Headache & Migraine

Key clinical point: A higher dose of onabotulinumtoxinA (Botox®) may decrease the number of headache and severe headache days in patients with chronic migraine who had an unsatisfactory response to the conventional 150-unit dose.

Major finding: After receiving 3 rounds of 200 units onabotulinumtoxinA, patients had a significant reduction in headache (13.62±10.79 to 11.02±10.61) and severe headache (5.88±6.73 to 4.01±4.89) days (both P< .001).

Study details: This retrospective paired comparison study included 175 patients with chronic migraine who received ≥3 rounds of 150 units onabotulinumtoxinA followed by ≥3 rounds of 200 units onabotulinumtoxinA.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Zandieh A, Cutrer FM. OnabotulinumtoxinA in chronic migraine: Is the response dose dependent?BMC Neurol. 2022;22:218(Jun 13). Doi:10.1186/s12883-022-02742-x

Key clinical point: A higher dose of onabotulinumtoxinA (Botox®) may decrease the number of headache and severe headache days in patients with chronic migraine who had an unsatisfactory response to the conventional 150-unit dose.

Major finding: After receiving 3 rounds of 200 units onabotulinumtoxinA, patients had a significant reduction in headache (13.62±10.79 to 11.02±10.61) and severe headache (5.88±6.73 to 4.01±4.89) days (both P< .001).

Study details: This retrospective paired comparison study included 175 patients with chronic migraine who received ≥3 rounds of 150 units onabotulinumtoxinA followed by ≥3 rounds of 200 units onabotulinumtoxinA.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Zandieh A, Cutrer FM. OnabotulinumtoxinA in chronic migraine: Is the response dose dependent?BMC Neurol. 2022;22:218(Jun 13). Doi:10.1186/s12883-022-02742-x

Key clinical point: A higher dose of onabotulinumtoxinA (Botox®) may decrease the number of headache and severe headache days in patients with chronic migraine who had an unsatisfactory response to the conventional 150-unit dose.

Major finding: After receiving 3 rounds of 200 units onabotulinumtoxinA, patients had a significant reduction in headache (13.62±10.79 to 11.02±10.61) and severe headache (5.88±6.73 to 4.01±4.89) days (both P< .001).

Study details: This retrospective paired comparison study included 175 patients with chronic migraine who received ≥3 rounds of 150 units onabotulinumtoxinA followed by ≥3 rounds of 200 units onabotulinumtoxinA.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Zandieh A, Cutrer FM. OnabotulinumtoxinA in chronic migraine: Is the response dose dependent?BMC Neurol. 2022;22:218(Jun 13). Doi:10.1186/s12883-022-02742-x

In June, the Concord, Mass.–based company Tremeau Pharmaceuticals announced that the Food and Drug Administration was letting it proceed with a phase 3 clinical trial to test rofecoxib, the once-bestselling painkiller known as Vioxx, in patients with migraine.

The anti-inflammatory drug, a cyclooxygenase-2 (COX-2) inhibitor, received its first FDA approval in 1999 and became widely prescribed for arthritis and acute pain. In 2004 it was withdrawn by its manufacturer, Merck, after being shown to raise the risk of cardiovascular events.

In clinical trials and in real-world epidemiological studies, rofecoxib was associated with elevated heart attack, stroke, and related deaths; one 2005 study estimated that it had been responsible for some 38,000 excess deaths in the United States before being withdrawn. In 2007 Merck, beset with allegations that it had suppressed and mischaracterized rofecoxib’s safety data, paid out nearly $5 billion to settle thousands of lawsuits filed by patients and their families.

Shortly before its withdrawal, rofecoxib was approved for the treatment of migraine. Now, with its original patents expired, Tremeau hopes to gain approval for its reformulated version of the drug in both migraine and in hemophilia arthropathy, an indication for which it received an orphan drug designation in 2017 and the agency’s green light for trials in 2020.

Brad Sippy, Tremeau’s chief executive officer, said that his company chose the two indications in part because both patient populations have low cardiovascular risk. Migraine patients are generally younger than the arthritis populations formerly treated with rofecoxib and are unlikely to take the drug for more than a day or 2 at time, avoiding the risks associated with extended exposure.
 

A crowded market

The past several years have seen the emergence of a cornucopia of new migraine treatments, including monoclonal antibodies such as erenumab (Aimovig, Amgen), which help prevent attacks by blocking the vasodilator calcitonin gene-related peptide, or CGRP. In addition to the standard arsenal of triptans and nonsteroidal anti-inflammatory drugs for acute pain relief, migraine patients can now choose among serotonin-blocking agents such as lasmiditan (Reyvow, Eli Lilly), known as “ditans,” and small-molecule CGRP antagonists such as ubrogepant (Ubrelvy, Abbie), known as “gepants.” Some NSAIDs, including one COX inhibitor, have been formulated into rapidly absorbed powders or liquids for migraine.

