group
- 75% of active-treatment participants reported being completely free of their most bothersome symptom vs 47% of control patients
- The rates of complete freedom from migraine symptoms were 47% and 11%, respectively
- The rates of pain relief after 2 hours were 60% and 37%, respectively
- No serious adverse events were noted
A systematic review and meta-analysis of 13 studies involving 221 individuals published earlier this year looked at changes in pain scores and response rates to implantable peripheral nerve stimulation for trigeminal neuropathic pain. The response rate to neuromodulation therapy was 61%, the reduction in overall pain scores (2.363) was significant, and a subgroup assessment revealed that the stimulation target (peripheral branch, trigeminal ganglion, or trigeminal nerve root) was responsible for heterogeneity across the studies analyzed. Furthermore, stimulating the trigeminal peripheral branch resulted in better clinical outcomes. The authors noted that their findings reinforce the promise of implantable therapy, particularly for individuals who do not tolerate traditional therapies.12
Looking forward, new data are scheduled to be presented at the International Headache Virtual Congress in September 2021 showing that neuromodulation therapy is highly effective in reducing monthly headache days in individuals who suffer from difficult-to-treat migraine. A larger-scale, double-blind, sham-controlled study is planned to further establish these findings.
Other FDA-Approved Therapies
A number of other devices are available for treatment of migraine headache, including:
- Transcranial magnetic stimulation (TMS). In a randomized trial involving 164 individuals with migraine, 39% of the individuals receiving treatment were pain-free at 2 hours vs 22% of those given sham treatment13
- Noninvasive vagal nerve stimulation (nVNS). This is performed using a handheld device that is controlled by the patient, which preferentially activates afferent A and large B fibers. In a randomized trial involving 243 individuals, pain-free rates at 30, 60, and 120 minutes for patients receiving active treatment were 13%, 21%, and 30%, respectively. Rates for those receiving sham treatment were 4%, 10%, and 20%, respectively.14
- Sumatriptan nasal spray (10 mg) with a permeation enhancer. A randomized phase 2 trial involving 107 individuals found that 44% of participants in the treatment group achieved pain freedom at 2 hours vs 23% who received placebo. The spray appears to work quickly and with fewer adverse events than generic sumatriptan 20 mg nasal spray.15
- Transcutaneous supraorbital nerve stimulation (tSNS). Available without a prescription, there are 3 devices that can treat acute migraine; prevent acute migraine; or both.
Therapies Awaiting FDA Approval
There are several therapeutic options in the pipeline that have not yet been authorized by the FDA.
- Zavegepant (formerly known as vazegepant) nasal spray.16 This third-generation small molecule calcitonin gene-related peptide (CGRP) receptor antagonist has been demonstrated to work as a nasal spray in individuals with migraine. In a phase 1 study, the spray was shown to reach maximal concentration earlier than with other CGRP receptor antagonists.17 A phase 2/3 placebo-controlled trial demonstrated sustained pain freedom from 2 to 48 hours with 5-mg, 10-mg, and 20-mg dosages. The 10-mg and 20-mg doses were statistically superior to placebo on the co-primary endpoints of pain freedom and freedom from most bothersome symptom at 2 hours using a single dose. Sustained pain relief from 2 to 48 hours was seen with the 5-mg and 10-mg dosages18
- Sphenopalatine ganglion (SPG) stimulation. This is a microstimulator that is inserted orally, designed to fit the face, and directly targets SPG. Stimulation is active and controlled by the patient. A randomized, sham-controlled trial evaluated acute pain relief as well as pain freedom and found that those receiving treatment were more than twice as likely to experience pain relief and pain freedom19
- Adhesive dermally applied microneedle system (ADAM). This is a transdermal patch containing microprojections, which can be coated with both large and small molecules. In a randomized trial, 42% of treated participants reported being pain free at 2 hours vs 14% of placebo-treated patients. Rates of freedom from most bothersome symptom were 68% and 43%, respectively20
- Dihydroergotamine (DHE) nasal powder spray and intranasal liquid. Both therapies are awaiting FDA approval. The mucoadhesive powder formulation facilitates rapid drug absorption and is offered in a single-use nasal delivery device. In clinical trials, the spray demonstrated the device’s simplicity, reliability, and ease of use.21 The intranasal liquid is designed to deliver the drug into the vascular-rich upper nasal space. In the phase 3 trial that included 354 patients, 66.3% of patients reported pain relief, 38% of patients reported pain freedom, and 52% had freedom from their most bothersome migraine symptom at 2 hours following their first dose.22
References
1. Rapoport AM. Medication overuse headache: preventive treatment with or without detoxification? Published May 24, 2021. Accessed August 13, 2021. https://www.mdedge.com/migraine-icymi/article/240472/headache-migraine/medication-overuse-headache-preventive-treatment-or
2. How to prescribe Nerivio. Theranica. Accessed August 13, 2021. https://nerivio.co/prescribe/
3. Yarnitsky D, Dodick DW, Grosberg BM, et al. Remote electrical neuromodulation (REN) relieves acute migraine: a randomized, double-blind, placebo-controlled, multicenter trial. Headache. 2019;59(8):1240-1252.
4. Nierenburg H, Vieira JR, Lev N, et al. Remote electrical neuromodulation for the acute treatment of migraine in patients with chronic migraine: an open-label pilot study. Pain Ther. 2020;9(2):531-543.
5. Grosberg B, Lin T, Vizel M, Schim J. Remote electrical neuromodulation for the acute treatment of chronic migraine (2007). Neurology. 2021;96(15 Suppl) 2007.
6. Hershey AD, Irwin S, Rabany L, et al. Comparison of remote electrical neuromodulation (REN) and standard-care medications for acute treatment of migraine in adolescents: a post-hoc analysis. Pain Med. 2021 June 29;pnab197. doi: 10.1093/pm/pnab197. [Epub ahead of print].
7. Nierenburg H, Rabany L, Lin T, et al. Remote electrical neuromodulation (REN) for the acute treatment of menstrual migraine: a retrospective survey study of effectiveness and tolerability. Pain Ther. 2021 Jun 17. doi: 10.1007/s40122-021-00276-7. [Epub ahead of print].
8. Brooks M. FDA clears neuromodulation device for acute migraine pain. Published March 2, 2021. Accessed August 13, 2021. https://www.medscape.com/viewarticle/946700
9. A new ecosystem for brain neuromodulation. Neurolief. Accessed August 13, 2021. https://www.neurolief.com/technology/
10. Daniel O, Tepper SJ. First non-invasive combined occipital & trigeminal nerve stimulation digital therapeutics system for treatment of migraine: a randomized, sham-controlled, double-blind clinical trial. Published 2019. Accessed August 13, 2021. https://www.neurolief.com/wp-content/uploads/2019/07/American-Headache-Society2019-Abstract-Oved-Daniel-Stewart-Tepper.pdf
11. Neurolief announces positive results from RIME clinical study of its brain neuromodulation system for treating acute migraine. BusinessWire. Published January 6, 2021. Accessed August 13, 2021. https://www.businesswire.com/news/home/20210106005510/en/Neurolief-Announces-Positive-Results-From-RIME-Clinical-Study-of-Its-Brain-Neuromodulation-System-for-Treating-Acute-Migraine
12. Ni Y, Yang L, Han R, et al. Implantable peripheral nerve stimulation for trigeminal neuropathic pain: a systematic review and meta-analysis. Neuromodulation. 2021 May 18. doi: 10.1111/ner.13421. [Epub ahead of print].
13. Lipton RB, Dodick DW, Silberstein SD, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomized, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 2010;9(4):373-380.
14. PRESTO clinical trial overview. electroCore. Published 2018. Accessed August 13, 2021. https://www.electrocore.com/wp-content/themes/wp-starter/includes/images/PRESTO_Clinical_Trial_Fact_Sheet_3.29.18.pdf
15. Lipton RB, Munjal S, Brand-Schieber E, Rapoport AM. DFN-02 (sumatriptan 10 mg with a permeation enhancer) nasal spray vs placebo in the acute treatment of migraine: a double-blind, placebo-controlled study. Headache. 2018;58(5):676-687.
16. Clinical trials. Biohaven Pharmaceuticals. Accessed August 14, 2021. https://www.biohavenpharma.com/science-pipeline/resources/clinical-trials
17. Biohaven achieves targeted therapeutic exposures of BHV-3500, a third-generation small molecule CGRP receptor antagonist. Biohaven Pharmaceuticals. Published February 4, 2019. Accessed August 14, 2021. https://www.biohavenpharma.com/investors/news-events/press-releases/02-04-2019
18. Biohaven achieves positive topline results in pivotal phase 2/3 study of vazegepant, the first and only intranasal CGRP receptor antagonist in clinical development for the acute treatment of migraine. Biospace. Published December 17, 2019. Accessed August 14, 2021. https://www.biospace.com/article/releases/biohaven-achieves-positive-topline-results-in-pivotal-phase-2-3-study-of-vazegepant-the-first-and-only-intranasal-cgrp-receptor-antagonist-in-clinical-development-for-the-acute-treatment-of-migraine/
19. Schoenen J, Jensen RH, Lantéri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33(10):816-830.
20. Spierings EL, Brandes JL, Kudrow DB, et al. Randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the safety and efficacy of ADAM zolmitriptan for the acute treatment of migraine. Cephalalgia. 2018;38(2):215-224.
21. STS101 (DHE Nasal Powder). Satsuma Pharmaceuticals. Accessed August 14, 2021. https://www.satsumarx.com/our-research/sts101/
22. Impel NeuroPharma announces U.S. Food & Drug Administration acceptance of new drug application for INP104 for the acute treatment of migraine. PRNewswire. Published January 20, 2021. Accessed August 14, 2021. https://www.prnewswire.com/news-releases/impel-neuropharma-announces-us-food--drug-administration-acceptance-of-new-drug-application-for-inp104-for-the-acute-treatment-of-migraine-301211380.html
Remote upper arm neuromodulation and combined occipital and trigeminal neuromodulation lead the way as the newest entries to the field, followed by 8 other devices that are now available or are expected to be soon.
The increasing array of prescription medications for the treatment of migraine are welcome additions for patients who suffer from this life-altering condition and the clinicians who treat it; but not all individuals tolerate oral and injectable therapies, and others face the risk of adverse events and medication overuse headache.1 Fortunately, there are a number of devices available to consider, and still others are awaiting approval from the US Food and Drug Administration (FDA).
Two of the most promising devices are remote upper arm neuromodulation (REN) and combined occipital and trigeminal neuromodulation. Here we highlight data from pivotal trials evaluating these 2 treatment options and provide information about other devices worth consideration.
Remote Upper Arm Neuromodulation (REN)
Nerivio was initially authorized by the FDA for the acute treatment of episodic migraine. Available by prescription, the device is administered by the patient at home.2 It stimulates upper arm peripheral nerves, which induces conditioned pain modulation (CPM) that inhibits pain in remote parts of the body. In other words, a descending, endogenous analgesic “pain inhibits pain” mechanism is used.
The initial authorization was based on the results of a randomized, double-blind, sham-controlled, multicenter study involving 252 individuals who were experiencing 2 to 8 migraine headaches per month. Participants were assigned to either a treatment group (n=126), where the device was applied for 30 to 45 minutes within an hour of a migraine attack, or to a sham treatment group (n=126). Investigators looked at migraine pain levels at baseline and at 2 and 48 hours post-treatment, as well as patient-reported most bothersome symptoms. They found that REN provided superior, clinically meaningful relief from migraine pain and the most bothersome symptoms, as follows3:
- 67% of patients in the active treatment group achieved a response at 2 hours vs 39% of individuals in the sham-treatment group
- Pain-free rates at 2 hours in each group were 37% and 18%, respectively
- Most bothersome symptom relief rates at 2 hours were 46% and 22%, respectively
Additionally, pain relief and pain-free responses were sustained at 48 hours. Nearly 40% of active treatment participants still reported pain relief at 48 hours, with pain-free rates at 48 hours in each group of 21% and 8%, respectively. The adverse event rate was low. The most commonly reported adverse event in the active-treatment group was a sensation of warmth (2.4%). Arm pain (1.6%), redness (1.6%), and numbness (0.8%) were also reported in those receiving active treatment.3
In 2020, REN received authorization for the acute treatment of chronic migraine in adults, and the following year authorization was expanded to include adolescent migraine. This development offered a nonpharmacologic treatment approach for migraine sufferers who experience 15 or more headache days per month, which is significant because it reduces the likelihood of medication overuse headache.
