Headache & Migraine

Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.

For practicing neurologists today, headache is one subspecialty in which options and opportunities abound. But this is largely thanks to the sea change that occurred 30 years ago.

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.

After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.

But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
 

The early years

Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.

On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”

DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.

“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.

“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.

Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
 

The triptan era

Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)

Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.

Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
 

Medication overuse headache

The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.

Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.

Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”

Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
 

The next revolution: CGRP and gepants

Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.

In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”

The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.

Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.

In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
 

Headache treatment today

Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.

Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.

“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”

Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.

“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”

Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.

*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.

Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.

For practicing neurologists today, headache is one subspecialty in which options and opportunities abound. But this is largely thanks to the sea change that occurred 30 years ago.

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.

After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.

But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
 

The early years

Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.

On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”

DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.

“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.

“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.

Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
 

The triptan era

Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)

Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.

Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
 

Medication overuse headache

The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.

Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.

Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”

Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
 

The next revolution: CGRP and gepants

Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.

In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”

The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.

Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.

In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
 

Headache treatment today

Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.

Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.

“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”

Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.

“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”

Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.

*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.

Headache treatment before the early 1990s was marked by decades of improvisation with mostly unapproved agents, followed by an explosion of scientific interest and new treatments developed specifically for migraine.

For practicing neurologists today, headache is one subspecialty in which options and opportunities abound. But this is largely thanks to the sea change that occurred 30 years ago.

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, past president of the International Headache Society and clinical professor of neurology at UCLA’s David Geffen School of Medicine in Los Angeles, recalled what it was like to treat patients before and after triptan medications came onto the market.

After the first of these anti-migraine agents, sumatriptan, was approved by the Food and Drug Administration in late December 1992, headache specialists found themselves with a powerful, approved treatment that validated their commitment to solving the disorder, and helped put to rest a persistent but mistaken notion that migraine was a psychiatric condition affecting young women.

But in the 1970s and 1980s, “there wasn’t great science explaining the pathophysiology of common primary headaches like tension-type headache, cluster headache, and migraine,” Dr. Rapoport recalled. “There is often comorbid depression and anxiety with migraine, and sometimes more serious psychiatric disease, but it doesn’t mean migraine is caused by psychological issues. Now we see it clearly as a disease of the brain, but it took years of investigation to prove that.”
 

The early years

Dr. Rapoport’s journey with headache began in 1972, when he joined a private neurology practice in Stamford and Greenwich, Conn. Neurologists were frowned upon then for having too much interest in headache, he said. There was poor remuneration for doctors treating headache patients, who were hard to properly diagnose and effectively care for. Few medications could effectively stop a migraine attack or reliably reduce the frequency of headaches or the disability they caused.

On weekends Dr. Rapoport covered emergency departments and ICUs at three hospitals, where standard treatment for a migraine attack was injectable opiates. Not only did this treatment aggravate nausea, a common migraine symptom, “but it did not stop the migraine process.” Once the pain relief wore off, patients woke up with the same headache, Dr. Rapoport recalled. “The other drug that was available was ergotamine tartrate” – a fungal alkaloid used since medieval times to treat headache – “given sublingually. It helped the headache slightly but increased the nausea. DHE, or dihydroergotamine, was available only by injection and not used very much.”

DHE, a semi-synthetic molecule based on ergotamine, had FDA approval for migraine, but was complicated to administer. Like the opioids, it provoked vomiting when given intravenously, in patients already suffering migraine-induced nausea. But Dr. Rapoport, along with some of his colleagues, felt that there was a role for DHE for the most severe subtypes of patients, those with long histories of frequent migraines.

“We put people in the hospital and we gave them intravenous DHE. Eventually I got the idea to give it intramuscularly or subcutaneously in the emergency room or my office. When you give it that way, it doesn’t work as quickly but has fewer side effects.” Dr. Rapoport designed a cocktail by coadministering promethazine for nausea, and eventually added a steroid, dexamethasone. The triple shots worked on most patients experiencing severe daily or near-daily migraine attacks, Dr. Rapoport saw, and he began administering the drug combination at The New England Center for Headache in Stamford and Greenwich, Conn., which he opened with Dr. Fred D. Sheftell in 1979.

“The triple shots really worked,” Dr. Rapoport recalled. “There was no need to keep patients in the office or emergency room for intravenous therapy. The patients never called to complain or came back the next day,” he said, as often occurred with opioid treatment.

Dr. Rapoport had learned early in his residency, in the late 1960s, from Dr. David R. Coddon, a neurologist at Mount Sinai hospital in New York, that a tricyclic antidepressant, imipramine, could be helpful in some patients with frequent migraine attacks. As evidence trickled in that other antidepressants, beta-blockers, and antiepileptic drugs might have preventive properties, Dr. Rapoport and others prescribed them for certain patients. But of all the drugs in the headache specialists’ repertoire, few were approved for either treatment or prevention. “And this continued until the triptans,” Dr. Rapoport said.
 

The triptan era

Sumatriptan was developed by Glaxo for the acute treatment of migraine. The medication, first available only as self-administered subcutaneous injections, was originally designed to bind to vascular serotonin receptors to allow selective constriction of cranial vessels that dilate, causing pain, during a migraine attack. (Years later it was discovered that triptans also worked as anti-inflammatory agents that decreased the release of the neurotransmitter calcitonin gene-related peptide, or CGRP.)

Triptans “changed the world for migraine patients and for me,” Dr. Rapoport said. “I could now prescribe a medication that people could take at home to decrease or stop the migraine process in an hour or two.” The success of the triptans prompted pharmaceutical companies to search for new, more effective ways to treat migraine attacks, with better tolerability.

Seven different triptans were developed, some as injections or tablets and others as nasal sprays. “If one triptan didn’t work, we’d give a second and rarely a third,” Dr. Rapoport said. “We learned that if oral triptans did not work, the most likely issue was that it was not rapidly absorbed from the small intestine, as migraine patients have nausea, poor GI absorption, and slow transit times. This prompted the greater use of injections and nasal sprays.” Headache specialists began combining triptan treatment with nonsteroidal anti-inflammatory drugs, offering further relief for the acute care of migraine.
 

Medication overuse headache

The years between 1993 and 2000, which saw all the current triptan drugs come onto the market, was an exhilarating one for headache specialists. But even those who were thrilled by the possibilities of the triptans, like Dr. Rapoport, soon came to recognize their limitations, in terms of side effects and poor tolerability for some patients.

Specialists also noticed something unsettling about the triptans: that patients’ headaches seemed to recur within a day, or occur more frequently over time, with higher medication use.

Medication overuse headache (MOH) was known to occur when patients treated migraine too often with acute care medications, especially over-the-counter analgesics and prescription opioids and barbiturates. Dr. Rapoport began warning at conferences and in seminars that MOH seemed to occur with the triptans as well. “In the beginning other doctors didn’t think the triptans could cause MOH, but I observed that patients who were taking triptans daily or almost daily were having increased headache frequency and the triptans stopped being effective. If they didn’t take the drug they were overusing, they were going to get much worse, almost like a withdrawal.”

Today, all seven triptans are now generic, and they remain a mainstay of migraine treatment: “Almost all of my patients are using, or have used a triptan,” Dr. Rapoport said. Yet researchers came to recognize the need for treatments targeting different pathways, both for prevention and acute care.
 

The next revolution: CGRP and gepants

Studies in the early 2000s began to show a link between the release of one ubiquitous nervous system neurotransmitter, calcitonin gene-related peptide, or CGRP, and migraine. They also noticed that blocking meningeal inflammation could lead to improvement in headache. Two new drug classes emerged from this science: monoclonal antibodies against CGRP or its receptor that had to be given by injection, and oral CGRP receptor blockers that could be used both as a preventive or as an acute care medication.

In 2018 the first monoclonal antibody against the CGRP receptor, erenumab (Aimovig, marketed by Amgen), delivered by injection, was approved for migraine prevention. Three others followed, most given by autoinjector, and one by IV infusion in office or hospital settings. “Those drugs are great,” Dr. Rapoport said. “You take one shot a month or every 3 months, and your headaches drop by 50% or more with very few side effects. Some patients actually see their migraines disappear.”

The following year ubrogepant (Ubrelvy, marketed by AbbVie), the first of a novel class of oral CGRP receptor blockers known as “gepants,” was approved to treat acute migraine. The FDA soon approved another gepant, rimegepant (Nurtec, marketed by Pfizer), which received indications both for prevention and for stopping a migraine attack acutely.

Both classes of therapies – the antibodies and the gepants – are far costlier than the triptans, which are all generic, and may not be needed for every migraine patient. With the gepants, for example, insurers may restrict use to people who have not responded to triptans or for whom triptans are contraindicated or cause too many adverse events. But the CGRP-targeted therapies as a whole “have been every bit as revolutionary” as the triptans, Dr. Rapoport said. The treatments work quickly to resolve headache and disability and get the patient functioning within an hour or two, and there are fewer side effects.

In a review article published in CNS Drugs in 2021, Dr. Rapoport and his colleagues reported that the anti-CGRP treatment with gepants did not appear linked to medication overuse headache, as virtually all previous acute care medication classes did, and could be used in patients who had previously reported MOH. “I am confident that over the next few years, more people will be using them as insurance coverage will improve for patients living with migraine,” he said.
 

Headache treatment today

Migraine specialists and patients now have a staggering range of therapeutic options. Approved treatments now include prevention of migraine with onabotulinumtoxinA (Botox, marketed by the Allergan division of AbbVie) injections, which work alone and with other medicines; acute care treatment with ditans like lasmiditan (Reyvow, marketed by Lilly*), a category of acute care medicines that work like triptans but target different serotonin receptors. Five devices have been cleared for migraine and other types of headache by the FDA. These work alone or along with medication and can be used acutely or preventively. The devices “should be used more,” Dr. Rapoport said, but are not yet well covered by insurance.

Thirty years after the triptans, scientists and researchers continue to explore the pathophysiology of headache disorders, finding new pathways and identifying new potential targets.

“There are many parts of the brain and brain stem that are involved, as well as the thalamus and hypothalamus,” Dr. Rapoport said. “It’s interesting that the newer medications, and some of the older ones, work in the peripheral nervous system, outside the brain stem in the trigeminovascular system, to modulate the central nervous system. We also know that the CGRP system is involved with cellular second-order messengers. Stimulating and blocking this chain of reactions with newer drugs may become treatments in the future.”

Recent research has focused on a blood vessel dilating neurotransmitter, pituitary adenylate-cyclase-activating polypeptide, or PACAP-38, as a potential therapeutic target. Psychedelic medications such as psilocybin, strong pain medications such as ketamine, and even cannabinoids such as marijuana have all been investigated in migraine. Biofeedback therapies, mindfulness, and other behavioral interventions also have proved effective.

“I expect the next 2-5 years to bring us many important clinical trials on new types of pharmacological treatments,” Dr. Rapoport said. “This is a wonderful time to be a doctor or nurse treating patients living with migraine. When I started out treating headache, 51 years ago, we had only ergotamine tartrate. Today we have so many therapies and combinations of therapies that I hardly know where to start.”

Dr. Rapoport has served as a consultant to or speaker for AbbVie, Amgen, Biohaven, Cala Health, Lundbeck, Satsuma, and Teva, among others.

*Correction, 3/30/23: An earlier version of this article misstated the name of the company that markets Reyvow.

Children who experience migraine headaches in the aftermath of a concussion are more likely to experience prolonged symptoms of the head injury than are those with other forms of headache or no headaches at all, researchers have found.

“Early assessment of headache – and whether it has migraine features – after concussion can be helpful in predicting which children are at risk for poor outcomes and identifying children who require targeted intervention,” said senior author Keith Owen Yeates, PhD, the Ronald and Irene Ward Chair in Pediatric Brain Injury Professor and head of the department of psychology at the University of Calgary (Alta.). “Posttraumatic headache, especially when it involves migraine features, is a strong predictor of persisting symptoms and poorer quality of life after childhood concussion.”

Approximately 840,000 children per year visit an emergency department in the United States after having a traumatic brain injury. As many as 90% of those visits are considered to involve a concussion, according to the investigators. Although most children recover quickly, approximately one-third continue to report symptoms a month after the event.

Posttraumatic headache occurs in up to 90% of children, most commonly with features of migraine.

The new study, published in JAMA Network Open, was a secondary analysis of the Advancing Concussion Assessment in Pediatrics (A-CAP) prospective cohort study. The study was conducted at five emergency departments in Canada from September 2016 to July 2019 and included children and adolescents aged 8-17 years who presented with acute concussion or an orthopedic injury.

Children were included in the concussion group if they had a history of blunt head trauma resulting in at least one of three criteria consistent with the World Health Organization definition of mild traumatic brain injury. The criteria include loss of consciousness for less than 30 minutes, a Glasgow Coma Scale score of 13 or 14, or at least one acute sign or symptom of concussion, as noted by emergency clinicians.

