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Mindfulness training for migraine just beginning to gather steam
SAN FRANCISCO – A brief course of mindfulness training for chronic migraine patients after their withdrawal from overuse of acute migraine medications proved as effective as prophylactic medication over the course of 12 months of follow-up, Frank Andrasik, PhD, reported at the annual meeting of the American Headache Society.
“The effects of mindfulness by and large rivaled those for medication alone. And although not specifically assessed, patients commented that mindfulness didn’t have side effects and promoted greater involvement and adherence,” said Dr. Andrasik, professor and chair, department of psychology, and director of the Center for Behavioral Medicine at the University of Memphis.
He noted that his recently published study (J Headache Pain. 2017 Dec;18[1]:15. doi: 10.1186/s10194-017-0728-z) is best considered exploratory because of its small size and nonrandomized design. Participants, after 5 days of structured acute medication withdrawal in a day hospital setting, got to choose whether to opt for pharmacologic prophylaxis for migraine – most often using botulinum toxin – or a brief course in mindfulness training entailing six once-weekly 45-minute sessions plus home practice for 7-10 minutes per day. And while this study design doesn’t rise to the status of level 1 randomized trial evidence, it does reflect real-world clinical practice, where patients often have a big say in choosing their treatment plan, the psychologist observed.
At baseline, all 44 patients met diagnostic criteria for chronic migraine with associated acute medication overuse. They averaged 20.5 headache days per month, with 18.4 days of acute migraine medication use.
At 3, 6, and 12 months of follow-up, the 22 patients in the mindfulness group averaged 8.3, 10.4, and 12.4 headache days per month, while the 22 on preventive migraine drugs averaged 8.8, 11, and 8.6 headache days per month. Both groups averaged similar 7- to 10-day reductions in days of acute migraine medication use per month.
Using the widely accepted endpoint of at least a 50% reduction in headache days per month, 50% of the mindfulness-only group and 52.6% of the prophylactic medication-only group met that standard at 12 months of follow-up. Moreover, at 12 months, 65% of the mindfulness therapy group and a similar 73.7% of the preventive medication group no longer met diagnostic criteria for chronic migraine.
The mindfulness protocol used in the study was based upon the popular mindfulness-based stress reduction program developed by Jon Kabat-Zinn, PhD.
Scores on the Migraine Disability Assessment (MIDAS) measure improved significantly and to a similar extent over baseline in both groups. So did scores on the Beck Depression Inventory. In contrast, scores on the State-Trait Anxiety Inventory didn’t change significantly in either study arm.
Both Dr. Andrasik and session chair Elizabeth K. Seng, PhD, cautioned that despite solid evidence of efficacy for mindfulness training in the treatment of depression and a number of chronic pain disorders, . Large randomized, controlled clinical trials are ongoing or in the planning stages, with no results yet available.
Dr. Seng, a clinical psychologist at Albert Einstein College of Medicine in New York, described mindfulness and acceptance as “third wave” behavioral treatments for migraine. The first wave therapies focused on fostering behavioral changes to reduce perceived stress in order to avoid triggering migraine attacks. The second wave involved therapeutic interactions aimed at helping patients reframe maladaptive automatic thoughts to reduce stress stemming from the daily hassles of life.
“The focus in the first- and second-wave therapies is, ‘Change something and your life will be better. Change your behaviors, clean up your act, change your thoughts because your thoughts are not helping you, and thereby reduce stress and reduce migraine.’ These mindfulness therapies are incredibly different from that,” she explained.
Indeed, the third-wave therapies aren’t trying to change daily hassles or automatic thoughts; instead, they seek to change the patient’s relationship to them such that they no longer create barriers to engaging in life activities that the patient finds nourishing and meaningful. It’s a matter of creating a willingness to experience pain in order to achieve worthwhile objectives, Dr. Seng continued.
It’s unclear that a reduction in migraine days – the traditional yardstick for therapeutic efficacy in migraine research – is the right primary outcome measure for third-wave therapies, according to the psychologist.
“So far, our evidence would suggest that mindfulness-based therapies do not reduce migraine days as much as other behavioral treatments, but what they’re doing is increasing migraine-related quality of life and reducing migraine-related disability to the same or possibly larger extent than our other behavioral treatments,“ she said. “Maybe what these third-wave therapies are actually doing is impacting our cognitive and emotional functioning, and that even if patients still experience similar levels of headache frequency, their reaction to those headache days no longer leads to a bunch of suffering. And that could be a clinically relevant outcome.”
Dr. Seng is particularly eager to formally study mindfulness therapies in a subgroup of migraine patients with high levels of depression. They might respond especially well, since mindfulness was originally developed as a treatment for severe depression. “Patients who are depressed have a hard time overcoming barriers to engaging in nourishing life activities, and when they have a headache day it’s even worse. That’s one of the things that’s leading them to have migraine-related disability,” she said.
Dr. Andrasik, whose study was supported by the European Commission and an Italian research foundation, reported having no financial conflicts of interest regarding his presentation. Dr. Seng reported serving as a consultant to GlaxoSmithKline.
SAN FRANCISCO – A brief course of mindfulness training for chronic migraine patients after their withdrawal from overuse of acute migraine medications proved as effective as prophylactic medication over the course of 12 months of follow-up, Frank Andrasik, PhD, reported at the annual meeting of the American Headache Society.
“The effects of mindfulness by and large rivaled those for medication alone. And although not specifically assessed, patients commented that mindfulness didn’t have side effects and promoted greater involvement and adherence,” said Dr. Andrasik, professor and chair, department of psychology, and director of the Center for Behavioral Medicine at the University of Memphis.
He noted that his recently published study (J Headache Pain. 2017 Dec;18[1]:15. doi: 10.1186/s10194-017-0728-z) is best considered exploratory because of its small size and nonrandomized design. Participants, after 5 days of structured acute medication withdrawal in a day hospital setting, got to choose whether to opt for pharmacologic prophylaxis for migraine – most often using botulinum toxin – or a brief course in mindfulness training entailing six once-weekly 45-minute sessions plus home practice for 7-10 minutes per day. And while this study design doesn’t rise to the status of level 1 randomized trial evidence, it does reflect real-world clinical practice, where patients often have a big say in choosing their treatment plan, the psychologist observed.
At baseline, all 44 patients met diagnostic criteria for chronic migraine with associated acute medication overuse. They averaged 20.5 headache days per month, with 18.4 days of acute migraine medication use.
At 3, 6, and 12 months of follow-up, the 22 patients in the mindfulness group averaged 8.3, 10.4, and 12.4 headache days per month, while the 22 on preventive migraine drugs averaged 8.8, 11, and 8.6 headache days per month. Both groups averaged similar 7- to 10-day reductions in days of acute migraine medication use per month.
Using the widely accepted endpoint of at least a 50% reduction in headache days per month, 50% of the mindfulness-only group and 52.6% of the prophylactic medication-only group met that standard at 12 months of follow-up. Moreover, at 12 months, 65% of the mindfulness therapy group and a similar 73.7% of the preventive medication group no longer met diagnostic criteria for chronic migraine.
The mindfulness protocol used in the study was based upon the popular mindfulness-based stress reduction program developed by Jon Kabat-Zinn, PhD.
Scores on the Migraine Disability Assessment (MIDAS) measure improved significantly and to a similar extent over baseline in both groups. So did scores on the Beck Depression Inventory. In contrast, scores on the State-Trait Anxiety Inventory didn’t change significantly in either study arm.
Both Dr. Andrasik and session chair Elizabeth K. Seng, PhD, cautioned that despite solid evidence of efficacy for mindfulness training in the treatment of depression and a number of chronic pain disorders, . Large randomized, controlled clinical trials are ongoing or in the planning stages, with no results yet available.
Dr. Seng, a clinical psychologist at Albert Einstein College of Medicine in New York, described mindfulness and acceptance as “third wave” behavioral treatments for migraine. The first wave therapies focused on fostering behavioral changes to reduce perceived stress in order to avoid triggering migraine attacks. The second wave involved therapeutic interactions aimed at helping patients reframe maladaptive automatic thoughts to reduce stress stemming from the daily hassles of life.
“The focus in the first- and second-wave therapies is, ‘Change something and your life will be better. Change your behaviors, clean up your act, change your thoughts because your thoughts are not helping you, and thereby reduce stress and reduce migraine.’ These mindfulness therapies are incredibly different from that,” she explained.
Indeed, the third-wave therapies aren’t trying to change daily hassles or automatic thoughts; instead, they seek to change the patient’s relationship to them such that they no longer create barriers to engaging in life activities that the patient finds nourishing and meaningful. It’s a matter of creating a willingness to experience pain in order to achieve worthwhile objectives, Dr. Seng continued.
It’s unclear that a reduction in migraine days – the traditional yardstick for therapeutic efficacy in migraine research – is the right primary outcome measure for third-wave therapies, according to the psychologist.
“So far, our evidence would suggest that mindfulness-based therapies do not reduce migraine days as much as other behavioral treatments, but what they’re doing is increasing migraine-related quality of life and reducing migraine-related disability to the same or possibly larger extent than our other behavioral treatments,“ she said. “Maybe what these third-wave therapies are actually doing is impacting our cognitive and emotional functioning, and that even if patients still experience similar levels of headache frequency, their reaction to those headache days no longer leads to a bunch of suffering. And that could be a clinically relevant outcome.”
Dr. Seng is particularly eager to formally study mindfulness therapies in a subgroup of migraine patients with high levels of depression. They might respond especially well, since mindfulness was originally developed as a treatment for severe depression. “Patients who are depressed have a hard time overcoming barriers to engaging in nourishing life activities, and when they have a headache day it’s even worse. That’s one of the things that’s leading them to have migraine-related disability,” she said.
Dr. Andrasik, whose study was supported by the European Commission and an Italian research foundation, reported having no financial conflicts of interest regarding his presentation. Dr. Seng reported serving as a consultant to GlaxoSmithKline.
SAN FRANCISCO – A brief course of mindfulness training for chronic migraine patients after their withdrawal from overuse of acute migraine medications proved as effective as prophylactic medication over the course of 12 months of follow-up, Frank Andrasik, PhD, reported at the annual meeting of the American Headache Society.
“The effects of mindfulness by and large rivaled those for medication alone. And although not specifically assessed, patients commented that mindfulness didn’t have side effects and promoted greater involvement and adherence,” said Dr. Andrasik, professor and chair, department of psychology, and director of the Center for Behavioral Medicine at the University of Memphis.
He noted that his recently published study (J Headache Pain. 2017 Dec;18[1]:15. doi: 10.1186/s10194-017-0728-z) is best considered exploratory because of its small size and nonrandomized design. Participants, after 5 days of structured acute medication withdrawal in a day hospital setting, got to choose whether to opt for pharmacologic prophylaxis for migraine – most often using botulinum toxin – or a brief course in mindfulness training entailing six once-weekly 45-minute sessions plus home practice for 7-10 minutes per day. And while this study design doesn’t rise to the status of level 1 randomized trial evidence, it does reflect real-world clinical practice, where patients often have a big say in choosing their treatment plan, the psychologist observed.
At baseline, all 44 patients met diagnostic criteria for chronic migraine with associated acute medication overuse. They averaged 20.5 headache days per month, with 18.4 days of acute migraine medication use.
At 3, 6, and 12 months of follow-up, the 22 patients in the mindfulness group averaged 8.3, 10.4, and 12.4 headache days per month, while the 22 on preventive migraine drugs averaged 8.8, 11, and 8.6 headache days per month. Both groups averaged similar 7- to 10-day reductions in days of acute migraine medication use per month.
Using the widely accepted endpoint of at least a 50% reduction in headache days per month, 50% of the mindfulness-only group and 52.6% of the prophylactic medication-only group met that standard at 12 months of follow-up. Moreover, at 12 months, 65% of the mindfulness therapy group and a similar 73.7% of the preventive medication group no longer met diagnostic criteria for chronic migraine.
The mindfulness protocol used in the study was based upon the popular mindfulness-based stress reduction program developed by Jon Kabat-Zinn, PhD.
Scores on the Migraine Disability Assessment (MIDAS) measure improved significantly and to a similar extent over baseline in both groups. So did scores on the Beck Depression Inventory. In contrast, scores on the State-Trait Anxiety Inventory didn’t change significantly in either study arm.
Both Dr. Andrasik and session chair Elizabeth K. Seng, PhD, cautioned that despite solid evidence of efficacy for mindfulness training in the treatment of depression and a number of chronic pain disorders, . Large randomized, controlled clinical trials are ongoing or in the planning stages, with no results yet available.
Dr. Seng, a clinical psychologist at Albert Einstein College of Medicine in New York, described mindfulness and acceptance as “third wave” behavioral treatments for migraine. The first wave therapies focused on fostering behavioral changes to reduce perceived stress in order to avoid triggering migraine attacks. The second wave involved therapeutic interactions aimed at helping patients reframe maladaptive automatic thoughts to reduce stress stemming from the daily hassles of life.
“The focus in the first- and second-wave therapies is, ‘Change something and your life will be better. Change your behaviors, clean up your act, change your thoughts because your thoughts are not helping you, and thereby reduce stress and reduce migraine.’ These mindfulness therapies are incredibly different from that,” she explained.
Indeed, the third-wave therapies aren’t trying to change daily hassles or automatic thoughts; instead, they seek to change the patient’s relationship to them such that they no longer create barriers to engaging in life activities that the patient finds nourishing and meaningful. It’s a matter of creating a willingness to experience pain in order to achieve worthwhile objectives, Dr. Seng continued.
It’s unclear that a reduction in migraine days – the traditional yardstick for therapeutic efficacy in migraine research – is the right primary outcome measure for third-wave therapies, according to the psychologist.
“So far, our evidence would suggest that mindfulness-based therapies do not reduce migraine days as much as other behavioral treatments, but what they’re doing is increasing migraine-related quality of life and reducing migraine-related disability to the same or possibly larger extent than our other behavioral treatments,“ she said. “Maybe what these third-wave therapies are actually doing is impacting our cognitive and emotional functioning, and that even if patients still experience similar levels of headache frequency, their reaction to those headache days no longer leads to a bunch of suffering. And that could be a clinically relevant outcome.”
Dr. Seng is particularly eager to formally study mindfulness therapies in a subgroup of migraine patients with high levels of depression. They might respond especially well, since mindfulness was originally developed as a treatment for severe depression. “Patients who are depressed have a hard time overcoming barriers to engaging in nourishing life activities, and when they have a headache day it’s even worse. That’s one of the things that’s leading them to have migraine-related disability,” she said.
Dr. Andrasik, whose study was supported by the European Commission and an Italian research foundation, reported having no financial conflicts of interest regarding his presentation. Dr. Seng reported serving as a consultant to GlaxoSmithKline.
REPORTING FROM THE AHS ANNUAL MEETING
High autonomic dysfunction distinguishes persistent posttraumatic headache
SAN FRANCISCO – Symptoms of autonomic dysfunction are significantly greater in patients with persistent posttraumatic headache than in migraine, raising the welcome possibility that this characteristic might serve to reliably differentiate the two disorders, Levi Howard, MD, said at the annual meeting of the American Headache Society.
“Interestingly enough, in looking at other studies evaluating dysautonomia, the [autonomic dysfunction scores] in our persistent posttraumatic headache group were on a par with scores previously reported for patients with diseases such as small-fiber polyneuropathy and postural orthostatic tachycardia syndrome,” observed Dr. Howard, an active duty military physician assigned to obtain neurology training at the Mayo Clinic Arizona in Phoenix.
“This brings up two questions: Do autonomic symptoms contribute to accurate classification of persistent posttraumatic headache versus migraine? And if we treat this autonomic dysfunction, does the headache also improve? In our clinical observation, this appears to be the case,” he continued.
Right now, posttraumatic headache (PTH) is defined on the basis of its temporal relationship to head injury. At this time, PTH has no defining clinical characteristics, although most often it has a phenotype that meets diagnostic criteria for migraine.
However, Dr. Howard and his coinvestigators have observed anecdotally in clinical practice that persistent PTH – defined as PTH lasting longer than 3 months – is often accompanied by orthostatic intolerance. This observation, coupled with reports in multiple prior studies that dysautonomia is common in patients with mild traumatic brain injury (TBI) and postconcussion syndrome, prompted Dr. Howard and his coworkers to conduct a cross-sectional cohort study. It included 56 patients with persistent PTH due to mild TBI, 30 patients with migraine, and 36 healthy controls. Most of the persistent PTH group were military veterans with mild TBI due to blast injuries.
All subjects were assessed for autonomic dysfunction using the well-validated COMPASS-31 questionnaire. This instrument assesses six domains of autonomic function: orthostatic intolerance, bladder, gastrointestinal, vasomotor, secretomotor, and pupillomotor.
Scores in each of the six domains were numerically higher in the persistent PTH group, with the differences achieving statistical significance in the orthostatic intolerance and bladder domains.
Of note, the migraine group had a greater headache burden, with a mean 23-year headache history, compared with 10.56 years in the persistent PTH group. The migraine patients also averaged 21.1 headache days per month, versus 16.2 in the persistent PTH group. Yet the investigators found no strong association between autonomic dysfunction and headache burden as reflected in headache duration or headache days per month.
The study was funded by the Department of Defense. Dr. Howard reported having no financial conflicts of interest.
SOURCE: Howard L et al. AHS 2018, Abstract FHM03.
SAN FRANCISCO – Symptoms of autonomic dysfunction are significantly greater in patients with persistent posttraumatic headache than in migraine, raising the welcome possibility that this characteristic might serve to reliably differentiate the two disorders, Levi Howard, MD, said at the annual meeting of the American Headache Society.
“Interestingly enough, in looking at other studies evaluating dysautonomia, the [autonomic dysfunction scores] in our persistent posttraumatic headache group were on a par with scores previously reported for patients with diseases such as small-fiber polyneuropathy and postural orthostatic tachycardia syndrome,” observed Dr. Howard, an active duty military physician assigned to obtain neurology training at the Mayo Clinic Arizona in Phoenix.
“This brings up two questions: Do autonomic symptoms contribute to accurate classification of persistent posttraumatic headache versus migraine? And if we treat this autonomic dysfunction, does the headache also improve? In our clinical observation, this appears to be the case,” he continued.
Right now, posttraumatic headache (PTH) is defined on the basis of its temporal relationship to head injury. At this time, PTH has no defining clinical characteristics, although most often it has a phenotype that meets diagnostic criteria for migraine.
However, Dr. Howard and his coinvestigators have observed anecdotally in clinical practice that persistent PTH – defined as PTH lasting longer than 3 months – is often accompanied by orthostatic intolerance. This observation, coupled with reports in multiple prior studies that dysautonomia is common in patients with mild traumatic brain injury (TBI) and postconcussion syndrome, prompted Dr. Howard and his coworkers to conduct a cross-sectional cohort study. It included 56 patients with persistent PTH due to mild TBI, 30 patients with migraine, and 36 healthy controls. Most of the persistent PTH group were military veterans with mild TBI due to blast injuries.
All subjects were assessed for autonomic dysfunction using the well-validated COMPASS-31 questionnaire. This instrument assesses six domains of autonomic function: orthostatic intolerance, bladder, gastrointestinal, vasomotor, secretomotor, and pupillomotor.
Scores in each of the six domains were numerically higher in the persistent PTH group, with the differences achieving statistical significance in the orthostatic intolerance and bladder domains.
Of note, the migraine group had a greater headache burden, with a mean 23-year headache history, compared with 10.56 years in the persistent PTH group. The migraine patients also averaged 21.1 headache days per month, versus 16.2 in the persistent PTH group. Yet the investigators found no strong association between autonomic dysfunction and headache burden as reflected in headache duration or headache days per month.
The study was funded by the Department of Defense. Dr. Howard reported having no financial conflicts of interest.
SOURCE: Howard L et al. AHS 2018, Abstract FHM03.
SAN FRANCISCO – Symptoms of autonomic dysfunction are significantly greater in patients with persistent posttraumatic headache than in migraine, raising the welcome possibility that this characteristic might serve to reliably differentiate the two disorders, Levi Howard, MD, said at the annual meeting of the American Headache Society.
“Interestingly enough, in looking at other studies evaluating dysautonomia, the [autonomic dysfunction scores] in our persistent posttraumatic headache group were on a par with scores previously reported for patients with diseases such as small-fiber polyneuropathy and postural orthostatic tachycardia syndrome,” observed Dr. Howard, an active duty military physician assigned to obtain neurology training at the Mayo Clinic Arizona in Phoenix.
“This brings up two questions: Do autonomic symptoms contribute to accurate classification of persistent posttraumatic headache versus migraine? And if we treat this autonomic dysfunction, does the headache also improve? In our clinical observation, this appears to be the case,” he continued.