Mr. Sippy said he sees a role for rofecoxib even in this crowded space. “Migraine as you know is a multimodal situation – few people say that only one drug works for them,” he said. “We think this is an option that would basically be like a high dose of ibuprofen,” but with less frequent dosing and lower gastrointestinal and platelet effects compared with ibuprofen and other NSAIDs.
 

An improved formulation

Rofecoxib “crosses the blood brain barrier very readily – better than other COX inhibitors on the market,” Mr. Sippy added. “It was well absorbed in its original formulation, and our product is even better absorbed than the original – we estimate it’s probably an hour quicker to [peak concentration].” In addition, he said, “our formulation is more efficient at delivering the drug so we don’t need as much active ingredient – our 17.5 milligrams gets you the same systemic exposure as 25 milligrams of the old product.”

A different mechanism of action

Neurologist Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews and professor of neurology at the University of California, Los Angeles, said that he was “cautiously optimistic” that “if used correctly and not too frequently, [rofecoxib] will find its niche in migraine treatment.”

“Patients liked Vioxx,” said Dr. Rapoport, past president of the International Headache Society. Even people currently on prevention “need to have an acute care drug handy.” While some patients on monoclonal antibodies have had success with gepants for acute care, “these both target the same pathway. It’s always nice to have options with a different mechanism of action.”

One of the arguments Tremeau has cited for reintroducing rofecoxib has been an urgent need for alternatives to opioid painkillers. Indeed some analysts have linked the demise of Vioxx with a subsequent increase in opioid prescribing.

Dr. Rapoport noted that he never prescribes opioids or butalbital, a barbiturate, for migraine, and that most headache specialists avoid them in clinical practice. But in the emergency setting, he said, patients receive them all too frequently.

Mr. Sippy said that opioid prescribing, while not unknown in migraine, was a bigger problem in hemophilic arthropathy, the first indication his company has pursued for rofecoxib. People with hemophilia “have a kind of arthritis that would respond well to an anti-inflammatory drug but they can’t take NSAIDs due to bleeding risk. This is why so many end up on opioids. Rofecoxib, as a COX-2 inhibitor, doesn’t have any effect on platelet aggregation, which would make it another option.”
 

No unique risks at prescribed doses

The migraine indication originally started out narrower: Patients with both migraine and bleeding disorders. “But in talking with the FDA, they encouraged us to develop it for migraine,” Mr. Sippy said. The company is considering pursuing a third indication: menstrual pain co-occurring with migraine. Tremeau has not ruled out seeking an indication in patients with arthritis who cannot take other painkillers, whether opioids or NSAIDs.

Five years ago, when Tremeau first announced its plans to bring rofecoxib back – indeed the company was set up for that purpose and has only this and another COX-2 inhibitor in development – some experts warned that there is little to prevent the drug from being used off-label, whether in higher doses or for other diseases.

“That’s something else we’re seeking to solve in addition to going for younger populations,” said Mr. Sippy, who worked at Merck during the Vioxx crisis and later headed neurology at Sunovion before starting his own company.

“We’re going for the former middle dose as our high dose and now we know that you don’t want to take more than the prescribed amount. If it doesn’t work you get off it; you don’t want to dose-creep on it. That’s been a key insight: At the appropriate dose, this product has no unique risk relative to the drug class and potentially some unique benefits,” he said.
 

Risk versus benefit

Joseph Ross, MD, a health policy researcher at Yale University in New Haven, Conn., who in a 2018 editorial expressed concerns about rofecoxib’s revival, said in an email that he felt its use in migraine could be justified, with caveats.

During Vioxx’s original approval and time on the market, “there was a cardiovascular risk associated with use that was not being transparently and clearly reported to patients and clinicians,” Dr. Ross said.

“In terms of testing the product for use in patients with migraine – a population of generally younger patients at lower risk of cardiovascular disease – my only concern is that the risk is clearly communicated and that there is adequate postmarket safety surveillance,” he said. “If patients are making fully informed decisions, the potential benefit of the drug with respect to pain control may be worth the risks.”

Dr. Rapoport serves as an adviser for AbbVie, Amgen, Biohaven, Cala Health, Collegium Pharmaceutical, Satsuma, Teva, Theranica and Xoc; he is on the speakers bureau of AbbVie, Amgen, Biohaven, Impel, Lundbeck, and Teva. Dr. Ross disclosed research support from Johnson and Johnson, the Medical Device Innovation Consortium, and the Laura and John Arnold Foundation, along with government grants; he is also an expert witness in a lawsuit against Biogen.