Patients were excluded from the concussion group if they had deteriorating neurologic status, underwent neurosurgical intervention, had posttraumatic amnesia that lasted more than 24 hours, or had a score higher than 4 on the Abbreviated Injury Scale (AIS). The orthopedic injury group included patients without symptoms of concussion and with blunt trauma associated with an AIS 13 score of 4 or less. Patients were excluded from both groups if they had an overnight hospitalization for traumatic brain injury, a concussion within the past 3 months, or a neurodevelopmental disorder.

The researchers analyzed data from 928 children of 967 enrolled in the study. The median age was 12.2 years, and 41.3% were female. The final study cohort included 239 children with orthopedic injuries but no headache, 160 with a concussion and no headache, 134 with a concussion and nonmigraine headaches, and 254 with a concussion and migraine headaches.

Children with posttraumatic migraines 10 days after a concussion had the most severe symptoms and worst quality of life 3 months following their head trauma, the researchers found. Children without headaches within 10 days after concussion had the best 3-month outcomes, comparable to those with orthopedic injuries alone.

The researchers said the strengths of their study included its large population and its inclusion of various causes of head trauma, not just sports-related concussions. Limitations included self-reports of headaches instead of a physician diagnosis and lack of control for clinical interventions that might have affected the outcomes.

Charles Tator, MD, PhD, director of the Canadian Concussion Centre at Toronto Western Hospital, said the findings were unsurprising.

“Headaches are the most common symptom after concussion,” Dr. Tator, who was not involved in the latest research, told this news organization. “In my practice and research with concussed kids 11 and up and with adults, those with preconcussion history of migraine are the most difficult to treat because their headaches don’t improve unless specific measures are taken.”

Dr. Tator, who also is a professor of neurosurgery at the University of Toronto, said clinicians who treat concussions must determine which type of headaches children are experiencing – and refer as early as possible for migraine prevention or treatment and medication, as warranted.

“Early recognition after concussion that migraine headaches are occurring will save kids a lot of suffering,” he said.

The study was supported by a Canadian Institute of Health Research Foundation Grant and by funds from the Alberta Children’s Hospital Foundation and the Alberta Children’s Hospital Research Institute. Dr. Tator has disclosed no relevant financial relationships.
 

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

Children who experience migraine headaches in the aftermath of a concussion are more likely to experience prolonged symptoms of the head injury than are those with other forms of headache or no headaches at all, researchers have found.

“Early assessment of headache – and whether it has migraine features – after concussion can be helpful in predicting which children are at risk for poor outcomes and identifying children who require targeted intervention,” said senior author Keith Owen Yeates, PhD, the Ronald and Irene Ward Chair in Pediatric Brain Injury Professor and head of the department of psychology at the University of Calgary (Alta.). “Posttraumatic headache, especially when it involves migraine features, is a strong predictor of persisting symptoms and poorer quality of life after childhood concussion.”

Approximately 840,000 children per year visit an emergency department in the United States after having a traumatic brain injury. As many as 90% of those visits are considered to involve a concussion, according to the investigators. Although most children recover quickly, approximately one-third continue to report symptoms a month after the event.

Posttraumatic headache occurs in up to 90% of children, most commonly with features of migraine.

The new study, published in JAMA Network Open, was a secondary analysis of the Advancing Concussion Assessment in Pediatrics (A-CAP) prospective cohort study. The study was conducted at five emergency departments in Canada from September 2016 to July 2019 and included children and adolescents aged 8-17 years who presented with acute concussion or an orthopedic injury.

Children were included in the concussion group if they had a history of blunt head trauma resulting in at least one of three criteria consistent with the World Health Organization definition of mild traumatic brain injury. The criteria include loss of consciousness for less than 30 minutes, a Glasgow Coma Scale score of 13 or 14, or at least one acute sign or symptom of concussion, as noted by emergency clinicians.

Patients were excluded from the concussion group if they had deteriorating neurologic status, underwent neurosurgical intervention, had posttraumatic amnesia that lasted more than 24 hours, or had a score higher than 4 on the Abbreviated Injury Scale (AIS). The orthopedic injury group included patients without symptoms of concussion and with blunt trauma associated with an AIS 13 score of 4 or less. Patients were excluded from both groups if they had an overnight hospitalization for traumatic brain injury, a concussion within the past 3 months, or a neurodevelopmental disorder.

The researchers analyzed data from 928 children of 967 enrolled in the study. The median age was 12.2 years, and 41.3% were female. The final study cohort included 239 children with orthopedic injuries but no headache, 160 with a concussion and no headache, 134 with a concussion and nonmigraine headaches, and 254 with a concussion and migraine headaches.

Children with posttraumatic migraines 10 days after a concussion had the most severe symptoms and worst quality of life 3 months following their head trauma, the researchers found. Children without headaches within 10 days after concussion had the best 3-month outcomes, comparable to those with orthopedic injuries alone.

The researchers said the strengths of their study included its large population and its inclusion of various causes of head trauma, not just sports-related concussions. Limitations included self-reports of headaches instead of a physician diagnosis and lack of control for clinical interventions that might have affected the outcomes.

Charles Tator, MD, PhD, director of the Canadian Concussion Centre at Toronto Western Hospital, said the findings were unsurprising.

“Headaches are the most common symptom after concussion,” Dr. Tator, who was not involved in the latest research, told this news organization. “In my practice and research with concussed kids 11 and up and with adults, those with preconcussion history of migraine are the most difficult to treat because their headaches don’t improve unless specific measures are taken.”

Dr. Tator, who also is a professor of neurosurgery at the University of Toronto, said clinicians who treat concussions must determine which type of headaches children are experiencing – and refer as early as possible for migraine prevention or treatment and medication, as warranted.

“Early recognition after concussion that migraine headaches are occurring will save kids a lot of suffering,” he said.

The study was supported by a Canadian Institute of Health Research Foundation Grant and by funds from the Alberta Children’s Hospital Foundation and the Alberta Children’s Hospital Research Institute. Dr. Tator has disclosed no relevant financial relationships.
 

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

Children who experience migraine headaches in the aftermath of a concussion are more likely to experience prolonged symptoms of the head injury than are those with other forms of headache or no headaches at all, researchers have found.

“Early assessment of headache – and whether it has migraine features – after concussion can be helpful in predicting which children are at risk for poor outcomes and identifying children who require targeted intervention,” said senior author Keith Owen Yeates, PhD, the Ronald and Irene Ward Chair in Pediatric Brain Injury Professor and head of the department of psychology at the University of Calgary (Alta.). “Posttraumatic headache, especially when it involves migraine features, is a strong predictor of persisting symptoms and poorer quality of life after childhood concussion.”

Approximately 840,000 children per year visit an emergency department in the United States after having a traumatic brain injury. As many as 90% of those visits are considered to involve a concussion, according to the investigators. Although most children recover quickly, approximately one-third continue to report symptoms a month after the event.

Posttraumatic headache occurs in up to 90% of children, most commonly with features of migraine.

The new study, published in JAMA Network Open, was a secondary analysis of the Advancing Concussion Assessment in Pediatrics (A-CAP) prospective cohort study. The study was conducted at five emergency departments in Canada from September 2016 to July 2019 and included children and adolescents aged 8-17 years who presented with acute concussion or an orthopedic injury.

Children were included in the concussion group if they had a history of blunt head trauma resulting in at least one of three criteria consistent with the World Health Organization definition of mild traumatic brain injury. The criteria include loss of consciousness for less than 30 minutes, a Glasgow Coma Scale score of 13 or 14, or at least one acute sign or symptom of concussion, as noted by emergency clinicians.

Patients were excluded from the concussion group if they had deteriorating neurologic status, underwent neurosurgical intervention, had posttraumatic amnesia that lasted more than 24 hours, or had a score higher than 4 on the Abbreviated Injury Scale (AIS). The orthopedic injury group included patients without symptoms of concussion and with blunt trauma associated with an AIS 13 score of 4 or less. Patients were excluded from both groups if they had an overnight hospitalization for traumatic brain injury, a concussion within the past 3 months, or a neurodevelopmental disorder.

The researchers analyzed data from 928 children of 967 enrolled in the study. The median age was 12.2 years, and 41.3% were female. The final study cohort included 239 children with orthopedic injuries but no headache, 160 with a concussion and no headache, 134 with a concussion and nonmigraine headaches, and 254 with a concussion and migraine headaches.

Children with posttraumatic migraines 10 days after a concussion had the most severe symptoms and worst quality of life 3 months following their head trauma, the researchers found. Children without headaches within 10 days after concussion had the best 3-month outcomes, comparable to those with orthopedic injuries alone.

The researchers said the strengths of their study included its large population and its inclusion of various causes of head trauma, not just sports-related concussions. Limitations included self-reports of headaches instead of a physician diagnosis and lack of control for clinical interventions that might have affected the outcomes.

Charles Tator, MD, PhD, director of the Canadian Concussion Centre at Toronto Western Hospital, said the findings were unsurprising.

“Headaches are the most common symptom after concussion,” Dr. Tator, who was not involved in the latest research, told this news organization. “In my practice and research with concussed kids 11 and up and with adults, those with preconcussion history of migraine are the most difficult to treat because their headaches don’t improve unless specific measures are taken.”

Dr. Tator, who also is a professor of neurosurgery at the University of Toronto, said clinicians who treat concussions must determine which type of headaches children are experiencing – and refer as early as possible for migraine prevention or treatment and medication, as warranted.

“Early recognition after concussion that migraine headaches are occurring will save kids a lot of suffering,” he said.

The study was supported by a Canadian Institute of Health Research Foundation Grant and by funds from the Alberta Children’s Hospital Foundation and the Alberta Children’s Hospital Research Institute. Dr. Tator has disclosed no relevant financial relationships.
 

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

Migraine is the single most common neurologic condition worldwide and is particularly predominant among women during their reproductive years. There are many important questions that arise when women with migraine start pregnancy planning, most of which involve acute and preventive medication use and red flags for headache in pregnancy. As of yet, there have been no large-scale epidemiologic studies looking at pregnancy risks for people with migraine. Specifically, if migraine is a statistically significant vascular risk factor, does it incur additional risks in pregnancy, which is a prothrombotic state?

Purdue-Smithe and colleagues reviewed a large longitudinal study, the Nurses' Health Study II, a biennial questionnaire that took place from 1989 to 2009 and in which the questions changed yearly. Migraine was assessed on the basis of whether the participants had been given a diagnosis of migraine (or migraine with aura) by a medical professional; outcomes of pregnancy were also determined on the basis of participants providing a comprehensive reproductive history, including pregnancy outcome, gestation length, birth weight, and pregnancy complications.

A total of 2234 participants were included in this study; 1989 of them reported a history of physician-diagnosed migraine, with 1078 classified as having migraine with aura and 1156 classified as having migraine without aura. Adverse pregnancy outcomes more frequently affect multiple gestations; a sensitivity analysis was conducted to restrict the data here to singleton pregnancies. Individuals with migraine were more likely to report a history of infertility, obesity, and oral contraceptive use than were those without migraine. A history of migraine was associated with greater risks for preterm delivery, gestational hypertension, and preeclampsia; however, it was not associated with gestational diabetes or low birth weight. Theses outcomes were independent of age during pregnancy.

This wide-ranging study does allow us to better discuss potential risks for our patients with migraine. In addition to discussions about estrogen contraception use and stroke risk, it is worth taking a minute to discuss potential pregnancy risks that are more associated with migraine. This will allow our patients to be better aligned with their obstetricians, who can determine if other factors may further elevate these risks. Highlighting areas of risk can allow for better recognition of these potential negative outcomes much earlier.

There is a well-known association between calcitonin gene related peptide (CGRP) and migraine, but what is less understood is how CGRP affects specific features of migraine. CGRP is found in the gut and is therefore thought to have an association with migraine-related nausea, but other migraine associated symptoms, such as photophobia, are less well understood. Schiano di Cola and colleagues sought to determine the effectiveness of galcanezumab specifically in regard to ictal photophobia pain.

They enrolled 80 patients with either high-frequency episodic migraine or chronic migraine who were taking galcanezumab; 47 were included as expressing photophobia as a significant migraine-associated symptom at baseline. The patients were evaluated after 3 months and again after 6 months of treatment. They were asked to record headache days, migraine days, consumption of acute medication, and pain intensity. Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores were also followed up. Improvement with photophobia was determined as either no improvement, slight improvement, moderate improvement, or high improvement. After 3 months of treatment, 68% of patients reported a significant improvement in ictal photophobia, 11 patients reported moderate improvement, and six patients a slight improvement. Two patients reported improvement only after 6 months of treatment.

Post hoc analysis revealed photophobia improvement was not statistically significant in patients who are considered responders to galcanezumab compared with nonresponders. Photophobia improvement was most apparent in patients who were considered triptan responders. It was also more common in people with high-frequency episodic migraine rather than in those with chronic migraine. Migraine disability scores were noted to be higher in participants who did not notice photophobia improvement.

This study highlights the necessity to focus on factors beyond simply migraine frequency and severity. Many of the most disabling characteristics of migraine may not be related to pain directly. More research is currently being undertaken regarding the mechanisms that underlie photophobia in migraine. Ultimately, this will lead to more focused treatment for patients who may have other disabling symptoms associated with their headache disorder.