Right now, posttraumatic headache (PTH) is defined on the basis of its temporal relationship to head injury. At this time, PTH has no defining clinical characteristics, although most often it has a phenotype that meets diagnostic criteria for migraine.
However, Dr. Howard and his coinvestigators have observed anecdotally in clinical practice that persistent PTH – defined as PTH lasting longer than 3 months – is often accompanied by orthostatic intolerance. This observation, coupled with reports in multiple prior studies that dysautonomia is common in patients with mild traumatic brain injury (TBI) and postconcussion syndrome, prompted Dr. Howard and his coworkers to conduct a cross-sectional cohort study. It included 56 patients with persistent PTH due to mild TBI, 30 patients with migraine, and 36 healthy controls. Most of the persistent PTH group were military veterans with mild TBI due to blast injuries.
All subjects were assessed for autonomic dysfunction using the well-validated COMPASS-31 questionnaire. This instrument assesses six domains of autonomic function: orthostatic intolerance, bladder, gastrointestinal, vasomotor, secretomotor, and pupillomotor.
Scores in each of the six domains were numerically higher in the persistent PTH group, with the differences achieving statistical significance in the orthostatic intolerance and bladder domains.
Of note, the migraine group had a greater headache burden, with a mean 23-year headache history, compared with 10.56 years in the persistent PTH group. The migraine patients also averaged 21.1 headache days per month, versus 16.2 in the persistent PTH group. Yet the investigators found no strong association between autonomic dysfunction and headache burden as reflected in headache duration or headache days per month.
The study was funded by the Department of Defense. Dr. Howard reported having no financial conflicts of interest.
SOURCE: Howard L et al. AHS 2018, Abstract FHM03.
REPORTING FROM THE AHS ANNUAL MEETING
Key clinical point: New evidence that patients with persistent posttraumatic headache have high levels of autonomic dysfunction could open the door to novel treatments.
Major finding: Scores on the COMPASS-31 questionnaire, a measure of autonomic dysfunction, averaged 37.22 in patients with persistent posttraumatic headache, indicative of significantly greater impairment than the 27.15 in migraine patients and 11.67 in healthy controls.
Study details: This cross-sectional cohort study included 56 patients with persistent posttraumatic headache, 30 with migraine, and 36 healthy controls.
Disclosures: The study was sponsored by the Department of Defense and presented by an active duty military physician.
Source: Howard L et al. AHS 2018, Abstract FHM03
Prescription opioid epidemic hits migraine patients hard
SAN FRANCISCO –
“Given the opioid epidemic in the U.S. and the high prevalence of opioid use in migraine patients shown in our study, especially in those with chronic migraine, our results suggest that improved management of treatment is needed to optimize care,” said Justin S. Yu, PharmD.
“We’re seeing a lot of opioid use in these migraine patients. It may not all be due to migraine – some had comorbid nonheadache pain conditions – but this still represents an opportunity to look at these patients more closely, maybe treat them better, because there are opportunities to improve their care, their outcomes, and their quality of life,” added Dr. Yu of Allergan in Irvine, Calif.
He presented an in-depth retrospective observational study of opioid use in 129 chronic migraine patients as defined by more than 15 headache days per month (at least 8 of which fulfilled the diagnostic criteria for migraine) and 63 others with less frequent episodic migraine. In the previous 12 months, according to claims data, 54% of the chronic migraine patients and 37% of the episodic migraine patient filled one or more prescriptions for an opioid.
More impressively, fully one-third of the chronic migraine group and 16% of episodic migraineurs filled three or more opioid prescriptions within that 12-month interval. In fact, the mean number of filled opioid prescriptions over the year was 4.0 among all chronic migraine patients and 2.8 in the overall episodic migraine cohort.
“Opioids have been used for acute treatment of chronic migraine and episodic migraine but are not recommended for regular use due to the risk of medication overuse, tolerance, dependence, and opioid hyperalgesia,” Dr. Yu noted.
Separately, Richard B. Lipton, MD, presented an analysis of 3,930 migraine patients currently using acute oral prescription headache medications who were among the larger group of 15,133 migraineurs who participated in the massive MAST (Migraine in America Symptoms and Treatment) study, an Internet-based epidemiologic survey of a nationally representative sample of patients with the disorder.
Topping the list of the most frequently used oral prescription acute headache medications were the oral triptans, used by 46% of subjects, followed by prescription NSAIDs, taken by 36%, and oral prescription opioids, used by 33.1%. And that eyebrow-raising rate of prescription opioid use is apparently par for the course.
“In lots of survey data now we’re seeing that among people with migraine who take acute prescription drugs, this one-third number is not unusual, although at least from my perspective it’s certainly a problem. Also, of people using oral acute prescription agents, a full 66% were also using OTC headache medications,” said Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine and director of the Montefiore Headache Center in New York.
In addition, oral prescription barbiturates were used for acute treatment of migraine by 11.2% of the MAST participants.
Acute medication overuse, as defined by use of oral prescription opioids and/or barbiturates on an average of more than 10 days per month, was identified in 8.1% of the total group. For them, the appropriate course of action is withdrawal of the overused medication, addition of a preventive agent – such drugs weren’t being used by the great majority of patients on acute prescription medications for migraine – and replacement of the opioid or barbiturate with a less problematic class of acute therapy, Dr. Lipton advised.
The MAST analysis identified a bevy of major unmet needs in people with migraine who are using acute prescription medications to treat their headaches. Fifty-three percent of participants said their severe headache attacks come on very rapidly, 50% indicated their attacks reach peak intensity in less than 2 hours no matter what they do, 39% said their head pain returns less than 24 hours after initial pain relief, and 41% complained of severe headache upon awakening. Nausea interfering with daily activities was frequently cited. Seventy-six percent of the sample had at least one of these major unmet needs.
Dr. Lipton stressed that although some of his colleagues have reacted defensively to these data highlighting numerous major unmet treatment needs in migraine patients, the MAST findings certainly aren’t an indictment that headache specialists are doing a poor job.
“I am not saying that. Of course, the vast majority of these people aren’t treated by headache specialists, they’re treated by primary care physicians. What I am saying is there are lots of opportunities to use new and emerging tools to improve the lives of our patients,” the neurologist said.
Dr. Yu noted that in his study, 14.7% of patients with chronic migraine and 15.9% with episodic migraine had been diagnosed with an anxiety disorder within the previous 12 months. Also, 24% with chronic and 11.1% with episodic migraine had been diagnosed with depression. A diagnosis of a comorbid nonheadache pain disorder was present in 13% of the chronic migraineurs and 8% of those with episodic migraine.
The MAST study was sponsored by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories. Dr. Lipton reported receiving research funding from and/or honoraria from that company and more than a dozen others.
Dr. Yu is employed by Allergan, which sponsored his study.
SOURCE: AHS annual meeting, Yu JS et al., Abstract PF11, and Lipton RB et al., Abstract OR02.
SAN FRANCISCO –
“Given the opioid epidemic in the U.S. and the high prevalence of opioid use in migraine patients shown in our study, especially in those with chronic migraine, our results suggest that improved management of treatment is needed to optimize care,” said Justin S. Yu, PharmD.
“We’re seeing a lot of opioid use in these migraine patients. It may not all be due to migraine – some had comorbid nonheadache pain conditions – but this still represents an opportunity to look at these patients more closely, maybe treat them better, because there are opportunities to improve their care, their outcomes, and their quality of life,” added Dr. Yu of Allergan in Irvine, Calif.
He presented an in-depth retrospective observational study of opioid use in 129 chronic migraine patients as defined by more than 15 headache days per month (at least 8 of which fulfilled the diagnostic criteria for migraine) and 63 others with less frequent episodic migraine. In the previous 12 months, according to claims data, 54% of the chronic migraine patients and 37% of the episodic migraine patient filled one or more prescriptions for an opioid.
More impressively, fully one-third of the chronic migraine group and 16% of episodic migraineurs filled three or more opioid prescriptions within that 12-month interval. In fact, the mean number of filled opioid prescriptions over the year was 4.0 among all chronic migraine patients and 2.8 in the overall episodic migraine cohort.
“Opioids have been used for acute treatment of chronic migraine and episodic migraine but are not recommended for regular use due to the risk of medication overuse, tolerance, dependence, and opioid hyperalgesia,” Dr. Yu noted.
Separately, Richard B. Lipton, MD, presented an analysis of 3,930 migraine patients currently using acute oral prescription headache medications who were among the larger group of 15,133 migraineurs who participated in the massive MAST (Migraine in America Symptoms and Treatment) study, an Internet-based epidemiologic survey of a nationally representative sample of patients with the disorder.
Topping the list of the most frequently used oral prescription acute headache medications were the oral triptans, used by 46% of subjects, followed by prescription NSAIDs, taken by 36%, and oral prescription opioids, used by 33.1%. And that eyebrow-raising rate of prescription opioid use is apparently par for the course.
“In lots of survey data now we’re seeing that among people with migraine who take acute prescription drugs, this one-third number is not unusual, although at least from my perspective it’s certainly a problem. Also, of people using oral acute prescription agents, a full 66% were also using OTC headache medications,” said Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine and director of the Montefiore Headache Center in New York.
In addition, oral prescription barbiturates were used for acute treatment of migraine by 11.2% of the MAST participants.
Acute medication overuse, as defined by use of oral prescription opioids and/or barbiturates on an average of more than 10 days per month, was identified in 8.1% of the total group. For them, the appropriate course of action is withdrawal of the overused medication, addition of a preventive agent – such drugs weren’t being used by the great majority of patients on acute prescription medications for migraine – and replacement of the opioid or barbiturate with a less problematic class of acute therapy, Dr. Lipton advised.
The MAST analysis identified a bevy of major unmet needs in people with migraine who are using acute prescription medications to treat their headaches. Fifty-three percent of participants said their severe headache attacks come on very rapidly, 50% indicated their attacks reach peak intensity in less than 2 hours no matter what they do, 39% said their head pain returns less than 24 hours after initial pain relief, and 41% complained of severe headache upon awakening. Nausea interfering with daily activities was frequently cited. Seventy-six percent of the sample had at least one of these major unmet needs.
Dr. Lipton stressed that although some of his colleagues have reacted defensively to these data highlighting numerous major unmet treatment needs in migraine patients, the MAST findings certainly aren’t an indictment that headache specialists are doing a poor job.
“I am not saying that. Of course, the vast majority of these people aren’t treated by headache specialists, they’re treated by primary care physicians. What I am saying is there are lots of opportunities to use new and emerging tools to improve the lives of our patients,” the neurologist said.
Dr. Yu noted that in his study, 14.7% of patients with chronic migraine and 15.9% with episodic migraine had been diagnosed with an anxiety disorder within the previous 12 months. Also, 24% with chronic and 11.1% with episodic migraine had been diagnosed with depression. A diagnosis of a comorbid nonheadache pain disorder was present in 13% of the chronic migraineurs and 8% of those with episodic migraine.
The MAST study was sponsored by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories. Dr. Lipton reported receiving research funding from and/or honoraria from that company and more than a dozen others.
Dr. Yu is employed by Allergan, which sponsored his study.
SOURCE: AHS annual meeting, Yu JS et al., Abstract PF11, and Lipton RB et al., Abstract OR02.
SAN FRANCISCO –
“Given the opioid epidemic in the U.S. and the high prevalence of opioid use in migraine patients shown in our study, especially in those with chronic migraine, our results suggest that improved management of treatment is needed to optimize care,” said Justin S. Yu, PharmD.
“We’re seeing a lot of opioid use in these migraine patients. It may not all be due to migraine – some had comorbid nonheadache pain conditions – but this still represents an opportunity to look at these patients more closely, maybe treat them better, because there are opportunities to improve their care, their outcomes, and their quality of life,” added Dr. Yu of Allergan in Irvine, Calif.
He presented an in-depth retrospective observational study of opioid use in 129 chronic migraine patients as defined by more than 15 headache days per month (at least 8 of which fulfilled the diagnostic criteria for migraine) and 63 others with less frequent episodic migraine. In the previous 12 months, according to claims data, 54% of the chronic migraine patients and 37% of the episodic migraine patient filled one or more prescriptions for an opioid.
More impressively, fully one-third of the chronic migraine group and 16% of episodic migraineurs filled three or more opioid prescriptions within that 12-month interval. In fact, the mean number of filled opioid prescriptions over the year was 4.0 among all chronic migraine patients and 2.8 in the overall episodic migraine cohort.
“Opioids have been used for acute treatment of chronic migraine and episodic migraine but are not recommended for regular use due to the risk of medication overuse, tolerance, dependence, and opioid hyperalgesia,” Dr. Yu noted.
Separately, Richard B. Lipton, MD, presented an analysis of 3,930 migraine patients currently using acute oral prescription headache medications who were among the larger group of 15,133 migraineurs who participated in the massive MAST (Migraine in America Symptoms and Treatment) study, an Internet-based epidemiologic survey of a nationally representative sample of patients with the disorder.
Topping the list of the most frequently used oral prescription acute headache medications were the oral triptans, used by 46% of subjects, followed by prescription NSAIDs, taken by 36%, and oral prescription opioids, used by 33.1%. And that eyebrow-raising rate of prescription opioid use is apparently par for the course.
“In lots of survey data now we’re seeing that among people with migraine who take acute prescription drugs, this one-third number is not unusual, although at least from my perspective it’s certainly a problem. Also, of people using oral acute prescription agents, a full 66% were also using OTC headache medications,” said Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine and director of the Montefiore Headache Center in New York.
In addition, oral prescription barbiturates were used for acute treatment of migraine by 11.2% of the MAST participants.
Acute medication overuse, as defined by use of oral prescription opioids and/or barbiturates on an average of more than 10 days per month, was identified in 8.1% of the total group. For them, the appropriate course of action is withdrawal of the overused medication, addition of a preventive agent – such drugs weren’t being used by the great majority of patients on acute prescription medications for migraine – and replacement of the opioid or barbiturate with a less problematic class of acute therapy, Dr. Lipton advised.
The MAST analysis identified a bevy of major unmet needs in people with migraine who are using acute prescription medications to treat their headaches. Fifty-three percent of participants said their severe headache attacks come on very rapidly, 50% indicated their attacks reach peak intensity in less than 2 hours no matter what they do, 39% said their head pain returns less than 24 hours after initial pain relief, and 41% complained of severe headache upon awakening. Nausea interfering with daily activities was frequently cited. Seventy-six percent of the sample had at least one of these major unmet needs.
Dr. Lipton stressed that although some of his colleagues have reacted defensively to these data highlighting numerous major unmet treatment needs in migraine patients, the MAST findings certainly aren’t an indictment that headache specialists are doing a poor job.
“I am not saying that. Of course, the vast majority of these people aren’t treated by headache specialists, they’re treated by primary care physicians. What I am saying is there are lots of opportunities to use new and emerging tools to improve the lives of our patients,” the neurologist said.
Dr. Yu noted that in his study, 14.7% of patients with chronic migraine and 15.9% with episodic migraine had been diagnosed with an anxiety disorder within the previous 12 months. Also, 24% with chronic and 11.1% with episodic migraine had been diagnosed with depression. A diagnosis of a comorbid nonheadache pain disorder was present in 13% of the chronic migraineurs and 8% of those with episodic migraine.
The MAST study was sponsored by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories. Dr. Lipton reported receiving research funding from and/or honoraria from that company and more than a dozen others.
Dr. Yu is employed by Allergan, which sponsored his study.
SOURCE: AHS annual meeting, Yu JS et al., Abstract PF11, and Lipton RB et al., Abstract OR02.
REPORTING FROM THE AHS ANNUAL MEETING
Migraine takes toll on intimate relationships
SAN FRANCISCO – Nearly 1 in 10 chronic migraine patients say they’ve delayed having children or had fewer children because of their headaches, according to a new analysis from the CaMEO study.
“I think this is the most heartbreaking of the survey responses; we asked, ‘Have you delayed having children or had fewer children because of your headaches?’ and 2.6% of patients with episodic migraine and 9.6% with chronic migraine said yes,” Dawn C. Buse, PhD, said at the annual meeting of the American Headache Society.
CaMEO (the Chronic Migraine Epidemiology and Outcomes study) is a longitudinal, prospective, Internet-based survey whose aim is to flesh out the full impact of migraine. Dr. Buse presented an analysis of 13,064 migraineur participants, which focused on the impact of migraine on intimate relationships and parenting, an aspect of the disease burden that hasn’t been closely examined. All subjects completed the in-depth Family Burden Module, which is concerned with the emotional consequences of migraine.
The bottom line is that “migraine has significant negative impact on the most important relationships in our life: with our spouses, partners, and children,” declared Dr. Buse, a clinical psychologist at the Albert Einstein College of Medicine and director of behavioral medicine for the Montefiore Headache Center in New York.
The extent to which migraineurs perceived their headaches to be a problem increased stepwise with their number of headache days per month. For example, when the 8,127 CaMEO participants in a relationship with a live-in partner were asked to respond to the statement, “If I did not have headaches, I would be a better partner,” somewhat or complete agreement was endorsed by 38% of those with low-frequency episodic migraine at a rate of up to 4 headache days per month, 68% of those with 5-9 headache days per month, 73% of those with high-frequency episodic migraine with 10-14 headache days per month, and 78% of those with chronic migraine, defined as 15 or more headache days per month.
“Not surprising, certainly, but something to keep in mind as we care for our patients; that just because someone has episodic migraine they may have a range of expressions of how much those migraines have impacted their life,” Dr. Buse observed.
Another example: The proportion of subjects who reported delaying having children or having fewer kids because of their headaches was 1.6%, 5.5%, and 6.5% in low-, moderate-, and high-frequency episodic migraineurs, respectively, before topping out at 9.6% among those with chronic migraine.
Although she and her coinvestigators broke down the data by gender, there were no significant gender differences in the impact of migraine on significant relationships. The major differences were between patients with episodic as compared with chronic migraine.
Among the more than 3,500 CaMEO participants not currently in a relationship, 37% of those with chronic migraine and 15% of those with episodic migraine indicated that their headaches had contributed to relationship problems.
Of those in a relationship but not living together, 44% of individuals with chronic migraine reported that their headaches were preventing a closer relationship, such as moving in together or getting married, as did 16% of those with episodic migraine.
About 47%of respondents with chronic migraine reported that their headaches had caused at least one previous break-up, as did 18% of those with episodic migraine.
“Health care professionals should consider the overall burden of disease when managing migraine, particularly for those with chronic migraine,” Dr. Buse concluded. “Personalized comprehensive treatment plans may include both acute and preventive pharmacologic treatments as well as behavioral treatment for the proband, marital dyad, and family members as appropriate.”
She reported receiving research support and honoraria from Allergan, the study sponsor, as well as from Avenir, Eli Lilly, and Promius.
SOURCE: Buse DC et al. AHS 2018, Abstract OR06.
SAN FRANCISCO – Nearly 1 in 10 chronic migraine patients say they’ve delayed having children or had fewer children because of their headaches, according to a new analysis from the CaMEO study.
“I think this is the most heartbreaking of the survey responses; we asked, ‘Have you delayed having children or had fewer children because of your headaches?’ and 2.6% of patients with episodic migraine and 9.6% with chronic migraine said yes,” Dawn C. Buse, PhD, said at the annual meeting of the American Headache Society.
CaMEO (the Chronic Migraine Epidemiology and Outcomes study) is a longitudinal, prospective, Internet-based survey whose aim is to flesh out the full impact of migraine. Dr. Buse presented an analysis of 13,064 migraineur participants, which focused on the impact of migraine on intimate relationships and parenting, an aspect of the disease burden that hasn’t been closely examined. All subjects completed the in-depth Family Burden Module, which is concerned with the emotional consequences of migraine.
The bottom line is that “migraine has significant negative impact on the most important relationships in our life: with our spouses, partners, and children,” declared Dr. Buse, a clinical psychologist at the Albert Einstein College of Medicine and director of behavioral medicine for the Montefiore Headache Center in New York.
The extent to which migraineurs perceived their headaches to be a problem increased stepwise with their number of headache days per month. For example, when the 8,127 CaMEO participants in a relationship with a live-in partner were asked to respond to the statement, “If I did not have headaches, I would be a better partner,” somewhat or complete agreement was endorsed by 38% of those with low-frequency episodic migraine at a rate of up to 4 headache days per month, 68% of those with 5-9 headache days per month, 73% of those with high-frequency episodic migraine with 10-14 headache days per month, and 78% of those with chronic migraine, defined as 15 or more headache days per month.
“Not surprising, certainly, but something to keep in mind as we care for our patients; that just because someone has episodic migraine they may have a range of expressions of how much those migraines have impacted their life,” Dr. Buse observed.
Another example: The proportion of subjects who reported delaying having children or having fewer kids because of their headaches was 1.6%, 5.5%, and 6.5% in low-, moderate-, and high-frequency episodic migraineurs, respectively, before topping out at 9.6% among those with chronic migraine.