Approval for chronic migraine was based on results of an open-label, single-arm, dual-center study involving 38 individuals with chronic migraine. Participants used the device over 4 weeks within 1 hour of a migraine attack. Investigators assessed pain levels at 2 and 24 hours after use; they defined consistency of response as response to at least half of the treatments. The study demonstrated the following4:
- 74% of patients attained pain relief at 2 hours
- 26% were pain free at 2 hours
- 84% achieved sustained pain relief at 24 hours
- 45% achieved sustained pain relief at 24 hours in at least half of their treated attacks
- <2% of participants experienced device-related adverse events
The authors concluded that REN could be used for a series of migraine attacks and is a safe and effective nonpharmacologic approach for individuals who suffer from chronic migraine.4
The findings from these trials are supported by a subsequent trial published earlier this year. This open-label, single-arm study evaluated 91 individuals with chronic migraine who were treated with REN for 4 weeks. Investigators assessed pain levels, associated pain symptoms, and functional disability at baseline as well as at 2 and 24 hours post-treatment. Of the patients in this study5:
- At 2 hours, 59% achieved pain relief, and 21% reported that their pain disappeared
- 73% noted sustained pain relief at 24 hours
- REN was shown to impact nausea, photophobia, and phonophobia favorably, and patients’ functional ability also improved after use
Results from 2 additional trials were also recently released. One study involving 35 adolescents treated with either REN or standard-of-care medications showed REN to be superior with regard to pain freedom (37% vs 9%), consistency of pain freedom (40% vs 9%), pain relief (71% vs 57%), and consistency of pain relief (80% vs 57%).6 The other study included 91 women with a history of menstrual migraine and at least 4 REN treatments. Nearly 75% of patients reported Nerivio to be at least moderately effective, 45% said they were satisfied with the treatment, and all participants noted that it was at least moderately tolerable.7
Combined Occipital and Trigeminal Neuromodulation
In March 2021, the FDA authorized combined occipital and trigeminal neuromodulation (Relivion) for self-treatment of acute migraine.8 It is not yet commercially available, but it will require a prescription. The headset-like device stimulates the occipital and trigeminal nerves by delivering precise modulated pulses simultaneously to 6 branches of the occipital and trigeminal nerves via 3 adaptive output channels. The occipital and trigeminal nerves conduct the signals directly to the brainstem, which maximizes the synergistic effect.9
The results of 2 clinical trials led to FDA approval. These studies have not yet been published in a peer-reviewed journal. The first study, presented at the 61st Annual Scientific Meeting of the American Headache Society in 2019, was a prospective, randomized, double-blind, parallel-group, sham-controlled clinical study involving 55 individuals with chronic or episodic migraine. Participants administered the device for 1 hour soon after migraine onset or administered a sham treatment. Researchers looked at pain score change from baseline to 1 hour post-treatment, as well as pain intensity at baseline and at 1, 2, and 24 hours post-treatment. The study showed that 76% of participants in the active-treatment group experienced headache relief at 2 hours vs 32% in the sham-treatment contingent. No serious adverse events were reported.10 The investigators hypothesized that the positive results observed were a result of the synergistic neuromodulatory effect elicited by concurrent activation of the occipital and trigeminal neural pathways.
Following this study, there was a multi-center, prospective, randomized, double-blind, placebo-controlled clinical trial involving 131 individuals with migraine with or without aura. Participants were assigned to either active treatment or placebo. Investigators assessed reported migraine pain reduction at 2 hours, as well as improvement in most bothersome symptoms after 2 hours, reported pain reduction at 1 hour, and being pain-free at 2 hours. At 2 hours post-treatment11:
- 46% of individuals who were actively treated reached complete freedom from pain vs 12% in the control group
- 75% of active-treatment participants reported being completely free of their most bothersome symptom vs 47% of control patients
- The rates of complete freedom from migraine symptoms were 47% and 11%, respectively
- The rates of pain relief after 2 hours were 60% and 37%, respectively
- No serious adverse events were noted
A systematic review and meta-analysis of 13 studies involving 221 individuals published earlier this year looked at changes in pain scores and response rates to implantable peripheral nerve stimulation for trigeminal neuropathic pain. The response rate to neuromodulation therapy was 61%, the reduction in overall pain scores (2.363) was significant, and a subgroup assessment revealed that the stimulation target (peripheral branch, trigeminal ganglion, or trigeminal nerve root) was responsible for heterogeneity across the studies analyzed. Furthermore, stimulating the trigeminal peripheral branch resulted in better clinical outcomes. The authors noted that their findings reinforce the promise of implantable therapy, particularly for individuals who do not tolerate traditional therapies.12
Looking forward, new data are scheduled to be presented at the International Headache Virtual Congress in September 2021 showing that neuromodulation therapy is highly effective in reducing monthly headache days in individuals who suffer from difficult-to-treat migraine. A larger-scale, double-blind, sham-controlled study is planned to further establish these findings.
Other FDA-Approved Therapies
A number of other devices are available for treatment of migraine headache, including:
- Transcranial magnetic stimulation (TMS). In a randomized trial involving 164 individuals with migraine, 39% of the individuals receiving treatment were pain-free at 2 hours vs 22% of those given sham treatment13
- Noninvasive vagal nerve stimulation (nVNS). This is performed using a handheld device that is controlled by the patient, which preferentially activates afferent A and large B fibers. In a randomized trial involving 243 individuals, pain-free rates at 30, 60, and 120 minutes for patients receiving active treatment were 13%, 21%, and 30%, respectively. Rates for those receiving sham treatment were 4%, 10%, and 20%, respectively.14
- Sumatriptan nasal spray (10 mg) with a permeation enhancer. A randomized phase 2 trial involving 107 individuals found that 44% of participants in the treatment group achieved pain freedom at 2 hours vs 23% who received placebo. The spray appears to work quickly and with fewer adverse events than generic sumatriptan 20 mg nasal spray.15
- Transcutaneous supraorbital nerve stimulation (tSNS). Available without a prescription, there are 3 devices that can treat acute migraine; prevent acute migraine; or both.
Therapies Awaiting FDA Approval
There are several therapeutic options in the pipeline that have not yet been authorized by the FDA.
- Zavegepant (formerly known as vazegepant) nasal spray.16 This third-generation small molecule calcitonin gene-related peptide (CGRP) receptor antagonist has been demonstrated to work as a nasal spray in individuals with migraine. In a phase 1 study, the spray was shown to reach maximal concentration earlier than with other CGRP receptor antagonists.17 A phase 2/3 placebo-controlled trial demonstrated sustained pain freedom from 2 to 48 hours with 5-mg, 10-mg, and 20-mg dosages. The 10-mg and 20-mg doses were statistically superior to placebo on the co-primary endpoints of pain freedom and freedom from most bothersome symptom at 2 hours using a single dose. Sustained pain relief from 2 to 48 hours was seen with the 5-mg and 10-mg dosages18
- Sphenopalatine ganglion (SPG) stimulation. This is a microstimulator that is inserted orally, designed to fit the face, and directly targets SPG. Stimulation is active and controlled by the patient. A randomized, sham-controlled trial evaluated acute pain relief as well as pain freedom and found that those receiving treatment were more than twice as likely to experience pain relief and pain freedom19
- Adhesive dermally applied microneedle system (ADAM). This is a transdermal patch containing microprojections, which can be coated with both large and small molecules. In a randomized trial, 42% of treated participants reported being pain free at 2 hours vs 14% of placebo-treated patients. Rates of freedom from most bothersome symptom were 68% and 43%, respectively20
- Dihydroergotamine (DHE) nasal powder spray and intranasal liquid. Both therapies are awaiting FDA approval. The mucoadhesive powder formulation facilitates rapid drug absorption and is offered in a single-use nasal delivery device. In clinical trials, the spray demonstrated the device’s simplicity, reliability, and ease of use.21 The intranasal liquid is designed to deliver the drug into the vascular-rich upper nasal space. In the phase 3 trial that included 354 patients, 66.3% of patients reported pain relief, 38% of patients reported pain freedom, and 52% had freedom from their most bothersome migraine symptom at 2 hours following their first dose.22
Remote upper arm neuromodulation and combined occipital and trigeminal neuromodulation lead the way as the newest entries to the field, followed by 8 other devices that are now available or are expected to be soon.
The increasing array of prescription medications for the treatment of migraine are welcome additions for patients who suffer from this life-altering condition and the clinicians who treat it; but not all individuals tolerate oral and injectable therapies, and others face the risk of adverse events and medication overuse headache.1 Fortunately, there are a number of devices available to consider, and still others are awaiting approval from the US Food and Drug Administration (FDA).
Two of the most promising devices are remote upper arm neuromodulation (REN) and combined occipital and trigeminal neuromodulation. Here we highlight data from pivotal trials evaluating these 2 treatment options and provide information about other devices worth consideration.
Remote Upper Arm Neuromodulation (REN)
Nerivio was initially authorized by the FDA for the acute treatment of episodic migraine. Available by prescription, the device is administered by the patient at home.2 It stimulates upper arm peripheral nerves, which induces conditioned pain modulation (CPM) that inhibits pain in remote parts of the body. In other words, a descending, endogenous analgesic “pain inhibits pain” mechanism is used.
The initial authorization was based on the results of a randomized, double-blind, sham-controlled, multicenter study involving 252 individuals who were experiencing 2 to 8 migraine headaches per month. Participants were assigned to either a treatment group (n=126), where the device was applied for 30 to 45 minutes within an hour of a migraine attack, or to a sham treatment group (n=126). Investigators looked at migraine pain levels at baseline and at 2 and 48 hours post-treatment, as well as patient-reported most bothersome symptoms. They found that REN provided superior, clinically meaningful relief from migraine pain and the most bothersome symptoms, as follows3:
- 67% of patients in the active treatment group achieved a response at 2 hours vs 39% of individuals in the sham-treatment group
- Pain-free rates at 2 hours in each group were 37% and 18%, respectively
- Most bothersome symptom relief rates at 2 hours were 46% and 22%, respectively
Additionally, pain relief and pain-free responses were sustained at 48 hours. Nearly 40% of active treatment participants still reported pain relief at 48 hours, with pain-free rates at 48 hours in each group of 21% and 8%, respectively. The adverse event rate was low. The most commonly reported adverse event in the active-treatment group was a sensation of warmth (2.4%). Arm pain (1.6%), redness (1.6%), and numbness (0.8%) were also reported in those receiving active treatment.3
In 2020, REN received authorization for the acute treatment of chronic migraine in adults, and the following year authorization was expanded to include adolescent migraine. This development offered a nonpharmacologic treatment approach for migraine sufferers who experience 15 or more headache days per month, which is significant because it reduces the likelihood of medication overuse headache.
Approval for chronic migraine was based on results of an open-label, single-arm, dual-center study involving 38 individuals with chronic migraine. Participants used the device over 4 weeks within 1 hour of a migraine attack. Investigators assessed pain levels at 2 and 24 hours after use; they defined consistency of response as response to at least half of the treatments. The study demonstrated the following4:
- 74% of patients attained pain relief at 2 hours
- 26% were pain free at 2 hours
- 84% achieved sustained pain relief at 24 hours
- 45% achieved sustained pain relief at 24 hours in at least half of their treated attacks
- <2% of participants experienced device-related adverse events
The authors concluded that REN could be used for a series of migraine attacks and is a safe and effective nonpharmacologic approach for individuals who suffer from chronic migraine.4
The findings from these trials are supported by a subsequent trial published earlier this year. This open-label, single-arm study evaluated 91 individuals with chronic migraine who were treated with REN for 4 weeks. Investigators assessed pain levels, associated pain symptoms, and functional disability at baseline as well as at 2 and 24 hours post-treatment. Of the patients in this study5:
- At 2 hours, 59% achieved pain relief, and 21% reported that their pain disappeared
- 73% noted sustained pain relief at 24 hours
- REN was shown to impact nausea, photophobia, and phonophobia favorably, and patients’ functional ability also improved after use
Results from 2 additional trials were also recently released. One study involving 35 adolescents treated with either REN or standard-of-care medications showed REN to be superior with regard to pain freedom (37% vs 9%), consistency of pain freedom (40% vs 9%), pain relief (71% vs 57%), and consistency of pain relief (80% vs 57%).6 The other study included 91 women with a history of menstrual migraine and at least 4 REN treatments. Nearly 75% of patients reported Nerivio to be at least moderately effective, 45% said they were satisfied with the treatment, and all participants noted that it was at least moderately tolerable.7
Combined Occipital and Trigeminal Neuromodulation
In March 2021, the FDA authorized combined occipital and trigeminal neuromodulation (Relivion) for self-treatment of acute migraine.8 It is not yet commercially available, but it will require a prescription. The headset-like device stimulates the occipital and trigeminal nerves by delivering precise modulated pulses simultaneously to 6 branches of the occipital and trigeminal nerves via 3 adaptive output channels. The occipital and trigeminal nerves conduct the signals directly to the brainstem, which maximizes the synergistic effect.9
The results of 2 clinical trials led to FDA approval. These studies have not yet been published in a peer-reviewed journal. The first study, presented at the 61st Annual Scientific Meeting of the American Headache Society in 2019, was a prospective, randomized, double-blind, parallel-group, sham-controlled clinical study involving 55 individuals with chronic or episodic migraine. Participants administered the device for 1 hour soon after migraine onset or administered a sham treatment. Researchers looked at pain score change from baseline to 1 hour post-treatment, as well as pain intensity at baseline and at 1, 2, and 24 hours post-treatment. The study showed that 76% of participants in the active-treatment group experienced headache relief at 2 hours vs 32% in the sham-treatment contingent. No serious adverse events were reported.10 The investigators hypothesized that the positive results observed were a result of the synergistic neuromodulatory effect elicited by concurrent activation of the occipital and trigeminal neural pathways.