So much has already been written regarding the association between migraine and vascular risk factors. Migraine is considered a statistically significant risk factor for stroke specifically; migraine with aura has been noted to have a stronger association. Acarsoy and colleagues longitudinally examined the risk for stroke for any cause as it relates to migraine in both middle-aged and older populations.

This prospective population-based trial was embedded in a large Netherlands-based study among middle-aged and older community residents of Rotterdam. A total of 7266 participants were interviewed; 6925 participants had both migraine and stroke information available. Migraine was assessed with a questionnaire based on The International Classification of Headache Disorders (ICHD) criteria. Stroke status was assessed based on World Health Organization criteria and verified from medical records. Participants in this study were continuously monitored for incident stroke through an automatic linking of the study database to national health database files.

Other risk factors selected were body mass index (BMI), smoking history, education level, and physical activity, as well as any history of coronary artery disease, hypertension, or hypercholesterolemia. The average age of the study population was 65.7 years. Among participants with migraine, 20% had a history of migraine with aura. Among all stroke events, 84% were ischemic, and 11% were hemorrhagic. There was no significant difference in stroke-free survival probability between people with and without migraine. Although there was an association between migraine and stroke risk in middle and older ages, this was not statistically significant.

This study highlights, the appropriateness of educating migraine patients in regard to stroke risk. Specifically, patients should not be overly concerned regarding their migraine history. However, this study suggests that there does remain an association, but that this still remains somewhat unclear and less statistically significant in relation to age. When weighing vascular risk factors, more appropriate risks, such as elevated BMI, smoking history, hypertension, and the like should be highlighted, much more so than a history of migraine.

Migraine is the single most common neurologic condition worldwide and is particularly predominant among women during their reproductive years. There are many important questions that arise when women with migraine start pregnancy planning, most of which involve acute and preventive medication use and red flags for headache in pregnancy. As of yet, there have been no large-scale epidemiologic studies looking at pregnancy risks for people with migraine. Specifically, if migraine is a statistically significant vascular risk factor, does it incur additional risks in pregnancy, which is a prothrombotic state?

Purdue-Smithe and colleagues reviewed a large longitudinal study, the Nurses' Health Study II, a biennial questionnaire that took place from 1989 to 2009 and in which the questions changed yearly. Migraine was assessed on the basis of whether the participants had been given a diagnosis of migraine (or migraine with aura) by a medical professional; outcomes of pregnancy were also determined on the basis of participants providing a comprehensive reproductive history, including pregnancy outcome, gestation length, birth weight, and pregnancy complications.

A total of 2234 participants were included in this study; 1989 of them reported a history of physician-diagnosed migraine, with 1078 classified as having migraine with aura and 1156 classified as having migraine without aura. Adverse pregnancy outcomes more frequently affect multiple gestations; a sensitivity analysis was conducted to restrict the data here to singleton pregnancies. Individuals with migraine were more likely to report a history of infertility, obesity, and oral contraceptive use than were those without migraine. A history of migraine was associated with greater risks for preterm delivery, gestational hypertension, and preeclampsia; however, it was not associated with gestational diabetes or low birth weight. Theses outcomes were independent of age during pregnancy.

This wide-ranging study does allow us to better discuss potential risks for our patients with migraine. In addition to discussions about estrogen contraception use and stroke risk, it is worth taking a minute to discuss potential pregnancy risks that are more associated with migraine. This will allow our patients to be better aligned with their obstetricians, who can determine if other factors may further elevate these risks. Highlighting areas of risk can allow for better recognition of these potential negative outcomes much earlier.

There is a well-known association between calcitonin gene related peptide (CGRP) and migraine, but what is less understood is how CGRP affects specific features of migraine. CGRP is found in the gut and is therefore thought to have an association with migraine-related nausea, but other migraine associated symptoms, such as photophobia, are less well understood. Schiano di Cola and colleagues sought to determine the effectiveness of galcanezumab specifically in regard to ictal photophobia pain.

They enrolled 80 patients with either high-frequency episodic migraine or chronic migraine who were taking galcanezumab; 47 were included as expressing photophobia as a significant migraine-associated symptom at baseline. The patients were evaluated after 3 months and again after 6 months of treatment. They were asked to record headache days, migraine days, consumption of acute medication, and pain intensity. Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores were also followed up. Improvement with photophobia was determined as either no improvement, slight improvement, moderate improvement, or high improvement. After 3 months of treatment, 68% of patients reported a significant improvement in ictal photophobia, 11 patients reported moderate improvement, and six patients a slight improvement. Two patients reported improvement only after 6 months of treatment.

Post hoc analysis revealed photophobia improvement was not statistically significant in patients who are considered responders to galcanezumab compared with nonresponders. Photophobia improvement was most apparent in patients who were considered triptan responders. It was also more common in people with high-frequency episodic migraine rather than in those with chronic migraine. Migraine disability scores were noted to be higher in participants who did not notice photophobia improvement.

This study highlights the necessity to focus on factors beyond simply migraine frequency and severity. Many of the most disabling characteristics of migraine may not be related to pain directly. More research is currently being undertaken regarding the mechanisms that underlie photophobia in migraine. Ultimately, this will lead to more focused treatment for patients who may have other disabling symptoms associated with their headache disorder.

So much has already been written regarding the association between migraine and vascular risk factors. Migraine is considered a statistically significant risk factor for stroke specifically; migraine with aura has been noted to have a stronger association. Acarsoy and colleagues longitudinally examined the risk for stroke for any cause as it relates to migraine in both middle-aged and older populations.

This prospective population-based trial was embedded in a large Netherlands-based study among middle-aged and older community residents of Rotterdam. A total of 7266 participants were interviewed; 6925 participants had both migraine and stroke information available. Migraine was assessed with a questionnaire based on The International Classification of Headache Disorders (ICHD) criteria. Stroke status was assessed based on World Health Organization criteria and verified from medical records. Participants in this study were continuously monitored for incident stroke through an automatic linking of the study database to national health database files.

Other risk factors selected were body mass index (BMI), smoking history, education level, and physical activity, as well as any history of coronary artery disease, hypertension, or hypercholesterolemia. The average age of the study population was 65.7 years. Among participants with migraine, 20% had a history of migraine with aura. Among all stroke events, 84% were ischemic, and 11% were hemorrhagic. There was no significant difference in stroke-free survival probability between people with and without migraine. Although there was an association between migraine and stroke risk in middle and older ages, this was not statistically significant.

This study highlights, the appropriateness of educating migraine patients in regard to stroke risk. Specifically, patients should not be overly concerned regarding their migraine history. However, this study suggests that there does remain an association, but that this still remains somewhat unclear and less statistically significant in relation to age. When weighing vascular risk factors, more appropriate risks, such as elevated BMI, smoking history, hypertension, and the like should be highlighted, much more so than a history of migraine.

Migraine is the single most common neurologic condition worldwide and is particularly predominant among women during their reproductive years. There are many important questions that arise when women with migraine start pregnancy planning, most of which involve acute and preventive medication use and red flags for headache in pregnancy. As of yet, there have been no large-scale epidemiologic studies looking at pregnancy risks for people with migraine. Specifically, if migraine is a statistically significant vascular risk factor, does it incur additional risks in pregnancy, which is a prothrombotic state?

Purdue-Smithe and colleagues reviewed a large longitudinal study, the Nurses' Health Study II, a biennial questionnaire that took place from 1989 to 2009 and in which the questions changed yearly. Migraine was assessed on the basis of whether the participants had been given a diagnosis of migraine (or migraine with aura) by a medical professional; outcomes of pregnancy were also determined on the basis of participants providing a comprehensive reproductive history, including pregnancy outcome, gestation length, birth weight, and pregnancy complications.

A total of 2234 participants were included in this study; 1989 of them reported a history of physician-diagnosed migraine, with 1078 classified as having migraine with aura and 1156 classified as having migraine without aura. Adverse pregnancy outcomes more frequently affect multiple gestations; a sensitivity analysis was conducted to restrict the data here to singleton pregnancies. Individuals with migraine were more likely to report a history of infertility, obesity, and oral contraceptive use than were those without migraine. A history of migraine was associated with greater risks for preterm delivery, gestational hypertension, and preeclampsia; however, it was not associated with gestational diabetes or low birth weight. Theses outcomes were independent of age during pregnancy.

This wide-ranging study does allow us to better discuss potential risks for our patients with migraine. In addition to discussions about estrogen contraception use and stroke risk, it is worth taking a minute to discuss potential pregnancy risks that are more associated with migraine. This will allow our patients to be better aligned with their obstetricians, who can determine if other factors may further elevate these risks. Highlighting areas of risk can allow for better recognition of these potential negative outcomes much earlier.

There is a well-known association between calcitonin gene related peptide (CGRP) and migraine, but what is less understood is how CGRP affects specific features of migraine. CGRP is found in the gut and is therefore thought to have an association with migraine-related nausea, but other migraine associated symptoms, such as photophobia, are less well understood. Schiano di Cola and colleagues sought to determine the effectiveness of galcanezumab specifically in regard to ictal photophobia pain.

They enrolled 80 patients with either high-frequency episodic migraine or chronic migraine who were taking galcanezumab; 47 were included as expressing photophobia as a significant migraine-associated symptom at baseline. The patients were evaluated after 3 months and again after 6 months of treatment. They were asked to record headache days, migraine days, consumption of acute medication, and pain intensity. Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores were also followed up. Improvement with photophobia was determined as either no improvement, slight improvement, moderate improvement, or high improvement. After 3 months of treatment, 68% of patients reported a significant improvement in ictal photophobia, 11 patients reported moderate improvement, and six patients a slight improvement. Two patients reported improvement only after 6 months of treatment.

Post hoc analysis revealed photophobia improvement was not statistically significant in patients who are considered responders to galcanezumab compared with nonresponders. Photophobia improvement was most apparent in patients who were considered triptan responders. It was also more common in people with high-frequency episodic migraine rather than in those with chronic migraine. Migraine disability scores were noted to be higher in participants who did not notice photophobia improvement.

This study highlights the necessity to focus on factors beyond simply migraine frequency and severity. Many of the most disabling characteristics of migraine may not be related to pain directly. More research is currently being undertaken regarding the mechanisms that underlie photophobia in migraine. Ultimately, this will lead to more focused treatment for patients who may have other disabling symptoms associated with their headache disorder.

So much has already been written regarding the association between migraine and vascular risk factors. Migraine is considered a statistically significant risk factor for stroke specifically; migraine with aura has been noted to have a stronger association. Acarsoy and colleagues longitudinally examined the risk for stroke for any cause as it relates to migraine in both middle-aged and older populations.

This prospective population-based trial was embedded in a large Netherlands-based study among middle-aged and older community residents of Rotterdam. A total of 7266 participants were interviewed; 6925 participants had both migraine and stroke information available. Migraine was assessed with a questionnaire based on The International Classification of Headache Disorders (ICHD) criteria. Stroke status was assessed based on World Health Organization criteria and verified from medical records. Participants in this study were continuously monitored for incident stroke through an automatic linking of the study database to national health database files.

Other risk factors selected were body mass index (BMI), smoking history, education level, and physical activity, as well as any history of coronary artery disease, hypertension, or hypercholesterolemia. The average age of the study population was 65.7 years. Among participants with migraine, 20% had a history of migraine with aura. Among all stroke events, 84% were ischemic, and 11% were hemorrhagic. There was no significant difference in stroke-free survival probability between people with and without migraine. Although there was an association between migraine and stroke risk in middle and older ages, this was not statistically significant.

This study highlights, the appropriateness of educating migraine patients in regard to stroke risk. Specifically, patients should not be overly concerned regarding their migraine history. However, this study suggests that there does remain an association, but that this still remains somewhat unclear and less statistically significant in relation to age. When weighing vascular risk factors, more appropriate risks, such as elevated BMI, smoking history, hypertension, and the like should be highlighted, much more so than a history of migraine.

Do you use nonpharmacologic approaches to treat your patients living with migraines? Which ones do you prefer?
I always like to start with nonpharmacologic approaches (also termed bio-behavioral approaches) with my patients. I talk to patients about sleep hygiene because if they don't sleep well, they're going to have more headaches. Most of my patients have issues with sleep and rarely feel refreshed in the morning. Most of them have middle insomnia; they wake up between 2 am and 4 am and cannot get back to sleep.

I also talk to my patients about eating properly. If patients don't eat on time or miss a meal, they often get headaches.  While timing is probably more critical, what they eat is important also. Poor diet can lead to decreased energy, and patients can become obese. Obesity impacts headache—especially migraine. I am not sure if there are any particularly good or bad foods for migraine patients, but in general, they should eat fewer fatty foods, fewer carbohydrates, more chicken, and fish than red meat, and a lot of fruits, vegetables, salads, nuts, and whole grains. A good trick is to limit the volume of each meal; do not go back for seconds and limit desserts and alcohol. 