Although she and her coinvestigators broke down the data by gender, there were no significant gender differences in the impact of migraine on significant relationships. The major differences were between patients with episodic as compared with chronic migraine.
Among the more than 3,500 CaMEO participants not currently in a relationship, 37% of those with chronic migraine and 15% of those with episodic migraine indicated that their headaches had contributed to relationship problems.
Of those in a relationship but not living together, 44% of individuals with chronic migraine reported that their headaches were preventing a closer relationship, such as moving in together or getting married, as did 16% of those with episodic migraine.
About 47%of respondents with chronic migraine reported that their headaches had caused at least one previous break-up, as did 18% of those with episodic migraine.
“Health care professionals should consider the overall burden of disease when managing migraine, particularly for those with chronic migraine,” Dr. Buse concluded. “Personalized comprehensive treatment plans may include both acute and preventive pharmacologic treatments as well as behavioral treatment for the proband, marital dyad, and family members as appropriate.”
She reported receiving research support and honoraria from Allergan, the study sponsor, as well as from Avenir, Eli Lilly, and Promius.
SOURCE: Buse DC et al. AHS 2018, Abstract OR06.
SAN FRANCISCO – Nearly 1 in 10 chronic migraine patients say they’ve delayed having children or had fewer children because of their headaches, according to a new analysis from the CaMEO study.
“I think this is the most heartbreaking of the survey responses; we asked, ‘Have you delayed having children or had fewer children because of your headaches?’ and 2.6% of patients with episodic migraine and 9.6% with chronic migraine said yes,” Dawn C. Buse, PhD, said at the annual meeting of the American Headache Society.
CaMEO (the Chronic Migraine Epidemiology and Outcomes study) is a longitudinal, prospective, Internet-based survey whose aim is to flesh out the full impact of migraine. Dr. Buse presented an analysis of 13,064 migraineur participants, which focused on the impact of migraine on intimate relationships and parenting, an aspect of the disease burden that hasn’t been closely examined. All subjects completed the in-depth Family Burden Module, which is concerned with the emotional consequences of migraine.
The bottom line is that “migraine has significant negative impact on the most important relationships in our life: with our spouses, partners, and children,” declared Dr. Buse, a clinical psychologist at the Albert Einstein College of Medicine and director of behavioral medicine for the Montefiore Headache Center in New York.
The extent to which migraineurs perceived their headaches to be a problem increased stepwise with their number of headache days per month. For example, when the 8,127 CaMEO participants in a relationship with a live-in partner were asked to respond to the statement, “If I did not have headaches, I would be a better partner,” somewhat or complete agreement was endorsed by 38% of those with low-frequency episodic migraine at a rate of up to 4 headache days per month, 68% of those with 5-9 headache days per month, 73% of those with high-frequency episodic migraine with 10-14 headache days per month, and 78% of those with chronic migraine, defined as 15 or more headache days per month.
“Not surprising, certainly, but something to keep in mind as we care for our patients; that just because someone has episodic migraine they may have a range of expressions of how much those migraines have impacted their life,” Dr. Buse observed.
Another example: The proportion of subjects who reported delaying having children or having fewer kids because of their headaches was 1.6%, 5.5%, and 6.5% in low-, moderate-, and high-frequency episodic migraineurs, respectively, before topping out at 9.6% among those with chronic migraine.
Although she and her coinvestigators broke down the data by gender, there were no significant gender differences in the impact of migraine on significant relationships. The major differences were between patients with episodic as compared with chronic migraine.
Among the more than 3,500 CaMEO participants not currently in a relationship, 37% of those with chronic migraine and 15% of those with episodic migraine indicated that their headaches had contributed to relationship problems.
Of those in a relationship but not living together, 44% of individuals with chronic migraine reported that their headaches were preventing a closer relationship, such as moving in together or getting married, as did 16% of those with episodic migraine.
About 47%of respondents with chronic migraine reported that their headaches had caused at least one previous break-up, as did 18% of those with episodic migraine.
“Health care professionals should consider the overall burden of disease when managing migraine, particularly for those with chronic migraine,” Dr. Buse concluded. “Personalized comprehensive treatment plans may include both acute and preventive pharmacologic treatments as well as behavioral treatment for the proband, marital dyad, and family members as appropriate.”
She reported receiving research support and honoraria from Allergan, the study sponsor, as well as from Avenir, Eli Lilly, and Promius.
SOURCE: Buse DC et al. AHS 2018, Abstract OR06.
REPORTING FROM THE AHS ANNUAL MEETING
Key clinical point: Migraine is a major contributor to relationship problems.
Major finding: Nearly 10% of chronic migraineurs say they’ve delayed having children or had fewer of them because of their headaches.
Study details: This analysis included more than 13,000 participants in the CaMEO study, a prospective, longitudinal, Internet-based survey.
Disclosures: The presenter reported receiving research support and honoraria from Allergan, the study sponsor, as well as from Avenir, Eli Lilly, and Promius.
Source: Buse DC et al. AHS 2018, Abstract OR06.
Spontaneous intracranial hypotension: a triple misnomer
SAN FRANCISCO – Spontaneous intracranial hypotension couldn’t have a more misleading moniker.
First of all, spontaneous intracranial hypotension (SIH) is not always spontaneous; often there is an antecedent causal event. Second, the main problem isn’t intracranial, it’s a leak in the spinal column, most often in the low cervical or thoracic zone. And cerebrospinal fluid (CSF) pressure is usually normal in these patients, Deborah I. Friedman, MD, said in the annual Seymour Solomon Award Lecture at the annual meeting of the American Headache Society.
Moreover, although SIH is usually labeled a rare disorder, with a published annual incidence of 5 cases per 100,000, that’s doubtless a gross underestimate stemming from the absence of an ICD-9 or -10 code for the condition, according to Dr. Friedman, chief of the division of headache medicine, professor of neurology, and professor of ophthalmology at the University of Texas Southwestern Medical Center, Dallas.
“[SIH is] much more common than we think,” she asserted. “These people are out there. They’re in your offices. I can guarantee you, there are patients you’ve been seeing for years in your practice that have [SIH]. I’ve missed it. I bet you have, too.”
She focused her award lecture on the diagnosis of SIH from the perspective of a headache specialist.
“Most of the literature that’s out there – and it is good literature – wasn’t written by headache medicine specialists, it was written by very famous and prominent neurosurgeons and neuroradiologists. But the people we see are not necessarily the people they see,” Dr. Friedman explained.
SIH can be a challenging diagnosis because of its myriad presentations.
“You need to be a detective,” she emphasized.
Headache is the most common symptom of SIH and the reason patients with the disorder seek out a headache specialist. It’s time to consider the diagnosis in a patient with a new daily persistent headache, or in the patient running around with a diagnosis of chronic migraine for which nothing works.
“The people who come in with a huge list of medications they’ve tried and nothing works? That’s unusual for migraine. Usually something works for migraine,” she observed.
The headache of SIH can be thunderclap in onset, although not necessarily so. The most common location is posterior, but the pain can be centered anywhere in the head or face. Bilateral pain is more common than unilateral.
The most typical headache pattern is one that’s orthostatic or gets worse at the end of the day. The longer a patient has SIH, though, the less likely that they’ll have a postural component. The majority of patients are awakened by their headache in the middle of the night. The headache is often exertional and usually worsens with Valsalva maneuvers, including coughing, sneezing, lifting, bending forward, straining, singing, and/or sexual activity. People with SIH often find that caffeine works very well for them. Ask nonleading questions about these issues, she suggested.
Besides headache, other common symptoms of SIH include tinnitus, abnormal hearing as if underwater, neck pain, imbalance, pain between the shoulder blades, and blurred or double vision.
Risk factors that are a tipoff include joint hypermobility, previous lumbar puncture, epidural or spinal anesthesia, known disc disease, or a personal or family history of retinal detachment at a young age, aneurysm, dissection, or valvular heart disease.
Joint hypermobility is really common in patients with SIH. These are often headache patients who enjoy yoga and were superflexible as children, participating in gymnastics, ballet, or cheerleading.
“We’re looking for Cirque du Soleil here, so you have to ask the Cirque du Soleil questions,” Dr. Friedman said.
On physical examination, she looks for joint hypermobility, makes sure that spontaneous retinal venous pulsations indicative of normal CSF pressure are present when she looks in the eyes, and puts the patient in 5 degrees of Trendelenburg position for 5-10 minutes to see if that improves the headache and other symptoms.
One of the first things Dr. Friedman does when she suspects the diagnosis is to send a patient to the recommended website of the Spinal CSF Leak Foundation. She asks them to take a look around the site and tell her if the descriptions sound like them.
There is broad agreement that the first-line diagnostic test is brain imaging via MRI with gadolinium enhancement. The diagnostic challenge posed by SIH is that the test is normal in 30% of affected patients.
At present there is no consensus as to the next move when the brain MRI is negative. Some favor CT with or without MR myelography, others a T2-weighted spine MRI. But despite a thorough search, no leak is found in about half of individuals with SIH.
Although Dr. Friedman focused on diagnosis, she turned briefly to treatment. She has found that conservative measures don’t work very well. A reasonable strategy, even if a leak site hasn’t been identified, is to treat with a high-volume epidural CT-guided targeted blood patch with fibrin sealant.
“It gives relief about a third of the time each time you do it,” according to Dr. Friedman.
SAN FRANCISCO – Spontaneous intracranial hypotension couldn’t have a more misleading moniker.
First of all, spontaneous intracranial hypotension (SIH) is not always spontaneous; often there is an antecedent causal event. Second, the main problem isn’t intracranial, it’s a leak in the spinal column, most often in the low cervical or thoracic zone. And cerebrospinal fluid (CSF) pressure is usually normal in these patients, Deborah I. Friedman, MD, said in the annual Seymour Solomon Award Lecture at the annual meeting of the American Headache Society.
Moreover, although SIH is usually labeled a rare disorder, with a published annual incidence of 5 cases per 100,000, that’s doubtless a gross underestimate stemming from the absence of an ICD-9 or -10 code for the condition, according to Dr. Friedman, chief of the division of headache medicine, professor of neurology, and professor of ophthalmology at the University of Texas Southwestern Medical Center, Dallas.
“[SIH is] much more common than we think,” she asserted. “These people are out there. They’re in your offices. I can guarantee you, there are patients you’ve been seeing for years in your practice that have [SIH]. I’ve missed it. I bet you have, too.”
She focused her award lecture on the diagnosis of SIH from the perspective of a headache specialist.
“Most of the literature that’s out there – and it is good literature – wasn’t written by headache medicine specialists, it was written by very famous and prominent neurosurgeons and neuroradiologists. But the people we see are not necessarily the people they see,” Dr. Friedman explained.
SIH can be a challenging diagnosis because of its myriad presentations.
“You need to be a detective,” she emphasized.
Headache is the most common symptom of SIH and the reason patients with the disorder seek out a headache specialist. It’s time to consider the diagnosis in a patient with a new daily persistent headache, or in the patient running around with a diagnosis of chronic migraine for which nothing works.
“The people who come in with a huge list of medications they’ve tried and nothing works? That’s unusual for migraine. Usually something works for migraine,” she observed.
The headache of SIH can be thunderclap in onset, although not necessarily so. The most common location is posterior, but the pain can be centered anywhere in the head or face. Bilateral pain is more common than unilateral.
The most typical headache pattern is one that’s orthostatic or gets worse at the end of the day. The longer a patient has SIH, though, the less likely that they’ll have a postural component. The majority of patients are awakened by their headache in the middle of the night. The headache is often exertional and usually worsens with Valsalva maneuvers, including coughing, sneezing, lifting, bending forward, straining, singing, and/or sexual activity. People with SIH often find that caffeine works very well for them. Ask nonleading questions about these issues, she suggested.
Besides headache, other common symptoms of SIH include tinnitus, abnormal hearing as if underwater, neck pain, imbalance, pain between the shoulder blades, and blurred or double vision.
Risk factors that are a tipoff include joint hypermobility, previous lumbar puncture, epidural or spinal anesthesia, known disc disease, or a personal or family history of retinal detachment at a young age, aneurysm, dissection, or valvular heart disease.
Joint hypermobility is really common in patients with SIH. These are often headache patients who enjoy yoga and were superflexible as children, participating in gymnastics, ballet, or cheerleading.
“We’re looking for Cirque du Soleil here, so you have to ask the Cirque du Soleil questions,” Dr. Friedman said.
On physical examination, she looks for joint hypermobility, makes sure that spontaneous retinal venous pulsations indicative of normal CSF pressure are present when she looks in the eyes, and puts the patient in 5 degrees of Trendelenburg position for 5-10 minutes to see if that improves the headache and other symptoms.
One of the first things Dr. Friedman does when she suspects the diagnosis is to send a patient to the recommended website of the Spinal CSF Leak Foundation. She asks them to take a look around the site and tell her if the descriptions sound like them.
There is broad agreement that the first-line diagnostic test is brain imaging via MRI with gadolinium enhancement. The diagnostic challenge posed by SIH is that the test is normal in 30% of affected patients.
At present there is no consensus as to the next move when the brain MRI is negative. Some favor CT with or without MR myelography, others a T2-weighted spine MRI. But despite a thorough search, no leak is found in about half of individuals with SIH.
Although Dr. Friedman focused on diagnosis, she turned briefly to treatment. She has found that conservative measures don’t work very well. A reasonable strategy, even if a leak site hasn’t been identified, is to treat with a high-volume epidural CT-guided targeted blood patch with fibrin sealant.
“It gives relief about a third of the time each time you do it,” according to Dr. Friedman.
SAN FRANCISCO – Spontaneous intracranial hypotension couldn’t have a more misleading moniker.
First of all, spontaneous intracranial hypotension (SIH) is not always spontaneous; often there is an antecedent causal event. Second, the main problem isn’t intracranial, it’s a leak in the spinal column, most often in the low cervical or thoracic zone. And cerebrospinal fluid (CSF) pressure is usually normal in these patients, Deborah I. Friedman, MD, said in the annual Seymour Solomon Award Lecture at the annual meeting of the American Headache Society.
Moreover, although SIH is usually labeled a rare disorder, with a published annual incidence of 5 cases per 100,000, that’s doubtless a gross underestimate stemming from the absence of an ICD-9 or -10 code for the condition, according to Dr. Friedman, chief of the division of headache medicine, professor of neurology, and professor of ophthalmology at the University of Texas Southwestern Medical Center, Dallas.
“[SIH is] much more common than we think,” she asserted. “These people are out there. They’re in your offices. I can guarantee you, there are patients you’ve been seeing for years in your practice that have [SIH]. I’ve missed it. I bet you have, too.”
She focused her award lecture on the diagnosis of SIH from the perspective of a headache specialist.
“Most of the literature that’s out there – and it is good literature – wasn’t written by headache medicine specialists, it was written by very famous and prominent neurosurgeons and neuroradiologists. But the people we see are not necessarily the people they see,” Dr. Friedman explained.
SIH can be a challenging diagnosis because of its myriad presentations.
“You need to be a detective,” she emphasized.
Headache is the most common symptom of SIH and the reason patients with the disorder seek out a headache specialist. It’s time to consider the diagnosis in a patient with a new daily persistent headache, or in the patient running around with a diagnosis of chronic migraine for which nothing works.
“The people who come in with a huge list of medications they’ve tried and nothing works? That’s unusual for migraine. Usually something works for migraine,” she observed.
The headache of SIH can be thunderclap in onset, although not necessarily so. The most common location is posterior, but the pain can be centered anywhere in the head or face. Bilateral pain is more common than unilateral.
The most typical headache pattern is one that’s orthostatic or gets worse at the end of the day. The longer a patient has SIH, though, the less likely that they’ll have a postural component. The majority of patients are awakened by their headache in the middle of the night. The headache is often exertional and usually worsens with Valsalva maneuvers, including coughing, sneezing, lifting, bending forward, straining, singing, and/or sexual activity. People with SIH often find that caffeine works very well for them. Ask nonleading questions about these issues, she suggested.
Besides headache, other common symptoms of SIH include tinnitus, abnormal hearing as if underwater, neck pain, imbalance, pain between the shoulder blades, and blurred or double vision.
Risk factors that are a tipoff include joint hypermobility, previous lumbar puncture, epidural or spinal anesthesia, known disc disease, or a personal or family history of retinal detachment at a young age, aneurysm, dissection, or valvular heart disease.
Joint hypermobility is really common in patients with SIH. These are often headache patients who enjoy yoga and were superflexible as children, participating in gymnastics, ballet, or cheerleading.
“We’re looking for Cirque du Soleil here, so you have to ask the Cirque du Soleil questions,” Dr. Friedman said.
On physical examination, she looks for joint hypermobility, makes sure that spontaneous retinal venous pulsations indicative of normal CSF pressure are present when she looks in the eyes, and puts the patient in 5 degrees of Trendelenburg position for 5-10 minutes to see if that improves the headache and other symptoms.
One of the first things Dr. Friedman does when she suspects the diagnosis is to send a patient to the recommended website of the Spinal CSF Leak Foundation. She asks them to take a look around the site and tell her if the descriptions sound like them.
There is broad agreement that the first-line diagnostic test is brain imaging via MRI with gadolinium enhancement. The diagnostic challenge posed by SIH is that the test is normal in 30% of affected patients.
At present there is no consensus as to the next move when the brain MRI is negative. Some favor CT with or without MR myelography, others a T2-weighted spine MRI. But despite a thorough search, no leak is found in about half of individuals with SIH.
Although Dr. Friedman focused on diagnosis, she turned briefly to treatment. She has found that conservative measures don’t work very well. A reasonable strategy, even if a leak site hasn’t been identified, is to treat with a high-volume epidural CT-guided targeted blood patch with fibrin sealant.
“It gives relief about a third of the time each time you do it,” according to Dr. Friedman.
REPORTING FROM THE AHS ANNUAL MEETING
What to expect from next-gen CGRP inhibitors for migraine, cluster headache
SAN FRANCISCO – Galcanezumab, the investigational calcitonin gene-related peptide inhibitor under development as preventive therapy for migraine, looks like a triple threat: Multiple phase 3 randomized trials have not only demonstrated safety and efficacy of the monoclonal antibody for prevention of both episodic and chronic migraine but for prevention of episodic cluster headache as well.
Galcanezumab’s demonstrated preventive benefit in patients with episodic cluster headache, if confirmed, would be a big deal. This type of headache is far less common than migraine, but often characterized as not merely debilitating but devastating. Phase 3 evidence of galcanezumab’s safety and efficacy for prevention of episodic cluster headache constitutes a unique advantage over fremanezumab and eptinezumab, the other two monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) for which new phase 3 data were presented at the annual meeting of the American Headache Society. But the latter two novel agents showed advantages of their own.
While the efficacy of the CGRP inhibitors isn’t light-years ahead of the long-standard preventive therapies for migraine, such as topiramate, beta-blockers, antidepressants, and valproate, the new agents offer far greater tolerability and safety – side effect profiles are essentially the same as for placebo except for a modest increase in mild injection site reactions – along with documented substantial quality of life improvements using validated measures. And onset of benefit is far more rapid than with the long-time standard oral preventive medications.
Here are the highlights from the AHS annual meeting:
Galcanezumab
Sheena K. Aurora, MD, presented the results of the GCAL study, a phase 3 randomized, double-blind, 8-week study of subcutaneous galcanezumab at 300 mg once monthly or placebo administered for 2 months in 106 patients with ongoing episodic cluster headache attacks at baseline.
“This is really uncharted territory. The American Headache Society, in its 2016 cluster headache guidelines, reported that there was no high-quality evidence for prophylactic therapy,” noted Dr. Aurora of Eli Lilly in Indianapolis.
After the GCAL study, that’s no longer true. Study participants were a typical population of episodic cluster headache patients: that is, mostly middle-aged men. They averaged more than 17 cluster headache attacks per week during the baseline period, or 2-3 daily, with roughly a 16-year history of episodic cluster headaches, which typically occur in bursts lasting 6-8 weeks before temporarily fading. Of note, 14 of the 106 patients reported a history of prior suicidal ideation; while disturbing, that’s actually a lower rate than in some epidemiologic studies examining patients with this excruciating form of head pain.
The primary endpoint was the mean change in weekly cluster headache attack frequency during weeks 1-3. The difference was significant: a reduction of 8.7 attacks per week in the galcanezumab group, compared with 5.2 fewer in controls. The key secondary endpoint was the proportion of patients with at least a 50% reduction in weekly cluster attack frequency from baseline at week 3: This was achieved in 76% in the galcanezumab arm, versus 57% for placebo, again a significant difference.
At week 4, 73% of patients on galcanezumab rated themselves as very much or much better on the Patient Global Impression of Improvement, significantly greater than the 46% rate in controls. By week 8, this difference – while trending favorably – was no longer statistically significant, but it must be noted that by then 8 of the original 57 patients randomized to placebo had discontinued treatment because of the lack of efficacy, compared with just 1 of 49 in the galcanezumab group.