Following this study, there was a multi-center, prospective, randomized, double-blind, placebo-controlled clinical trial involving 131 individuals with migraine with or without aura. Participants were assigned to either active treatment or placebo. Investigators assessed reported migraine pain reduction at 2 hours, as well as improvement in most bothersome symptoms after 2 hours, reported pain reduction at 1 hour, and being pain-free at 2 hours. At 2 hours post-treatment11:
- 46% of individuals who were actively treated reached complete freedom from pain vs 12% in the control group
- 75% of active-treatment participants reported being completely free of their most bothersome symptom vs 47% of control patients
- The rates of complete freedom from migraine symptoms were 47% and 11%, respectively
- The rates of pain relief after 2 hours were 60% and 37%, respectively
- No serious adverse events were noted
A systematic review and meta-analysis of 13 studies involving 221 individuals published earlier this year looked at changes in pain scores and response rates to implantable peripheral nerve stimulation for trigeminal neuropathic pain. The response rate to neuromodulation therapy was 61%, the reduction in overall pain scores (2.363) was significant, and a subgroup assessment revealed that the stimulation target (peripheral branch, trigeminal ganglion, or trigeminal nerve root) was responsible for heterogeneity across the studies analyzed. Furthermore, stimulating the trigeminal peripheral branch resulted in better clinical outcomes. The authors noted that their findings reinforce the promise of implantable therapy, particularly for individuals who do not tolerate traditional therapies.12
Looking forward, new data are scheduled to be presented at the International Headache Virtual Congress in September 2021 showing that neuromodulation therapy is highly effective in reducing monthly headache days in individuals who suffer from difficult-to-treat migraine. A larger-scale, double-blind, sham-controlled study is planned to further establish these findings.
Other FDA-Approved Therapies
A number of other devices are available for treatment of migraine headache, including:
- Transcranial magnetic stimulation (TMS). In a randomized trial involving 164 individuals with migraine, 39% of the individuals receiving treatment were pain-free at 2 hours vs 22% of those given sham treatment13
- Noninvasive vagal nerve stimulation (nVNS). This is performed using a handheld device that is controlled by the patient, which preferentially activates afferent A and large B fibers. In a randomized trial involving 243 individuals, pain-free rates at 30, 60, and 120 minutes for patients receiving active treatment were 13%, 21%, and 30%, respectively. Rates for those receiving sham treatment were 4%, 10%, and 20%, respectively.14
- Sumatriptan nasal spray (10 mg) with a permeation enhancer. A randomized phase 2 trial involving 107 individuals found that 44% of participants in the treatment group achieved pain freedom at 2 hours vs 23% who received placebo. The spray appears to work quickly and with fewer adverse events than generic sumatriptan 20 mg nasal spray.15
- Transcutaneous supraorbital nerve stimulation (tSNS). Available without a prescription, there are 3 devices that can treat acute migraine; prevent acute migraine; or both.
Therapies Awaiting FDA Approval
There are several therapeutic options in the pipeline that have not yet been authorized by the FDA.
- Zavegepant (formerly known as vazegepant) nasal spray.16 This third-generation small molecule calcitonin gene-related peptide (CGRP) receptor antagonist has been demonstrated to work as a nasal spray in individuals with migraine. In a phase 1 study, the spray was shown to reach maximal concentration earlier than with other CGRP receptor antagonists.17 A phase 2/3 placebo-controlled trial demonstrated sustained pain freedom from 2 to 48 hours with 5-mg, 10-mg, and 20-mg dosages. The 10-mg and 20-mg doses were statistically superior to placebo on the co-primary endpoints of pain freedom and freedom from most bothersome symptom at 2 hours using a single dose. Sustained pain relief from 2 to 48 hours was seen with the 5-mg and 10-mg dosages18
- Sphenopalatine ganglion (SPG) stimulation. This is a microstimulator that is inserted orally, designed to fit the face, and directly targets SPG. Stimulation is active and controlled by the patient. A randomized, sham-controlled trial evaluated acute pain relief as well as pain freedom and found that those receiving treatment were more than twice as likely to experience pain relief and pain freedom19
- Adhesive dermally applied microneedle system (ADAM). This is a transdermal patch containing microprojections, which can be coated with both large and small molecules. In a randomized trial, 42% of treated participants reported being pain free at 2 hours vs 14% of placebo-treated patients. Rates of freedom from most bothersome symptom were 68% and 43%, respectively20
- Dihydroergotamine (DHE) nasal powder spray and intranasal liquid. Both therapies are awaiting FDA approval. The mucoadhesive powder formulation facilitates rapid drug absorption and is offered in a single-use nasal delivery device. In clinical trials, the spray demonstrated the device’s simplicity, reliability, and ease of use.21 The intranasal liquid is designed to deliver the drug into the vascular-rich upper nasal space. In the phase 3 trial that included 354 patients, 66.3% of patients reported pain relief, 38% of patients reported pain freedom, and 52% had freedom from their most bothersome migraine symptom at 2 hours following their first dose.22
References
1. Rapoport AM. Medication overuse headache: preventive treatment with or without detoxification? Published May 24, 2021. Accessed August 13, 2021. https://www.mdedge.com/migraine-icymi/article/240472/headache-migraine/medication-overuse-headache-preventive-treatment-or
2. How to prescribe Nerivio. Theranica. Accessed August 13, 2021. https://nerivio.co/prescribe/
3. Yarnitsky D, Dodick DW, Grosberg BM, et al. Remote electrical neuromodulation (REN) relieves acute migraine: a randomized, double-blind, placebo-controlled, multicenter trial. Headache. 2019;59(8):1240-1252.
4. Nierenburg H, Vieira JR, Lev N, et al. Remote electrical neuromodulation for the acute treatment of migraine in patients with chronic migraine: an open-label pilot study. Pain Ther. 2020;9(2):531-543.
5. Grosberg B, Lin T, Vizel M, Schim J. Remote electrical neuromodulation for the acute treatment of chronic migraine (2007). Neurology. 2021;96(15 Suppl) 2007.
6. Hershey AD, Irwin S, Rabany L, et al. Comparison of remote electrical neuromodulation (REN) and standard-care medications for acute treatment of migraine in adolescents: a post-hoc analysis. Pain Med. 2021 June 29;pnab197. doi: 10.1093/pm/pnab197. [Epub ahead of print].
7. Nierenburg H, Rabany L, Lin T, et al. Remote electrical neuromodulation (REN) for the acute treatment of menstrual migraine: a retrospective survey study of effectiveness and tolerability. Pain Ther. 2021 Jun 17. doi: 10.1007/s40122-021-00276-7. [Epub ahead of print].
8. Brooks M. FDA clears neuromodulation device for acute migraine pain. Published March 2, 2021. Accessed August 13, 2021. https://www.medscape.com/viewarticle/946700
9. A new ecosystem for brain neuromodulation. Neurolief. Accessed August 13, 2021. https://www.neurolief.com/technology/
10. Daniel O, Tepper SJ. First non-invasive combined occipital & trigeminal nerve stimulation digital therapeutics system for treatment of migraine: a randomized, sham-controlled, double-blind clinical trial. Published 2019. Accessed August 13, 2021. https://www.neurolief.com/wp-content/uploads/2019/07/American-Headache-Society2019-Abstract-Oved-Daniel-Stewart-Tepper.pdf
11. Neurolief announces positive results from RIME clinical study of its brain neuromodulation system for treating acute migraine. BusinessWire. Published January 6, 2021. Accessed August 13, 2021. https://www.businesswire.com/news/home/20210106005510/en/Neurolief-Announces-Positive-Results-From-RIME-Clinical-Study-of-Its-Brain-Neuromodulation-System-for-Treating-Acute-Migraine
12. Ni Y, Yang L, Han R, et al. Implantable peripheral nerve stimulation for trigeminal neuropathic pain: a systematic review and meta-analysis. Neuromodulation. 2021 May 18. doi: 10.1111/ner.13421. [Epub ahead of print].
13. Lipton RB, Dodick DW, Silberstein SD, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomized, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 2010;9(4):373-380.
14. PRESTO clinical trial overview. electroCore. Published 2018. Accessed August 13, 2021. https://www.electrocore.com/wp-content/themes/wp-starter/includes/images/PRESTO_Clinical_Trial_Fact_Sheet_3.29.18.pdf
15. Lipton RB, Munjal S, Brand-Schieber E, Rapoport AM. DFN-02 (sumatriptan 10 mg with a permeation enhancer) nasal spray vs placebo in the acute treatment of migraine: a double-blind, placebo-controlled study. Headache. 2018;58(5):676-687.
16. Clinical trials. Biohaven Pharmaceuticals. Accessed August 14, 2021. https://www.biohavenpharma.com/science-pipeline/resources/clinical-trials
17. Biohaven achieves targeted therapeutic exposures of BHV-3500, a third-generation small molecule CGRP receptor antagonist. Biohaven Pharmaceuticals. Published February 4, 2019. Accessed August 14, 2021. https://www.biohavenpharma.com/investors/news-events/press-releases/02-04-2019
18. Biohaven achieves positive topline results in pivotal phase 2/3 study of vazegepant, the first and only intranasal CGRP receptor antagonist in clinical development for the acute treatment of migraine. Biospace. Published December 17, 2019. Accessed August 14, 2021. https://www.biospace.com/article/releases/biohaven-achieves-positive-topline-results-in-pivotal-phase-2-3-study-of-vazegepant-the-first-and-only-intranasal-cgrp-receptor-antagonist-in-clinical-development-for-the-acute-treatment-of-migraine/
19. Schoenen J, Jensen RH, Lantéri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33(10):816-830.
20. Spierings EL, Brandes JL, Kudrow DB, et al. Randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the safety and efficacy of ADAM zolmitriptan for the acute treatment of migraine. Cephalalgia. 2018;38(2):215-224.
21. STS101 (DHE Nasal Powder). Satsuma Pharmaceuticals. Accessed August 14, 2021. https://www.satsumarx.com/our-research/sts101/
22. Impel NeuroPharma announces U.S. Food & Drug Administration acceptance of new drug application for INP104 for the acute treatment of migraine. PRNewswire. Published January 20, 2021. Accessed August 14, 2021. https://www.prnewswire.com/news-releases/impel-neuropharma-announces-us-food--drug-administration-acceptance-of-new-drug-application-for-inp104-for-the-acute-treatment-of-migraine-301211380.html
References
1. Rapoport AM. Medication overuse headache: preventive treatment with or without detoxification? Published May 24, 2021. Accessed August 13, 2021. https://www.mdedge.com/migraine-icymi/article/240472/headache-migraine/medication-overuse-headache-preventive-treatment-or
2. How to prescribe Nerivio. Theranica. Accessed August 13, 2021. https://nerivio.co/prescribe/
3. Yarnitsky D, Dodick DW, Grosberg BM, et al. Remote electrical neuromodulation (REN) relieves acute migraine: a randomized, double-blind, placebo-controlled, multicenter trial. Headache. 2019;59(8):1240-1252.
4. Nierenburg H, Vieira JR, Lev N, et al. Remote electrical neuromodulation for the acute treatment of migraine in patients with chronic migraine: an open-label pilot study. Pain Ther. 2020;9(2):531-543.
5. Grosberg B, Lin T, Vizel M, Schim J. Remote electrical neuromodulation for the acute treatment of chronic migraine (2007). Neurology. 2021;96(15 Suppl) 2007.
6. Hershey AD, Irwin S, Rabany L, et al. Comparison of remote electrical neuromodulation (REN) and standard-care medications for acute treatment of migraine in adolescents: a post-hoc analysis. Pain Med. 2021 June 29;pnab197. doi: 10.1093/pm/pnab197. [Epub ahead of print].
7. Nierenburg H, Rabany L, Lin T, et al. Remote electrical neuromodulation (REN) for the acute treatment of menstrual migraine: a retrospective survey study of effectiveness and tolerability. Pain Ther. 2021 Jun 17. doi: 10.1007/s40122-021-00276-7. [Epub ahead of print].
8. Brooks M. FDA clears neuromodulation device for acute migraine pain. Published March 2, 2021. Accessed August 13, 2021. https://www.medscape.com/viewarticle/946700
9. A new ecosystem for brain neuromodulation. Neurolief. Accessed August 13, 2021. https://www.neurolief.com/technology/
10. Daniel O, Tepper SJ. First non-invasive combined occipital & trigeminal nerve stimulation digital therapeutics system for treatment of migraine: a randomized, sham-controlled, double-blind clinical trial. Published 2019. Accessed August 13, 2021. https://www.neurolief.com/wp-content/uploads/2019/07/American-Headache-Society2019-Abstract-Oved-Daniel-Stewart-Tepper.pdf
11. Neurolief announces positive results from RIME clinical study of its brain neuromodulation system for treating acute migraine. BusinessWire. Published January 6, 2021. Accessed August 13, 2021. https://www.businesswire.com/news/home/20210106005510/en/Neurolief-Announces-Positive-Results-From-RIME-Clinical-Study-of-Its-Brain-Neuromodulation-System-for-Treating-Acute-Migraine
12. Ni Y, Yang L, Han R, et al. Implantable peripheral nerve stimulation for trigeminal neuropathic pain: a systematic review and meta-analysis. Neuromodulation. 2021 May 18. doi: 10.1111/ner.13421. [Epub ahead of print].
13. Lipton RB, Dodick DW, Silberstein SD, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomized, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 2010;9(4):373-380.