Exercise is beneficial to decrease headaches, and the converse is even more true. Patients should start with low-impact, brief exercise like short walks and slowly build up to 20 minutes of cardio as tolerated, 3 to 5 times per week. Like poor diet choices, a sedentary lifestyle can lead to obesity and then not doing well with headaches and so on. 

What are your goals for treating your patients at the start of a migraine attack?

The goals for treating a migraine attack are to reduce the intensity of the pain quickly and, if possible, make the patient pain-free in ≤2 hours. We also try to reduce their most bothersome symptom, which is usually sensitivity to light or nausea, without causing any adverse effects from the treatment. Possibly as important, we want to get the patient back to functioning at work or at home, so they need no further treatment for that attack.

Unfortunately, many of the medicines we have available do cause adverse events, which are sometimes worse than the headache itself.  A patient can't continue to take a medication that causes significant side effects.

It is also critical to stop the headache quickly, as we don't want patients to take the prescribed acute care medicine and then, if they don’t feel like it’s working, proceed to take aspirin and then acetaminophen and then an anti-inflammatory tablet. The more medicine they take, the more likely they'll get medication overuse headache (MOH).  

MOH is not a great name, but it does imply that patients are taking one or many medications per week to stop their headaches, not realizing that this can worsen and prolong their headaches rather than helping them. They can also experience adverse events from taking so much medication. 

Finally, we want the patients to get rid of a headache so that they do not need to go to an emergency room, and we want to use medication that is cost effective and gets the patient functioning. Some medicines and devices are extremely expensive and not well covered by insurance companies but imagine the patient who takes a new medicine or uses a new device and gets better rapidly. If they hadn't done that, they may have lost a day or 2 of pay from missing work, or they might have gone to work and not done a very effective job because they were feeling miserable and couldn’t think or speak well. 

Do you prescribe triptans?

Definitely. The triptans first became available 30 years ago. There are 7 different triptans, and some work better for some patients than others. They come in tablets, injections, and nasal sprays. Sometimes patients need to try 2 or 3 different triptans to see which one is the most effective for them. If a patient has no success with tablets, there's a possibility that an injection or even a nasal spray would be more effective.
There are 2 triptans available as a nasal spray. I happen to like a triptan nasal spray called zolmitriptan, which usually works faster with fewer adverse events than the tablets.

There's also an injection of sumatriptan available, which is the fastest way to get relief from a triptan. Patients usually don't prefer it because it is an injection that they give themselves via an auto injector, and it may hurt and can be a bit complex to administer. There are definitely more adverse events when sumatriptan is given by injection, but because an injection can deliver very fast results that stop the headache reliably, some patients prefer it.

Triptans have been the mainstay treatment to stop an ongoing migraine attack for 30 years. We have always known there is some constriction of blood vessels and triptan-related side effects such as dizziness, drowsiness, and tingling sensations, so not every patient can take them. The newer medications that block calcitonin gene-related peptide (CGRP) do not constrict blood vessels and have fewer adverse events but cost a lot more if not covered by insurance.

Another newer, nontriptan nasal spray is dihydroergotamine (DHE) mesylate for acute care. It is one of the best medications to use if the patient’s migraine has been going on for 24 hours, as it tends to work well for a long-lasting headache. It also works for a long period, giving the patient a rest before their next attack. A nasal spray works faster than a tablet form, as the medication is absorbed from the nasal mucosa and does not have to make its way through the GI tract, then to the liver for metabolism, and finally, up to the brain before it begins to work. There can be some side effects in the nose such as discomfort or stuffiness, but if it works well, patients usually tolerate it. 

There's also a newer class of medicine called ditans. In a recent study, lasmiditan, which comes in a 50-mg and a 100-mg tablet for acute care of migraine, showed no vasoconstrictive effects, suggesting that ditans could be a safe option for patients living with chronic cardio- and cerebrovascular disease. Lasmiditan could be an alternative to triptans when they are contraindicated in patients with blood vessel disease, obesity, high blood pressure or cholesterol levels, or in nonresponsive patients. Lasmiditan does cause some dizziness and drowsiness, so patients cannot drive for 8 hours after taking it. However, it does have good efficacy.

When do you prescribe gepants?

Gepants are small-molecule CGRP receptor blockers. They are tablets that sit on the receptor, preventing the CGRP from docking on the receptor and increasing the headache during a migraine attack. There are 2 gepants that can be used to stop a headache that is just starting or in progress: ubrogepant and rimegepant. 

Ubrogepant is a regular tablet that is available in 50-mg or 100-mg strengths. If the first dose does not make a patient pain free, a second dose is recommended about 2 hours later. Rimegepant is a meltaway tablet and only comes in a 75-mg strength. It should be taken early in the attack, and usually the patient does not need further treatment that day. If they do, they need to switch to another treatment, as rimegepant should not be repeated that day. Rimegepant may be used for both acute care and prevention. It is the only tablet that can be used for both. 

Both drugs have been shown to provide pain freedom for about 20% of patients at 2 hours, which is statistically better than the patients that received the placebo. These drugs generally don’t cause many adverse events but can cause a little nausea or drowsiness in some patients. Ubrogepant has a few contraindications; patients on certain medications such as antibiotics or antifungals cannot take it. If a patient is not doing well on a triptan or should not be given a drug that constricts blood vessels, I often switch them to one of these gepants (if covered by insurance). Both drugs have a plan to let the patient try them at a low cost. 

How are the gepants used acutely?

Gepants are used just like a triptan. As soon as the patient has a migraine headache starting, they take either ubrogepant or rimegepant as quickly as possible. Some patients say they feel the gepant begin to work within an hour or less, and some patients say it doesn't work at all, so I have them try the other gepant. 

Gepants are probably a better option than triptans if the patient is >40 years because triptans can constrict blood vessels. Older patients, and certainly those who have any kind of cardiac or cerebral blood vessel issues or even peripheral blood vessel disease, should not be given triptans.

When do you consider using preventive treatment in migraine?

If a patient has ≥4 moderate-to-severe headache days a month, or fewer with severe disability, or does not respond to acute care medications or those drugs are contraindicated, I consider giving them preventive therapy for migraine. The goal is to decrease the number of migraine days per month and to decrease the intensity, duration, and disability of the attacks.

Which gepants can you use for prevention of migraine?

I discussed rimegepant as an acute care medication, but the same 75-mg meltaway tablet given every other day works preventively to decrease the number of headaches. I like it, as it has few adverse events—<3% of patients experience nausea and abdominal pain—and it can also be used to stop a headache on days the patient did not take a tablet.

Atogepant is a newer, US Food and Drug Administration (FDA)-approved gepant taken once daily by mouth for prevention of migraine, and it works to decrease headache days per month. It has more side effects than the other gepants, including constipation, drowsiness, and nausea. If a patient does not have many adverse events while taking it, it is a good migraine preventive. 

How do you feel about monoclonal antibodies that bind to CGRP or its receptor for migraine preventive treatment?

Before the gepants became available, 4 different pharmaceutical companies were making monoclonal antibodies (mAbs) that bind to either CGRP or its receptor. This class of medication can be quite effective for most patients needing migraine prevention, as these medications last for a long time if the patient keeps taking it. 

Antibodies, when injected, continue to work for 1 to 3 months, making them perfect for migraine prevention, but they must be given either by the patient using an autoinjector with a tiny needle or by intravenous (IV) infusion in a hospital or office. They tend to be quite effective and have few adverse events.  

The first one to come out was erenumab, then frenanezumab, and galcanezumab. The newest one is eptinezumab, given by IV infusion over 30 minutes. Erenumab is the only mAb that sits on the receptor to prevent the CGRP from docking on the receptor, and it's the only one that seems to cause adverse events such as constipation and increased blood pressure in some patients. Eptinezumab is the only drug in this category given by IV infusion; patients must come to the office to receive the injection every 3 months. Even though eptinezumab is a powerful drug, I find that patients generally don't like coming in for IV treatment. I reserve it for when a patient has failed several other preventive treatments. The other 3 drugs (erenumab, fremanezumab, galcanezumab) are subcutaneous injections that the patient can self-administer at home. Fremanezumab can be taken once a month or once every 3 months, depending on the dose prescribed. 

What migraine devices do you like to prescribe?

The device that I tend to have my patients use is called Nerivio®; it has been cleared by the FDA for acute treatment of migraine in patients ≥12 years. An article was just published in the journal Headache on its use in prevention of migraine. The company expects the FDA to clear it very soon for prevention when used for 45 minutes every other day.

Nerivio® is an electrical stimulator that is placed on the upper arm like a blood pressure cuff. It is battery-powered and links to an app on a smartphone. I have my patients turn it up slowly to a higher gain, and when they feel a slight discomfort, they lower down until they do not feel it. That's where I recommend that they keep it for 45 minutes of treatment, starting at the beginning of a migraine attack. 

Nerivio® also has a behavioral medicine program incorporated into the smartphone app that lasts for 25 minutes. While the patient is receiving the 45 minutes of electrical stimulation, they are also being guided through relaxation techniques to help ease the headache. The company has done a controlled study comparing the efficacy of Nerivio® with and without the behavioral treatment and found that the 2 together are more effective than Nerivio® alone. 

The early double-blind studies of this device, as sent to the FDA for clearance, have excellent efficacy data with very few adverse events. Thus, it is used by many patients. The company has arranged a lower cost for the first month of treatment so a patient can see whether the device is effective.

There's also a device called Relivion®, which is worn like a tiara on the head to stimulate 4 nerves above the eyebrows that are part of the trigeminal system and 2 in the back of the head that affect the occipital nerves.

One of the earliest devices to launch is the gammaCore vagal nerve stimulator. It is handheld and controlled by the patient. It is placed on the front and side of the neck in the region of the vagal nerve. For acute care of migraine, the patient stimulates for 2 minutes and then waits several minutes before repeating 2 minutes of treatment. If you want to prescribe it for the prevention of migraine, a patient could do this sequence twice per day. It has been approved for acute care and prevention of migraine and, along with other medication for cluster headaches, it is easy to use and approved for almost any kind of headache. Unfortunately, it is extremely expensive for patients and is not covered well by insurance unless the patient is a veteran or goes to a Veterans Health Administration hospital for care. 

There are a few other devices that also work for migraine. Most electrical stimulation devices are costly, but we do hope that insurance companies will begin to cover them soon. Most devices cause few adverse events, have few contraindications, and will be used more as they become more affordable.

Can you summarize migraine treatment for us in one paragraph?

No, but I will try. We have many acute care treatments for migraine that are effective. Some, such as the triptans, do constrict blood vessels, and certain patients should not be taking medications that affect blood vessels. Some medications cause certain side effects or take too long to work, and we have other options for those patients. If a patient has ≥4 headache days per month or fewer associated with a lot of disability, we need to consider prevention. We have older preventives such as beta blockers and epilepsy medications, which are less expensive and can work but usually have many side effects. Now we have 4 mAbs that bind to CGRP or its receptor, which work well for a month or more with few adverse events. We also have 2 oral gepants for prevention. When you add in several devices, I have so many options for my patients today that I am a lucky neurologist, and my patients are even luckier!

Do you use nonpharmacologic approaches to treat your patients living with migraines? Which ones do you prefer?
I always like to start with nonpharmacologic approaches (also termed bio-behavioral approaches) with my patients. I talk to patients about sleep hygiene because if they don't sleep well, they're going to have more headaches. Most of my patients have issues with sleep and rarely feel refreshed in the morning. Most of them have middle insomnia; they wake up between 2 am and 4 am and cannot get back to sleep.

I also talk to my patients about eating properly. If patients don't eat on time or miss a meal, they often get headaches.  While timing is probably more critical, what they eat is important also. Poor diet can lead to decreased energy, and patients can become obese. Obesity impacts headache—especially migraine. I am not sure if there are any particularly good or bad foods for migraine patients, but in general, they should eat fewer fatty foods, fewer carbohydrates, more chicken, and fish than red meat, and a lot of fruits, vegetables, salads, nuts, and whole grains. A good trick is to limit the volume of each meal; do not go back for seconds and limit desserts and alcohol. 

Exercise is beneficial to decrease headaches, and the converse is even more true. Patients should start with low-impact, brief exercise like short walks and slowly build up to 20 minutes of cardio as tolerated, 3 to 5 times per week. Like poor diet choices, a sedentary lifestyle can lead to obesity and then not doing well with headaches and so on. 

What are your goals for treating your patients at the start of a migraine attack?

The goals for treating a migraine attack are to reduce the intensity of the pain quickly and, if possible, make the patient pain-free in ≤2 hours. We also try to reduce their most bothersome symptom, which is usually sensitivity to light or nausea, without causing any adverse effects from the treatment. Possibly as important, we want to get the patient back to functioning at work or at home, so they need no further treatment for that attack.

Unfortunately, many of the medicines we have available do cause adverse events, which are sometimes worse than the headache itself.  A patient can't continue to take a medication that causes significant side effects.