Adverse events in the two treatment arms were essentially the same as placebo except for an 8% rate of mild injection site reactions in the active treatment group.
Another double-blind, placebo-controlled phase 3 trial known as the CGAM study was conducted in 237 patients with chronic rather than episodic cluster headache. However, it proved negative for the same endpoints, Dr. Aurora said.
Separately, she presented a new post hoc analysis of the recently published EVOLVE-1 (JAMA Neurol. 2018 May 29. doi: 10.1001/jamaneurol.2018.1212) and EVOLVE-2 (Cephalalgia. 2018 Jul;38[8]:1442-54) trials. These two mirror-image pivotal phase 3, double-blind, placebo-controlled, 6-month studies of galcanezumab at 120 or 240 mg once monthly included a collective 1,773 episodic migraine patients with a baseline mean of 9.1 migraine headache days per month. Her analysis focused on the rapidity of onset of the humanized monoclonal antibody’s preventive effect.
“As most clinicians are aware, the current oral preventive treatments that we use require titration, and we don’t really see a good effect for maybe 2-3 months,” she observed.
In an ordinal logistic regression analysis, she and her coinvestigators first determined that the galcanezumab group separated from placebo in terms of reduced migraine headache days as early as 1 month in both studies. Next, they drilled down deeper into the participants’ daily headache diaries and determined that the onset of effect was seen at week 1, at which point the odds of a significant reduction in weekly migraine headache days were 2.71-fold greater with galcanezumab than placebo in EVOLVE-1 and 2.88-fold greater in EVOLVE-2.
“Patients would like to know how quickly they might see an effect, so the fact that we start seeing it for patients who’ve had migraine for 20 years with an average of 9.1 migraine headache days per month as early as week 1 is gratifying, even though the absolute numbers who benefit at that point are small,” Dr. Aurora said.
Fremanezumab
Fremanezumab is a fully humanized monoclonal antibody selectively targeting CGRP. Like galcanezumab and eptinezumab, it is now supported by phase 3 data from short-term, double-blind, placebo-controlled trials backed up by reassuring results from long-term, open-label studies.
During the 28 days prior to the start of the long-term, double-blind study, the chronic migraine patients averaged 16.4 migraine days, while the episodic migraine patients averaged 9.2. After 6 months on their assigned dosing regimen, the episodic migraine patients in the 225 mg monthly group had a mean 4.9 fewer monthly migraine days than at baseline, and the 675 mg quarterly group averaged 5.0 fewer days. The chronic migraine patients on 225 mg monthly had a mean 7.9-day reduction, while the 675 mg quarterly group averaged a 6.5-day reduction in monthly migraine days.
The key point in this interim analysis is that these clinically meaningful reductions in monthly number of migraine days at 6 months were of the same magnitude as at month 1, demonstrating solid maintenance of efficacy over time, noted Dr. Goadsby, professor of neurology at the University of California, San Francisco, and AHS president-elect.
Jessica Ailani, MD, presented evidence that fremanezumab is not only an effective migraine preventive therapy, it also shows potential as a medication for reversion from chronic migraine to episodic migraine.
She presented a post hoc analysis of the 1,130 chronic migraine patients who participated in the 12-week, placebo-controlled HALO CM trial. Thirty-two percent of them who were randomized to 675 mg of fremanezumab quarterly reverted from chronic to episodic migraine, meaning they had fewer than 15 headache days per month during all 3 months of the treatment period. So did 35% of patients who received 225 mg monthly. Both results were significantly better than the 23% placebo reversion rate, which is consistent with the effect of placebo in other studies.
The mean number of monthly headache days of at least moderate severity fell by 4.3 days from baseline in the fremanezumab quarterly group and by 4.6 with monthly therapy, significantly outperforming the 2.5-day reduction with placebo. And the patients who did well did very well indeed: those who reverted from chronic to episodic migraine went from a mean of 18-19 headache days per month at baseline to about 7 days during any month in the treatment period, she reported.
Two patients on 675 mg of fremanezumab quarterly developed antidrug antibodies.
Patients with MOH at baseline experienced a mean reduction of 4.7 headache days of at least moderate severity per month on fremanezumab at 675 mg quarterly and a 5.2-day reduction with monthly fremanezumab, both significantly better than the 2.5-day reduction with placebo. A total of 35% of the fremanezumab quarterly group achieved a 50% or greater reduction in the monthly average number of at least moderately severe headaches, as did 39% of patients on monthly fremanezumab and 14% on placebo.
Moreover, during the 12-week study period, 55% of patients with MOH at baseline who were on fremanezumab quarterly reported no medication overuse, as did 61% of those on 225 mg of fremanezumab once monthly and 46% of controls, according to Dr. Silberstein, professor of neurology and director of the headache center at Thomas Jefferson University in Philadelphia.
For the 1,034 participants who completed testing, the average baseline HIT-6 score was 64 points on a test that can range from 36-78, with higher scores indicating greater adverse impact. At repeat testing 4 weeks after the last dose, the quarterly dosing group showed a statistically significant and clinically meaningful 6.4-point reduction from baseline, and the monthly fremanezumab group had a 6.8-point reduction. Both of those outcomes were significantly better than the placebo group’s 4.5-point decrease, reported Dr. Winner, director of Palm Beach Neurology in West Palm Beach, Fla.
Those HIT-6 changes in fremanezumab-treated patients moved them from the severe disability category to moderate disability, he noted.
“We also evaluated other disability components in this study. The MSQ – the Migraine Specific Quality-of-Life Questionnaire – also showed significant improvement by patient assessment, and on a patient global assessment measure, over 50% of patients who got fremanezumab noted improvement in that 12-week study, getting back to work, functioning normally, etc.,” the neurologist added.
Eptinezumab
Unlike other anti-CGRP antibodies, eptinezumab is administered intravenously, once every 3 months, rather than by subcutaneous injection. This IgG1 anti-CGRP monoclonal antibody was engineered for reduced immune activation and a 30-day half-life. It’s onset of action is extremely rapid, with 100% of the agent being bioavailable within a few hours after administration.
The positive 12-week outcomes of the phase 3 randomized, double-blind, placebo-controlled PROMISE-2 trial of eptinezumab for prophylaxis against chronic migraine have previously been presented, as have the 1-year results in episodic migraine patients in PROMISE-1.
Of those on the higher dose of eptinezumab, 33% had at least a 75% reduction in monthly migraine days from baseline, a figure that climbed to 43% after the second infusion; and of those who received eptinezumab at the 300-mg dose, 61% experienced a 50% or greater reduction in monthly migraine days from baseline during weeks 1-12, as did 64% during weeks 13-24 following a second infusion.
A key secondary endpoint in PROMISE-2 was the proportion of patients having a migraine on any given day. During the 28-day baseline period, that figure was 58%. But the day after the first infusion that proportion dropped to 28% in both the eptinezumab 100- and 300-mg groups, and that rate held through the next 12 weeks. In contrast, roughly 45% of placebo-treated controls had a migraine on any given day during the 12 weeks.
“The key thing is on the day following infusion you have established pretty much the full preventive value of eptinezumab, and it is maintained stable all the way through 12 weeks,” according to Dr. Cady, vice president of neurology at Alder BioPharmaceuticals, which is developing the biologic.
When an audience member remarked on the placebo response rates in the CRGP inhibitor studies and indeed in clinical trials in migraine generally, Dr. Cady responded with one of the meeting’s more memorable comments: “If placebo brought you to the dance, you’re still at the party.”
Dr. Winner reported serving as a consultant to Alder BioPharmaceuticals, which sponsored the HALO trials and is developing eptinezumab, as well as to numerous other pharmaceutical companies. Similarly, Dr. Goadsby, Dr. Ailani, and Dr. Silberstein are consultants to many companies, including Teva Pharmaceuticals, which is developing fremanezumab.
SAN FRANCISCO – Galcanezumab, the investigational calcitonin gene-related peptide inhibitor under development as preventive therapy for migraine, looks like a triple threat: Multiple phase 3 randomized trials have not only demonstrated safety and efficacy of the monoclonal antibody for prevention of both episodic and chronic migraine but for prevention of episodic cluster headache as well.
Galcanezumab’s demonstrated preventive benefit in patients with episodic cluster headache, if confirmed, would be a big deal. This type of headache is far less common than migraine, but often characterized as not merely debilitating but devastating. Phase 3 evidence of galcanezumab’s safety and efficacy for prevention of episodic cluster headache constitutes a unique advantage over fremanezumab and eptinezumab, the other two monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) for which new phase 3 data were presented at the annual meeting of the American Headache Society. But the latter two novel agents showed advantages of their own.
While the efficacy of the CGRP inhibitors isn’t light-years ahead of the long-standard preventive therapies for migraine, such as topiramate, beta-blockers, antidepressants, and valproate, the new agents offer far greater tolerability and safety – side effect profiles are essentially the same as for placebo except for a modest increase in mild injection site reactions – along with documented substantial quality of life improvements using validated measures. And onset of benefit is far more rapid than with the long-time standard oral preventive medications.
Here are the highlights from the AHS annual meeting:
Galcanezumab
Sheena K. Aurora, MD, presented the results of the GCAL study, a phase 3 randomized, double-blind, 8-week study of subcutaneous galcanezumab at 300 mg once monthly or placebo administered for 2 months in 106 patients with ongoing episodic cluster headache attacks at baseline.
“This is really uncharted territory. The American Headache Society, in its 2016 cluster headache guidelines, reported that there was no high-quality evidence for prophylactic therapy,” noted Dr. Aurora of Eli Lilly in Indianapolis.
After the GCAL study, that’s no longer true. Study participants were a typical population of episodic cluster headache patients: that is, mostly middle-aged men. They averaged more than 17 cluster headache attacks per week during the baseline period, or 2-3 daily, with roughly a 16-year history of episodic cluster headaches, which typically occur in bursts lasting 6-8 weeks before temporarily fading. Of note, 14 of the 106 patients reported a history of prior suicidal ideation; while disturbing, that’s actually a lower rate than in some epidemiologic studies examining patients with this excruciating form of head pain.
The primary endpoint was the mean change in weekly cluster headache attack frequency during weeks 1-3. The difference was significant: a reduction of 8.7 attacks per week in the galcanezumab group, compared with 5.2 fewer in controls. The key secondary endpoint was the proportion of patients with at least a 50% reduction in weekly cluster attack frequency from baseline at week 3: This was achieved in 76% in the galcanezumab arm, versus 57% for placebo, again a significant difference.
At week 4, 73% of patients on galcanezumab rated themselves as very much or much better on the Patient Global Impression of Improvement, significantly greater than the 46% rate in controls. By week 8, this difference – while trending favorably – was no longer statistically significant, but it must be noted that by then 8 of the original 57 patients randomized to placebo had discontinued treatment because of the lack of efficacy, compared with just 1 of 49 in the galcanezumab group.
Adverse events in the two treatment arms were essentially the same as placebo except for an 8% rate of mild injection site reactions in the active treatment group.
Another double-blind, placebo-controlled phase 3 trial known as the CGAM study was conducted in 237 patients with chronic rather than episodic cluster headache. However, it proved negative for the same endpoints, Dr. Aurora said.
Separately, she presented a new post hoc analysis of the recently published EVOLVE-1 (JAMA Neurol. 2018 May 29. doi: 10.1001/jamaneurol.2018.1212) and EVOLVE-2 (Cephalalgia. 2018 Jul;38[8]:1442-54) trials. These two mirror-image pivotal phase 3, double-blind, placebo-controlled, 6-month studies of galcanezumab at 120 or 240 mg once monthly included a collective 1,773 episodic migraine patients with a baseline mean of 9.1 migraine headache days per month. Her analysis focused on the rapidity of onset of the humanized monoclonal antibody’s preventive effect.
“As most clinicians are aware, the current oral preventive treatments that we use require titration, and we don’t really see a good effect for maybe 2-3 months,” she observed.
In an ordinal logistic regression analysis, she and her coinvestigators first determined that the galcanezumab group separated from placebo in terms of reduced migraine headache days as early as 1 month in both studies. Next, they drilled down deeper into the participants’ daily headache diaries and determined that the onset of effect was seen at week 1, at which point the odds of a significant reduction in weekly migraine headache days were 2.71-fold greater with galcanezumab than placebo in EVOLVE-1 and 2.88-fold greater in EVOLVE-2.
“Patients would like to know how quickly they might see an effect, so the fact that we start seeing it for patients who’ve had migraine for 20 years with an average of 9.1 migraine headache days per month as early as week 1 is gratifying, even though the absolute numbers who benefit at that point are small,” Dr. Aurora said.
Fremanezumab
Fremanezumab is a fully humanized monoclonal antibody selectively targeting CGRP. Like galcanezumab and eptinezumab, it is now supported by phase 3 data from short-term, double-blind, placebo-controlled trials backed up by reassuring results from long-term, open-label studies.
During the 28 days prior to the start of the long-term, double-blind study, the chronic migraine patients averaged 16.4 migraine days, while the episodic migraine patients averaged 9.2. After 6 months on their assigned dosing regimen, the episodic migraine patients in the 225 mg monthly group had a mean 4.9 fewer monthly migraine days than at baseline, and the 675 mg quarterly group averaged 5.0 fewer days. The chronic migraine patients on 225 mg monthly had a mean 7.9-day reduction, while the 675 mg quarterly group averaged a 6.5-day reduction in monthly migraine days.
The key point in this interim analysis is that these clinically meaningful reductions in monthly number of migraine days at 6 months were of the same magnitude as at month 1, demonstrating solid maintenance of efficacy over time, noted Dr. Goadsby, professor of neurology at the University of California, San Francisco, and AHS president-elect.
Jessica Ailani, MD, presented evidence that fremanezumab is not only an effective migraine preventive therapy, it also shows potential as a medication for reversion from chronic migraine to episodic migraine.
She presented a post hoc analysis of the 1,130 chronic migraine patients who participated in the 12-week, placebo-controlled HALO CM trial. Thirty-two percent of them who were randomized to 675 mg of fremanezumab quarterly reverted from chronic to episodic migraine, meaning they had fewer than 15 headache days per month during all 3 months of the treatment period. So did 35% of patients who received 225 mg monthly. Both results were significantly better than the 23% placebo reversion rate, which is consistent with the effect of placebo in other studies.
The mean number of monthly headache days of at least moderate severity fell by 4.3 days from baseline in the fremanezumab quarterly group and by 4.6 with monthly therapy, significantly outperforming the 2.5-day reduction with placebo. And the patients who did well did very well indeed: those who reverted from chronic to episodic migraine went from a mean of 18-19 headache days per month at baseline to about 7 days during any month in the treatment period, she reported.
Two patients on 675 mg of fremanezumab quarterly developed antidrug antibodies.
Patients with MOH at baseline experienced a mean reduction of 4.7 headache days of at least moderate severity per month on fremanezumab at 675 mg quarterly and a 5.2-day reduction with monthly fremanezumab, both significantly better than the 2.5-day reduction with placebo. A total of 35% of the fremanezumab quarterly group achieved a 50% or greater reduction in the monthly average number of at least moderately severe headaches, as did 39% of patients on monthly fremanezumab and 14% on placebo.
Moreover, during the 12-week study period, 55% of patients with MOH at baseline who were on fremanezumab quarterly reported no medication overuse, as did 61% of those on 225 mg of fremanezumab once monthly and 46% of controls, according to Dr. Silberstein, professor of neurology and director of the headache center at Thomas Jefferson University in Philadelphia.
For the 1,034 participants who completed testing, the average baseline HIT-6 score was 64 points on a test that can range from 36-78, with higher scores indicating greater adverse impact. At repeat testing 4 weeks after the last dose, the quarterly dosing group showed a statistically significant and clinically meaningful 6.4-point reduction from baseline, and the monthly fremanezumab group had a 6.8-point reduction. Both of those outcomes were significantly better than the placebo group’s 4.5-point decrease, reported Dr. Winner, director of Palm Beach Neurology in West Palm Beach, Fla.
Those HIT-6 changes in fremanezumab-treated patients moved them from the severe disability category to moderate disability, he noted.
“We also evaluated other disability components in this study. The MSQ – the Migraine Specific Quality-of-Life Questionnaire – also showed significant improvement by patient assessment, and on a patient global assessment measure, over 50% of patients who got fremanezumab noted improvement in that 12-week study, getting back to work, functioning normally, etc.,” the neurologist added.
Eptinezumab
Unlike other anti-CGRP antibodies, eptinezumab is administered intravenously, once every 3 months, rather than by subcutaneous injection. This IgG1 anti-CGRP monoclonal antibody was engineered for reduced immune activation and a 30-day half-life. It’s onset of action is extremely rapid, with 100% of the agent being bioavailable within a few hours after administration.
The positive 12-week outcomes of the phase 3 randomized, double-blind, placebo-controlled PROMISE-2 trial of eptinezumab for prophylaxis against chronic migraine have previously been presented, as have the 1-year results in episodic migraine patients in PROMISE-1.
Of those on the higher dose of eptinezumab, 33% had at least a 75% reduction in monthly migraine days from baseline, a figure that climbed to 43% after the second infusion; and of those who received eptinezumab at the 300-mg dose, 61% experienced a 50% or greater reduction in monthly migraine days from baseline during weeks 1-12, as did 64% during weeks 13-24 following a second infusion.
A key secondary endpoint in PROMISE-2 was the proportion of patients having a migraine on any given day. During the 28-day baseline period, that figure was 58%. But the day after the first infusion that proportion dropped to 28% in both the eptinezumab 100- and 300-mg groups, and that rate held through the next 12 weeks. In contrast, roughly 45% of placebo-treated controls had a migraine on any given day during the 12 weeks.
“The key thing is on the day following infusion you have established pretty much the full preventive value of eptinezumab, and it is maintained stable all the way through 12 weeks,” according to Dr. Cady, vice president of neurology at Alder BioPharmaceuticals, which is developing the biologic.
When an audience member remarked on the placebo response rates in the CRGP inhibitor studies and indeed in clinical trials in migraine generally, Dr. Cady responded with one of the meeting’s more memorable comments: “If placebo brought you to the dance, you’re still at the party.”
Dr. Winner reported serving as a consultant to Alder BioPharmaceuticals, which sponsored the HALO trials and is developing eptinezumab, as well as to numerous other pharmaceutical companies. Similarly, Dr. Goadsby, Dr. Ailani, and Dr. Silberstein are consultants to many companies, including Teva Pharmaceuticals, which is developing fremanezumab.
SAN FRANCISCO – Galcanezumab, the investigational calcitonin gene-related peptide inhibitor under development as preventive therapy for migraine, looks like a triple threat: Multiple phase 3 randomized trials have not only demonstrated safety and efficacy of the monoclonal antibody for prevention of both episodic and chronic migraine but for prevention of episodic cluster headache as well.
Galcanezumab’s demonstrated preventive benefit in patients with episodic cluster headache, if confirmed, would be a big deal. This type of headache is far less common than migraine, but often characterized as not merely debilitating but devastating. Phase 3 evidence of galcanezumab’s safety and efficacy for prevention of episodic cluster headache constitutes a unique advantage over fremanezumab and eptinezumab, the other two monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) for which new phase 3 data were presented at the annual meeting of the American Headache Society. But the latter two novel agents showed advantages of their own.
While the efficacy of the CGRP inhibitors isn’t light-years ahead of the long-standard preventive therapies for migraine, such as topiramate, beta-blockers, antidepressants, and valproate, the new agents offer far greater tolerability and safety – side effect profiles are essentially the same as for placebo except for a modest increase in mild injection site reactions – along with documented substantial quality of life improvements using validated measures. And onset of benefit is far more rapid than with the long-time standard oral preventive medications.
Here are the highlights from the AHS annual meeting:
Galcanezumab
Sheena K. Aurora, MD, presented the results of the GCAL study, a phase 3 randomized, double-blind, 8-week study of subcutaneous galcanezumab at 300 mg once monthly or placebo administered for 2 months in 106 patients with ongoing episodic cluster headache attacks at baseline.
“This is really uncharted territory. The American Headache Society, in its 2016 cluster headache guidelines, reported that there was no high-quality evidence for prophylactic therapy,” noted Dr. Aurora of Eli Lilly in Indianapolis.
After the GCAL study, that’s no longer true. Study participants were a typical population of episodic cluster headache patients: that is, mostly middle-aged men. They averaged more than 17 cluster headache attacks per week during the baseline period, or 2-3 daily, with roughly a 16-year history of episodic cluster headaches, which typically occur in bursts lasting 6-8 weeks before temporarily fading. Of note, 14 of the 106 patients reported a history of prior suicidal ideation; while disturbing, that’s actually a lower rate than in some epidemiologic studies examining patients with this excruciating form of head pain.