14. PRESTO clinical trial overview. electroCore. Published 2018. Accessed August 13, 2021. https://www.electrocore.com/wp-content/themes/wp-starter/includes/images/PRESTO_Clinical_Trial_Fact_Sheet_3.29.18.pdf
15. Lipton RB, Munjal S, Brand-Schieber E, Rapoport AM. DFN-02 (sumatriptan 10 mg with a permeation enhancer) nasal spray vs placebo in the acute treatment of migraine: a double-blind, placebo-controlled study. Headache. 2018;58(5):676-687.
16. Clinical trials. Biohaven Pharmaceuticals. Accessed August 14, 2021. https://www.biohavenpharma.com/science-pipeline/resources/clinical-trials
17. Biohaven achieves targeted therapeutic exposures of BHV-3500, a third-generation small molecule CGRP receptor antagonist. Biohaven Pharmaceuticals. Published February 4, 2019. Accessed August 14, 2021. https://www.biohavenpharma.com/investors/news-events/press-releases/02-04-2019
18. Biohaven achieves positive topline results in pivotal phase 2/3 study of vazegepant, the first and only intranasal CGRP receptor antagonist in clinical development for the acute treatment of migraine. Biospace. Published December 17, 2019. Accessed August 14, 2021. https://www.biospace.com/article/releases/biohaven-achieves-positive-topline-results-in-pivotal-phase-2-3-study-of-vazegepant-the-first-and-only-intranasal-cgrp-receptor-antagonist-in-clinical-development-for-the-acute-treatment-of-migraine/
19. Schoenen J, Jensen RH, Lantéri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33(10):816-830.
20. Spierings EL, Brandes JL, Kudrow DB, et al. Randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the safety and efficacy of ADAM zolmitriptan for the acute treatment of migraine. Cephalalgia. 2018;38(2):215-224.
21. STS101 (DHE Nasal Powder). Satsuma Pharmaceuticals. Accessed August 14, 2021. https://www.satsumarx.com/our-research/sts101/
22. Impel NeuroPharma announces U.S. Food & Drug Administration acceptance of new drug application for INP104 for the acute treatment of migraine. PRNewswire. Published January 20, 2021. Accessed August 14, 2021. https://www.prnewswire.com/news-releases/impel-neuropharma-announces-us-food--drug-administration-acceptance-of-new-drug-application-for-inp104-for-the-acute-treatment-of-migraine-301211380.html
Trial finds that intranasal DHE is well tolerated and may reduce migraine symptoms
, a new study suggests.
A phase 3, open-label trial of INP104, or Trudhesa – Impel NeuroPharma’s proprietary Precision Olfactory Delivery of DHE – found that most patients experienced symptom relief within 2 hours and reported that the medication was easy to use and preferable to their current therapy.
Another treatment option?
Of about 18 million diagnosed migraine patients in the United States, 4 million receive prescription treatment. Nearly 80% of migraine therapies involve triptans, but 30%-40% of patients don’t find adequate relief with triptans. Moreover, the majority of patients who do respond to triptans report that they’d like to try a different therapy.
“INP104 has the potential to deliver rapid symptom relief, without injection, that is well tolerated and suitable for outpatient us,” lead author Timothy Smith, MD, of StudyMetrix Research, St. Louis, and colleagues wrote in the paper.
The results were published online Aug. 7 in Headache.
A total of 360 patients aged 18-65 years with a diagnosis of migraine with or without aura with at least two attacks per month over the course of the previous 6 months were enrolled in the 24-week safety study, which had a 28-week extension period. Participants used their “best usual care” to treat their migraines during the initial 28-day screening period. Afterward, they were given 1.45-mg doses of INP04 to self-administer into the upper nasal space to treat self-recognized attacks. No more than two doses per 24 hours and three doses per 7 days were allowed. The Full Safety Set analysis comprised 354 patients who dosed at least once. The Primary Safety Set involved 185 patients who administered an average of two or more doses per 28-day period during the 24-week treatment period. A total of 4,515 self-recognized migraines were treated during the 24-week period; 6,332 doses of INP04 were analyzed.
Nearly 37% (130/354) of patients reported treatment-emergent adverse events (TEAEs); 6.8% (24/354) discontinued treatment because of the TEAEs over the 24 weeks. The most common TEAE was nasal congestion (15%, 53/354), followed by nausea (6.8%, 24/354).
Within an hour of INP104 administration, 47.6% of patients reported pain relief. After 2 hours of INP104 administration, 38% reported pain freedom and 66.3% reported pain relief. Headache recurrence was observed in 7.1% and 14.3% of patients at 24 and 48 hours, respectively.
In a questionnaire, 84% of patients agreed or strongly agreed that INP04 was easy to use. Most reported that INP104 slowed the recurrence of their migraines and was more rapidly and consistently effective than their previous best usual care treatment.
Intranasal delivery of DHE was developed in response to the challenges of traditional IV administration.
“While intravenous (IV) dihydroergotamine (DHE) mesylate has a long, established history as an effective migraine therapy, its use as an acute treatment can be limited by the high rate of nausea and vomiting reported by patients, which often requires pretreatment with antiemetics,” Dr. Smith and colleagues wrote. “Furthermore, IV DHE mesylate needs to be administered in emergency room settings or by headache specialists, limiting convenience.”
A novel delivery system
“There’s already a nasal spray on the market right now which doesn’t seem to work that well in a large number of people. This device [INP04] was designed to get the same substances to a part of the nose that’s higher and farther back, where there may be better absorption,” said Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said in an interview. Dr. Rapoport was not involved with the study.
The proprietary Precision Olfactory Delivery (POD) is meant to improve on current nasal delivery methods such as sprays, droppers, and pumps, which may deliver “less than 5% of the active drug to the upper nasal space,” according to a press release from Impel NeuroPharma.
Nasal delivery also may have advantages over oral medications. People with migraines may be more likely to have gastroparesis – delayed stomach emptying – which may affect their ability to absorb oral medications and delay symptom relief. However, patients may hesitate to agree to a medication that involves nasal delivery, Dr. Rapoport said.
“I will say it’s a little more difficult getting your patients to take a nasal spray,” Dr. Rapoport said. “Patients are used to taking tablets for their headaches,” he said. “But if the doctor spends a little more time with the patient and says, ‘Look, this could work faster for your migraine as a nasal spray. Why don’t you try it a couple of times and see if you like it or not?’ patients are usually willing to give it a try.”
The study’s limitations include the lack of a control group given that it was an open-label trial. It was carried out at 38 sites in one geographical area, which may affect the generalizability of the results. The study did not assess patients with new-onset migraine or chronic migraine.
The Food and Drug Administration approved Trudhesa on Sept. 2, 2021.
The study was funded by Impel NeuroPharma. Dr. Smith has received funding from a number of pharmaceutical companies. Dr. Rapoport disclosed no relevant financial relationships.
, a new study suggests.
A phase 3, open-label trial of INP104, or Trudhesa – Impel NeuroPharma’s proprietary Precision Olfactory Delivery of DHE – found that most patients experienced symptom relief within 2 hours and reported that the medication was easy to use and preferable to their current therapy.
Another treatment option?
Of about 18 million diagnosed migraine patients in the United States, 4 million receive prescription treatment. Nearly 80% of migraine therapies involve triptans, but 30%-40% of patients don’t find adequate relief with triptans. Moreover, the majority of patients who do respond to triptans report that they’d like to try a different therapy.
“INP104 has the potential to deliver rapid symptom relief, without injection, that is well tolerated and suitable for outpatient us,” lead author Timothy Smith, MD, of StudyMetrix Research, St. Louis, and colleagues wrote in the paper.
The results were published online Aug. 7 in Headache.
A total of 360 patients aged 18-65 years with a diagnosis of migraine with or without aura with at least two attacks per month over the course of the previous 6 months were enrolled in the 24-week safety study, which had a 28-week extension period. Participants used their “best usual care” to treat their migraines during the initial 28-day screening period. Afterward, they were given 1.45-mg doses of INP04 to self-administer into the upper nasal space to treat self-recognized attacks. No more than two doses per 24 hours and three doses per 7 days were allowed. The Full Safety Set analysis comprised 354 patients who dosed at least once. The Primary Safety Set involved 185 patients who administered an average of two or more doses per 28-day period during the 24-week treatment period. A total of 4,515 self-recognized migraines were treated during the 24-week period; 6,332 doses of INP04 were analyzed.
Nearly 37% (130/354) of patients reported treatment-emergent adverse events (TEAEs); 6.8% (24/354) discontinued treatment because of the TEAEs over the 24 weeks. The most common TEAE was nasal congestion (15%, 53/354), followed by nausea (6.8%, 24/354).
Within an hour of INP104 administration, 47.6% of patients reported pain relief. After 2 hours of INP104 administration, 38% reported pain freedom and 66.3% reported pain relief. Headache recurrence was observed in 7.1% and 14.3% of patients at 24 and 48 hours, respectively.
In a questionnaire, 84% of patients agreed or strongly agreed that INP04 was easy to use. Most reported that INP104 slowed the recurrence of their migraines and was more rapidly and consistently effective than their previous best usual care treatment.
Intranasal delivery of DHE was developed in response to the challenges of traditional IV administration.
“While intravenous (IV) dihydroergotamine (DHE) mesylate has a long, established history as an effective migraine therapy, its use as an acute treatment can be limited by the high rate of nausea and vomiting reported by patients, which often requires pretreatment with antiemetics,” Dr. Smith and colleagues wrote. “Furthermore, IV DHE mesylate needs to be administered in emergency room settings or by headache specialists, limiting convenience.”
A novel delivery system
“There’s already a nasal spray on the market right now which doesn’t seem to work that well in a large number of people. This device [INP04] was designed to get the same substances to a part of the nose that’s higher and farther back, where there may be better absorption,” said Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said in an interview. Dr. Rapoport was not involved with the study.
The proprietary Precision Olfactory Delivery (POD) is meant to improve on current nasal delivery methods such as sprays, droppers, and pumps, which may deliver “less than 5% of the active drug to the upper nasal space,” according to a press release from Impel NeuroPharma.
Nasal delivery also may have advantages over oral medications. People with migraines may be more likely to have gastroparesis – delayed stomach emptying – which may affect their ability to absorb oral medications and delay symptom relief. However, patients may hesitate to agree to a medication that involves nasal delivery, Dr. Rapoport said.
“I will say it’s a little more difficult getting your patients to take a nasal spray,” Dr. Rapoport said. “Patients are used to taking tablets for their headaches,” he said. “But if the doctor spends a little more time with the patient and says, ‘Look, this could work faster for your migraine as a nasal spray. Why don’t you try it a couple of times and see if you like it or not?’ patients are usually willing to give it a try.”
The study’s limitations include the lack of a control group given that it was an open-label trial. It was carried out at 38 sites in one geographical area, which may affect the generalizability of the results. The study did not assess patients with new-onset migraine or chronic migraine.
The Food and Drug Administration approved Trudhesa on Sept. 2, 2021.
The study was funded by Impel NeuroPharma. Dr. Smith has received funding from a number of pharmaceutical companies. Dr. Rapoport disclosed no relevant financial relationships.
, a new study suggests.
A phase 3, open-label trial of INP104, or Trudhesa – Impel NeuroPharma’s proprietary Precision Olfactory Delivery of DHE – found that most patients experienced symptom relief within 2 hours and reported that the medication was easy to use and preferable to their current therapy.
Another treatment option?
Of about 18 million diagnosed migraine patients in the United States, 4 million receive prescription treatment. Nearly 80% of migraine therapies involve triptans, but 30%-40% of patients don’t find adequate relief with triptans. Moreover, the majority of patients who do respond to triptans report that they’d like to try a different therapy.
“INP104 has the potential to deliver rapid symptom relief, without injection, that is well tolerated and suitable for outpatient us,” lead author Timothy Smith, MD, of StudyMetrix Research, St. Louis, and colleagues wrote in the paper.
The results were published online Aug. 7 in Headache.
A total of 360 patients aged 18-65 years with a diagnosis of migraine with or without aura with at least two attacks per month over the course of the previous 6 months were enrolled in the 24-week safety study, which had a 28-week extension period. Participants used their “best usual care” to treat their migraines during the initial 28-day screening period. Afterward, they were given 1.45-mg doses of INP04 to self-administer into the upper nasal space to treat self-recognized attacks. No more than two doses per 24 hours and three doses per 7 days were allowed. The Full Safety Set analysis comprised 354 patients who dosed at least once. The Primary Safety Set involved 185 patients who administered an average of two or more doses per 28-day period during the 24-week treatment period. A total of 4,515 self-recognized migraines were treated during the 24-week period; 6,332 doses of INP04 were analyzed.
Nearly 37% (130/354) of patients reported treatment-emergent adverse events (TEAEs); 6.8% (24/354) discontinued treatment because of the TEAEs over the 24 weeks. The most common TEAE was nasal congestion (15%, 53/354), followed by nausea (6.8%, 24/354).
Within an hour of INP104 administration, 47.6% of patients reported pain relief. After 2 hours of INP104 administration, 38% reported pain freedom and 66.3% reported pain relief. Headache recurrence was observed in 7.1% and 14.3% of patients at 24 and 48 hours, respectively.
In a questionnaire, 84% of patients agreed or strongly agreed that INP04 was easy to use. Most reported that INP104 slowed the recurrence of their migraines and was more rapidly and consistently effective than their previous best usual care treatment.