It is also critical to stop the headache quickly, as we don't want patients to take the prescribed acute care medicine and then, if they don’t feel like it’s working, proceed to take aspirin and then acetaminophen and then an anti-inflammatory tablet. The more medicine they take, the more likely they'll get medication overuse headache (MOH).  

MOH is not a great name, but it does imply that patients are taking one or many medications per week to stop their headaches, not realizing that this can worsen and prolong their headaches rather than helping them. They can also experience adverse events from taking so much medication. 

Finally, we want the patients to get rid of a headache so that they do not need to go to an emergency room, and we want to use medication that is cost effective and gets the patient functioning. Some medicines and devices are extremely expensive and not well covered by insurance companies but imagine the patient who takes a new medicine or uses a new device and gets better rapidly. If they hadn't done that, they may have lost a day or 2 of pay from missing work, or they might have gone to work and not done a very effective job because they were feeling miserable and couldn’t think or speak well. 

Do you prescribe triptans?

Definitely. The triptans first became available 30 years ago. There are 7 different triptans, and some work better for some patients than others. They come in tablets, injections, and nasal sprays. Sometimes patients need to try 2 or 3 different triptans to see which one is the most effective for them. If a patient has no success with tablets, there's a possibility that an injection or even a nasal spray would be more effective.
There are 2 triptans available as a nasal spray. I happen to like a triptan nasal spray called zolmitriptan, which usually works faster with fewer adverse events than the tablets.

There's also an injection of sumatriptan available, which is the fastest way to get relief from a triptan. Patients usually don't prefer it because it is an injection that they give themselves via an auto injector, and it may hurt and can be a bit complex to administer. There are definitely more adverse events when sumatriptan is given by injection, but because an injection can deliver very fast results that stop the headache reliably, some patients prefer it.

Triptans have been the mainstay treatment to stop an ongoing migraine attack for 30 years. We have always known there is some constriction of blood vessels and triptan-related side effects such as dizziness, drowsiness, and tingling sensations, so not every patient can take them. The newer medications that block calcitonin gene-related peptide (CGRP) do not constrict blood vessels and have fewer adverse events but cost a lot more if not covered by insurance.

Another newer, nontriptan nasal spray is dihydroergotamine (DHE) mesylate for acute care. It is one of the best medications to use if the patient’s migraine has been going on for 24 hours, as it tends to work well for a long-lasting headache. It also works for a long period, giving the patient a rest before their next attack. A nasal spray works faster than a tablet form, as the medication is absorbed from the nasal mucosa and does not have to make its way through the GI tract, then to the liver for metabolism, and finally, up to the brain before it begins to work. There can be some side effects in the nose such as discomfort or stuffiness, but if it works well, patients usually tolerate it. 

There's also a newer class of medicine called ditans. In a recent study, lasmiditan, which comes in a 50-mg and a 100-mg tablet for acute care of migraine, showed no vasoconstrictive effects, suggesting that ditans could be a safe option for patients living with chronic cardio- and cerebrovascular disease. Lasmiditan could be an alternative to triptans when they are contraindicated in patients with blood vessel disease, obesity, high blood pressure or cholesterol levels, or in nonresponsive patients. Lasmiditan does cause some dizziness and drowsiness, so patients cannot drive for 8 hours after taking it. However, it does have good efficacy.

When do you prescribe gepants?

Gepants are small-molecule CGRP receptor blockers. They are tablets that sit on the receptor, preventing the CGRP from docking on the receptor and increasing the headache during a migraine attack. There are 2 gepants that can be used to stop a headache that is just starting or in progress: ubrogepant and rimegepant. 

Ubrogepant is a regular tablet that is available in 50-mg or 100-mg strengths. If the first dose does not make a patient pain free, a second dose is recommended about 2 hours later. Rimegepant is a meltaway tablet and only comes in a 75-mg strength. It should be taken early in the attack, and usually the patient does not need further treatment that day. If they do, they need to switch to another treatment, as rimegepant should not be repeated that day. Rimegepant may be used for both acute care and prevention. It is the only tablet that can be used for both. 

Both drugs have been shown to provide pain freedom for about 20% of patients at 2 hours, which is statistically better than the patients that received the placebo. These drugs generally don’t cause many adverse events but can cause a little nausea or drowsiness in some patients. Ubrogepant has a few contraindications; patients on certain medications such as antibiotics or antifungals cannot take it. If a patient is not doing well on a triptan or should not be given a drug that constricts blood vessels, I often switch them to one of these gepants (if covered by insurance). Both drugs have a plan to let the patient try them at a low cost. 

How are the gepants used acutely?

Gepants are used just like a triptan. As soon as the patient has a migraine headache starting, they take either ubrogepant or rimegepant as quickly as possible. Some patients say they feel the gepant begin to work within an hour or less, and some patients say it doesn't work at all, so I have them try the other gepant. 

Gepants are probably a better option than triptans if the patient is >40 years because triptans can constrict blood vessels. Older patients, and certainly those who have any kind of cardiac or cerebral blood vessel issues or even peripheral blood vessel disease, should not be given triptans.

When do you consider using preventive treatment in migraine?

If a patient has ≥4 moderate-to-severe headache days a month, or fewer with severe disability, or does not respond to acute care medications or those drugs are contraindicated, I consider giving them preventive therapy for migraine. The goal is to decrease the number of migraine days per month and to decrease the intensity, duration, and disability of the attacks.

Which gepants can you use for prevention of migraine?

I discussed rimegepant as an acute care medication, but the same 75-mg meltaway tablet given every other day works preventively to decrease the number of headaches. I like it, as it has few adverse events—<3% of patients experience nausea and abdominal pain—and it can also be used to stop a headache on days the patient did not take a tablet.

Atogepant is a newer, US Food and Drug Administration (FDA)-approved gepant taken once daily by mouth for prevention of migraine, and it works to decrease headache days per month. It has more side effects than the other gepants, including constipation, drowsiness, and nausea. If a patient does not have many adverse events while taking it, it is a good migraine preventive. 

How do you feel about monoclonal antibodies that bind to CGRP or its receptor for migraine preventive treatment?

Before the gepants became available, 4 different pharmaceutical companies were making monoclonal antibodies (mAbs) that bind to either CGRP or its receptor. This class of medication can be quite effective for most patients needing migraine prevention, as these medications last for a long time if the patient keeps taking it. 

Antibodies, when injected, continue to work for 1 to 3 months, making them perfect for migraine prevention, but they must be given either by the patient using an autoinjector with a tiny needle or by intravenous (IV) infusion in a hospital or office. They tend to be quite effective and have few adverse events.  

The first one to come out was erenumab, then frenanezumab, and galcanezumab. The newest one is eptinezumab, given by IV infusion over 30 minutes. Erenumab is the only mAb that sits on the receptor to prevent the CGRP from docking on the receptor, and it's the only one that seems to cause adverse events such as constipation and increased blood pressure in some patients. Eptinezumab is the only drug in this category given by IV infusion; patients must come to the office to receive the injection every 3 months. Even though eptinezumab is a powerful drug, I find that patients generally don't like coming in for IV treatment. I reserve it for when a patient has failed several other preventive treatments. The other 3 drugs (erenumab, fremanezumab, galcanezumab) are subcutaneous injections that the patient can self-administer at home. Fremanezumab can be taken once a month or once every 3 months, depending on the dose prescribed. 

What migraine devices do you like to prescribe?

The device that I tend to have my patients use is called Nerivio®; it has been cleared by the FDA for acute treatment of migraine in patients ≥12 years. An article was just published in the journal Headache on its use in prevention of migraine. The company expects the FDA to clear it very soon for prevention when used for 45 minutes every other day.

Nerivio® is an electrical stimulator that is placed on the upper arm like a blood pressure cuff. It is battery-powered and links to an app on a smartphone. I have my patients turn it up slowly to a higher gain, and when they feel a slight discomfort, they lower down until they do not feel it. That's where I recommend that they keep it for 45 minutes of treatment, starting at the beginning of a migraine attack. 

Nerivio® also has a behavioral medicine program incorporated into the smartphone app that lasts for 25 minutes. While the patient is receiving the 45 minutes of electrical stimulation, they are also being guided through relaxation techniques to help ease the headache. The company has done a controlled study comparing the efficacy of Nerivio® with and without the behavioral treatment and found that the 2 together are more effective than Nerivio® alone. 

The early double-blind studies of this device, as sent to the FDA for clearance, have excellent efficacy data with very few adverse events. Thus, it is used by many patients. The company has arranged a lower cost for the first month of treatment so a patient can see whether the device is effective.

There's also a device called Relivion®, which is worn like a tiara on the head to stimulate 4 nerves above the eyebrows that are part of the trigeminal system and 2 in the back of the head that affect the occipital nerves.

One of the earliest devices to launch is the gammaCore vagal nerve stimulator. It is handheld and controlled by the patient. It is placed on the front and side of the neck in the region of the vagal nerve. For acute care of migraine, the patient stimulates for 2 minutes and then waits several minutes before repeating 2 minutes of treatment. If you want to prescribe it for the prevention of migraine, a patient could do this sequence twice per day. It has been approved for acute care and prevention of migraine and, along with other medication for cluster headaches, it is easy to use and approved for almost any kind of headache. Unfortunately, it is extremely expensive for patients and is not covered well by insurance unless the patient is a veteran or goes to a Veterans Health Administration hospital for care. 

There are a few other devices that also work for migraine. Most electrical stimulation devices are costly, but we do hope that insurance companies will begin to cover them soon. Most devices cause few adverse events, have few contraindications, and will be used more as they become more affordable.

Can you summarize migraine treatment for us in one paragraph?

No, but I will try. We have many acute care treatments for migraine that are effective. Some, such as the triptans, do constrict blood vessels, and certain patients should not be taking medications that affect blood vessels. Some medications cause certain side effects or take too long to work, and we have other options for those patients. If a patient has ≥4 headache days per month or fewer associated with a lot of disability, we need to consider prevention. We have older preventives such as beta blockers and epilepsy medications, which are less expensive and can work but usually have many side effects. Now we have 4 mAbs that bind to CGRP or its receptor, which work well for a month or more with few adverse events. We also have 2 oral gepants for prevention. When you add in several devices, I have so many options for my patients today that I am a lucky neurologist, and my patients are even luckier!

Do you use nonpharmacologic approaches to treat your patients living with migraines? Which ones do you prefer?
I always like to start with nonpharmacologic approaches (also termed bio-behavioral approaches) with my patients. I talk to patients about sleep hygiene because if they don't sleep well, they're going to have more headaches. Most of my patients have issues with sleep and rarely feel refreshed in the morning. Most of them have middle insomnia; they wake up between 2 am and 4 am and cannot get back to sleep.

I also talk to my patients about eating properly. If patients don't eat on time or miss a meal, they often get headaches.  While timing is probably more critical, what they eat is important also. Poor diet can lead to decreased energy, and patients can become obese. Obesity impacts headache—especially migraine. I am not sure if there are any particularly good or bad foods for migraine patients, but in general, they should eat fewer fatty foods, fewer carbohydrates, more chicken, and fish than red meat, and a lot of fruits, vegetables, salads, nuts, and whole grains. A good trick is to limit the volume of each meal; do not go back for seconds and limit desserts and alcohol. 

Exercise is beneficial to decrease headaches, and the converse is even more true. Patients should start with low-impact, brief exercise like short walks and slowly build up to 20 minutes of cardio as tolerated, 3 to 5 times per week. Like poor diet choices, a sedentary lifestyle can lead to obesity and then not doing well with headaches and so on. 

What are your goals for treating your patients at the start of a migraine attack?

The goals for treating a migraine attack are to reduce the intensity of the pain quickly and, if possible, make the patient pain-free in ≤2 hours. We also try to reduce their most bothersome symptom, which is usually sensitivity to light or nausea, without causing any adverse effects from the treatment. Possibly as important, we want to get the patient back to functioning at work or at home, so they need no further treatment for that attack.

Unfortunately, many of the medicines we have available do cause adverse events, which are sometimes worse than the headache itself.  A patient can't continue to take a medication that causes significant side effects.

It is also critical to stop the headache quickly, as we don't want patients to take the prescribed acute care medicine and then, if they don’t feel like it’s working, proceed to take aspirin and then acetaminophen and then an anti-inflammatory tablet. The more medicine they take, the more likely they'll get medication overuse headache (MOH).  

MOH is not a great name, but it does imply that patients are taking one or many medications per week to stop their headaches, not realizing that this can worsen and prolong their headaches rather than helping them. They can also experience adverse events from taking so much medication. 

Finally, we want the patients to get rid of a headache so that they do not need to go to an emergency room, and we want to use medication that is cost effective and gets the patient functioning. Some medicines and devices are extremely expensive and not well covered by insurance companies but imagine the patient who takes a new medicine or uses a new device and gets better rapidly. If they hadn't done that, they may have lost a day or 2 of pay from missing work, or they might have gone to work and not done a very effective job because they were feeling miserable and couldn’t think or speak well. 

Do you prescribe triptans?