The primary endpoint was the mean change in weekly cluster headache attack frequency during weeks 1-3. The difference was significant: a reduction of 8.7 attacks per week in the galcanezumab group, compared with 5.2 fewer in controls. The key secondary endpoint was the proportion of patients with at least a 50% reduction in weekly cluster attack frequency from baseline at week 3: This was achieved in 76% in the galcanezumab arm, versus 57% for placebo, again a significant difference.
At week 4, 73% of patients on galcanezumab rated themselves as very much or much better on the Patient Global Impression of Improvement, significantly greater than the 46% rate in controls. By week 8, this difference – while trending favorably – was no longer statistically significant, but it must be noted that by then 8 of the original 57 patients randomized to placebo had discontinued treatment because of the lack of efficacy, compared with just 1 of 49 in the galcanezumab group.
Adverse events in the two treatment arms were essentially the same as placebo except for an 8% rate of mild injection site reactions in the active treatment group.
Another double-blind, placebo-controlled phase 3 trial known as the CGAM study was conducted in 237 patients with chronic rather than episodic cluster headache. However, it proved negative for the same endpoints, Dr. Aurora said.
Separately, she presented a new post hoc analysis of the recently published EVOLVE-1 (JAMA Neurol. 2018 May 29. doi: 10.1001/jamaneurol.2018.1212) and EVOLVE-2 (Cephalalgia. 2018 Jul;38[8]:1442-54) trials. These two mirror-image pivotal phase 3, double-blind, placebo-controlled, 6-month studies of galcanezumab at 120 or 240 mg once monthly included a collective 1,773 episodic migraine patients with a baseline mean of 9.1 migraine headache days per month. Her analysis focused on the rapidity of onset of the humanized monoclonal antibody’s preventive effect.
“As most clinicians are aware, the current oral preventive treatments that we use require titration, and we don’t really see a good effect for maybe 2-3 months,” she observed.
In an ordinal logistic regression analysis, she and her coinvestigators first determined that the galcanezumab group separated from placebo in terms of reduced migraine headache days as early as 1 month in both studies. Next, they drilled down deeper into the participants’ daily headache diaries and determined that the onset of effect was seen at week 1, at which point the odds of a significant reduction in weekly migraine headache days were 2.71-fold greater with galcanezumab than placebo in EVOLVE-1 and 2.88-fold greater in EVOLVE-2.
“Patients would like to know how quickly they might see an effect, so the fact that we start seeing it for patients who’ve had migraine for 20 years with an average of 9.1 migraine headache days per month as early as week 1 is gratifying, even though the absolute numbers who benefit at that point are small,” Dr. Aurora said.
Fremanezumab
Fremanezumab is a fully humanized monoclonal antibody selectively targeting CGRP. Like galcanezumab and eptinezumab, it is now supported by phase 3 data from short-term, double-blind, placebo-controlled trials backed up by reassuring results from long-term, open-label studies.
During the 28 days prior to the start of the long-term, double-blind study, the chronic migraine patients averaged 16.4 migraine days, while the episodic migraine patients averaged 9.2. After 6 months on their assigned dosing regimen, the episodic migraine patients in the 225 mg monthly group had a mean 4.9 fewer monthly migraine days than at baseline, and the 675 mg quarterly group averaged 5.0 fewer days. The chronic migraine patients on 225 mg monthly had a mean 7.9-day reduction, while the 675 mg quarterly group averaged a 6.5-day reduction in monthly migraine days.
The key point in this interim analysis is that these clinically meaningful reductions in monthly number of migraine days at 6 months were of the same magnitude as at month 1, demonstrating solid maintenance of efficacy over time, noted Dr. Goadsby, professor of neurology at the University of California, San Francisco, and AHS president-elect.
Jessica Ailani, MD, presented evidence that fremanezumab is not only an effective migraine preventive therapy, it also shows potential as a medication for reversion from chronic migraine to episodic migraine.
She presented a post hoc analysis of the 1,130 chronic migraine patients who participated in the 12-week, placebo-controlled HALO CM trial. Thirty-two percent of them who were randomized to 675 mg of fremanezumab quarterly reverted from chronic to episodic migraine, meaning they had fewer than 15 headache days per month during all 3 months of the treatment period. So did 35% of patients who received 225 mg monthly. Both results were significantly better than the 23% placebo reversion rate, which is consistent with the effect of placebo in other studies.
The mean number of monthly headache days of at least moderate severity fell by 4.3 days from baseline in the fremanezumab quarterly group and by 4.6 with monthly therapy, significantly outperforming the 2.5-day reduction with placebo. And the patients who did well did very well indeed: those who reverted from chronic to episodic migraine went from a mean of 18-19 headache days per month at baseline to about 7 days during any month in the treatment period, she reported.
Two patients on 675 mg of fremanezumab quarterly developed antidrug antibodies.
Patients with MOH at baseline experienced a mean reduction of 4.7 headache days of at least moderate severity per month on fremanezumab at 675 mg quarterly and a 5.2-day reduction with monthly fremanezumab, both significantly better than the 2.5-day reduction with placebo. A total of 35% of the fremanezumab quarterly group achieved a 50% or greater reduction in the monthly average number of at least moderately severe headaches, as did 39% of patients on monthly fremanezumab and 14% on placebo.
Moreover, during the 12-week study period, 55% of patients with MOH at baseline who were on fremanezumab quarterly reported no medication overuse, as did 61% of those on 225 mg of fremanezumab once monthly and 46% of controls, according to Dr. Silberstein, professor of neurology and director of the headache center at Thomas Jefferson University in Philadelphia.
For the 1,034 participants who completed testing, the average baseline HIT-6 score was 64 points on a test that can range from 36-78, with higher scores indicating greater adverse impact. At repeat testing 4 weeks after the last dose, the quarterly dosing group showed a statistically significant and clinically meaningful 6.4-point reduction from baseline, and the monthly fremanezumab group had a 6.8-point reduction. Both of those outcomes were significantly better than the placebo group’s 4.5-point decrease, reported Dr. Winner, director of Palm Beach Neurology in West Palm Beach, Fla.
Those HIT-6 changes in fremanezumab-treated patients moved them from the severe disability category to moderate disability, he noted.
“We also evaluated other disability components in this study. The MSQ – the Migraine Specific Quality-of-Life Questionnaire – also showed significant improvement by patient assessment, and on a patient global assessment measure, over 50% of patients who got fremanezumab noted improvement in that 12-week study, getting back to work, functioning normally, etc.,” the neurologist added.
Eptinezumab
Unlike other anti-CGRP antibodies, eptinezumab is administered intravenously, once every 3 months, rather than by subcutaneous injection. This IgG1 anti-CGRP monoclonal antibody was engineered for reduced immune activation and a 30-day half-life. It’s onset of action is extremely rapid, with 100% of the agent being bioavailable within a few hours after administration.
The positive 12-week outcomes of the phase 3 randomized, double-blind, placebo-controlled PROMISE-2 trial of eptinezumab for prophylaxis against chronic migraine have previously been presented, as have the 1-year results in episodic migraine patients in PROMISE-1.
Of those on the higher dose of eptinezumab, 33% had at least a 75% reduction in monthly migraine days from baseline, a figure that climbed to 43% after the second infusion; and of those who received eptinezumab at the 300-mg dose, 61% experienced a 50% or greater reduction in monthly migraine days from baseline during weeks 1-12, as did 64% during weeks 13-24 following a second infusion.
A key secondary endpoint in PROMISE-2 was the proportion of patients having a migraine on any given day. During the 28-day baseline period, that figure was 58%. But the day after the first infusion that proportion dropped to 28% in both the eptinezumab 100- and 300-mg groups, and that rate held through the next 12 weeks. In contrast, roughly 45% of placebo-treated controls had a migraine on any given day during the 12 weeks.
“The key thing is on the day following infusion you have established pretty much the full preventive value of eptinezumab, and it is maintained stable all the way through 12 weeks,” according to Dr. Cady, vice president of neurology at Alder BioPharmaceuticals, which is developing the biologic.
When an audience member remarked on the placebo response rates in the CRGP inhibitor studies and indeed in clinical trials in migraine generally, Dr. Cady responded with one of the meeting’s more memorable comments: “If placebo brought you to the dance, you’re still at the party.”
Dr. Winner reported serving as a consultant to Alder BioPharmaceuticals, which sponsored the HALO trials and is developing eptinezumab, as well as to numerous other pharmaceutical companies. Similarly, Dr. Goadsby, Dr. Ailani, and Dr. Silberstein are consultants to many companies, including Teva Pharmaceuticals, which is developing fremanezumab.
REPORTING FROM THE AHS ANNUAL MEETING
Positive pivotal trials for new headache drugs abound
SAN FRANCISCO – After a lengthy drought in the development of major new headache medications, it was finally raining successful phase 3 clinical trials for novel drugs at the annual meeting of the American Headache Society.
From the podium, as a prelude to presenting one of many positive trials, Richard B. Lipton, MD, was moved to paraphrase Charles Dickens: “ ‘It was the best of times’ ... and these are truly the best of times,” the neurologist observed.
“This morning we’ve heard about seven new molecular entities that are effective in the acute and/or preventive treatment of migraine, a couple of novel ways of delivering older drugs, and some interesting comparative effectiveness research. I have this compulsion to say over and over again – because I also work in Alzheimer’s disease – it just isn’t like this in other fields. This is truly a remarkable time in our field,” observed Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine in New York.
In addition to new studies of erenumab-aooe, which has been approved as Aimovig, the first-in-class calcitonin gene-related peptide (CGRP) inhibitor for the preventive treatment of migraine, the headache meeting also featured new positive phase 3 results for three other anti-CGRP monoclonal antibodies – galcanezumab, fremanezumab, and eptinezumab – as migraine-preventive therapy, with galcanezumab also demonstrating efficacy in episodic cluster headache; the oral small-molecule CGRP antagonists rimegepant and ubrogepant for acute treatment of migraine attacks; and the selective serotonin 5-HT 1F agonist lasmiditan, also for acute treatment of migraine.
Although the mechanisms of action and therapeutic purposes of the novel agents differ, they share in common what appears to be far better safety and tolerability than the current market leaders, topiramate (Topamax) for migraine prevention and the triptans for acute treatment.
Here are study highlights for the three potential new treatments for acute migraine attacks:
Rimegepant
Dr. Lipton presented the results of two virtually identical phase-3, double-blind, randomized trials in which a total of 2,162 patients with episodic migraine self-administered a 75-mg oral tablet of rimegepant or placebo to treat a single migraine attack when their headache pain reached moderate or severe intensity. The clinical trials, which lacked the customary snazzy acronyms, were simply called Study 301 and Study 302.
The two co-primary endpoints now required by the Food and Drug Administration for candidate agents for acute treatment of migraine attacks are freedom from pain and absence of the most bothersome symptom, both as assessed 2 hours post dose. The oral CGRP receptor antagonist met both endpoints, as well as key secondary endpoints.
In Study 302, for example, the pain-free rate 2 hours post dose was 19.6% in the rimegepant group, significantly higher than the 12% rate in placebo-treated controls. The rate of freedom from the most bothersome symptom, which was photophobia in the majority of patients, was 37.6% in the rimegepant group and 25.2% with placebo.
Dr. Lipton characterized the benefits seen with a single dose of rimegepant as “broad and clinically important.”
“The majority of patients achieved pain relief, durability of benefit at 24 and 48 hours, lower use of rescue medications, and a greater proportion of patients achieved normal function,” the neurologist reported.
The safety and tolerability profiles of rimegepant mirrored those of placebo, he added.
Ubrogepant
Dr. Lipton also presented the results of ACHIEVE II, a multicenter, double-blind, phase 3, placebo-controlled study of the oral CGRP receptor antagonist ubrogepant at 25 or 50 mg versus placebo in 1,355 patients with episodic migraine. Like rimegepant, it met both FDA-required primary endpoints. The pain freedom rate 2 hours post dose was 20.7% with ubrogepant at 25 mg, 21.8% with 50 mg, and 14.3% with placebo. The most bothersome symptom was gone at 2 hours in 34.1% of patients who received the CGRP receptor antagonist at 25 mg, 38.9% of those who got the 50-mg dose, and 27.4% of controls.
David W. Dodick, MD, explained the rationale for CGRP inhibition: CGRP and its receptors are highly expressed in pain-sensitive trigeminal sensory neurons, which innervate the dura and meningeal blood vessels. During the headache phase of migraine, the peptide is released in excess, making CGRP a key player in the pathophysiology of migraine.
Dr. Dodick presented an update focused on secondary endpoints in the phase 3, double-blind ACHIEVE I trial, whose positive co-primary outcomes have previously been reported. The analysis included 1,327 episodic migraine patients who were randomized to ubrogepant at 50 or 100 mg or placebo. Among the notable secondary outcomes was the clinically important rate of pain relief at 2 hours: 61% in both ubrogepant groups, significantly better than the 49% rate with placebo. Also, in terms of pain freedom, the 2-hour rate underestimated the true efficacy patients would experience in clinical practice: the maximum pain freedom rate occurred at 3 hours and was sustained to 8 hours post dose.
At the time study participants took their pill, only 30% indicated they were capable of functioning normally. Two hours later, this was still the case in 29.8% of placebo-treated controls, as compared with 40.6% on ubrogepant at 50 mg and 42.9% who took 100 mg of the drug. The proportion of patients who said they were satisfied or extremely satisfied with their treatment at the 2-hour mark was 24.1% in the placebo arm and 36.3% and 35.8% in the lower- and higher-dose ubrogepant arms, reported Dr. Dodick, professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Lasmiditan
Sheena K. Aurora, MD, presented the results of SAMURAI and SPARTAN, two randomized, double-blind, phase 3 clinical trials comparing lasmiditan versus placebo for the treatment of acute migraine in a collective 3,701 patients with longstanding episodic migraine, one-third of whom had a history of aura.
Lasmiditan is a novel oral serotonin receptor agonist that penetrates the CNS and selectively targets the 5-HT 1F receptor. The drug doesn’t cause the vasoconstrictive effects that make triptans, which target 5-HT 1B/1D receptors, contraindicated in patients with cardiovascular disease.
Indeed, SPARTAN included patients with known cardiovascular disease. SAMURAI did not; however, migraine is now recognized as an independent cardiovascular risk factor, and 80% of SAMURAI participants had one additional standard cardiovascular risk factor, such as diabetes, smoking, or hypertension.
SAMURAI randomized patients to lasmiditan at 100 or 200 mg or placebo to be taken within 4 hours of migraine onset, when the pain was of at least moderate severity. SPARTAN randomized patients to lasmiditan at 50, 100, or 200 mg or placebo.
A dose-response effect was noted. At 2 hours post dose of lasmiditan at 200 mg, 32.2% of patients in SAMURAI and 38.8% in SPARTAN were pain-free, compared with 15.3% and 21.3% on placebo, respectively. At the top dose of lasmiditan, 40.7% of patients in SAMURAI were free of their most bothersome baseline symptom, as were 48.7% in SPARTAN, with placebo response rates of 29.5% and 33.5%, respectively, for this endpoint. A significant separation from placebo was noted in 1 hour for the pain freedom endpoint, and in about 30 minutes for freedom from the most bothersome symptom, reported Dr. Aurora of Eli Lilly, which sponsored the trials.
Lasmiditan at 50 and 100 mg also significantly outperformed placebo for the co-primary endpoints.
As in the phase 3 trials of the two investigational oral CGRP antagonists, a secondary endpoint in SPARTAN and SAMURAI was pain relief at 2 hours, a lower bar than pain freedom. The rates in the lasmiditan 200 mg arms were 60%-65%, compared with about 40% with placebo.
Treatment-emergent adverse event rates were 11%-15% with placebo and in the 40% range for lasmiditan. Because the drug penetrates the CNS, centrally acting side effects were an issue. Dizziness was the most common, followed by paresthesia, somnolence, then fatigue. The dizziness was dose dependent: In SPARTAN, the complaint was noted in 2.5% of placebo-treated controls, 25.4% of patients on 50 mg of lasmiditan, 36.1% with 100 mg, and 39% at 200 mg.
Chest tightness, a common side effect with triptans, did not occur.
A large multicenter, open-label safety assessment study, called GLADIATOR, is ongoing.
Triptans, what have you done for me lately?
A recurring theme at the headache meeting was the vast unmet need for better treatments for acute migraine attacks.
“You all know very well that triptans have been the most widely prescribed acute treatments for migraine in North America now for decades, but there are people with unmet treatment needs,” Dr. Lipton said. “Depending on how you define it, perhaps 34% of patients do not respond, 30%-40% have attack recurrence, and 3.5 million people have absolute or relative contraindications to triptans among the 40 million people who have migraine in the United States.”
This was underscored by an analysis presented by Aftab Alam, MD, from the MAST (Migraine in America Symptoms and Treatment) study, a nationally representative cohort of 15,133 American adults with migraine and a mean monthly headache frequency of 3.3 days per month. Even though triptans are considered the gold standard acute migraine therapy, only 37% of participants in the detailed 30- to 40-minute survey had ever used a triptan, and just 15.9% of the overall study population were current users. Current triptan users averaged 7.3 headache days per month. A total of 85% of current users took oral formulations, 17% used nasal spray, and 8% utilized injectable triptans.
Among ever-users of triptans, 56.7% had discontinued them. The No.1 reason cited was lack of efficacy, named by 38% of those who stopped oral agents, 40% with the nasal spray, and 26% who discontinued injectables.
The second most common reason for triptan discontinuation was side effects, the most common of which was dizziness, followed by nausea and fatigue. Lack of insurance coverage was cited by only 6% of patients as a reason they discontinued triptans.
These MAST results suggest “there is a lot of unmet need in this area,” commented Dr. Alam, director of clinical development and medical affairs at Dr. Reddy’s Laboratories, Princeton, N.J. The MAST study was funded by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories.
Dr. Lipton reported serving as a consultant to more than a dozen pharmaceutical and medical device companies and holding stock options for Biohaven Pharmaceuticals, which is developing rimegepant.
Dr. Dodick reported serving as a consultant to Allergan, which sponsored the ubrogepant studies, as well as numerous other companies.
SOURCES: AHS Annual Meeting Abstracts. Alam A et al. Headache. 2018;58(Suppl 2):68. Abstract OR11; Wietecha L et al. Headache. 2018;58(Suppl 2):73. Abstract IOR02; Dodick D et al. AHS 2018 Abstract IOR01LB; Lipton R et al. AHS 2018 Abstract IOR02LB.
SAN FRANCISCO – After a lengthy drought in the development of major new headache medications, it was finally raining successful phase 3 clinical trials for novel drugs at the annual meeting of the American Headache Society.
From the podium, as a prelude to presenting one of many positive trials, Richard B. Lipton, MD, was moved to paraphrase Charles Dickens: “ ‘It was the best of times’ ... and these are truly the best of times,” the neurologist observed.
“This morning we’ve heard about seven new molecular entities that are effective in the acute and/or preventive treatment of migraine, a couple of novel ways of delivering older drugs, and some interesting comparative effectiveness research. I have this compulsion to say over and over again – because I also work in Alzheimer’s disease – it just isn’t like this in other fields. This is truly a remarkable time in our field,” observed Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine in New York.
In addition to new studies of erenumab-aooe, which has been approved as Aimovig, the first-in-class calcitonin gene-related peptide (CGRP) inhibitor for the preventive treatment of migraine, the headache meeting also featured new positive phase 3 results for three other anti-CGRP monoclonal antibodies – galcanezumab, fremanezumab, and eptinezumab – as migraine-preventive therapy, with galcanezumab also demonstrating efficacy in episodic cluster headache; the oral small-molecule CGRP antagonists rimegepant and ubrogepant for acute treatment of migraine attacks; and the selective serotonin 5-HT 1F agonist lasmiditan, also for acute treatment of migraine.
Although the mechanisms of action and therapeutic purposes of the novel agents differ, they share in common what appears to be far better safety and tolerability than the current market leaders, topiramate (Topamax) for migraine prevention and the triptans for acute treatment.
Here are study highlights for the three potential new treatments for acute migraine attacks:
Rimegepant
Dr. Lipton presented the results of two virtually identical phase-3, double-blind, randomized trials in which a total of 2,162 patients with episodic migraine self-administered a 75-mg oral tablet of rimegepant or placebo to treat a single migraine attack when their headache pain reached moderate or severe intensity. The clinical trials, which lacked the customary snazzy acronyms, were simply called Study 301 and Study 302.
The two co-primary endpoints now required by the Food and Drug Administration for candidate agents for acute treatment of migraine attacks are freedom from pain and absence of the most bothersome symptom, both as assessed 2 hours post dose. The oral CGRP receptor antagonist met both endpoints, as well as key secondary endpoints.