Intranasal delivery of DHE was developed in response to the challenges of traditional IV administration.
“While intravenous (IV) dihydroergotamine (DHE) mesylate has a long, established history as an effective migraine therapy, its use as an acute treatment can be limited by the high rate of nausea and vomiting reported by patients, which often requires pretreatment with antiemetics,” Dr. Smith and colleagues wrote. “Furthermore, IV DHE mesylate needs to be administered in emergency room settings or by headache specialists, limiting convenience.”
A novel delivery system
“There’s already a nasal spray on the market right now which doesn’t seem to work that well in a large number of people. This device [INP04] was designed to get the same substances to a part of the nose that’s higher and farther back, where there may be better absorption,” said Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said in an interview. Dr. Rapoport was not involved with the study.
The proprietary Precision Olfactory Delivery (POD) is meant to improve on current nasal delivery methods such as sprays, droppers, and pumps, which may deliver “less than 5% of the active drug to the upper nasal space,” according to a press release from Impel NeuroPharma.
Nasal delivery also may have advantages over oral medications. People with migraines may be more likely to have gastroparesis – delayed stomach emptying – which may affect their ability to absorb oral medications and delay symptom relief. However, patients may hesitate to agree to a medication that involves nasal delivery, Dr. Rapoport said.
“I will say it’s a little more difficult getting your patients to take a nasal spray,” Dr. Rapoport said. “Patients are used to taking tablets for their headaches,” he said. “But if the doctor spends a little more time with the patient and says, ‘Look, this could work faster for your migraine as a nasal spray. Why don’t you try it a couple of times and see if you like it or not?’ patients are usually willing to give it a try.”
The study’s limitations include the lack of a control group given that it was an open-label trial. It was carried out at 38 sites in one geographical area, which may affect the generalizability of the results. The study did not assess patients with new-onset migraine or chronic migraine.
The Food and Drug Administration approved Trudhesa on Sept. 2, 2021.
The study was funded by Impel NeuroPharma. Dr. Smith has received funding from a number of pharmaceutical companies. Dr. Rapoport disclosed no relevant financial relationships.
From Headache
Virtual roller-coaster may explain the ups and downs of migraine
and may explain the mechanisms underlying common symptoms and increased activity in certain brain regions in migraine patients.
In a new study, the prevalence of dizziness was 65% among patients with migraine who underwent a virtual roller-coaster ride versus 30% among those without migraine. In addition, imaging showed greater neuronal activity after the simulation in those with migraine.
“Migraine patients reported more dizziness and motion sickness, as well as longer symptom duration and intensity, in a virtual roller-coaster ride,” even though the videos and timing were identical for both groups, said study investigator Arne May, MD, PhD, professor of neurology at the University of Hamburg (Germany).
“We found differences not just in behavioral results but also in specific activations of areas within the cerebellum and the frontal gyrus. Migraine patients process such visual input differently from controls and activate a specific brain network to do so,” he added.
The findings were published online July 21, 2021, in Neurology.
The brain’s response
Nausea, which is among the diagnostic criteria for migraine, is the main symptom of motion sickness. Vestibular symptoms such as dizziness are also components of migraine.
Previous research has examined how the brain processes visual and motion stimuli in migraine, but the reasons patients with migraine are susceptible to motion sickness and dizziness remain unclear.
The researchers used a simulated roller-coaster ride to study the clinical and brain responses to motion among participants with and participants without migraine. They enrolled 20 consecutive patients with migraine who presented to a tertiary headache clinic between January and March 2020 and enrolled 20 healthy participants from a university hospital and the community. The average age of the study population was 30 years, and more than 80% were women.
In response to a questionnaire, participants provided information about demographics and headache features, including onset, frequency, and intensity. They also provided information about their status within the migraine phase and about vestibular symptoms experienced in daily life.
While undergoing functional MRI (fMRI), all participants watched two short videos that provided a first-person perspective of a roller-coaster ride. During the videos, they wore ear buds that conveyed the sound of a car riding over the rails.
The first video included more horizontal perspectives, and the second had more vertical perspectives. Each video was shown three times in random order.
During fMRI, participants reported intensity of nausea and vestibular symptoms using an 11-point Likert scale. After the experiment, they responded to a questionnaire that evaluated intensity and duration of nausea, dizziness, and vertigo experienced during the videos.
Participants also were given the Simulator Sickness Questionnaire (SSQ), which assessed motion sickness. A 100-point visual analog scale (VAS) was used to rate how realistic the roller-coaster experience had been.
There were no differences in sex or age between the migraine group and the healthy control group. Half of the patients with migraine reported aura. The mean number of migraine attacks within the previous month was 3.7. The mean Migraine Disability Assessment score was 21.5, which indicates severe disability.
Nausea, dizziness often neglected
Baseline prevalence of vestibular symptoms was 75% in the migraine group and 5% in the control group (P < .0001). These symptoms included dizziness (60% and 5%, respectively; P < .0001) and postural symptoms (40% and 0%, respectively; P = .003).
At baseline, vestibular symptoms were more frequent (P = .001), more intense (P < .0001), and were associated with greater disability (P = .001) in patients with migraine, compared with participants without migraine. The patients with migraine were also more susceptible to motion sickness (P = .02) and had higher depression scores (P = .001).
During the roller-coaster simulation, dizziness was more prevalent among patients with migraine than among those without migraine (65% vs. 30%; P = .03). Patients with migraine also reported more motion sickness (SSQ score, 47.3 vs. 24.3; P = .004), longer symptom duration (1:19 minutes vs. 00:27 minutes; P = .03), and symptoms of greater intensity (VAS, 22.0 vs. 9.9; P = .03).
Brain activity also differed between groups. Among patients with migraine, neuronal activity was greater in clusters within the right superior and left inferior occipital gyrus, the left pontine nuclei, and the left cerebellar lobules V and VI.
There was a moderately negative correlation of activation of the inferior occipital gyrus with migraine disability (r = –0.46; P = .04). Activation within the pontine nuclei correlated positively with motion sickness scores (r = 0.32; P = .04).
In addition, among patients with migraine, activity in the cerebellar lobule VIIb and in the left middle frontal gyrus was decreased in comparison with persons without migraine. Also among patients with migraine, there was enhanced connectivity between the pontine nuclei, cerebellar areas V and VI, and the interior and superior occipital gyrus and numerous cortical areas.
Clinicians often neglect to treat dizziness and nausea in patients with migraine, said Dr. May. However, these symptoms are part of migraine, even when attacks are not occurring.
“I have learned that if we can explain such symptoms, they are better accepted,” said Dr. May. “We need more and better basic research because we need to understand before we treat.”
Toward faster, more effective treatment
Commenting on the study, Erik Viirre, MD, PhD, professor in the department of neurosciences, University of California, San Diego, said, “we can be excited and celebrate that these researchers are using these news tools to investigate the operation of the migraine brain.
“That will combine with the new therapies and the genomics to give us a powerful approach to this particular condition,” said Dr. Viirre, who was not involved with the research.
The findings provide significant detail about the interconnections between the various brain regions affected by migraine, he noted. These regions include not just the sensory centers but also areas involved in higher executive function and emotional responses.
By identifying these regions, the findings show “some of the underlying mechanisms of these clinically relevant features,” said Dr. Viirre, who is also director of UCSD’s Arthur C. Clarke Center for Human Imagination.
The investigators set up the motion simulation well and used sound fMRI methodology, he added. However, imaging studies of the brain’s response to motion pose several challenges.
“The biggest challenge in any of these circumstances is that you can’t put an actual fMRI scanner on a roller-coaster,” said Dr. Viirre. “The actual acceleration and gravitational sensations delivered by a roller-coaster and gravity, of course, do not occur when you’re lying still in an MRI scanner.” Nevertheless, the pseudoacceleration produced by a visual stimulus is a reasonable proxy.
The findings also suggest that researchers in the future could examine whether any new therapeutic interventions for migraine modulate the brain functions differently for individuals with migraine than for those without migraine, he noted.
“That’s going to lead us to a faster, more effective, more reliable suite of migraine therapies,” said Dr. Viirre.
The study also reminds clinicians to take a broader approach to patients with migraine, and it underscores the value of strategies such as self-calming techniques, which can reduce the number and intensity of headaches, he said.
“Literally demonstrating these functional differences in the migraine brain is a hugely important message of advocacy for people with migraine,” Dr. Viirre concluded.
The study was funded by the German Research Foundation. Drs. May and Viirre have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
and may explain the mechanisms underlying common symptoms and increased activity in certain brain regions in migraine patients.
In a new study, the prevalence of dizziness was 65% among patients with migraine who underwent a virtual roller-coaster ride versus 30% among those without migraine. In addition, imaging showed greater neuronal activity after the simulation in those with migraine.
“Migraine patients reported more dizziness and motion sickness, as well as longer symptom duration and intensity, in a virtual roller-coaster ride,” even though the videos and timing were identical for both groups, said study investigator Arne May, MD, PhD, professor of neurology at the University of Hamburg (Germany).
“We found differences not just in behavioral results but also in specific activations of areas within the cerebellum and the frontal gyrus. Migraine patients process such visual input differently from controls and activate a specific brain network to do so,” he added.
The findings were published online July 21, 2021, in Neurology.
The brain’s response
Nausea, which is among the diagnostic criteria for migraine, is the main symptom of motion sickness. Vestibular symptoms such as dizziness are also components of migraine.
Previous research has examined how the brain processes visual and motion stimuli in migraine, but the reasons patients with migraine are susceptible to motion sickness and dizziness remain unclear.
The researchers used a simulated roller-coaster ride to study the clinical and brain responses to motion among participants with and participants without migraine. They enrolled 20 consecutive patients with migraine who presented to a tertiary headache clinic between January and March 2020 and enrolled 20 healthy participants from a university hospital and the community. The average age of the study population was 30 years, and more than 80% were women.
In response to a questionnaire, participants provided information about demographics and headache features, including onset, frequency, and intensity. They also provided information about their status within the migraine phase and about vestibular symptoms experienced in daily life.
While undergoing functional MRI (fMRI), all participants watched two short videos that provided a first-person perspective of a roller-coaster ride. During the videos, they wore ear buds that conveyed the sound of a car riding over the rails.
The first video included more horizontal perspectives, and the second had more vertical perspectives. Each video was shown three times in random order.
During fMRI, participants reported intensity of nausea and vestibular symptoms using an 11-point Likert scale. After the experiment, they responded to a questionnaire that evaluated intensity and duration of nausea, dizziness, and vertigo experienced during the videos.
Participants also were given the Simulator Sickness Questionnaire (SSQ), which assessed motion sickness. A 100-point visual analog scale (VAS) was used to rate how realistic the roller-coaster experience had been.
There were no differences in sex or age between the migraine group and the healthy control group. Half of the patients with migraine reported aura. The mean number of migraine attacks within the previous month was 3.7. The mean Migraine Disability Assessment score was 21.5, which indicates severe disability.
Nausea, dizziness often neglected
Baseline prevalence of vestibular symptoms was 75% in the migraine group and 5% in the control group (P < .0001). These symptoms included dizziness (60% and 5%, respectively; P < .0001) and postural symptoms (40% and 0%, respectively; P = .003).
At baseline, vestibular symptoms were more frequent (P = .001), more intense (P < .0001), and were associated with greater disability (P = .001) in patients with migraine, compared with participants without migraine. The patients with migraine were also more susceptible to motion sickness (P = .02) and had higher depression scores (P = .001).
During the roller-coaster simulation, dizziness was more prevalent among patients with migraine than among those without migraine (65% vs. 30%; P = .03). Patients with migraine also reported more motion sickness (SSQ score, 47.3 vs. 24.3; P = .004), longer symptom duration (1:19 minutes vs. 00:27 minutes; P = .03), and symptoms of greater intensity (VAS, 22.0 vs. 9.9; P = .03).
Brain activity also differed between groups. Among patients with migraine, neuronal activity was greater in clusters within the right superior and left inferior occipital gyrus, the left pontine nuclei, and the left cerebellar lobules V and VI.
There was a moderately negative correlation of activation of the inferior occipital gyrus with migraine disability (r = –0.46; P = .04). Activation within the pontine nuclei correlated positively with motion sickness scores (r = 0.32; P = .04).
In addition, among patients with migraine, activity in the cerebellar lobule VIIb and in the left middle frontal gyrus was decreased in comparison with persons without migraine. Also among patients with migraine, there was enhanced connectivity between the pontine nuclei, cerebellar areas V and VI, and the interior and superior occipital gyrus and numerous cortical areas.
Clinicians often neglect to treat dizziness and nausea in patients with migraine, said Dr. May. However, these symptoms are part of migraine, even when attacks are not occurring.
“I have learned that if we can explain such symptoms, they are better accepted,” said Dr. May. “We need more and better basic research because we need to understand before we treat.”
Toward faster, more effective treatment
Commenting on the study, Erik Viirre, MD, PhD, professor in the department of neurosciences, University of California, San Diego, said, “we can be excited and celebrate that these researchers are using these news tools to investigate the operation of the migraine brain.
“That will combine with the new therapies and the genomics to give us a powerful approach to this particular condition,” said Dr. Viirre, who was not involved with the research.