Definitely. The triptans first became available 30 years ago. There are 7 different triptans, and some work better for some patients than others. They come in tablets, injections, and nasal sprays. Sometimes patients need to try 2 or 3 different triptans to see which one is the most effective for them. If a patient has no success with tablets, there's a possibility that an injection or even a nasal spray would be more effective.
There are 2 triptans available as a nasal spray. I happen to like a triptan nasal spray called zolmitriptan, which usually works faster with fewer adverse events than the tablets.

There's also an injection of sumatriptan available, which is the fastest way to get relief from a triptan. Patients usually don't prefer it because it is an injection that they give themselves via an auto injector, and it may hurt and can be a bit complex to administer. There are definitely more adverse events when sumatriptan is given by injection, but because an injection can deliver very fast results that stop the headache reliably, some patients prefer it.

Triptans have been the mainstay treatment to stop an ongoing migraine attack for 30 years. We have always known there is some constriction of blood vessels and triptan-related side effects such as dizziness, drowsiness, and tingling sensations, so not every patient can take them. The newer medications that block calcitonin gene-related peptide (CGRP) do not constrict blood vessels and have fewer adverse events but cost a lot more if not covered by insurance.

Another newer, nontriptan nasal spray is dihydroergotamine (DHE) mesylate for acute care. It is one of the best medications to use if the patient’s migraine has been going on for 24 hours, as it tends to work well for a long-lasting headache. It also works for a long period, giving the patient a rest before their next attack. A nasal spray works faster than a tablet form, as the medication is absorbed from the nasal mucosa and does not have to make its way through the GI tract, then to the liver for metabolism, and finally, up to the brain before it begins to work. There can be some side effects in the nose such as discomfort or stuffiness, but if it works well, patients usually tolerate it. 

There's also a newer class of medicine called ditans. In a recent study, lasmiditan, which comes in a 50-mg and a 100-mg tablet for acute care of migraine, showed no vasoconstrictive effects, suggesting that ditans could be a safe option for patients living with chronic cardio- and cerebrovascular disease. Lasmiditan could be an alternative to triptans when they are contraindicated in patients with blood vessel disease, obesity, high blood pressure or cholesterol levels, or in nonresponsive patients. Lasmiditan does cause some dizziness and drowsiness, so patients cannot drive for 8 hours after taking it. However, it does have good efficacy.

When do you prescribe gepants?

Gepants are small-molecule CGRP receptor blockers. They are tablets that sit on the receptor, preventing the CGRP from docking on the receptor and increasing the headache during a migraine attack. There are 2 gepants that can be used to stop a headache that is just starting or in progress: ubrogepant and rimegepant. 

Ubrogepant is a regular tablet that is available in 50-mg or 100-mg strengths. If the first dose does not make a patient pain free, a second dose is recommended about 2 hours later. Rimegepant is a meltaway tablet and only comes in a 75-mg strength. It should be taken early in the attack, and usually the patient does not need further treatment that day. If they do, they need to switch to another treatment, as rimegepant should not be repeated that day. Rimegepant may be used for both acute care and prevention. It is the only tablet that can be used for both. 

Both drugs have been shown to provide pain freedom for about 20% of patients at 2 hours, which is statistically better than the patients that received the placebo. These drugs generally don’t cause many adverse events but can cause a little nausea or drowsiness in some patients. Ubrogepant has a few contraindications; patients on certain medications such as antibiotics or antifungals cannot take it. If a patient is not doing well on a triptan or should not be given a drug that constricts blood vessels, I often switch them to one of these gepants (if covered by insurance). Both drugs have a plan to let the patient try them at a low cost. 

How are the gepants used acutely?

Gepants are used just like a triptan. As soon as the patient has a migraine headache starting, they take either ubrogepant or rimegepant as quickly as possible. Some patients say they feel the gepant begin to work within an hour or less, and some patients say it doesn't work at all, so I have them try the other gepant. 

Gepants are probably a better option than triptans if the patient is >40 years because triptans can constrict blood vessels. Older patients, and certainly those who have any kind of cardiac or cerebral blood vessel issues or even peripheral blood vessel disease, should not be given triptans.

When do you consider using preventive treatment in migraine?

If a patient has ≥4 moderate-to-severe headache days a month, or fewer with severe disability, or does not respond to acute care medications or those drugs are contraindicated, I consider giving them preventive therapy for migraine. The goal is to decrease the number of migraine days per month and to decrease the intensity, duration, and disability of the attacks.

Which gepants can you use for prevention of migraine?

I discussed rimegepant as an acute care medication, but the same 75-mg meltaway tablet given every other day works preventively to decrease the number of headaches. I like it, as it has few adverse events—<3% of patients experience nausea and abdominal pain—and it can also be used to stop a headache on days the patient did not take a tablet.

Atogepant is a newer, US Food and Drug Administration (FDA)-approved gepant taken once daily by mouth for prevention of migraine, and it works to decrease headache days per month. It has more side effects than the other gepants, including constipation, drowsiness, and nausea. If a patient does not have many adverse events while taking it, it is a good migraine preventive. 

How do you feel about monoclonal antibodies that bind to CGRP or its receptor for migraine preventive treatment?

Before the gepants became available, 4 different pharmaceutical companies were making monoclonal antibodies (mAbs) that bind to either CGRP or its receptor. This class of medication can be quite effective for most patients needing migraine prevention, as these medications last for a long time if the patient keeps taking it. 

Antibodies, when injected, continue to work for 1 to 3 months, making them perfect for migraine prevention, but they must be given either by the patient using an autoinjector with a tiny needle or by intravenous (IV) infusion in a hospital or office. They tend to be quite effective and have few adverse events.  

The first one to come out was erenumab, then frenanezumab, and galcanezumab. The newest one is eptinezumab, given by IV infusion over 30 minutes. Erenumab is the only mAb that sits on the receptor to prevent the CGRP from docking on the receptor, and it's the only one that seems to cause adverse events such as constipation and increased blood pressure in some patients. Eptinezumab is the only drug in this category given by IV infusion; patients must come to the office to receive the injection every 3 months. Even though eptinezumab is a powerful drug, I find that patients generally don't like coming in for IV treatment. I reserve it for when a patient has failed several other preventive treatments. The other 3 drugs (erenumab, fremanezumab, galcanezumab) are subcutaneous injections that the patient can self-administer at home. Fremanezumab can be taken once a month or once every 3 months, depending on the dose prescribed. 

What migraine devices do you like to prescribe?

The device that I tend to have my patients use is called Nerivio®; it has been cleared by the FDA for acute treatment of migraine in patients ≥12 years. An article was just published in the journal Headache on its use in prevention of migraine. The company expects the FDA to clear it very soon for prevention when used for 45 minutes every other day.

Nerivio® is an electrical stimulator that is placed on the upper arm like a blood pressure cuff. It is battery-powered and links to an app on a smartphone. I have my patients turn it up slowly to a higher gain, and when they feel a slight discomfort, they lower down until they do not feel it. That's where I recommend that they keep it for 45 minutes of treatment, starting at the beginning of a migraine attack. 

Nerivio® also has a behavioral medicine program incorporated into the smartphone app that lasts for 25 minutes. While the patient is receiving the 45 minutes of electrical stimulation, they are also being guided through relaxation techniques to help ease the headache. The company has done a controlled study comparing the efficacy of Nerivio® with and without the behavioral treatment and found that the 2 together are more effective than Nerivio® alone. 

The early double-blind studies of this device, as sent to the FDA for clearance, have excellent efficacy data with very few adverse events. Thus, it is used by many patients. The company has arranged a lower cost for the first month of treatment so a patient can see whether the device is effective.

There's also a device called Relivion®, which is worn like a tiara on the head to stimulate 4 nerves above the eyebrows that are part of the trigeminal system and 2 in the back of the head that affect the occipital nerves.

One of the earliest devices to launch is the gammaCore vagal nerve stimulator. It is handheld and controlled by the patient. It is placed on the front and side of the neck in the region of the vagal nerve. For acute care of migraine, the patient stimulates for 2 minutes and then waits several minutes before repeating 2 minutes of treatment. If you want to prescribe it for the prevention of migraine, a patient could do this sequence twice per day. It has been approved for acute care and prevention of migraine and, along with other medication for cluster headaches, it is easy to use and approved for almost any kind of headache. Unfortunately, it is extremely expensive for patients and is not covered well by insurance unless the patient is a veteran or goes to a Veterans Health Administration hospital for care. 

There are a few other devices that also work for migraine. Most electrical stimulation devices are costly, but we do hope that insurance companies will begin to cover them soon. Most devices cause few adverse events, have few contraindications, and will be used more as they become more affordable.

Can you summarize migraine treatment for us in one paragraph?

No, but I will try. We have many acute care treatments for migraine that are effective. Some, such as the triptans, do constrict blood vessels, and certain patients should not be taking medications that affect blood vessels. Some medications cause certain side effects or take too long to work, and we have other options for those patients. If a patient has ≥4 headache days per month or fewer associated with a lot of disability, we need to consider prevention. We have older preventives such as beta blockers and epilepsy medications, which are less expensive and can work but usually have many side effects. Now we have 4 mAbs that bind to CGRP or its receptor, which work well for a month or more with few adverse events. We also have 2 oral gepants for prevention. When you add in several devices, I have so many options for my patients today that I am a lucky neurologist, and my patients are even luckier!

Testing for nonictal cephalic allodynia can help predict response to the anti–calcitonin gene-related peptide (CGRP) galcanezumab (Emgality, Eli Lilly) for patients with migraine, new research suggests.

The ictal phase refers to “sensitization occurring during a time when central trigeminovascular neurons receive massive nociceptive input from active meningeal nociceptors,” whereas the nonictal phase refers to “sensitization occurring during a time when central trigeminovascular neurons receive no or subliminal nociceptive input from meningeal nociceptors,” investigators noted.

In an observational, open-label cohort study, pretreatment nonictal cephalic allodynia identified galcanezumab responders with nearly 80% accuracy, and it identified nonresponders with nearly 85% accuracy.

“Detection of nonictal allodynia with a simplified paradigm of Quantitative Sensory Testing (QST) may provide a quick, affordable, noninvasive, and patient-friendly way to prospectively distinguish between responders and nonresponders to the prophylactic treatment of chronic and high-frequency episodic migraine with drugs that reduce CGRP signaling,” Sait Ashina, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, and colleagues wrote.

The findings were published online in Cephalalgia.
 

Immediate clinical relevance

Investigator Rami Burstein, PhD, also with Beth Israel Deaconess Medical Center and Harvard Medical School, developed the concept of predicting response to anti-CGRP treatment by testing for the presence or absence of nonictal cephalic allodynia in collaboration with the company CGRP Diagnostics.

In 43 anti–CGRP-naive patients with migraine, the researchers used a simplified QST algorithm to determine the presence/absence of cephalic or extracephalic allodynia during the nonictal phase of migraine – defined as the period from less than 12 hours after a migraine attack to less than 12 hours before the next attack.

Patients were considered to have allodynia if heat pain thresholds were between 32° C and 40° C, if cold pain thresholds were between 32° C and 20° C, or if the mechanical pain was threshold was less than 60 g.

Using these strict criteria, pretreatment nonictal cephalic allodynia was a statistically significant predictor of response to anti-CGRP therapy. It was present in 84% of the 19 nonresponders and was absent in 79% of the 24 responders, for an overall accuracy rate of 86% (P < .0001).

Nonictal cephalic allodynia was “consistently” predictive of response for patients with chronic migraine as well as for those with high-frequency episodic migraine, the researchers reported.

In contrast, they noted that assessing nonictal extracephalic allodynia with QST missed nearly 50% of the patients with allodynia among the nonresponders (accuracy rate of 42%) and added little to the assessment of allodynia among the responders.

Mark Hasleton, PhD, CEO of CGRP Diagnostics, said in an interview that the study shows it’s possible to determine response to anti-CGRP therapy and to prescribe these medications to patients who are most likely to respond.

Dr. Hasleton, who was not personally involved with the current study, noted that pretreatment testing for nonictal cephalic allodynia may also allow for earlier prescription of anti-CGRP therapy and potentially dispense without the need for the current trial-and-error approach to prescribing. He noted that if one anti-CGRP fails the patient, it is highly likely that others will also fail.

Given the “very high correlation of the presence of nonictal cephalic allodynia in responders to galcanezumab, our recommendation would be to routinely pretest all potential anti-CGRP candidates prior to prescription,” he said.
 

End of trial-and-error prescribing

In a comment, Shaheen Lakhan, MD, a neurologist and researcher in Boston, said this research is “very noteworthy, moving us one step closer to predictive, precision medicine and away from the practice of trial-and-error prescribing.

“The trial-and-error approach to migraine management is daunting. These are very costly therapies, and when they don’t work, there is continued tremendous suffering and loss of quality of life for patients,” said Dr. Lakhan, who was not involved in the study.

He added that the failure of drugs to benefit individual patients “may lead to distrust of the health care provider” and to the system as a whole, which in turn could lead to less access to care for other conditions or for preventive measures.