In Study 302, for example, the pain-free rate 2 hours post dose was 19.6% in the rimegepant group, significantly higher than the 12% rate in placebo-treated controls. The rate of freedom from the most bothersome symptom, which was photophobia in the majority of patients, was 37.6% in the rimegepant group and 25.2% with placebo.
Dr. Lipton characterized the benefits seen with a single dose of rimegepant as “broad and clinically important.”
“The majority of patients achieved pain relief, durability of benefit at 24 and 48 hours, lower use of rescue medications, and a greater proportion of patients achieved normal function,” the neurologist reported.
The safety and tolerability profiles of rimegepant mirrored those of placebo, he added.
Ubrogepant
Dr. Lipton also presented the results of ACHIEVE II, a multicenter, double-blind, phase 3, placebo-controlled study of the oral CGRP receptor antagonist ubrogepant at 25 or 50 mg versus placebo in 1,355 patients with episodic migraine. Like rimegepant, it met both FDA-required primary endpoints. The pain freedom rate 2 hours post dose was 20.7% with ubrogepant at 25 mg, 21.8% with 50 mg, and 14.3% with placebo. The most bothersome symptom was gone at 2 hours in 34.1% of patients who received the CGRP receptor antagonist at 25 mg, 38.9% of those who got the 50-mg dose, and 27.4% of controls.
David W. Dodick, MD, explained the rationale for CGRP inhibition: CGRP and its receptors are highly expressed in pain-sensitive trigeminal sensory neurons, which innervate the dura and meningeal blood vessels. During the headache phase of migraine, the peptide is released in excess, making CGRP a key player in the pathophysiology of migraine.
Dr. Dodick presented an update focused on secondary endpoints in the phase 3, double-blind ACHIEVE I trial, whose positive co-primary outcomes have previously been reported. The analysis included 1,327 episodic migraine patients who were randomized to ubrogepant at 50 or 100 mg or placebo. Among the notable secondary outcomes was the clinically important rate of pain relief at 2 hours: 61% in both ubrogepant groups, significantly better than the 49% rate with placebo. Also, in terms of pain freedom, the 2-hour rate underestimated the true efficacy patients would experience in clinical practice: the maximum pain freedom rate occurred at 3 hours and was sustained to 8 hours post dose.
At the time study participants took their pill, only 30% indicated they were capable of functioning normally. Two hours later, this was still the case in 29.8% of placebo-treated controls, as compared with 40.6% on ubrogepant at 50 mg and 42.9% who took 100 mg of the drug. The proportion of patients who said they were satisfied or extremely satisfied with their treatment at the 2-hour mark was 24.1% in the placebo arm and 36.3% and 35.8% in the lower- and higher-dose ubrogepant arms, reported Dr. Dodick, professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Lasmiditan
Sheena K. Aurora, MD, presented the results of SAMURAI and SPARTAN, two randomized, double-blind, phase 3 clinical trials comparing lasmiditan versus placebo for the treatment of acute migraine in a collective 3,701 patients with longstanding episodic migraine, one-third of whom had a history of aura.
Lasmiditan is a novel oral serotonin receptor agonist that penetrates the CNS and selectively targets the 5-HT 1F receptor. The drug doesn’t cause the vasoconstrictive effects that make triptans, which target 5-HT 1B/1D receptors, contraindicated in patients with cardiovascular disease.
Indeed, SPARTAN included patients with known cardiovascular disease. SAMURAI did not; however, migraine is now recognized as an independent cardiovascular risk factor, and 80% of SAMURAI participants had one additional standard cardiovascular risk factor, such as diabetes, smoking, or hypertension.
SAMURAI randomized patients to lasmiditan at 100 or 200 mg or placebo to be taken within 4 hours of migraine onset, when the pain was of at least moderate severity. SPARTAN randomized patients to lasmiditan at 50, 100, or 200 mg or placebo.
A dose-response effect was noted. At 2 hours post dose of lasmiditan at 200 mg, 32.2% of patients in SAMURAI and 38.8% in SPARTAN were pain-free, compared with 15.3% and 21.3% on placebo, respectively. At the top dose of lasmiditan, 40.7% of patients in SAMURAI were free of their most bothersome baseline symptom, as were 48.7% in SPARTAN, with placebo response rates of 29.5% and 33.5%, respectively, for this endpoint. A significant separation from placebo was noted in 1 hour for the pain freedom endpoint, and in about 30 minutes for freedom from the most bothersome symptom, reported Dr. Aurora of Eli Lilly, which sponsored the trials.
Lasmiditan at 50 and 100 mg also significantly outperformed placebo for the co-primary endpoints.
As in the phase 3 trials of the two investigational oral CGRP antagonists, a secondary endpoint in SPARTAN and SAMURAI was pain relief at 2 hours, a lower bar than pain freedom. The rates in the lasmiditan 200 mg arms were 60%-65%, compared with about 40% with placebo.
Treatment-emergent adverse event rates were 11%-15% with placebo and in the 40% range for lasmiditan. Because the drug penetrates the CNS, centrally acting side effects were an issue. Dizziness was the most common, followed by paresthesia, somnolence, then fatigue. The dizziness was dose dependent: In SPARTAN, the complaint was noted in 2.5% of placebo-treated controls, 25.4% of patients on 50 mg of lasmiditan, 36.1% with 100 mg, and 39% at 200 mg.
Chest tightness, a common side effect with triptans, did not occur.
A large multicenter, open-label safety assessment study, called GLADIATOR, is ongoing.
Triptans, what have you done for me lately?
A recurring theme at the headache meeting was the vast unmet need for better treatments for acute migraine attacks.
“You all know very well that triptans have been the most widely prescribed acute treatments for migraine in North America now for decades, but there are people with unmet treatment needs,” Dr. Lipton said. “Depending on how you define it, perhaps 34% of patients do not respond, 30%-40% have attack recurrence, and 3.5 million people have absolute or relative contraindications to triptans among the 40 million people who have migraine in the United States.”
This was underscored by an analysis presented by Aftab Alam, MD, from the MAST (Migraine in America Symptoms and Treatment) study, a nationally representative cohort of 15,133 American adults with migraine and a mean monthly headache frequency of 3.3 days per month. Even though triptans are considered the gold standard acute migraine therapy, only 37% of participants in the detailed 30- to 40-minute survey had ever used a triptan, and just 15.9% of the overall study population were current users. Current triptan users averaged 7.3 headache days per month. A total of 85% of current users took oral formulations, 17% used nasal spray, and 8% utilized injectable triptans.
Among ever-users of triptans, 56.7% had discontinued them. The No.1 reason cited was lack of efficacy, named by 38% of those who stopped oral agents, 40% with the nasal spray, and 26% who discontinued injectables.
The second most common reason for triptan discontinuation was side effects, the most common of which was dizziness, followed by nausea and fatigue. Lack of insurance coverage was cited by only 6% of patients as a reason they discontinued triptans.
These MAST results suggest “there is a lot of unmet need in this area,” commented Dr. Alam, director of clinical development and medical affairs at Dr. Reddy’s Laboratories, Princeton, N.J. The MAST study was funded by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories.
Dr. Lipton reported serving as a consultant to more than a dozen pharmaceutical and medical device companies and holding stock options for Biohaven Pharmaceuticals, which is developing rimegepant.
Dr. Dodick reported serving as a consultant to Allergan, which sponsored the ubrogepant studies, as well as numerous other companies.
SOURCES: AHS Annual Meeting Abstracts. Alam A et al. Headache. 2018;58(Suppl 2):68. Abstract OR11; Wietecha L et al. Headache. 2018;58(Suppl 2):73. Abstract IOR02; Dodick D et al. AHS 2018 Abstract IOR01LB; Lipton R et al. AHS 2018 Abstract IOR02LB.
SAN FRANCISCO – After a lengthy drought in the development of major new headache medications, it was finally raining successful phase 3 clinical trials for novel drugs at the annual meeting of the American Headache Society.
From the podium, as a prelude to presenting one of many positive trials, Richard B. Lipton, MD, was moved to paraphrase Charles Dickens: “ ‘It was the best of times’ ... and these are truly the best of times,” the neurologist observed.
“This morning we’ve heard about seven new molecular entities that are effective in the acute and/or preventive treatment of migraine, a couple of novel ways of delivering older drugs, and some interesting comparative effectiveness research. I have this compulsion to say over and over again – because I also work in Alzheimer’s disease – it just isn’t like this in other fields. This is truly a remarkable time in our field,” observed Dr. Lipton, professor and vice chair of the department of neurology at Albert Einstein College of Medicine in New York.
In addition to new studies of erenumab-aooe, which has been approved as Aimovig, the first-in-class calcitonin gene-related peptide (CGRP) inhibitor for the preventive treatment of migraine, the headache meeting also featured new positive phase 3 results for three other anti-CGRP monoclonal antibodies – galcanezumab, fremanezumab, and eptinezumab – as migraine-preventive therapy, with galcanezumab also demonstrating efficacy in episodic cluster headache; the oral small-molecule CGRP antagonists rimegepant and ubrogepant for acute treatment of migraine attacks; and the selective serotonin 5-HT 1F agonist lasmiditan, also for acute treatment of migraine.
Although the mechanisms of action and therapeutic purposes of the novel agents differ, they share in common what appears to be far better safety and tolerability than the current market leaders, topiramate (Topamax) for migraine prevention and the triptans for acute treatment.
Here are study highlights for the three potential new treatments for acute migraine attacks:
Rimegepant
Dr. Lipton presented the results of two virtually identical phase-3, double-blind, randomized trials in which a total of 2,162 patients with episodic migraine self-administered a 75-mg oral tablet of rimegepant or placebo to treat a single migraine attack when their headache pain reached moderate or severe intensity. The clinical trials, which lacked the customary snazzy acronyms, were simply called Study 301 and Study 302.
The two co-primary endpoints now required by the Food and Drug Administration for candidate agents for acute treatment of migraine attacks are freedom from pain and absence of the most bothersome symptom, both as assessed 2 hours post dose. The oral CGRP receptor antagonist met both endpoints, as well as key secondary endpoints.
In Study 302, for example, the pain-free rate 2 hours post dose was 19.6% in the rimegepant group, significantly higher than the 12% rate in placebo-treated controls. The rate of freedom from the most bothersome symptom, which was photophobia in the majority of patients, was 37.6% in the rimegepant group and 25.2% with placebo.
Dr. Lipton characterized the benefits seen with a single dose of rimegepant as “broad and clinically important.”
“The majority of patients achieved pain relief, durability of benefit at 24 and 48 hours, lower use of rescue medications, and a greater proportion of patients achieved normal function,” the neurologist reported.
The safety and tolerability profiles of rimegepant mirrored those of placebo, he added.
Ubrogepant
Dr. Lipton also presented the results of ACHIEVE II, a multicenter, double-blind, phase 3, placebo-controlled study of the oral CGRP receptor antagonist ubrogepant at 25 or 50 mg versus placebo in 1,355 patients with episodic migraine. Like rimegepant, it met both FDA-required primary endpoints. The pain freedom rate 2 hours post dose was 20.7% with ubrogepant at 25 mg, 21.8% with 50 mg, and 14.3% with placebo. The most bothersome symptom was gone at 2 hours in 34.1% of patients who received the CGRP receptor antagonist at 25 mg, 38.9% of those who got the 50-mg dose, and 27.4% of controls.
David W. Dodick, MD, explained the rationale for CGRP inhibition: CGRP and its receptors are highly expressed in pain-sensitive trigeminal sensory neurons, which innervate the dura and meningeal blood vessels. During the headache phase of migraine, the peptide is released in excess, making CGRP a key player in the pathophysiology of migraine.
Dr. Dodick presented an update focused on secondary endpoints in the phase 3, double-blind ACHIEVE I trial, whose positive co-primary outcomes have previously been reported. The analysis included 1,327 episodic migraine patients who were randomized to ubrogepant at 50 or 100 mg or placebo. Among the notable secondary outcomes was the clinically important rate of pain relief at 2 hours: 61% in both ubrogepant groups, significantly better than the 49% rate with placebo. Also, in terms of pain freedom, the 2-hour rate underestimated the true efficacy patients would experience in clinical practice: the maximum pain freedom rate occurred at 3 hours and was sustained to 8 hours post dose.
At the time study participants took their pill, only 30% indicated they were capable of functioning normally. Two hours later, this was still the case in 29.8% of placebo-treated controls, as compared with 40.6% on ubrogepant at 50 mg and 42.9% who took 100 mg of the drug. The proportion of patients who said they were satisfied or extremely satisfied with their treatment at the 2-hour mark was 24.1% in the placebo arm and 36.3% and 35.8% in the lower- and higher-dose ubrogepant arms, reported Dr. Dodick, professor of neurology at the Mayo Clinic in Scottsdale, Ariz.
Lasmiditan
Sheena K. Aurora, MD, presented the results of SAMURAI and SPARTAN, two randomized, double-blind, phase 3 clinical trials comparing lasmiditan versus placebo for the treatment of acute migraine in a collective 3,701 patients with longstanding episodic migraine, one-third of whom had a history of aura.
Lasmiditan is a novel oral serotonin receptor agonist that penetrates the CNS and selectively targets the 5-HT 1F receptor. The drug doesn’t cause the vasoconstrictive effects that make triptans, which target 5-HT 1B/1D receptors, contraindicated in patients with cardiovascular disease.
Indeed, SPARTAN included patients with known cardiovascular disease. SAMURAI did not; however, migraine is now recognized as an independent cardiovascular risk factor, and 80% of SAMURAI participants had one additional standard cardiovascular risk factor, such as diabetes, smoking, or hypertension.
SAMURAI randomized patients to lasmiditan at 100 or 200 mg or placebo to be taken within 4 hours of migraine onset, when the pain was of at least moderate severity. SPARTAN randomized patients to lasmiditan at 50, 100, or 200 mg or placebo.
A dose-response effect was noted. At 2 hours post dose of lasmiditan at 200 mg, 32.2% of patients in SAMURAI and 38.8% in SPARTAN were pain-free, compared with 15.3% and 21.3% on placebo, respectively. At the top dose of lasmiditan, 40.7% of patients in SAMURAI were free of their most bothersome baseline symptom, as were 48.7% in SPARTAN, with placebo response rates of 29.5% and 33.5%, respectively, for this endpoint. A significant separation from placebo was noted in 1 hour for the pain freedom endpoint, and in about 30 minutes for freedom from the most bothersome symptom, reported Dr. Aurora of Eli Lilly, which sponsored the trials.
Lasmiditan at 50 and 100 mg also significantly outperformed placebo for the co-primary endpoints.
As in the phase 3 trials of the two investigational oral CGRP antagonists, a secondary endpoint in SPARTAN and SAMURAI was pain relief at 2 hours, a lower bar than pain freedom. The rates in the lasmiditan 200 mg arms were 60%-65%, compared with about 40% with placebo.
Treatment-emergent adverse event rates were 11%-15% with placebo and in the 40% range for lasmiditan. Because the drug penetrates the CNS, centrally acting side effects were an issue. Dizziness was the most common, followed by paresthesia, somnolence, then fatigue. The dizziness was dose dependent: In SPARTAN, the complaint was noted in 2.5% of placebo-treated controls, 25.4% of patients on 50 mg of lasmiditan, 36.1% with 100 mg, and 39% at 200 mg.
Chest tightness, a common side effect with triptans, did not occur.
A large multicenter, open-label safety assessment study, called GLADIATOR, is ongoing.
Triptans, what have you done for me lately?
A recurring theme at the headache meeting was the vast unmet need for better treatments for acute migraine attacks.
“You all know very well that triptans have been the most widely prescribed acute treatments for migraine in North America now for decades, but there are people with unmet treatment needs,” Dr. Lipton said. “Depending on how you define it, perhaps 34% of patients do not respond, 30%-40% have attack recurrence, and 3.5 million people have absolute or relative contraindications to triptans among the 40 million people who have migraine in the United States.”
This was underscored by an analysis presented by Aftab Alam, MD, from the MAST (Migraine in America Symptoms and Treatment) study, a nationally representative cohort of 15,133 American adults with migraine and a mean monthly headache frequency of 3.3 days per month. Even though triptans are considered the gold standard acute migraine therapy, only 37% of participants in the detailed 30- to 40-minute survey had ever used a triptan, and just 15.9% of the overall study population were current users. Current triptan users averaged 7.3 headache days per month. A total of 85% of current users took oral formulations, 17% used nasal spray, and 8% utilized injectable triptans.
Among ever-users of triptans, 56.7% had discontinued them. The No.1 reason cited was lack of efficacy, named by 38% of those who stopped oral agents, 40% with the nasal spray, and 26% who discontinued injectables.
The second most common reason for triptan discontinuation was side effects, the most common of which was dizziness, followed by nausea and fatigue. Lack of insurance coverage was cited by only 6% of patients as a reason they discontinued triptans.
These MAST results suggest “there is a lot of unmet need in this area,” commented Dr. Alam, director of clinical development and medical affairs at Dr. Reddy’s Laboratories, Princeton, N.J. The MAST study was funded by Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories.
Dr. Lipton reported serving as a consultant to more than a dozen pharmaceutical and medical device companies and holding stock options for Biohaven Pharmaceuticals, which is developing rimegepant.
Dr. Dodick reported serving as a consultant to Allergan, which sponsored the ubrogepant studies, as well as numerous other companies.
SOURCES: AHS Annual Meeting Abstracts. Alam A et al. Headache. 2018;58(Suppl 2):68. Abstract OR11; Wietecha L et al. Headache. 2018;58(Suppl 2):73. Abstract IOR02; Dodick D et al. AHS 2018 Abstract IOR01LB; Lipton R et al. AHS 2018 Abstract IOR02LB.
REPORTING FROM THE AHS ANNUAL MEETING
Weather changes trigger migraine
SAN FRANCISCO – Many migraineurs claim that changes in the weather can trigger their headache attacks. It took a headache specialist together with a meteorologist poring over surface weather maps to prove they are right.
“When patients tell you they can predict a headache from the weather, they really can,” Vincent T. Martin, MD, declared in presenting the evidence at the annual meeting of the American Headache Society.
Many physicians have been skeptical of patient self-reports of a weather/migraine connection because of mixed results in prior studies examining the impact of a single meteorologic factor at a time, such as barometric pressure, temperature, humidity, or wind speed.
“These studies, however, fail to account for the fact that weather events represent a confluence of meteorologic factors that occur in a specific temporal sequence. It may be necessary to model several variables together to achieve the optimal weather models,” explained Dr. Martin, a general internist, professor of medicine, and director of the Headache and Facial Pain Center at the University of Cincinnati.
He presented a retrospective cohort study of 218 patients with episodic migraine with a mean of 8.9 headache days per month who kept a daily electronic headache diary during two prior studies conducted in the St. Louis area. Their diary data were matched with hourly measurements of barometric pressure, temperature, relative humidity, and wind speed recorded at five St. Louis–area weather stations and archived at the National Climatic Data Center. Dr. Martin and his coinvestigators then created a series of models that predicted the weather conditions that were associated with each individual patient being in the top tertile for the presence of headache on a given day with no headache on the day before.
Preliminary analysis indicated that the most important predictor of new-onset headache in winter, spring, and fall was the barometric pressure differential between 2 consecutive days. These differentials were much smaller in the summer, so a separate model was created for that season. Multiple models were developed to identify binary cutpoints for each weather variable.
From fall through spring, during periods when barometric pressure was in the top tertile – that is, a high-pressure system was in play – a day-to-day difference in mean daily barometric pressure greater than 0.1 mm Hg was associated with a 4.9-fold increased risk of being in the top tertile for new-onset headache, and less than a 25% difference in minimal daily relative humidity was associated with a 4.6-fold increased risk.
In contrast, when barometric pressure was in the lowest tertile, a drop in mean daily barometric pressure of 0.05 mm Hg or less from one day to the next was associated with a 3.17-fold increased risk of entering the top tertile for new-onset headache, and a day-to-day increase in maximal wind speed of 7 mph or more was associated with a 2.64-fold increased risk.
In middle-tertile periods of barometric pressure, a drop in mean pressure of 0.05 mm Hg or less was associated with a 2.21-fold increase in new-onset headache, and a mean daily relative humidity of 79% or greater conferred a 4.43-fold relative risk.
“It’s very rare in epidemiologic studies to get magnitudes of association to those degrees,” Dr. Martin observed. “Our results provide strong evidence that weather is associated with days with a high probability of new-onset headache in persons with migraine.”
The mechanisms underlying this association aren’t known. Possibilities worthy of investigation include stimulation of hyperactivity of the sympathetic nervous system, increases in airborne environmental allergens or pollutants, or direct activation of trigeminal afferent nerve fibers, he said.
Dr. Martin reported having no financial conflicts of interest.