The findings provide significant detail about the interconnections between the various brain regions affected by migraine, he noted. These regions include not just the sensory centers but also areas involved in higher executive function and emotional responses.
By identifying these regions, the findings show “some of the underlying mechanisms of these clinically relevant features,” said Dr. Viirre, who is also director of UCSD’s Arthur C. Clarke Center for Human Imagination.
The investigators set up the motion simulation well and used sound fMRI methodology, he added. However, imaging studies of the brain’s response to motion pose several challenges.
“The biggest challenge in any of these circumstances is that you can’t put an actual fMRI scanner on a roller-coaster,” said Dr. Viirre. “The actual acceleration and gravitational sensations delivered by a roller-coaster and gravity, of course, do not occur when you’re lying still in an MRI scanner.” Nevertheless, the pseudoacceleration produced by a visual stimulus is a reasonable proxy.
The findings also suggest that researchers in the future could examine whether any new therapeutic interventions for migraine modulate the brain functions differently for individuals with migraine than for those without migraine, he noted.
“That’s going to lead us to a faster, more effective, more reliable suite of migraine therapies,” said Dr. Viirre.
The study also reminds clinicians to take a broader approach to patients with migraine, and it underscores the value of strategies such as self-calming techniques, which can reduce the number and intensity of headaches, he said.
“Literally demonstrating these functional differences in the migraine brain is a hugely important message of advocacy for people with migraine,” Dr. Viirre concluded.
The study was funded by the German Research Foundation. Drs. May and Viirre have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
and may explain the mechanisms underlying common symptoms and increased activity in certain brain regions in migraine patients.
In a new study, the prevalence of dizziness was 65% among patients with migraine who underwent a virtual roller-coaster ride versus 30% among those without migraine. In addition, imaging showed greater neuronal activity after the simulation in those with migraine.
“Migraine patients reported more dizziness and motion sickness, as well as longer symptom duration and intensity, in a virtual roller-coaster ride,” even though the videos and timing were identical for both groups, said study investigator Arne May, MD, PhD, professor of neurology at the University of Hamburg (Germany).
“We found differences not just in behavioral results but also in specific activations of areas within the cerebellum and the frontal gyrus. Migraine patients process such visual input differently from controls and activate a specific brain network to do so,” he added.
The findings were published online July 21, 2021, in Neurology.
The brain’s response
Nausea, which is among the diagnostic criteria for migraine, is the main symptom of motion sickness. Vestibular symptoms such as dizziness are also components of migraine.
Previous research has examined how the brain processes visual and motion stimuli in migraine, but the reasons patients with migraine are susceptible to motion sickness and dizziness remain unclear.
The researchers used a simulated roller-coaster ride to study the clinical and brain responses to motion among participants with and participants without migraine. They enrolled 20 consecutive patients with migraine who presented to a tertiary headache clinic between January and March 2020 and enrolled 20 healthy participants from a university hospital and the community. The average age of the study population was 30 years, and more than 80% were women.
In response to a questionnaire, participants provided information about demographics and headache features, including onset, frequency, and intensity. They also provided information about their status within the migraine phase and about vestibular symptoms experienced in daily life.
While undergoing functional MRI (fMRI), all participants watched two short videos that provided a first-person perspective of a roller-coaster ride. During the videos, they wore ear buds that conveyed the sound of a car riding over the rails.
The first video included more horizontal perspectives, and the second had more vertical perspectives. Each video was shown three times in random order.
During fMRI, participants reported intensity of nausea and vestibular symptoms using an 11-point Likert scale. After the experiment, they responded to a questionnaire that evaluated intensity and duration of nausea, dizziness, and vertigo experienced during the videos.
Participants also were given the Simulator Sickness Questionnaire (SSQ), which assessed motion sickness. A 100-point visual analog scale (VAS) was used to rate how realistic the roller-coaster experience had been.
There were no differences in sex or age between the migraine group and the healthy control group. Half of the patients with migraine reported aura. The mean number of migraine attacks within the previous month was 3.7. The mean Migraine Disability Assessment score was 21.5, which indicates severe disability.
Nausea, dizziness often neglected
Baseline prevalence of vestibular symptoms was 75% in the migraine group and 5% in the control group (P < .0001). These symptoms included dizziness (60% and 5%, respectively; P < .0001) and postural symptoms (40% and 0%, respectively; P = .003).
At baseline, vestibular symptoms were more frequent (P = .001), more intense (P < .0001), and were associated with greater disability (P = .001) in patients with migraine, compared with participants without migraine. The patients with migraine were also more susceptible to motion sickness (P = .02) and had higher depression scores (P = .001).
During the roller-coaster simulation, dizziness was more prevalent among patients with migraine than among those without migraine (65% vs. 30%; P = .03). Patients with migraine also reported more motion sickness (SSQ score, 47.3 vs. 24.3; P = .004), longer symptom duration (1:19 minutes vs. 00:27 minutes; P = .03), and symptoms of greater intensity (VAS, 22.0 vs. 9.9; P = .03).
Brain activity also differed between groups. Among patients with migraine, neuronal activity was greater in clusters within the right superior and left inferior occipital gyrus, the left pontine nuclei, and the left cerebellar lobules V and VI.
There was a moderately negative correlation of activation of the inferior occipital gyrus with migraine disability (r = –0.46; P = .04). Activation within the pontine nuclei correlated positively with motion sickness scores (r = 0.32; P = .04).
In addition, among patients with migraine, activity in the cerebellar lobule VIIb and in the left middle frontal gyrus was decreased in comparison with persons without migraine. Also among patients with migraine, there was enhanced connectivity between the pontine nuclei, cerebellar areas V and VI, and the interior and superior occipital gyrus and numerous cortical areas.
Clinicians often neglect to treat dizziness and nausea in patients with migraine, said Dr. May. However, these symptoms are part of migraine, even when attacks are not occurring.
“I have learned that if we can explain such symptoms, they are better accepted,” said Dr. May. “We need more and better basic research because we need to understand before we treat.”
Toward faster, more effective treatment
Commenting on the study, Erik Viirre, MD, PhD, professor in the department of neurosciences, University of California, San Diego, said, “we can be excited and celebrate that these researchers are using these news tools to investigate the operation of the migraine brain.
“That will combine with the new therapies and the genomics to give us a powerful approach to this particular condition,” said Dr. Viirre, who was not involved with the research.
The findings provide significant detail about the interconnections between the various brain regions affected by migraine, he noted. These regions include not just the sensory centers but also areas involved in higher executive function and emotional responses.
By identifying these regions, the findings show “some of the underlying mechanisms of these clinically relevant features,” said Dr. Viirre, who is also director of UCSD’s Arthur C. Clarke Center for Human Imagination.
The investigators set up the motion simulation well and used sound fMRI methodology, he added. However, imaging studies of the brain’s response to motion pose several challenges.
“The biggest challenge in any of these circumstances is that you can’t put an actual fMRI scanner on a roller-coaster,” said Dr. Viirre. “The actual acceleration and gravitational sensations delivered by a roller-coaster and gravity, of course, do not occur when you’re lying still in an MRI scanner.” Nevertheless, the pseudoacceleration produced by a visual stimulus is a reasonable proxy.
The findings also suggest that researchers in the future could examine whether any new therapeutic interventions for migraine modulate the brain functions differently for individuals with migraine than for those without migraine, he noted.
“That’s going to lead us to a faster, more effective, more reliable suite of migraine therapies,” said Dr. Viirre.
The study also reminds clinicians to take a broader approach to patients with migraine, and it underscores the value of strategies such as self-calming techniques, which can reduce the number and intensity of headaches, he said.
“Literally demonstrating these functional differences in the migraine brain is a hugely important message of advocacy for people with migraine,” Dr. Viirre concluded.
The study was funded by the German Research Foundation. Drs. May and Viirre have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Occipital nerve stimulation offers relief for patients with intractable chronic cluster headache
Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.
Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.
The findings were published online.
The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
Safe and well tolerated
“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.
From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.
The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).
At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).
The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
Low intensity stimulation may be best
“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.
Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”
While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”
Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.
The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.
Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.
Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.
The findings were published online.
The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
Safe and well tolerated
“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.
From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.
The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).
At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).
The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
Low intensity stimulation may be best
“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.
Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”
While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”
Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.
The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.
Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.
Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.
The findings were published online.
The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
Safe and well tolerated
“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.
From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.
The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).
At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).
The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
Low intensity stimulation may be best
“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.
Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”
While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”
Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.
The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.
FROM LANCET NEUROLOGY
Updated consensus statement assesses new migraine treatments
“Because the benefit–risk profiles of newer treatments will continue to evolve as clinical trial and real-world data accrue, the American Headache Society intends to review this statement regularly and update, if appropriate, based on the emergence of evidence with implications for clinical practice,” wrote lead author Jessica Ailani, MD, of the department of neurology at Medstar Georgetown University Hospital, Washington, and colleagues. The statement was published in Headache.
To assess recent data on the efficacy, safety, and clinical use of newly introduced acute and preventive migraine treatments, the AHS convened a small task force to review relevant literature published from December 2018 through February 2021. The society’s board of directors, along with patients and patient advocates associated with the American Migraine Foundation, also provided pertinent commentary.
New migraine treatment
Five recently approved acute migraine treatments were specifically noted: two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists – rimegepant and ubrogepant – along with the nonsteroidal anti-inflammatory drug celecoxib, the serotonin 5-HT1F agonist lasmiditan, and remote electrical neuromodulation (REN). Highlighted risks include serious cardiovascular thrombotic events in patients on celecoxib, along with driving impairment, sleepiness, and the possibility of overuse in patients on lasmiditan. The authors added, however, that REN “has shown good tolerability and safety in clinical trials” and that frequent use of rimegepant or ubrogepant does not appear to lead to medication-overuse headache.
Regarding acute treatment overall, the statement recommended nonsteroidal anti-inflammatory drugs (NSAIDs), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations – such as aspirin plus acetaminophen plus caffeine – for mild to moderate attacks. For moderate or severe attacks, they recommended migraine-specific agents such as triptans, small-molecule CGRP receptor antagonists (gepants), or selective serotonin 5-HT1F receptor agonists (ditans). No matter the prescribed treatment, the statement pushed for patients to “treat at the first sign of pain to improve the probability of achieving freedom from pain and reduce attack-related disability.”
The authors added that 30% of patients on triptans have an “insufficient response” and as such may benefit from a second triptan or – if certain criteria are met – switching to a gepant, a ditan, or a neuromodulatory device. They also recommended a nonoral formulation for patients whose attacks are often accompanied by severe nausea or vomiting.
More broadly, they addressed the tolerability and safety issues associated with certain treatments, including the gastrointestinal and cardiovascular side effects of NSAIDs and the dangers of using triptans in patients with coronary artery disease or other vascular disorders. And while gepants and ditans appeared in clinical trials to be safe choices for patients with stable cardiovascular disease, “benefit-risk should be assessed in each patient as the real-world database for these therapies grows,” they wrote.
Only one recently approved preventive treatment – eptinezumab, an intravenous anti-CGRP ligand monoclonal antibody (MAB) – was highlighted. The authors noted that its benefits can begin within 24 hours, and it can reduce acute medication use and therefore the risk of medication-overuse headache.
Regarding preventive treatments overall, the authors stated that prevention should be offered if patients suffer from 6 or more days of headache per month, or 3-4 days of headache plus some-to-severe disability. Preventive treatments should be considered in patients who range from at least 2 days of headache per month plus severe disability to 4 or 5 days of headache. Prevention should also be considered in patients with uncommon migraine subtypes, including hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura.
Initiating treatment
When considering initiation of treatment with one of the four Food and Drug Administration–approved CGRP MABs – eptinezumab, erenumab, fremanezumab, or galcanezumab – the authors recommend their use if migraine patients show an inability to tolerate or respond to a trial of two or more older oral medications or other established effective therapies. Though they emphasized that oral preventive medications should be started at a low dose and titrated slowly until the target response is reached or tolerability issues emerge, no such need was specified for the parenteral treatments. They also endorsed the approach of patients staying on oral preventive drugs for a minimum of 8 weeks to determine effectiveness or a lack thereof; at that point, switching to another treatment is recommended.
The dual use of therapies such as neuromodulation, biobehavioral therapies, and gepants were also examined, including gepants’ potential as a “continuum between the acute and preventive treatment of migraine” and the limited use of neuromodulatory devices in clinical practice despite clear benefits in patients who prefer to avoid medication or those suffering from frequent attacks and subsequent medication overuse. In addition, it was stated that biobehavioral therapies have “grade A evidence” supporting their use in patients who either prefer nonpharmacologic treatments or have an adverse or poor reaction to the drugs.
From the patient perspective, one of the six reviewers shared concerns about migraine patients being required to try two established preventive medications before starting a recently introduced option, noting that the older drugs have lower efficacy and tolerability. Two reviewers would have liked to see the statement focus more on nonpharmacologic and device-related therapies, and one reviewer noted the possible value in guidance regarding “exploratory approaches” such as cannabis.
The authors acknowledged numerous potential conflicts of interest, including receiving speaking and consulting fees, grants, personal fees, and honoraria from various pharmaceutical and publishing companies.