“I envision a time when these predictive measures collectively (interictal allodynia, as in this study, plus biobehavioral data) will assist us neurologists in appropriately selecting migraine therapies,” Dr. Lakhan said.

“Beyond that, we will eventually test new therapies not in cells, animals, and even humans but in silico. In the very near future, we will have solutions tailored to not people suffering a disease but to you – an individual with a unique genetic, protein, physical, developmental, psychological, and behavioral makeup,” he added.

The study was funded in part by Eli Lilly, the National Institutes of Health, and the anesthesia department at Beth Israel Deaconess Medical Center. Galcanezumab was provided by Eli Lilly. Dr. Lakhan reported no relevant financial relationships.

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

Testing for nonictal cephalic allodynia can help predict response to the anti–calcitonin gene-related peptide (CGRP) galcanezumab (Emgality, Eli Lilly) for patients with migraine, new research suggests.

The ictal phase refers to “sensitization occurring during a time when central trigeminovascular neurons receive massive nociceptive input from active meningeal nociceptors,” whereas the nonictal phase refers to “sensitization occurring during a time when central trigeminovascular neurons receive no or subliminal nociceptive input from meningeal nociceptors,” investigators noted.

In an observational, open-label cohort study, pretreatment nonictal cephalic allodynia identified galcanezumab responders with nearly 80% accuracy, and it identified nonresponders with nearly 85% accuracy.

“Detection of nonictal allodynia with a simplified paradigm of Quantitative Sensory Testing (QST) may provide a quick, affordable, noninvasive, and patient-friendly way to prospectively distinguish between responders and nonresponders to the prophylactic treatment of chronic and high-frequency episodic migraine with drugs that reduce CGRP signaling,” Sait Ashina, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, and colleagues wrote.

The findings were published online in Cephalalgia.
 

Immediate clinical relevance

Investigator Rami Burstein, PhD, also with Beth Israel Deaconess Medical Center and Harvard Medical School, developed the concept of predicting response to anti-CGRP treatment by testing for the presence or absence of nonictal cephalic allodynia in collaboration with the company CGRP Diagnostics.

In 43 anti–CGRP-naive patients with migraine, the researchers used a simplified QST algorithm to determine the presence/absence of cephalic or extracephalic allodynia during the nonictal phase of migraine – defined as the period from less than 12 hours after a migraine attack to less than 12 hours before the next attack.

Patients were considered to have allodynia if heat pain thresholds were between 32° C and 40° C, if cold pain thresholds were between 32° C and 20° C, or if the mechanical pain was threshold was less than 60 g.

Using these strict criteria, pretreatment nonictal cephalic allodynia was a statistically significant predictor of response to anti-CGRP therapy. It was present in 84% of the 19 nonresponders and was absent in 79% of the 24 responders, for an overall accuracy rate of 86% (P < .0001).

Nonictal cephalic allodynia was “consistently” predictive of response for patients with chronic migraine as well as for those with high-frequency episodic migraine, the researchers reported.

In contrast, they noted that assessing nonictal extracephalic allodynia with QST missed nearly 50% of the patients with allodynia among the nonresponders (accuracy rate of 42%) and added little to the assessment of allodynia among the responders.

Mark Hasleton, PhD, CEO of CGRP Diagnostics, said in an interview that the study shows it’s possible to determine response to anti-CGRP therapy and to prescribe these medications to patients who are most likely to respond.

Dr. Hasleton, who was not personally involved with the current study, noted that pretreatment testing for nonictal cephalic allodynia may also allow for earlier prescription of anti-CGRP therapy and potentially dispense without the need for the current trial-and-error approach to prescribing. He noted that if one anti-CGRP fails the patient, it is highly likely that others will also fail.

Given the “very high correlation of the presence of nonictal cephalic allodynia in responders to galcanezumab, our recommendation would be to routinely pretest all potential anti-CGRP candidates prior to prescription,” he said.
 

End of trial-and-error prescribing

In a comment, Shaheen Lakhan, MD, a neurologist and researcher in Boston, said this research is “very noteworthy, moving us one step closer to predictive, precision medicine and away from the practice of trial-and-error prescribing.

“The trial-and-error approach to migraine management is daunting. These are very costly therapies, and when they don’t work, there is continued tremendous suffering and loss of quality of life for patients,” said Dr. Lakhan, who was not involved in the study.

He added that the failure of drugs to benefit individual patients “may lead to distrust of the health care provider” and to the system as a whole, which in turn could lead to less access to care for other conditions or for preventive measures.

“I envision a time when these predictive measures collectively (interictal allodynia, as in this study, plus biobehavioral data) will assist us neurologists in appropriately selecting migraine therapies,” Dr. Lakhan said.

“Beyond that, we will eventually test new therapies not in cells, animals, and even humans but in silico. In the very near future, we will have solutions tailored to not people suffering a disease but to you – an individual with a unique genetic, protein, physical, developmental, psychological, and behavioral makeup,” he added.

The study was funded in part by Eli Lilly, the National Institutes of Health, and the anesthesia department at Beth Israel Deaconess Medical Center. Galcanezumab was provided by Eli Lilly. Dr. Lakhan reported no relevant financial relationships.

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

Testing for nonictal cephalic allodynia can help predict response to the anti–calcitonin gene-related peptide (CGRP) galcanezumab (Emgality, Eli Lilly) for patients with migraine, new research suggests.

The ictal phase refers to “sensitization occurring during a time when central trigeminovascular neurons receive massive nociceptive input from active meningeal nociceptors,” whereas the nonictal phase refers to “sensitization occurring during a time when central trigeminovascular neurons receive no or subliminal nociceptive input from meningeal nociceptors,” investigators noted.

In an observational, open-label cohort study, pretreatment nonictal cephalic allodynia identified galcanezumab responders with nearly 80% accuracy, and it identified nonresponders with nearly 85% accuracy.

“Detection of nonictal allodynia with a simplified paradigm of Quantitative Sensory Testing (QST) may provide a quick, affordable, noninvasive, and patient-friendly way to prospectively distinguish between responders and nonresponders to the prophylactic treatment of chronic and high-frequency episodic migraine with drugs that reduce CGRP signaling,” Sait Ashina, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, and colleagues wrote.

The findings were published online in Cephalalgia.
 

Immediate clinical relevance

Investigator Rami Burstein, PhD, also with Beth Israel Deaconess Medical Center and Harvard Medical School, developed the concept of predicting response to anti-CGRP treatment by testing for the presence or absence of nonictal cephalic allodynia in collaboration with the company CGRP Diagnostics.

In 43 anti–CGRP-naive patients with migraine, the researchers used a simplified QST algorithm to determine the presence/absence of cephalic or extracephalic allodynia during the nonictal phase of migraine – defined as the period from less than 12 hours after a migraine attack to less than 12 hours before the next attack.

Patients were considered to have allodynia if heat pain thresholds were between 32° C and 40° C, if cold pain thresholds were between 32° C and 20° C, or if the mechanical pain was threshold was less than 60 g.

Using these strict criteria, pretreatment nonictal cephalic allodynia was a statistically significant predictor of response to anti-CGRP therapy. It was present in 84% of the 19 nonresponders and was absent in 79% of the 24 responders, for an overall accuracy rate of 86% (P < .0001).

Nonictal cephalic allodynia was “consistently” predictive of response for patients with chronic migraine as well as for those with high-frequency episodic migraine, the researchers reported.

In contrast, they noted that assessing nonictal extracephalic allodynia with QST missed nearly 50% of the patients with allodynia among the nonresponders (accuracy rate of 42%) and added little to the assessment of allodynia among the responders.

Mark Hasleton, PhD, CEO of CGRP Diagnostics, said in an interview that the study shows it’s possible to determine response to anti-CGRP therapy and to prescribe these medications to patients who are most likely to respond.

Dr. Hasleton, who was not personally involved with the current study, noted that pretreatment testing for nonictal cephalic allodynia may also allow for earlier prescription of anti-CGRP therapy and potentially dispense without the need for the current trial-and-error approach to prescribing. He noted that if one anti-CGRP fails the patient, it is highly likely that others will also fail.

Given the “very high correlation of the presence of nonictal cephalic allodynia in responders to galcanezumab, our recommendation would be to routinely pretest all potential anti-CGRP candidates prior to prescription,” he said.
 

End of trial-and-error prescribing

In a comment, Shaheen Lakhan, MD, a neurologist and researcher in Boston, said this research is “very noteworthy, moving us one step closer to predictive, precision medicine and away from the practice of trial-and-error prescribing.

“The trial-and-error approach to migraine management is daunting. These are very costly therapies, and when they don’t work, there is continued tremendous suffering and loss of quality of life for patients,” said Dr. Lakhan, who was not involved in the study.

He added that the failure of drugs to benefit individual patients “may lead to distrust of the health care provider” and to the system as a whole, which in turn could lead to less access to care for other conditions or for preventive measures.

“I envision a time when these predictive measures collectively (interictal allodynia, as in this study, plus biobehavioral data) will assist us neurologists in appropriately selecting migraine therapies,” Dr. Lakhan said.

“Beyond that, we will eventually test new therapies not in cells, animals, and even humans but in silico. In the very near future, we will have solutions tailored to not people suffering a disease but to you – an individual with a unique genetic, protein, physical, developmental, psychological, and behavioral makeup,” he added.

The study was funded in part by Eli Lilly, the National Institutes of Health, and the anesthesia department at Beth Israel Deaconess Medical Center. Galcanezumab was provided by Eli Lilly. Dr. Lakhan reported no relevant financial relationships.

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

Key clinical point: Migraine history was associated with poor sleep quality in premenopausal women, but not in perimenopausal women.

Major finding: A significant association was observed between migraine history and poor sleep quality in premenopausal women (odds ratio [OR] 1.4; 95% CI 1.01-2.04; P  =  .044) but not in perimenopausal women (OR 1.14; 95% CI 0.80-1.64; P  =  .46).

Study details: The data come from a cross-sectional analysis of 2067 women (premenopausal n = 962; perimenopausal n = 1105) from the Data Registry on the Experiences of Aging, Menopause, and Sexuality, of which 594 (28.7%) had a migraine history.

Disclosures: This study did not receive any funding. Some authors declared being consultants for or receiving past funding, consulting fees, grant support, or honoraria from various organizations.

Source: Faubion SS et al. Migraine and sleep quality: Does the association change in midlife women? Menopause. 2023 (Jan 31). Doi: 10.1097/GME.0000000000002149

Key clinical point: Migraine history was associated with poor sleep quality in premenopausal women, but not in perimenopausal women.

Major finding: A significant association was observed between migraine history and poor sleep quality in premenopausal women (odds ratio [OR] 1.4; 95% CI 1.01-2.04; P  =  .044) but not in perimenopausal women (OR 1.14; 95% CI 0.80-1.64; P  =  .46).

Study details: The data come from a cross-sectional analysis of 2067 women (premenopausal n = 962; perimenopausal n = 1105) from the Data Registry on the Experiences of Aging, Menopause, and Sexuality, of which 594 (28.7%) had a migraine history.

Disclosures: This study did not receive any funding. Some authors declared being consultants for or receiving past funding, consulting fees, grant support, or honoraria from various organizations.

Source: Faubion SS et al. Migraine and sleep quality: Does the association change in midlife women? Menopause. 2023 (Jan 31). Doi: 10.1097/GME.0000000000002149

Key clinical point: Migraine history was associated with poor sleep quality in premenopausal women, but not in perimenopausal women.

Major finding: A significant association was observed between migraine history and poor sleep quality in premenopausal women (odds ratio [OR] 1.4; 95% CI 1.01-2.04; P  =  .044) but not in perimenopausal women (OR 1.14; 95% CI 0.80-1.64; P  =  .46).

Study details: The data come from a cross-sectional analysis of 2067 women (premenopausal n = 962; perimenopausal n = 1105) from the Data Registry on the Experiences of Aging, Menopause, and Sexuality, of which 594 (28.7%) had a migraine history.

Disclosures: This study did not receive any funding. Some authors declared being consultants for or receiving past funding, consulting fees, grant support, or honoraria from various organizations.

Source: Faubion SS et al. Migraine and sleep quality: Does the association change in midlife women? Menopause. 2023 (Jan 31). Doi: 10.1097/GME.0000000000002149

Key clinical point: Migraine may be associated with an increased risk for any stroke and ischemic stroke in middle-aged and elderly populations.

Major finding: Findings suggested an association between migraine and risk for any stroke (adjusted hazard ratio [aHR] 1.44; P  =  .076) and ischemic stroke (aHR 1.50; P  =  .067), but without statistical significance.

Study details: This ongoing prospective population-based cohort study included 6925 stroke-free participants, of which 1030 participants had a lifetime history of migraine and 195 participants developed incident stroke.

Disclosures: This study received funding from Erasmus Medical Center, Erasmus University, Netherlands, and other sources. AMVD Brink declared receiving support from the Dutch Research Council and research grants or consulting fees from AbbVie/Allergan and other sources.