SAN FRANCISCO – Many migraineurs claim that changes in the weather can trigger their headache attacks. It took a headache specialist together with a meteorologist poring over surface weather maps to prove they are right.
“When patients tell you they can predict a headache from the weather, they really can,” Vincent T. Martin, MD, declared in presenting the evidence at the annual meeting of the American Headache Society.
Many physicians have been skeptical of patient self-reports of a weather/migraine connection because of mixed results in prior studies examining the impact of a single meteorologic factor at a time, such as barometric pressure, temperature, humidity, or wind speed.
“These studies, however, fail to account for the fact that weather events represent a confluence of meteorologic factors that occur in a specific temporal sequence. It may be necessary to model several variables together to achieve the optimal weather models,” explained Dr. Martin, a general internist, professor of medicine, and director of the Headache and Facial Pain Center at the University of Cincinnati.
He presented a retrospective cohort study of 218 patients with episodic migraine with a mean of 8.9 headache days per month who kept a daily electronic headache diary during two prior studies conducted in the St. Louis area. Their diary data were matched with hourly measurements of barometric pressure, temperature, relative humidity, and wind speed recorded at five St. Louis–area weather stations and archived at the National Climatic Data Center. Dr. Martin and his coinvestigators then created a series of models that predicted the weather conditions that were associated with each individual patient being in the top tertile for the presence of headache on a given day with no headache on the day before.
Preliminary analysis indicated that the most important predictor of new-onset headache in winter, spring, and fall was the barometric pressure differential between 2 consecutive days. These differentials were much smaller in the summer, so a separate model was created for that season. Multiple models were developed to identify binary cutpoints for each weather variable.
From fall through spring, during periods when barometric pressure was in the top tertile – that is, a high-pressure system was in play – a day-to-day difference in mean daily barometric pressure greater than 0.1 mm Hg was associated with a 4.9-fold increased risk of being in the top tertile for new-onset headache, and less than a 25% difference in minimal daily relative humidity was associated with a 4.6-fold increased risk.
In contrast, when barometric pressure was in the lowest tertile, a drop in mean daily barometric pressure of 0.05 mm Hg or less from one day to the next was associated with a 3.17-fold increased risk of entering the top tertile for new-onset headache, and a day-to-day increase in maximal wind speed of 7 mph or more was associated with a 2.64-fold increased risk.
In middle-tertile periods of barometric pressure, a drop in mean pressure of 0.05 mm Hg or less was associated with a 2.21-fold increase in new-onset headache, and a mean daily relative humidity of 79% or greater conferred a 4.43-fold relative risk.
“It’s very rare in epidemiologic studies to get magnitudes of association to those degrees,” Dr. Martin observed. “Our results provide strong evidence that weather is associated with days with a high probability of new-onset headache in persons with migraine.”
The mechanisms underlying this association aren’t known. Possibilities worthy of investigation include stimulation of hyperactivity of the sympathetic nervous system, increases in airborne environmental allergens or pollutants, or direct activation of trigeminal afferent nerve fibers, he said.
Dr. Martin reported having no financial conflicts of interest.
SAN FRANCISCO – Many migraineurs claim that changes in the weather can trigger their headache attacks. It took a headache specialist together with a meteorologist poring over surface weather maps to prove they are right.
“When patients tell you they can predict a headache from the weather, they really can,” Vincent T. Martin, MD, declared in presenting the evidence at the annual meeting of the American Headache Society.
Many physicians have been skeptical of patient self-reports of a weather/migraine connection because of mixed results in prior studies examining the impact of a single meteorologic factor at a time, such as barometric pressure, temperature, humidity, or wind speed.
“These studies, however, fail to account for the fact that weather events represent a confluence of meteorologic factors that occur in a specific temporal sequence. It may be necessary to model several variables together to achieve the optimal weather models,” explained Dr. Martin, a general internist, professor of medicine, and director of the Headache and Facial Pain Center at the University of Cincinnati.
He presented a retrospective cohort study of 218 patients with episodic migraine with a mean of 8.9 headache days per month who kept a daily electronic headache diary during two prior studies conducted in the St. Louis area. Their diary data were matched with hourly measurements of barometric pressure, temperature, relative humidity, and wind speed recorded at five St. Louis–area weather stations and archived at the National Climatic Data Center. Dr. Martin and his coinvestigators then created a series of models that predicted the weather conditions that were associated with each individual patient being in the top tertile for the presence of headache on a given day with no headache on the day before.
Preliminary analysis indicated that the most important predictor of new-onset headache in winter, spring, and fall was the barometric pressure differential between 2 consecutive days. These differentials were much smaller in the summer, so a separate model was created for that season. Multiple models were developed to identify binary cutpoints for each weather variable.
From fall through spring, during periods when barometric pressure was in the top tertile – that is, a high-pressure system was in play – a day-to-day difference in mean daily barometric pressure greater than 0.1 mm Hg was associated with a 4.9-fold increased risk of being in the top tertile for new-onset headache, and less than a 25% difference in minimal daily relative humidity was associated with a 4.6-fold increased risk.
In contrast, when barometric pressure was in the lowest tertile, a drop in mean daily barometric pressure of 0.05 mm Hg or less from one day to the next was associated with a 3.17-fold increased risk of entering the top tertile for new-onset headache, and a day-to-day increase in maximal wind speed of 7 mph or more was associated with a 2.64-fold increased risk.
In middle-tertile periods of barometric pressure, a drop in mean pressure of 0.05 mm Hg or less was associated with a 2.21-fold increase in new-onset headache, and a mean daily relative humidity of 79% or greater conferred a 4.43-fold relative risk.
“It’s very rare in epidemiologic studies to get magnitudes of association to those degrees,” Dr. Martin observed. “Our results provide strong evidence that weather is associated with days with a high probability of new-onset headache in persons with migraine.”
The mechanisms underlying this association aren’t known. Possibilities worthy of investigation include stimulation of hyperactivity of the sympathetic nervous system, increases in airborne environmental allergens or pollutants, or direct activation of trigeminal afferent nerve fibers, he said.
Dr. Martin reported having no financial conflicts of interest.
REPORTING FROM THE AHS ANNUAL MEETING
Key clinical point: Specific weather patterns can trigger migraine.
Major finding: During a low pressure front, a maximum wind speed of 7 mph or more on a given day was associated with a 2.6-fold increased relative risk of new-onset headache the next day.
Study details: This retrospective study of 218 episodic migraine patients linked their daily headache diary data to hourly measurements from local weather stations.
Disclosures: The presenter reported having no financial conflicts of interest.
New studies expand on Aimovig for migraine
SAN FRANCISCO – Now that erenumab has won approval as the first-in-class calcitonin gene-related peptide inhibitor for prevention of episodic and chronic migraine, a flurry of new studies shedding light on how the drug might best be used in clinical practice emerged as a highlight of the annual meeting of the American Headache Society.
Erenumab (Aimovig) is a fully human monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. It was approved by the Food and Drug Administration at 140 and 70 mg monthly by subcutaneous injection on the strength of the required 12-week, double-blind, placebo-controlled clinical trial data. Among the fresh data presented at the headache meeting was reassuring evidence of the monoclonal antibody’s continued high degree of safety and tolerability for episodic migraine after more than 3 years of therapy, as well as a suggestion that the biologic’s efficacy for chronic migraine was not only sustained but actually increased over the course of a 1-year study.
Also, erenumab appears to be a novel treatment option for patients who have previously failed adequate trials of two to four standard preventive therapies. In addition, it has now demonstrated efficacy in reducing overuse of acute migraine drugs such as triptans, ergots, and opioids.
Here are the highlights:
One-year safety and efficacy for chronic migraine
Stewart J. Tepper, MD, presented results of a 1-year, open-label extension study that began after participants completed a pivotal 12-week, placebo-controlled, double-blind, randomized trial whose findings have been published (Lancet Neurol. 2017 Jun;16[6]:425-34). At the end of the 12-week, double-blind period, the mean number of monthly migraine days (MMD) in the erenumab group had dropped by 6.6 days from 18.1 at baseline. Subsequently, after 52 weeks of open-label erenumab at 140 mg monthly, that figure had further improved to 10.5 fewer MMDs than at baseline.
“That’s encouraging for our patients in that we will be able to tell them that if you’re a responder, you’re likely to show some continued improvement over time,” observed Dr. Tepper, professor of neurology and director of the headache clinic at Dartmouth University in Hanover, N.H.
During 527 patient-years of open-label therapy, at least a 50% reduction in MMDs was achieved by 67% of patients in the 140-mg group and 53% in the 70-mg group.
“I think it’s also important to look at the rate of 75% or greater reduction in MMDs, which is the responder rate most closely linked to a drop in disability. That rate at 52 weeks was 42% at 140 mg and 27% at 70 mg,” the neurologist continued.
At week 52, 12.7% of patients on erenumab at 140 mg monthly had no migraines at all during the previous month.
The mean number of acute migraine-specific medication days per month decreased by about 4 days in the erenumab group during the 12-week, double-blind trial and continued to fall during the open-label extension study, with a mean reduction from baseline of 6.7 days at week 52.
“That’s clearly sustained efficacy, and it looks like some accumulating efficacy,” Dr. Tepper said.
Safety and tolerability continued to be excellent, as in the parent 12-week study.
“One of the very interesting findings we saw which differentiates erenumab from, say, onabotulinumtoxinA, is that if you looked at the patients who were on placebo during the 12 weeks of the double-blind study and then looked at the first month they went on erenumab, they caught up immediately to the patients who’d been receiving the monoclonal antibody from the beginning. That’s unlike onabotulinumtoxinA in the regulatory trials, where the patients who initially received placebo never quite caught up to those who received active therapy from the beginning,” he said.
Dr. Tepper emphasized that a clear-eyed view of an open-label study needs to recognize that only responders would have stayed in the erenumab study for a full 52 weeks, so the results paint an overly rosy picture of overall efficacy. Even so, he found the results impressive. Of 609 patients who enrolled in the study, 74% completed it.
“It’s a very encouraging 1-year study for erenumab,” he concluded.
Safety and tolerability for episodic migraine at 3-plus years
Among 383 episodic migraine patients who enrolled in an ongoing 5-year, open-label extension study of erenumab after completing a 12-week, placebo-controlled, double-blind clinical trial, there have been no new safety signals at a mean 3.2 years of follow-up. The incidence rates and types of adverse events remain indistinguishable from placebo as noted in the parent 12-week double-blind trial, with the exception of an increased rate of mild injection site reactions, reported Daniel D. Mikol, MD, PhD, executive medical director for global neuroscience development at Amgen in Thousand Oaks, Calif.
Erenumab proves effective in patients who have failed multiple preventive therapies
Jan Klatt, MD, presented the results of the 12-week, double-blind portion of the phase 3b LIBERTY study, the first clinical trial specifically designed to assess the effects of CGRP-directed therapy in patients who have previously failed to respond to and/or tolerate two to four currently available preventive medications at adequate doses for at least 2-3 months.
The rationale for the trial was straightforward: “There is a particularly high unmet need in patients who have failed currently available preventive therapies, and who are usually considered difficult to treat,” explained Dr. Klatt of Novartis in Basel, Switzerland.
LIBERTY included 246 such patients with episodic migraine who were randomized to 12 weeks of erenumab at 140 mg monthly or placebo. The primary endpoint – the proportion of patients with at least a 50% reduction in MMDs during weeks 9-12 from the baseline of 9.3 – occurred in 30.3% of the erenumab group, significantly better than the 13.7% rate with placebo, with an adjusted odds ratio of 2.73 for success with erenumab. An open-label extension study is ongoing.
A clear separation was already evident at week 4 of the randomized trial, a prespecified secondary endpoint. A 50% or greater reduction in MMDs was seen at that point in 23.5% of the erenumab group versus 4.8% in placebo-treated controls, for a response odds ratio of 6.16. A 75% or greater reduction in MMDs during weeks 9-12 occurred in 11.8% of the erenumab group and 4% of controls. A 100% response rate – that is, no migraines during weeks 9-12 – occurred in 5.9% of the active treatment arm and none of the controls. Outcomes on two novel patient-reported outcomes – the Migraine Physical Function Impact Diary–physical impairment and –everyday activities subscales – were also significantly better in the active treatment arm.
Treatment outcomes with erenumab were similar regardless of which drug classes patients had previously failed on, the three most common of which were beta-blockers, topiramate, and amitriptyline, which is approved for migraine prevention in Europe, where the LIBERTY trial was conducted.
One audience member observed that the 13.7% primary endpoint placebo response rate was far lower than typically seen in double-blind migraine trials.
“This is something we see quite consistently,” Dr. Klatt replied. “Once you proceed to this kind of more difficult-to-treat population, your placebo response rates drop to really low levels. It’s probably due to the fact that those patients have low expectations for any new therapy.”
Erenumab quells acute migraine medication overuse
Dr. Tepper presented a separate analysis of the 52-week, open-label extension study of erenumab, this time comparing outcomes in 252 chronic migraine patients who met criteria for acute medication overuse (AMO) at baseline and 357 who did not. Overuse was defined via International Headache Society criteria: The use of triptans, ergots, or combination analgesics on 10 or more days per month, or simple analgesics on at least 15 days monthly. Combination analgesics feature a simple analgesic plus opiates or butalbital.
“The bottom line here is that the drug worked about the same and in a very encouraging way in the AMO and nonoveruse patients,” he said. “This is obviously something that’s very, very important to us because we’d like to take our patients who are overusing acute migraine medications and use the monoclonal antibody as a way of getting them off overuse and into episodic migraine.”
After 52 weeks of open-label erenumab, 61% of the non-AMO group and 56% of those with baseline AMO had at least a 50% reduction from baseline in MMDs. The use of acute migraine-specific medications fell by 3.7 days in the non-AMO group and by 6.7 days in those with AMO at baseline.
Safety in patients with stable angina
Although no signal of any cardiovascular issues arose in four randomized, double-blind clinical trials or in the long-term extension studies, it was appropriate to take a more focused look at erenumab’s effects in a high-risk population with stable angina and proven ischemic coronary artery disease. That’s because CGRP is a neuropeptide that not only affects migraine, it also acts as a cytoprotective mediator released by cardiac nerve fibers during myocardial ischemia. Thus, erenumab posed a theoretic cardiovascular risk, explained Christophe Depre, MD, PhD, of Amgen.
He presented a 12-week, randomized, double-blind study in which 89 patients with stable angina were assigned to a single IV infusion of 140 mg of erenumab or placebo followed by an exercise treadmill test. Reassuringly, the CGRP inhibitor had no adverse effect on exercise time, time to onset of at least 1 mm of ST segment depression. Nor did it affect heart rate or blood pressure during or after exercise.
Dr. Tepper reported serving as a consultant to numerous pharmaceutical and medical device companies, including Amgen and Novartis, which sponsored the erenumab studies. Dr. Depre and Dr. Mikol are Amgen employees, while Dr. Klatt is employed by Novartis.
SAN FRANCISCO – Now that erenumab has won approval as the first-in-class calcitonin gene-related peptide inhibitor for prevention of episodic and chronic migraine, a flurry of new studies shedding light on how the drug might best be used in clinical practice emerged as a highlight of the annual meeting of the American Headache Society.
Erenumab (Aimovig) is a fully human monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. It was approved by the Food and Drug Administration at 140 and 70 mg monthly by subcutaneous injection on the strength of the required 12-week, double-blind, placebo-controlled clinical trial data. Among the fresh data presented at the headache meeting was reassuring evidence of the monoclonal antibody’s continued high degree of safety and tolerability for episodic migraine after more than 3 years of therapy, as well as a suggestion that the biologic’s efficacy for chronic migraine was not only sustained but actually increased over the course of a 1-year study.
Also, erenumab appears to be a novel treatment option for patients who have previously failed adequate trials of two to four standard preventive therapies. In addition, it has now demonstrated efficacy in reducing overuse of acute migraine drugs such as triptans, ergots, and opioids.
Here are the highlights:
One-year safety and efficacy for chronic migraine
Stewart J. Tepper, MD, presented results of a 1-year, open-label extension study that began after participants completed a pivotal 12-week, placebo-controlled, double-blind, randomized trial whose findings have been published (Lancet Neurol. 2017 Jun;16[6]:425-34). At the end of the 12-week, double-blind period, the mean number of monthly migraine days (MMD) in the erenumab group had dropped by 6.6 days from 18.1 at baseline. Subsequently, after 52 weeks of open-label erenumab at 140 mg monthly, that figure had further improved to 10.5 fewer MMDs than at baseline.
“That’s encouraging for our patients in that we will be able to tell them that if you’re a responder, you’re likely to show some continued improvement over time,” observed Dr. Tepper, professor of neurology and director of the headache clinic at Dartmouth University in Hanover, N.H.
During 527 patient-years of open-label therapy, at least a 50% reduction in MMDs was achieved by 67% of patients in the 140-mg group and 53% in the 70-mg group.
“I think it’s also important to look at the rate of 75% or greater reduction in MMDs, which is the responder rate most closely linked to a drop in disability. That rate at 52 weeks was 42% at 140 mg and 27% at 70 mg,” the neurologist continued.
At week 52, 12.7% of patients on erenumab at 140 mg monthly had no migraines at all during the previous month.
The mean number of acute migraine-specific medication days per month decreased by about 4 days in the erenumab group during the 12-week, double-blind trial and continued to fall during the open-label extension study, with a mean reduction from baseline of 6.7 days at week 52.
“That’s clearly sustained efficacy, and it looks like some accumulating efficacy,” Dr. Tepper said.
Safety and tolerability continued to be excellent, as in the parent 12-week study.
“One of the very interesting findings we saw which differentiates erenumab from, say, onabotulinumtoxinA, is that if you looked at the patients who were on placebo during the 12 weeks of the double-blind study and then looked at the first month they went on erenumab, they caught up immediately to the patients who’d been receiving the monoclonal antibody from the beginning. That’s unlike onabotulinumtoxinA in the regulatory trials, where the patients who initially received placebo never quite caught up to those who received active therapy from the beginning,” he said.
Dr. Tepper emphasized that a clear-eyed view of an open-label study needs to recognize that only responders would have stayed in the erenumab study for a full 52 weeks, so the results paint an overly rosy picture of overall efficacy. Even so, he found the results impressive. Of 609 patients who enrolled in the study, 74% completed it.
“It’s a very encouraging 1-year study for erenumab,” he concluded.
Safety and tolerability for episodic migraine at 3-plus years
Among 383 episodic migraine patients who enrolled in an ongoing 5-year, open-label extension study of erenumab after completing a 12-week, placebo-controlled, double-blind clinical trial, there have been no new safety signals at a mean 3.2 years of follow-up. The incidence rates and types of adverse events remain indistinguishable from placebo as noted in the parent 12-week double-blind trial, with the exception of an increased rate of mild injection site reactions, reported Daniel D. Mikol, MD, PhD, executive medical director for global neuroscience development at Amgen in Thousand Oaks, Calif.
Erenumab proves effective in patients who have failed multiple preventive therapies
Jan Klatt, MD, presented the results of the 12-week, double-blind portion of the phase 3b LIBERTY study, the first clinical trial specifically designed to assess the effects of CGRP-directed therapy in patients who have previously failed to respond to and/or tolerate two to four currently available preventive medications at adequate doses for at least 2-3 months.
The rationale for the trial was straightforward: “There is a particularly high unmet need in patients who have failed currently available preventive therapies, and who are usually considered difficult to treat,” explained Dr. Klatt of Novartis in Basel, Switzerland.
LIBERTY included 246 such patients with episodic migraine who were randomized to 12 weeks of erenumab at 140 mg monthly or placebo. The primary endpoint – the proportion of patients with at least a 50% reduction in MMDs during weeks 9-12 from the baseline of 9.3 – occurred in 30.3% of the erenumab group, significantly better than the 13.7% rate with placebo, with an adjusted odds ratio of 2.73 for success with erenumab. An open-label extension study is ongoing.
A clear separation was already evident at week 4 of the randomized trial, a prespecified secondary endpoint. A 50% or greater reduction in MMDs was seen at that point in 23.5% of the erenumab group versus 4.8% in placebo-treated controls, for a response odds ratio of 6.16. A 75% or greater reduction in MMDs during weeks 9-12 occurred in 11.8% of the erenumab group and 4% of controls. A 100% response rate – that is, no migraines during weeks 9-12 – occurred in 5.9% of the active treatment arm and none of the controls. Outcomes on two novel patient-reported outcomes – the Migraine Physical Function Impact Diary–physical impairment and –everyday activities subscales – were also significantly better in the active treatment arm.
Treatment outcomes with erenumab were similar regardless of which drug classes patients had previously failed on, the three most common of which were beta-blockers, topiramate, and amitriptyline, which is approved for migraine prevention in Europe, where the LIBERTY trial was conducted.
One audience member observed that the 13.7% primary endpoint placebo response rate was far lower than typically seen in double-blind migraine trials.