Not everyone agrees
Commenting on the AHS consensus statement, James A Charles, MD, and Ira Turner, MD, had this to say: “This Consensus Statement incorporates the best available evidence including the newer CGRP therapies as well as the older treatments. The AHS posture is that the CGRP abortive and preventive treatments have a lesser amount of data and experience than the older treatments which have a wealth of literature and data because they have been around longer. As a result, there are 2 statements in these guidelines that the insurance companies quote in their manual of policies:
1. Inadequate response to two or more oral triptans before using a gepant as abortive treatment
2. Inadequate response to an 8-week trial at a dose established to be potentially effective of two or more of the following before using CGRP MAB for preventive treatment: topiramate, divalproex sodium/valproate sodium; beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol; tricyclic antidepressant: amitriptyline, nortriptyline; serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine; other Level A or B treatments.”
Dr. Charles, who is affiliated with Holy Name Medical Center in Teaneck N.J., and Dr. Turner, who is affiliated with the Center for Headache Care and Research at Island Neurological Associates in Plainview, N.Y., further said that “giving the CGRP MABs and gepants second-class status because they have not been around as long as the old boys is an insult to the research, development, and successful execution of gepant and CGRP MAB therapies in the last several years. The authors omitted the Hepp study and the long list of adverse effects of triptans leading to high discontinuance rates, and how trying a second triptan will probably not work.” Importantly, they said, “the authors have given the insurance carriers a weapon to deny direct access to gepants and CGRP MABs making direct access to these agents difficult for patients and physicians and their staffs.”
Dr. Charles and Dr. Turner point out that the AHS guidelines use the term “cost effective” – that it is better to use the cheaper, older drugs first. “Ineffective treatment of a patient for 8 weeks before using CGRP blocking therapies and using 2 triptans before a gepant is cost ineffective,” they said. “Inadequate delayed treatment results in loss of work productivity and loss of school and family participation and excessive use of ER visits. These guidelines forget that we ameliorate current disability and prevent chronification by treating with the most effective abortive and preventive therapies which may not commence with the cheaper old drugs.”
They explain: “Of course, we would use a beta-blocker for comorbid hypertension and/or anxiety, and venlafaxine for comorbid depression. And if a patient is pain free in 2 hrs with no adverse effects from a triptan used less than 10 times a month, it would not be appropriate to switch to a gepant. However, a treatment naive migraineur with accelerating migraine should have the option of going directly to a gepant and CGRP blocking MAB.” Dr. Charles and Dr. Turner concur that the phrase in the AHS consensus statement regarding the staging of therapy – two triptans before a gepant and two oral preventatives for 8 weeks before a CGRP MAB – “should be removed so that the CGRP drugs get the equal credit they deserve, as can be attested to by the migraine voices of lives saved by the sound research that led to their development and approval by the FDA.”
Ultimately, Dr. Charles and Dr. Turner said, “the final decision on treatment should be made by the physician and patient, not the insurance company or consensus statements.”
Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, former president of the International Headache Society, and editor-in-chief of Neurology Reviews, said, “Although I think the consensus statement is well done, and the authors have the right to make the statements they have made, Drs. Charles and Turner are excellent experienced clinicians and they should be heard. They properly state that the restrictive statements highlighted by the authors have already been used by insurance companies to prevent access to the more expensive but more effective therapies with fewer adverse effects.”
Dr. Rapoport goes on to say, “I believe that the patient’s individual headache history and past responses to therapies must be analyzed by the treating physician and an appropriate treatment be agreed upon between the patient and doctor. It is time to let experienced headache-interested doctors make their own correct decision about treatment without the heavy hand of the insurance company, which is often more intent on saving money than helping the patient.
Suggested reading
Hepp Z et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-88.
Alam A et al. Triptan use and discontinuation in a representative sample of persons with migraine: Results from Migraine in America Symptoms and Treatment (MAST) study. Headache. 2018;58:68‐69.
Buse DC et al. Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2015 Jun;55(6):825-39.
“Because the benefit–risk profiles of newer treatments will continue to evolve as clinical trial and real-world data accrue, the American Headache Society intends to review this statement regularly and update, if appropriate, based on the emergence of evidence with implications for clinical practice,” wrote lead author Jessica Ailani, MD, of the department of neurology at Medstar Georgetown University Hospital, Washington, and colleagues. The statement was published in Headache.
To assess recent data on the efficacy, safety, and clinical use of newly introduced acute and preventive migraine treatments, the AHS convened a small task force to review relevant literature published from December 2018 through February 2021. The society’s board of directors, along with patients and patient advocates associated with the American Migraine Foundation, also provided pertinent commentary.
New migraine treatment
Five recently approved acute migraine treatments were specifically noted: two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists – rimegepant and ubrogepant – along with the nonsteroidal anti-inflammatory drug celecoxib, the serotonin 5-HT1F agonist lasmiditan, and remote electrical neuromodulation (REN). Highlighted risks include serious cardiovascular thrombotic events in patients on celecoxib, along with driving impairment, sleepiness, and the possibility of overuse in patients on lasmiditan. The authors added, however, that REN “has shown good tolerability and safety in clinical trials” and that frequent use of rimegepant or ubrogepant does not appear to lead to medication-overuse headache.
Regarding acute treatment overall, the statement recommended nonsteroidal anti-inflammatory drugs (NSAIDs), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations – such as aspirin plus acetaminophen plus caffeine – for mild to moderate attacks. For moderate or severe attacks, they recommended migraine-specific agents such as triptans, small-molecule CGRP receptor antagonists (gepants), or selective serotonin 5-HT1F receptor agonists (ditans). No matter the prescribed treatment, the statement pushed for patients to “treat at the first sign of pain to improve the probability of achieving freedom from pain and reduce attack-related disability.”
The authors added that 30% of patients on triptans have an “insufficient response” and as such may benefit from a second triptan or – if certain criteria are met – switching to a gepant, a ditan, or a neuromodulatory device. They also recommended a nonoral formulation for patients whose attacks are often accompanied by severe nausea or vomiting.
More broadly, they addressed the tolerability and safety issues associated with certain treatments, including the gastrointestinal and cardiovascular side effects of NSAIDs and the dangers of using triptans in patients with coronary artery disease or other vascular disorders. And while gepants and ditans appeared in clinical trials to be safe choices for patients with stable cardiovascular disease, “benefit-risk should be assessed in each patient as the real-world database for these therapies grows,” they wrote.
Only one recently approved preventive treatment – eptinezumab, an intravenous anti-CGRP ligand monoclonal antibody (MAB) – was highlighted. The authors noted that its benefits can begin within 24 hours, and it can reduce acute medication use and therefore the risk of medication-overuse headache.
Regarding preventive treatments overall, the authors stated that prevention should be offered if patients suffer from 6 or more days of headache per month, or 3-4 days of headache plus some-to-severe disability. Preventive treatments should be considered in patients who range from at least 2 days of headache per month plus severe disability to 4 or 5 days of headache. Prevention should also be considered in patients with uncommon migraine subtypes, including hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura.
Initiating treatment
When considering initiation of treatment with one of the four Food and Drug Administration–approved CGRP MABs – eptinezumab, erenumab, fremanezumab, or galcanezumab – the authors recommend their use if migraine patients show an inability to tolerate or respond to a trial of two or more older oral medications or other established effective therapies. Though they emphasized that oral preventive medications should be started at a low dose and titrated slowly until the target response is reached or tolerability issues emerge, no such need was specified for the parenteral treatments. They also endorsed the approach of patients staying on oral preventive drugs for a minimum of 8 weeks to determine effectiveness or a lack thereof; at that point, switching to another treatment is recommended.
The dual use of therapies such as neuromodulation, biobehavioral therapies, and gepants were also examined, including gepants’ potential as a “continuum between the acute and preventive treatment of migraine” and the limited use of neuromodulatory devices in clinical practice despite clear benefits in patients who prefer to avoid medication or those suffering from frequent attacks and subsequent medication overuse. In addition, it was stated that biobehavioral therapies have “grade A evidence” supporting their use in patients who either prefer nonpharmacologic treatments or have an adverse or poor reaction to the drugs.
From the patient perspective, one of the six reviewers shared concerns about migraine patients being required to try two established preventive medications before starting a recently introduced option, noting that the older drugs have lower efficacy and tolerability. Two reviewers would have liked to see the statement focus more on nonpharmacologic and device-related therapies, and one reviewer noted the possible value in guidance regarding “exploratory approaches” such as cannabis.
The authors acknowledged numerous potential conflicts of interest, including receiving speaking and consulting fees, grants, personal fees, and honoraria from various pharmaceutical and publishing companies.
Not everyone agrees
Commenting on the AHS consensus statement, James A Charles, MD, and Ira Turner, MD, had this to say: “This Consensus Statement incorporates the best available evidence including the newer CGRP therapies as well as the older treatments. The AHS posture is that the CGRP abortive and preventive treatments have a lesser amount of data and experience than the older treatments which have a wealth of literature and data because they have been around longer. As a result, there are 2 statements in these guidelines that the insurance companies quote in their manual of policies:
1. Inadequate response to two or more oral triptans before using a gepant as abortive treatment
2. Inadequate response to an 8-week trial at a dose established to be potentially effective of two or more of the following before using CGRP MAB for preventive treatment: topiramate, divalproex sodium/valproate sodium; beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol; tricyclic antidepressant: amitriptyline, nortriptyline; serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine; other Level A or B treatments.”
Dr. Charles, who is affiliated with Holy Name Medical Center in Teaneck N.J., and Dr. Turner, who is affiliated with the Center for Headache Care and Research at Island Neurological Associates in Plainview, N.Y., further said that “giving the CGRP MABs and gepants second-class status because they have not been around as long as the old boys is an insult to the research, development, and successful execution of gepant and CGRP MAB therapies in the last several years. The authors omitted the Hepp study and the long list of adverse effects of triptans leading to high discontinuance rates, and how trying a second triptan will probably not work.” Importantly, they said, “the authors have given the insurance carriers a weapon to deny direct access to gepants and CGRP MABs making direct access to these agents difficult for patients and physicians and their staffs.”
Dr. Charles and Dr. Turner point out that the AHS guidelines use the term “cost effective” – that it is better to use the cheaper, older drugs first. “Ineffective treatment of a patient for 8 weeks before using CGRP blocking therapies and using 2 triptans before a gepant is cost ineffective,” they said. “Inadequate delayed treatment results in loss of work productivity and loss of school and family participation and excessive use of ER visits. These guidelines forget that we ameliorate current disability and prevent chronification by treating with the most effective abortive and preventive therapies which may not commence with the cheaper old drugs.”
They explain: “Of course, we would use a beta-blocker for comorbid hypertension and/or anxiety, and venlafaxine for comorbid depression. And if a patient is pain free in 2 hrs with no adverse effects from a triptan used less than 10 times a month, it would not be appropriate to switch to a gepant. However, a treatment naive migraineur with accelerating migraine should have the option of going directly to a gepant and CGRP blocking MAB.” Dr. Charles and Dr. Turner concur that the phrase in the AHS consensus statement regarding the staging of therapy – two triptans before a gepant and two oral preventatives for 8 weeks before a CGRP MAB – “should be removed so that the CGRP drugs get the equal credit they deserve, as can be attested to by the migraine voices of lives saved by the sound research that led to their development and approval by the FDA.”
Ultimately, Dr. Charles and Dr. Turner said, “the final decision on treatment should be made by the physician and patient, not the insurance company or consensus statements.”
Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, former president of the International Headache Society, and editor-in-chief of Neurology Reviews, said, “Although I think the consensus statement is well done, and the authors have the right to make the statements they have made, Drs. Charles and Turner are excellent experienced clinicians and they should be heard. They properly state that the restrictive statements highlighted by the authors have already been used by insurance companies to prevent access to the more expensive but more effective therapies with fewer adverse effects.”
Dr. Rapoport goes on to say, “I believe that the patient’s individual headache history and past responses to therapies must be analyzed by the treating physician and an appropriate treatment be agreed upon between the patient and doctor. It is time to let experienced headache-interested doctors make their own correct decision about treatment without the heavy hand of the insurance company, which is often more intent on saving money than helping the patient.
Suggested reading
Hepp Z et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-88.
Alam A et al. Triptan use and discontinuation in a representative sample of persons with migraine: Results from Migraine in America Symptoms and Treatment (MAST) study. Headache. 2018;58:68‐69.
Buse DC et al. Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2015 Jun;55(6):825-39.
“Because the benefit–risk profiles of newer treatments will continue to evolve as clinical trial and real-world data accrue, the American Headache Society intends to review this statement regularly and update, if appropriate, based on the emergence of evidence with implications for clinical practice,” wrote lead author Jessica Ailani, MD, of the department of neurology at Medstar Georgetown University Hospital, Washington, and colleagues. The statement was published in Headache.
To assess recent data on the efficacy, safety, and clinical use of newly introduced acute and preventive migraine treatments, the AHS convened a small task force to review relevant literature published from December 2018 through February 2021. The society’s board of directors, along with patients and patient advocates associated with the American Migraine Foundation, also provided pertinent commentary.
New migraine treatment
Five recently approved acute migraine treatments were specifically noted: two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists – rimegepant and ubrogepant – along with the nonsteroidal anti-inflammatory drug celecoxib, the serotonin 5-HT1F agonist lasmiditan, and remote electrical neuromodulation (REN). Highlighted risks include serious cardiovascular thrombotic events in patients on celecoxib, along with driving impairment, sleepiness, and the possibility of overuse in patients on lasmiditan. The authors added, however, that REN “has shown good tolerability and safety in clinical trials” and that frequent use of rimegepant or ubrogepant does not appear to lead to medication-overuse headache.