Source: Acarsoy C et al. Migraine and the risk of stroke in a middle-aged and elderly population: A prospective cohort study. Cephalalgia. 2023;43(1):3331024221132008 (Jan 9). Doi: 10.1177/03331024221132008

Key clinical point: Migraine may be associated with an increased risk for any stroke and ischemic stroke in middle-aged and elderly populations.

Major finding: Findings suggested an association between migraine and risk for any stroke (adjusted hazard ratio [aHR] 1.44; P  =  .076) and ischemic stroke (aHR 1.50; P  =  .067), but without statistical significance.

Study details: This ongoing prospective population-based cohort study included 6925 stroke-free participants, of which 1030 participants had a lifetime history of migraine and 195 participants developed incident stroke.

Disclosures: This study received funding from Erasmus Medical Center, Erasmus University, Netherlands, and other sources. AMVD Brink declared receiving support from the Dutch Research Council and research grants or consulting fees from AbbVie/Allergan and other sources.

Source: Acarsoy C et al. Migraine and the risk of stroke in a middle-aged and elderly population: A prospective cohort study. Cephalalgia. 2023;43(1):3331024221132008 (Jan 9). Doi: 10.1177/03331024221132008

Key clinical point: Migraine may be associated with an increased risk for any stroke and ischemic stroke in middle-aged and elderly populations.

Major finding: Findings suggested an association between migraine and risk for any stroke (adjusted hazard ratio [aHR] 1.44; P  =  .076) and ischemic stroke (aHR 1.50; P  =  .067), but without statistical significance.

Study details: This ongoing prospective population-based cohort study included 6925 stroke-free participants, of which 1030 participants had a lifetime history of migraine and 195 participants developed incident stroke.

Disclosures: This study received funding from Erasmus Medical Center, Erasmus University, Netherlands, and other sources. AMVD Brink declared receiving support from the Dutch Research Council and research grants or consulting fees from AbbVie/Allergan and other sources.

Source: Acarsoy C et al. Migraine and the risk of stroke in a middle-aged and elderly population: A prospective cohort study. Cephalalgia. 2023;43(1):3331024221132008 (Jan 9). Doi: 10.1177/03331024221132008

Key clinical point: Acupuncture showed a similar preventive treatment effect to fremanezumab in patients with episodic migraine; however, acupuncture was associated with lower adverse event rates.

Major finding: Compared with acupuncture, monthly and single-dose fremanezumab showed similar decrease in monthly migraine days (P  =  .473 and P  =  .214, respectively) and 50% responder rate (P  =  .17 and P  =  .109, respectively).  The adverse event risk was lower with acupuncture (25%) vs monthly and single-dose fremanezumab (both 66%).

Study details: This study evaluated 302 patients with episodic migraine from an acupuncture trial (acupuncture n = 145; sham acupuncture n = 81; waiting-list control n = 76) and 875 patients with episodic migraine from the fremanezumab trial (monthly fremanezumab n = 290; single-dose fremanezumab n = 291; placebo n = 294).

Disclosures: This study did not declare a funding source. The authors declared no conflicts of interest.

Source: Zheng H et al. Matching adjusted indirect comparison of acupuncture versus fremanezumab in the preventive treatment of episodic migraine. Curr Med Res Opin. 2023 (Feb 8). Doi: 10.1080/03007995.2023.2174746

Key clinical point: Acupuncture showed a similar preventive treatment effect to fremanezumab in patients with episodic migraine; however, acupuncture was associated with lower adverse event rates.

Major finding: Compared with acupuncture, monthly and single-dose fremanezumab showed similar decrease in monthly migraine days (P  =  .473 and P  =  .214, respectively) and 50% responder rate (P  =  .17 and P  =  .109, respectively).  The adverse event risk was lower with acupuncture (25%) vs monthly and single-dose fremanezumab (both 66%).

Study details: This study evaluated 302 patients with episodic migraine from an acupuncture trial (acupuncture n = 145; sham acupuncture n = 81; waiting-list control n = 76) and 875 patients with episodic migraine from the fremanezumab trial (monthly fremanezumab n = 290; single-dose fremanezumab n = 291; placebo n = 294).

Disclosures: This study did not declare a funding source. The authors declared no conflicts of interest.

Source: Zheng H et al. Matching adjusted indirect comparison of acupuncture versus fremanezumab in the preventive treatment of episodic migraine. Curr Med Res Opin. 2023 (Feb 8). Doi: 10.1080/03007995.2023.2174746

Key clinical point: Acupuncture showed a similar preventive treatment effect to fremanezumab in patients with episodic migraine; however, acupuncture was associated with lower adverse event rates.

Major finding: Compared with acupuncture, monthly and single-dose fremanezumab showed similar decrease in monthly migraine days (P  =  .473 and P  =  .214, respectively) and 50% responder rate (P  =  .17 and P  =  .109, respectively).  The adverse event risk was lower with acupuncture (25%) vs monthly and single-dose fremanezumab (both 66%).

Study details: This study evaluated 302 patients with episodic migraine from an acupuncture trial (acupuncture n = 145; sham acupuncture n = 81; waiting-list control n = 76) and 875 patients with episodic migraine from the fremanezumab trial (monthly fremanezumab n = 290; single-dose fremanezumab n = 291; placebo n = 294).

Disclosures: This study did not declare a funding source. The authors declared no conflicts of interest.

Source: Zheng H et al. Matching adjusted indirect comparison of acupuncture versus fremanezumab in the preventive treatment of episodic migraine. Curr Med Res Opin. 2023 (Feb 8). Doi: 10.1080/03007995.2023.2174746

Key clinical point: Patients with difficult-to-treat chronic migraine and insufficient treatment response after the first 2 cycles of onabotulinumtoxinA showed improvements in migraine-related outcomes after switching to anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs).

Major finding: At 9 months, a higher proportion of patients achieved a ≥50% response rate (65.0% vs 22.4%) and reported a greater reduction in monthly headache days (change from baseline −12.0 vs −5.0 days) with anti-CGRP mAbs vs onabotulinumtoxinA treatment. No serious adverse events were reported. Treatment discontinuation due to adverse events was reported by 2 patients.

Study details: This retrospective analysis included 78 patients with difficult-to-treat chronic migraine with or without medication overuse and ≥2 migraine preventive treatment failures who discontinued onabotulinumtoxinA and switched to anti-CGRP mAbs.

Disclosures: This study did not receive any specific funding. Three authors declared receiving personal fees or grants or serving on a scientific advisory board and as a founding scientist for various sources.

Source: Iannone LF et al. Switching onabotulinumtoxinA to monoclonal anti-CGRP antibodies in drug-resistant chronic migraine. CNS Drugs. 2023;37(2):189-202 (Jan 19).  Doi: 10.1007/s40263-022-00983-5

Key clinical point: Patients with difficult-to-treat chronic migraine and insufficient treatment response after the first 2 cycles of onabotulinumtoxinA showed improvements in migraine-related outcomes after switching to anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs).

Major finding: At 9 months, a higher proportion of patients achieved a ≥50% response rate (65.0% vs 22.4%) and reported a greater reduction in monthly headache days (change from baseline −12.0 vs −5.0 days) with anti-CGRP mAbs vs onabotulinumtoxinA treatment. No serious adverse events were reported. Treatment discontinuation due to adverse events was reported by 2 patients.

Study details: This retrospective analysis included 78 patients with difficult-to-treat chronic migraine with or without medication overuse and ≥2 migraine preventive treatment failures who discontinued onabotulinumtoxinA and switched to anti-CGRP mAbs.

Disclosures: This study did not receive any specific funding. Three authors declared receiving personal fees or grants or serving on a scientific advisory board and as a founding scientist for various sources.

Source: Iannone LF et al. Switching onabotulinumtoxinA to monoclonal anti-CGRP antibodies in drug-resistant chronic migraine. CNS Drugs. 2023;37(2):189-202 (Jan 19).  Doi: 10.1007/s40263-022-00983-5

Key clinical point: Patients with difficult-to-treat chronic migraine and insufficient treatment response after the first 2 cycles of onabotulinumtoxinA showed improvements in migraine-related outcomes after switching to anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs).

Major finding: At 9 months, a higher proportion of patients achieved a ≥50% response rate (65.0% vs 22.4%) and reported a greater reduction in monthly headache days (change from baseline −12.0 vs −5.0 days) with anti-CGRP mAbs vs onabotulinumtoxinA treatment. No serious adverse events were reported. Treatment discontinuation due to adverse events was reported by 2 patients.

Study details: This retrospective analysis included 78 patients with difficult-to-treat chronic migraine with or without medication overuse and ≥2 migraine preventive treatment failures who discontinued onabotulinumtoxinA and switched to anti-CGRP mAbs.

Disclosures: This study did not receive any specific funding. Three authors declared receiving personal fees or grants or serving on a scientific advisory board and as a founding scientist for various sources.

Source: Iannone LF et al. Switching onabotulinumtoxinA to monoclonal anti-CGRP antibodies in drug-resistant chronic migraine. CNS Drugs. 2023;37(2):189-202 (Jan 19).  Doi: 10.1007/s40263-022-00983-5

Key clinical point: Eptinezumab vs placebo demonstrated early, sustained, and clinically meaningful improvements in patient-reported outcomes in patients with chronic migraine and medication-overuse headache.

Major finding: Higher proportions of patients receiving 100/300 mg eptinezumab vs placebo showed ≥6-point reduction in the 6-item Headache Impact Test total score (46.0%/57.1% vs 31.7%) at week 4 and improvements in Patient Global Impression of Change scores (58.5%/67.4% vs 35.8%) and patient-identified most bothersome symptom (57.1%/64.6% vs 29.9%) at week 12, which was sustained until week 24.

Study details: This post hoc analysis of the phase 3 PROMISE-2 trial included a subgroup of 431 patients with chronic migraine and medication-overuse headache who were randomly assigned to receive ≤2 doses of eptinezumab (100/300 mg) or placebo.

Disclosures: The trial was funded by Lundbeck Seattle BioPharmaceuticals, Inc. Three authors declared being current or former employees of Lundbeck or its subsidiaries or a company contracted by H Lundbeck A/S. Several authors reported ties with various sources, including Lundbeck.

Source: Starling AJ et al. Eptinezumab improved patient-reported outcomes in patients with migraine and medication-overuse headache: Subgroup analysis of the randomized PROMISE-2 trial. Headache. 2023 (Jan 12). Doi: 10.1111/head.14434

Key clinical point: Eptinezumab vs placebo demonstrated early, sustained, and clinically meaningful improvements in patient-reported outcomes in patients with chronic migraine and medication-overuse headache.

Major finding: Higher proportions of patients receiving 100/300 mg eptinezumab vs placebo showed ≥6-point reduction in the 6-item Headache Impact Test total score (46.0%/57.1% vs 31.7%) at week 4 and improvements in Patient Global Impression of Change scores (58.5%/67.4% vs 35.8%) and patient-identified most bothersome symptom (57.1%/64.6% vs 29.9%) at week 12, which was sustained until week 24.

Study details: This post hoc analysis of the phase 3 PROMISE-2 trial included a subgroup of 431 patients with chronic migraine and medication-overuse headache who were randomly assigned to receive ≤2 doses of eptinezumab (100/300 mg) or placebo.

Disclosures: The trial was funded by Lundbeck Seattle BioPharmaceuticals, Inc. Three authors declared being current or former employees of Lundbeck or its subsidiaries or a company contracted by H Lundbeck A/S. Several authors reported ties with various sources, including Lundbeck.

Source: Starling AJ et al. Eptinezumab improved patient-reported outcomes in patients with migraine and medication-overuse headache: Subgroup analysis of the randomized PROMISE-2 trial. Headache. 2023 (Jan 12). Doi: 10.1111/head.14434

Key clinical point: Eptinezumab vs placebo demonstrated early, sustained, and clinically meaningful improvements in patient-reported outcomes in patients with chronic migraine and medication-overuse headache.

Major finding: Higher proportions of patients receiving 100/300 mg eptinezumab vs placebo showed ≥6-point reduction in the 6-item Headache Impact Test total score (46.0%/57.1% vs 31.7%) at week 4 and improvements in Patient Global Impression of Change scores (58.5%/67.4% vs 35.8%) and patient-identified most bothersome symptom (57.1%/64.6% vs 29.9%) at week 12, which was sustained until week 24.

Study details: This post hoc analysis of the phase 3 PROMISE-2 trial included a subgroup of 431 patients with chronic migraine and medication-overuse headache who were randomly assigned to receive ≤2 doses of eptinezumab (100/300 mg) or placebo.

Disclosures: The trial was funded by Lundbeck Seattle BioPharmaceuticals, Inc. Three authors declared being current or former employees of Lundbeck or its subsidiaries or a company contracted by H Lundbeck A/S. Several authors reported ties with various sources, including Lundbeck.

Source: Starling AJ et al. Eptinezumab improved patient-reported outcomes in patients with migraine and medication-overuse headache: Subgroup analysis of the randomized PROMISE-2 trial. Headache. 2023 (Jan 12). Doi: 10.1111/head.14434