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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.
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.
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.
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.