Regarding acute treatment overall, the statement recommended nonsteroidal anti-inflammatory drugs (NSAIDs), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations – such as aspirin plus acetaminophen plus caffeine – for mild to moderate attacks. For moderate or severe attacks, they recommended migraine-specific agents such as triptans, small-molecule CGRP receptor antagonists (gepants), or selective serotonin 5-HT1F receptor agonists (ditans). No matter the prescribed treatment, the statement pushed for patients to “treat at the first sign of pain to improve the probability of achieving freedom from pain and reduce attack-related disability.”
The authors added that 30% of patients on triptans have an “insufficient response” and as such may benefit from a second triptan or – if certain criteria are met – switching to a gepant, a ditan, or a neuromodulatory device. They also recommended a nonoral formulation for patients whose attacks are often accompanied by severe nausea or vomiting.
More broadly, they addressed the tolerability and safety issues associated with certain treatments, including the gastrointestinal and cardiovascular side effects of NSAIDs and the dangers of using triptans in patients with coronary artery disease or other vascular disorders. And while gepants and ditans appeared in clinical trials to be safe choices for patients with stable cardiovascular disease, “benefit-risk should be assessed in each patient as the real-world database for these therapies grows,” they wrote.
Only one recently approved preventive treatment – eptinezumab, an intravenous anti-CGRP ligand monoclonal antibody (MAB) – was highlighted. The authors noted that its benefits can begin within 24 hours, and it can reduce acute medication use and therefore the risk of medication-overuse headache.
Regarding preventive treatments overall, the authors stated that prevention should be offered if patients suffer from 6 or more days of headache per month, or 3-4 days of headache plus some-to-severe disability. Preventive treatments should be considered in patients who range from at least 2 days of headache per month plus severe disability to 4 or 5 days of headache. Prevention should also be considered in patients with uncommon migraine subtypes, including hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura.
Initiating treatment
When considering initiation of treatment with one of the four Food and Drug Administration–approved CGRP MABs – eptinezumab, erenumab, fremanezumab, or galcanezumab – the authors recommend their use if migraine patients show an inability to tolerate or respond to a trial of two or more older oral medications or other established effective therapies. Though they emphasized that oral preventive medications should be started at a low dose and titrated slowly until the target response is reached or tolerability issues emerge, no such need was specified for the parenteral treatments. They also endorsed the approach of patients staying on oral preventive drugs for a minimum of 8 weeks to determine effectiveness or a lack thereof; at that point, switching to another treatment is recommended.
The dual use of therapies such as neuromodulation, biobehavioral therapies, and gepants were also examined, including gepants’ potential as a “continuum between the acute and preventive treatment of migraine” and the limited use of neuromodulatory devices in clinical practice despite clear benefits in patients who prefer to avoid medication or those suffering from frequent attacks and subsequent medication overuse. In addition, it was stated that biobehavioral therapies have “grade A evidence” supporting their use in patients who either prefer nonpharmacologic treatments or have an adverse or poor reaction to the drugs.
From the patient perspective, one of the six reviewers shared concerns about migraine patients being required to try two established preventive medications before starting a recently introduced option, noting that the older drugs have lower efficacy and tolerability. Two reviewers would have liked to see the statement focus more on nonpharmacologic and device-related therapies, and one reviewer noted the possible value in guidance regarding “exploratory approaches” such as cannabis.
The authors acknowledged numerous potential conflicts of interest, including receiving speaking and consulting fees, grants, personal fees, and honoraria from various pharmaceutical and publishing companies.
Not everyone agrees
Commenting on the AHS consensus statement, James A Charles, MD, and Ira Turner, MD, had this to say: “This Consensus Statement incorporates the best available evidence including the newer CGRP therapies as well as the older treatments. The AHS posture is that the CGRP abortive and preventive treatments have a lesser amount of data and experience than the older treatments which have a wealth of literature and data because they have been around longer. As a result, there are 2 statements in these guidelines that the insurance companies quote in their manual of policies:
1. Inadequate response to two or more oral triptans before using a gepant as abortive treatment
2. Inadequate response to an 8-week trial at a dose established to be potentially effective of two or more of the following before using CGRP MAB for preventive treatment: topiramate, divalproex sodium/valproate sodium; beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol; tricyclic antidepressant: amitriptyline, nortriptyline; serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine; other Level A or B treatments.”
Dr. Charles, who is affiliated with Holy Name Medical Center in Teaneck N.J., and Dr. Turner, who is affiliated with the Center for Headache Care and Research at Island Neurological Associates in Plainview, N.Y., further said that “giving the CGRP MABs and gepants second-class status because they have not been around as long as the old boys is an insult to the research, development, and successful execution of gepant and CGRP MAB therapies in the last several years. The authors omitted the Hepp study and the long list of adverse effects of triptans leading to high discontinuance rates, and how trying a second triptan will probably not work.” Importantly, they said, “the authors have given the insurance carriers a weapon to deny direct access to gepants and CGRP MABs making direct access to these agents difficult for patients and physicians and their staffs.”
Dr. Charles and Dr. Turner point out that the AHS guidelines use the term “cost effective” – that it is better to use the cheaper, older drugs first. “Ineffective treatment of a patient for 8 weeks before using CGRP blocking therapies and using 2 triptans before a gepant is cost ineffective,” they said. “Inadequate delayed treatment results in loss of work productivity and loss of school and family participation and excessive use of ER visits. These guidelines forget that we ameliorate current disability and prevent chronification by treating with the most effective abortive and preventive therapies which may not commence with the cheaper old drugs.”
They explain: “Of course, we would use a beta-blocker for comorbid hypertension and/or anxiety, and venlafaxine for comorbid depression. And if a patient is pain free in 2 hrs with no adverse effects from a triptan used less than 10 times a month, it would not be appropriate to switch to a gepant. However, a treatment naive migraineur with accelerating migraine should have the option of going directly to a gepant and CGRP blocking MAB.” Dr. Charles and Dr. Turner concur that the phrase in the AHS consensus statement regarding the staging of therapy – two triptans before a gepant and two oral preventatives for 8 weeks before a CGRP MAB – “should be removed so that the CGRP drugs get the equal credit they deserve, as can be attested to by the migraine voices of lives saved by the sound research that led to their development and approval by the FDA.”
Ultimately, Dr. Charles and Dr. Turner said, “the final decision on treatment should be made by the physician and patient, not the insurance company or consensus statements.”
Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, former president of the International Headache Society, and editor-in-chief of Neurology Reviews, said, “Although I think the consensus statement is well done, and the authors have the right to make the statements they have made, Drs. Charles and Turner are excellent experienced clinicians and they should be heard. They properly state that the restrictive statements highlighted by the authors have already been used by insurance companies to prevent access to the more expensive but more effective therapies with fewer adverse effects.”
Dr. Rapoport goes on to say, “I believe that the patient’s individual headache history and past responses to therapies must be analyzed by the treating physician and an appropriate treatment be agreed upon between the patient and doctor. It is time to let experienced headache-interested doctors make their own correct decision about treatment without the heavy hand of the insurance company, which is often more intent on saving money than helping the patient.
Suggested reading
Hepp Z et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-88.
Alam A et al. Triptan use and discontinuation in a representative sample of persons with migraine: Results from Migraine in America Symptoms and Treatment (MAST) study. Headache. 2018;58:68‐69.
Buse DC et al. Adding additional acute medications to a triptan regimen for migraine and observed changes in headache-related disability: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2015 Jun;55(6):825-39.
FROM HEADACHE
Novel NSAID–triptan drug effectively relieves migraine pain
, new research suggests. Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patients’ most bothersome symptom (MBS) compared with placebo.
In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.
Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.
“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” said study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth, Hanover, N.H. “That is why the whole is greater than the sum of the parts,” Dr. Tepper added.
The findings were presented at the American Headache Society’s 2021 annual meeting.
Acute treatments needed
For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.
The search for optimal acute treatments is therefore “really important for patients,” Dr. Tepper noted.
Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene-related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.
In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.
The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.
The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom and freedom from pain progression, functional disability, and use of rescue medication.
Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.
Reduced pain progression
Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).
Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).
The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs. 9.6%; P = .013).
In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, versus 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).
AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, versus 27.7% of the placebo group (P < .001).
The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, versus 2.1%; the rate of dizziness was 2.9%, versus 1.4%; and the rate of paresthesia was 2.1%, versus 0%. There were no serious AEs.
“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Dr. Tepper. “It’s not dramatically different for dizziness.”
Improved adherence?
Meloxicam is generally used not as an acute medication but for prevention, Dr. Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.
AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.
“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Dr. Tepper.
The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly. “We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Dr. Tepper said.
Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply. “It’s a big adherence issue,” said Dr. Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”
Uncertain therapeutic advantage
Commenting on the findings, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, Burlington, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.
“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Dr. Shapiro, who was not involved with the research.
It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.
In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Dr. Shapiro.
For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, versus 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs. 16.3% for the AXS-07 trial) were comparable.
Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, versus 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs. 12.6% for AXS-07).
The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, versus 7% and 5%, respectively for participants in the two sumatriptan–naproxen sodium trials.
“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Dr. Shapiro.
“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.
The study was funded by Axsome Therapeutics. Dr. Tepper is a consultant to Axsome Therapeutics. Dr. Shapiro has previously performed research consulting for Lilly and Lundbeck.
A version of this article first appeared on Medscape.com.
, new research suggests. Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patients’ most bothersome symptom (MBS) compared with placebo.
In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.
Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.
“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” said study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth, Hanover, N.H. “That is why the whole is greater than the sum of the parts,” Dr. Tepper added.
The findings were presented at the American Headache Society’s 2021 annual meeting.
Acute treatments needed
For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.
The search for optimal acute treatments is therefore “really important for patients,” Dr. Tepper noted.
Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene-related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.
In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.
The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.
The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom and freedom from pain progression, functional disability, and use of rescue medication.
Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.
Reduced pain progression
Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).
Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).
The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs. 9.6%; P = .013).
In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, versus 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).
AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, versus 27.7% of the placebo group (P < .001).
The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, versus 2.1%; the rate of dizziness was 2.9%, versus 1.4%; and the rate of paresthesia was 2.1%, versus 0%. There were no serious AEs.
“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Dr. Tepper. “It’s not dramatically different for dizziness.”
Improved adherence?
Meloxicam is generally used not as an acute medication but for prevention, Dr. Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.
AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.
“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Dr. Tepper.
The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly. “We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Dr. Tepper said.
Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply. “It’s a big adherence issue,” said Dr. Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”
Uncertain therapeutic advantage
Commenting on the findings, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, Burlington, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.
“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Dr. Shapiro, who was not involved with the research.
It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.
In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Dr. Shapiro.
For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, versus 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs. 16.3% for the AXS-07 trial) were comparable.
Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, versus 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs. 12.6% for AXS-07).
The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, versus 7% and 5%, respectively for participants in the two sumatriptan–naproxen sodium trials.
“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Dr. Shapiro.
“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.
The study was funded by Axsome Therapeutics. Dr. Tepper is a consultant to Axsome Therapeutics. Dr. Shapiro has previously performed research consulting for Lilly and Lundbeck.
A version of this article first appeared on Medscape.com.
, new research suggests. Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patients’ most bothersome symptom (MBS) compared with placebo.
In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.
Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.
“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” said study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth, Hanover, N.H. “That is why the whole is greater than the sum of the parts,” Dr. Tepper added.
The findings were presented at the American Headache Society’s 2021 annual meeting.
Acute treatments needed
For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.
The search for optimal acute treatments is therefore “really important for patients,” Dr. Tepper noted.
Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene-related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.
In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.
The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.
The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom and freedom from pain progression, functional disability, and use of rescue medication.
Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.
Reduced pain progression
Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).
Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).
The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs. 9.6%; P = .013).
In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, versus 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).
AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, versus 27.7% of the placebo group (P < .001).
The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, versus 2.1%; the rate of dizziness was 2.9%, versus 1.4%; and the rate of paresthesia was 2.1%, versus 0%. There were no serious AEs.
“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Dr. Tepper. “It’s not dramatically different for dizziness.”
Improved adherence?
Meloxicam is generally used not as an acute medication but for prevention, Dr. Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.
AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.
“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Dr. Tepper.
The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly. “We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Dr. Tepper said.
Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply. “It’s a big adherence issue,” said Dr. Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”
Uncertain therapeutic advantage
Commenting on the findings, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, Burlington, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.
“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Dr. Shapiro, who was not involved with the research.
It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.
In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Dr. Shapiro.
For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, versus 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs. 16.3% for the AXS-07 trial) were comparable.
Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, versus 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs. 12.6% for AXS-07).
The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, versus 7% and 5%, respectively for participants in the two sumatriptan–naproxen sodium trials.
“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Dr. Shapiro.
“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.
The study was funded by Axsome Therapeutics. Dr. Tepper is a consultant to Axsome Therapeutics. Dr. Shapiro has previously performed research consulting for Lilly and Lundbeck.
A version of this article first appeared on Medscape.com.
From AHS 2021