“This is something we see quite consistently,” Dr. Klatt replied. “Once you proceed to this kind of more difficult-to-treat population, your placebo response rates drop to really low levels. It’s probably due to the fact that those patients have low expectations for any new therapy.”
Erenumab quells acute migraine medication overuse
Dr. Tepper presented a separate analysis of the 52-week, open-label extension study of erenumab, this time comparing outcomes in 252 chronic migraine patients who met criteria for acute medication overuse (AMO) at baseline and 357 who did not. Overuse was defined via International Headache Society criteria: The use of triptans, ergots, or combination analgesics on 10 or more days per month, or simple analgesics on at least 15 days monthly. Combination analgesics feature a simple analgesic plus opiates or butalbital.
“The bottom line here is that the drug worked about the same and in a very encouraging way in the AMO and nonoveruse patients,” he said. “This is obviously something that’s very, very important to us because we’d like to take our patients who are overusing acute migraine medications and use the monoclonal antibody as a way of getting them off overuse and into episodic migraine.”
After 52 weeks of open-label erenumab, 61% of the non-AMO group and 56% of those with baseline AMO had at least a 50% reduction from baseline in MMDs. The use of acute migraine-specific medications fell by 3.7 days in the non-AMO group and by 6.7 days in those with AMO at baseline.
Safety in patients with stable angina
Although no signal of any cardiovascular issues arose in four randomized, double-blind clinical trials or in the long-term extension studies, it was appropriate to take a more focused look at erenumab’s effects in a high-risk population with stable angina and proven ischemic coronary artery disease. That’s because CGRP is a neuropeptide that not only affects migraine, it also acts as a cytoprotective mediator released by cardiac nerve fibers during myocardial ischemia. Thus, erenumab posed a theoretic cardiovascular risk, explained Christophe Depre, MD, PhD, of Amgen.
He presented a 12-week, randomized, double-blind study in which 89 patients with stable angina were assigned to a single IV infusion of 140 mg of erenumab or placebo followed by an exercise treadmill test. Reassuringly, the CGRP inhibitor had no adverse effect on exercise time, time to onset of at least 1 mm of ST segment depression. Nor did it affect heart rate or blood pressure during or after exercise.
Dr. Tepper reported serving as a consultant to numerous pharmaceutical and medical device companies, including Amgen and Novartis, which sponsored the erenumab studies. Dr. Depre and Dr. Mikol are Amgen employees, while Dr. Klatt is employed by Novartis.
SAN FRANCISCO – Now that erenumab has won approval as the first-in-class calcitonin gene-related peptide inhibitor for prevention of episodic and chronic migraine, a flurry of new studies shedding light on how the drug might best be used in clinical practice emerged as a highlight of the annual meeting of the American Headache Society.
Erenumab (Aimovig) is a fully human monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. It was approved by the Food and Drug Administration at 140 and 70 mg monthly by subcutaneous injection on the strength of the required 12-week, double-blind, placebo-controlled clinical trial data. Among the fresh data presented at the headache meeting was reassuring evidence of the monoclonal antibody’s continued high degree of safety and tolerability for episodic migraine after more than 3 years of therapy, as well as a suggestion that the biologic’s efficacy for chronic migraine was not only sustained but actually increased over the course of a 1-year study.
Also, erenumab appears to be a novel treatment option for patients who have previously failed adequate trials of two to four standard preventive therapies. In addition, it has now demonstrated efficacy in reducing overuse of acute migraine drugs such as triptans, ergots, and opioids.
Here are the highlights:
One-year safety and efficacy for chronic migraine
Stewart J. Tepper, MD, presented results of a 1-year, open-label extension study that began after participants completed a pivotal 12-week, placebo-controlled, double-blind, randomized trial whose findings have been published (Lancet Neurol. 2017 Jun;16[6]:425-34). At the end of the 12-week, double-blind period, the mean number of monthly migraine days (MMD) in the erenumab group had dropped by 6.6 days from 18.1 at baseline. Subsequently, after 52 weeks of open-label erenumab at 140 mg monthly, that figure had further improved to 10.5 fewer MMDs than at baseline.
“That’s encouraging for our patients in that we will be able to tell them that if you’re a responder, you’re likely to show some continued improvement over time,” observed Dr. Tepper, professor of neurology and director of the headache clinic at Dartmouth University in Hanover, N.H.
During 527 patient-years of open-label therapy, at least a 50% reduction in MMDs was achieved by 67% of patients in the 140-mg group and 53% in the 70-mg group.
“I think it’s also important to look at the rate of 75% or greater reduction in MMDs, which is the responder rate most closely linked to a drop in disability. That rate at 52 weeks was 42% at 140 mg and 27% at 70 mg,” the neurologist continued.
At week 52, 12.7% of patients on erenumab at 140 mg monthly had no migraines at all during the previous month.
The mean number of acute migraine-specific medication days per month decreased by about 4 days in the erenumab group during the 12-week, double-blind trial and continued to fall during the open-label extension study, with a mean reduction from baseline of 6.7 days at week 52.
“That’s clearly sustained efficacy, and it looks like some accumulating efficacy,” Dr. Tepper said.
Safety and tolerability continued to be excellent, as in the parent 12-week study.
“One of the very interesting findings we saw which differentiates erenumab from, say, onabotulinumtoxinA, is that if you looked at the patients who were on placebo during the 12 weeks of the double-blind study and then looked at the first month they went on erenumab, they caught up immediately to the patients who’d been receiving the monoclonal antibody from the beginning. That’s unlike onabotulinumtoxinA in the regulatory trials, where the patients who initially received placebo never quite caught up to those who received active therapy from the beginning,” he said.
Dr. Tepper emphasized that a clear-eyed view of an open-label study needs to recognize that only responders would have stayed in the erenumab study for a full 52 weeks, so the results paint an overly rosy picture of overall efficacy. Even so, he found the results impressive. Of 609 patients who enrolled in the study, 74% completed it.
“It’s a very encouraging 1-year study for erenumab,” he concluded.
Safety and tolerability for episodic migraine at 3-plus years
Among 383 episodic migraine patients who enrolled in an ongoing 5-year, open-label extension study of erenumab after completing a 12-week, placebo-controlled, double-blind clinical trial, there have been no new safety signals at a mean 3.2 years of follow-up. The incidence rates and types of adverse events remain indistinguishable from placebo as noted in the parent 12-week double-blind trial, with the exception of an increased rate of mild injection site reactions, reported Daniel D. Mikol, MD, PhD, executive medical director for global neuroscience development at Amgen in Thousand Oaks, Calif.
Erenumab proves effective in patients who have failed multiple preventive therapies
Jan Klatt, MD, presented the results of the 12-week, double-blind portion of the phase 3b LIBERTY study, the first clinical trial specifically designed to assess the effects of CGRP-directed therapy in patients who have previously failed to respond to and/or tolerate two to four currently available preventive medications at adequate doses for at least 2-3 months.
The rationale for the trial was straightforward: “There is a particularly high unmet need in patients who have failed currently available preventive therapies, and who are usually considered difficult to treat,” explained Dr. Klatt of Novartis in Basel, Switzerland.
LIBERTY included 246 such patients with episodic migraine who were randomized to 12 weeks of erenumab at 140 mg monthly or placebo. The primary endpoint – the proportion of patients with at least a 50% reduction in MMDs during weeks 9-12 from the baseline of 9.3 – occurred in 30.3% of the erenumab group, significantly better than the 13.7% rate with placebo, with an adjusted odds ratio of 2.73 for success with erenumab. An open-label extension study is ongoing.
A clear separation was already evident at week 4 of the randomized trial, a prespecified secondary endpoint. A 50% or greater reduction in MMDs was seen at that point in 23.5% of the erenumab group versus 4.8% in placebo-treated controls, for a response odds ratio of 6.16. A 75% or greater reduction in MMDs during weeks 9-12 occurred in 11.8% of the erenumab group and 4% of controls. A 100% response rate – that is, no migraines during weeks 9-12 – occurred in 5.9% of the active treatment arm and none of the controls. Outcomes on two novel patient-reported outcomes – the Migraine Physical Function Impact Diary–physical impairment and –everyday activities subscales – were also significantly better in the active treatment arm.
Treatment outcomes with erenumab were similar regardless of which drug classes patients had previously failed on, the three most common of which were beta-blockers, topiramate, and amitriptyline, which is approved for migraine prevention in Europe, where the LIBERTY trial was conducted.
One audience member observed that the 13.7% primary endpoint placebo response rate was far lower than typically seen in double-blind migraine trials.
“This is something we see quite consistently,” Dr. Klatt replied. “Once you proceed to this kind of more difficult-to-treat population, your placebo response rates drop to really low levels. It’s probably due to the fact that those patients have low expectations for any new therapy.”
Erenumab quells acute migraine medication overuse
Dr. Tepper presented a separate analysis of the 52-week, open-label extension study of erenumab, this time comparing outcomes in 252 chronic migraine patients who met criteria for acute medication overuse (AMO) at baseline and 357 who did not. Overuse was defined via International Headache Society criteria: The use of triptans, ergots, or combination analgesics on 10 or more days per month, or simple analgesics on at least 15 days monthly. Combination analgesics feature a simple analgesic plus opiates or butalbital.
“The bottom line here is that the drug worked about the same and in a very encouraging way in the AMO and nonoveruse patients,” he said. “This is obviously something that’s very, very important to us because we’d like to take our patients who are overusing acute migraine medications and use the monoclonal antibody as a way of getting them off overuse and into episodic migraine.”
After 52 weeks of open-label erenumab, 61% of the non-AMO group and 56% of those with baseline AMO had at least a 50% reduction from baseline in MMDs. The use of acute migraine-specific medications fell by 3.7 days in the non-AMO group and by 6.7 days in those with AMO at baseline.
Safety in patients with stable angina
Although no signal of any cardiovascular issues arose in four randomized, double-blind clinical trials or in the long-term extension studies, it was appropriate to take a more focused look at erenumab’s effects in a high-risk population with stable angina and proven ischemic coronary artery disease. That’s because CGRP is a neuropeptide that not only affects migraine, it also acts as a cytoprotective mediator released by cardiac nerve fibers during myocardial ischemia. Thus, erenumab posed a theoretic cardiovascular risk, explained Christophe Depre, MD, PhD, of Amgen.
He presented a 12-week, randomized, double-blind study in which 89 patients with stable angina were assigned to a single IV infusion of 140 mg of erenumab or placebo followed by an exercise treadmill test. Reassuringly, the CGRP inhibitor had no adverse effect on exercise time, time to onset of at least 1 mm of ST segment depression. Nor did it affect heart rate or blood pressure during or after exercise.
Dr. Tepper reported serving as a consultant to numerous pharmaceutical and medical device companies, including Amgen and Novartis, which sponsored the erenumab studies. Dr. Depre and Dr. Mikol are Amgen employees, while Dr. Klatt is employed by Novartis.
REPORTING FROM THE AHS ANNUAL MEETING
Opioid crisis brings bonanza for headache research
SAN FRANCISCO – Congressional funding of the National Institutes of Health’s HEAL Initiative represents an unprecedented golden opportunity for research funding on headache and other pain conditions, according to Michael L. Oshinsky, PhD, a neurobiologist who serves as program director for pain and migraine at the National Institute of Neurological Disorders and Stroke (NINDS).
“This is a once-in-a-lifetime opportunity for physician researchers and basic science researchers to identify projects and request funding from NIH. This is an amount of money that doesn’t come along very often. It’s really a once in a lifetime situation, and I implore you to take advantage of this tremendous opportunity,” he urged attendees at the annual meeting of the American Headache Society.
Congress gave the NIH $500 million for the HEAL (Helping to End Addiction Long-term) Initiative to be spent over the course of fiscal years 2018 and 2019. The money is to be split equally on the initiative’s two components: opioid use disorder and pain management.
“We’re going to spend $250 million on pain, be sure of it,” Dr. Oshinsky promised.
Pain management issues cut across all 27 NIH institutes and centers. However, the biggest chunk of the money goes to NINDS, which leads the NIH Pain Consortium, charged with enhancing pain research and promoting collaboration across NIH.
Within NINDS, funding for migraine research has been formally designated as an HPP, or high program priority, according to Dr. Oshinsky.
“Headache research gets funded. It really does. I want to dispel the myth that there isn’t an interest in headache research or migraine research at NIH. Currently, at NINDS, we have more than 60 funded projects that specifically address scientific questions about migraine and headache. That’s more than any other government in the world,” he said.
And it’s not all basic science research related to headache that NINDS is interested in fostering, either. The institute is eager to fund large clinical trials, pediatric headache research, studies of device therapies, and a wealth of other projects.
Among the HEAL initiatives that have already been approved is a project aimed at identifying and validating new pain targets. Another is focused upon finding risk factors with clinically meaningful predictive value for transition from acute to chronic pain, be they biomarkers, imaging findings, or genetic characteristics. Yet another program is an NIH-industry collaboration that aims to identify new treatments for pain that are nonaddictive, nonrewarding, nonsedating, and safe across age groups; candidate biologics, small molecules, devices, and natural products will be screened in vitro and in animal models, with the successful ones moving on to clinical trials.
Funding opportunity announcements are imminent for creation of a planned NIH clinical trials network for pain research, which will conduct phase 2 trials in specialized pain centers. The focus will be on well-characterized pain conditions with high unmet medical need, including headache as well as orofacial, pelvic, gastrointestinal, and cancer pain.
Dr. Oshinsky encouraged academicians to have their fellows apply for the NIH early career development awards known as K awards.
“They are much easier to get than R01 awards and they provide a tremendous opportunity for jump-starting the career of new scientists in the headache field. Have them reach out to me. I can help them through the process, help them develop their project, and get them funded with a K award. And the transition from a K award to an R01 is a much smoother transition,” he said.
Research funding proposals should use the NINDS Common Data Elements for headache, recently updated by more than 40 experts in headache medicine and research.
Dr. Oshinsky said most of the new pain management programs will be funded in fiscal year 2019. These novel programs have to be approved by oversight committees, and that takes time. The reason that the bulk of HEAL Initiative funding in fiscal year 2018 is going for opioid use disorder is that much of that money is being spent on expansion of existing programs, which can quickly be ramped up without the same degree of oversight required for new programs.
SAN FRANCISCO – Congressional funding of the National Institutes of Health’s HEAL Initiative represents an unprecedented golden opportunity for research funding on headache and other pain conditions, according to Michael L. Oshinsky, PhD, a neurobiologist who serves as program director for pain and migraine at the National Institute of Neurological Disorders and Stroke (NINDS).
“This is a once-in-a-lifetime opportunity for physician researchers and basic science researchers to identify projects and request funding from NIH. This is an amount of money that doesn’t come along very often. It’s really a once in a lifetime situation, and I implore you to take advantage of this tremendous opportunity,” he urged attendees at the annual meeting of the American Headache Society.
Congress gave the NIH $500 million for the HEAL (Helping to End Addiction Long-term) Initiative to be spent over the course of fiscal years 2018 and 2019. The money is to be split equally on the initiative’s two components: opioid use disorder and pain management.
“We’re going to spend $250 million on pain, be sure of it,” Dr. Oshinsky promised.
Pain management issues cut across all 27 NIH institutes and centers. However, the biggest chunk of the money goes to NINDS, which leads the NIH Pain Consortium, charged with enhancing pain research and promoting collaboration across NIH.
Within NINDS, funding for migraine research has been formally designated as an HPP, or high program priority, according to Dr. Oshinsky.
“Headache research gets funded. It really does. I want to dispel the myth that there isn’t an interest in headache research or migraine research at NIH. Currently, at NINDS, we have more than 60 funded projects that specifically address scientific questions about migraine and headache. That’s more than any other government in the world,” he said.
And it’s not all basic science research related to headache that NINDS is interested in fostering, either. The institute is eager to fund large clinical trials, pediatric headache research, studies of device therapies, and a wealth of other projects.
Among the HEAL initiatives that have already been approved is a project aimed at identifying and validating new pain targets. Another is focused upon finding risk factors with clinically meaningful predictive value for transition from acute to chronic pain, be they biomarkers, imaging findings, or genetic characteristics. Yet another program is an NIH-industry collaboration that aims to identify new treatments for pain that are nonaddictive, nonrewarding, nonsedating, and safe across age groups; candidate biologics, small molecules, devices, and natural products will be screened in vitro and in animal models, with the successful ones moving on to clinical trials.
Funding opportunity announcements are imminent for creation of a planned NIH clinical trials network for pain research, which will conduct phase 2 trials in specialized pain centers. The focus will be on well-characterized pain conditions with high unmet medical need, including headache as well as orofacial, pelvic, gastrointestinal, and cancer pain.
Dr. Oshinsky encouraged academicians to have their fellows apply for the NIH early career development awards known as K awards.
“They are much easier to get than R01 awards and they provide a tremendous opportunity for jump-starting the career of new scientists in the headache field. Have them reach out to me. I can help them through the process, help them develop their project, and get them funded with a K award. And the transition from a K award to an R01 is a much smoother transition,” he said.
Research funding proposals should use the NINDS Common Data Elements for headache, recently updated by more than 40 experts in headache medicine and research.
Dr. Oshinsky said most of the new pain management programs will be funded in fiscal year 2019. These novel programs have to be approved by oversight committees, and that takes time. The reason that the bulk of HEAL Initiative funding in fiscal year 2018 is going for opioid use disorder is that much of that money is being spent on expansion of existing programs, which can quickly be ramped up without the same degree of oversight required for new programs.
SAN FRANCISCO – Congressional funding of the National Institutes of Health’s HEAL Initiative represents an unprecedented golden opportunity for research funding on headache and other pain conditions, according to Michael L. Oshinsky, PhD, a neurobiologist who serves as program director for pain and migraine at the National Institute of Neurological Disorders and Stroke (NINDS).
“This is a once-in-a-lifetime opportunity for physician researchers and basic science researchers to identify projects and request funding from NIH. This is an amount of money that doesn’t come along very often. It’s really a once in a lifetime situation, and I implore you to take advantage of this tremendous opportunity,” he urged attendees at the annual meeting of the American Headache Society.
Congress gave the NIH $500 million for the HEAL (Helping to End Addiction Long-term) Initiative to be spent over the course of fiscal years 2018 and 2019. The money is to be split equally on the initiative’s two components: opioid use disorder and pain management.
“We’re going to spend $250 million on pain, be sure of it,” Dr. Oshinsky promised.
Pain management issues cut across all 27 NIH institutes and centers. However, the biggest chunk of the money goes to NINDS, which leads the NIH Pain Consortium, charged with enhancing pain research and promoting collaboration across NIH.
Within NINDS, funding for migraine research has been formally designated as an HPP, or high program priority, according to Dr. Oshinsky.
“Headache research gets funded. It really does. I want to dispel the myth that there isn’t an interest in headache research or migraine research at NIH. Currently, at NINDS, we have more than 60 funded projects that specifically address scientific questions about migraine and headache. That’s more than any other government in the world,” he said.
And it’s not all basic science research related to headache that NINDS is interested in fostering, either. The institute is eager to fund large clinical trials, pediatric headache research, studies of device therapies, and a wealth of other projects.
Among the HEAL initiatives that have already been approved is a project aimed at identifying and validating new pain targets. Another is focused upon finding risk factors with clinically meaningful predictive value for transition from acute to chronic pain, be they biomarkers, imaging findings, or genetic characteristics. Yet another program is an NIH-industry collaboration that aims to identify new treatments for pain that are nonaddictive, nonrewarding, nonsedating, and safe across age groups; candidate biologics, small molecules, devices, and natural products will be screened in vitro and in animal models, with the successful ones moving on to clinical trials.
Funding opportunity announcements are imminent for creation of a planned NIH clinical trials network for pain research, which will conduct phase 2 trials in specialized pain centers. The focus will be on well-characterized pain conditions with high unmet medical need, including headache as well as orofacial, pelvic, gastrointestinal, and cancer pain.
Dr. Oshinsky encouraged academicians to have their fellows apply for the NIH early career development awards known as K awards.
“They are much easier to get than R01 awards and they provide a tremendous opportunity for jump-starting the career of new scientists in the headache field. Have them reach out to me. I can help them through the process, help them develop their project, and get them funded with a K award. And the transition from a K award to an R01 is a much smoother transition,” he said.
Research funding proposals should use the NINDS Common Data Elements for headache, recently updated by more than 40 experts in headache medicine and research.
Dr. Oshinsky said most of the new pain management programs will be funded in fiscal year 2019. These novel programs have to be approved by oversight committees, and that takes time. The reason that the bulk of HEAL Initiative funding in fiscal year 2018 is going for opioid use disorder is that much of that money is being spent on expansion of existing programs, which can quickly be ramped up without the same degree of oversight required for new programs.
REPORTING FROM THE AHS ANNUAL MEETING