In June, the Concord, Mass.–based company Tremeau Pharmaceuticals announced that the Food and Drug Administration was letting it proceed with a phase 3 clinical trial to test rofecoxib, the once-bestselling painkiller known as Vioxx, in patients with migraine.

The anti-inflammatory drug, a cyclooxygenase-2 (COX-2) inhibitor, received its first FDA approval in 1999 and became widely prescribed for arthritis and acute pain. In 2004 it was withdrawn by its manufacturer, Merck, after being shown to raise the risk of cardiovascular events.

In clinical trials and in real-world epidemiological studies, rofecoxib was associated with elevated heart attack, stroke, and related deaths; one 2005 study estimated that it had been responsible for some 38,000 excess deaths in the United States before being withdrawn. In 2007 Merck, beset with allegations that it had suppressed and mischaracterized rofecoxib’s safety data, paid out nearly $5 billion to settle thousands of lawsuits filed by patients and their families.

Shortly before its withdrawal, rofecoxib was approved for the treatment of migraine. Now, with its original patents expired, Tremeau hopes to gain approval for its reformulated version of the drug in both migraine and in hemophilia arthropathy, an indication for which it received an orphan drug designation in 2017 and the agency’s green light for trials in 2020.

Brad Sippy, Tremeau’s chief executive officer, said that his company chose the two indications in part because both patient populations have low cardiovascular risk. Migraine patients are generally younger than the arthritis populations formerly treated with rofecoxib and are unlikely to take the drug for more than a day or 2 at time, avoiding the risks associated with extended exposure.
 

A crowded market

The past several years have seen the emergence of a cornucopia of new migraine treatments, including monoclonal antibodies such as erenumab (Aimovig, Amgen), which help prevent attacks by blocking the vasodilator calcitonin gene-related peptide, or CGRP. In addition to the standard arsenal of triptans and nonsteroidal anti-inflammatory drugs for acute pain relief, migraine patients can now choose among serotonin-blocking agents such as lasmiditan (Reyvow, Eli Lilly), known as “ditans,” and small-molecule CGRP antagonists such as ubrogepant (Ubrelvy, Abbie), known as “gepants.” Some NSAIDs, including one COX inhibitor, have been formulated into rapidly absorbed powders or liquids for migraine.

Mr. Sippy said he sees a role for rofecoxib even in this crowded space. “Migraine as you know is a multimodal situation – few people say that only one drug works for them,” he said. “We think this is an option that would basically be like a high dose of ibuprofen,” but with less frequent dosing and lower gastrointestinal and platelet effects compared with ibuprofen and other NSAIDs.
 

An improved formulation

Rofecoxib “crosses the blood brain barrier very readily – better than other COX inhibitors on the market,” Mr. Sippy added. “It was well absorbed in its original formulation, and our product is even better absorbed than the original – we estimate it’s probably an hour quicker to [peak concentration].” In addition, he said, “our formulation is more efficient at delivering the drug so we don’t need as much active ingredient – our 17.5 milligrams gets you the same systemic exposure as 25 milligrams of the old product.”

A different mechanism of action

Neurologist Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews and professor of neurology at the University of California, Los Angeles, said that he was “cautiously optimistic” that “if used correctly and not too frequently, [rofecoxib] will find its niche in migraine treatment.”

“Patients liked Vioxx,” said Dr. Rapoport, past president of the International Headache Society. Even people currently on prevention “need to have an acute care drug handy.” While some patients on monoclonal antibodies have had success with gepants for acute care, “these both target the same pathway. It’s always nice to have options with a different mechanism of action.”

One of the arguments Tremeau has cited for reintroducing rofecoxib has been an urgent need for alternatives to opioid painkillers. Indeed some analysts have linked the demise of Vioxx with a subsequent increase in opioid prescribing.

Dr. Rapoport noted that he never prescribes opioids or butalbital, a barbiturate, for migraine, and that most headache specialists avoid them in clinical practice. But in the emergency setting, he said, patients receive them all too frequently.

Mr. Sippy said that opioid prescribing, while not unknown in migraine, was a bigger problem in hemophilic arthropathy, the first indication his company has pursued for rofecoxib. People with hemophilia “have a kind of arthritis that would respond well to an anti-inflammatory drug but they can’t take NSAIDs due to bleeding risk. This is why so many end up on opioids. Rofecoxib, as a COX-2 inhibitor, doesn’t have any effect on platelet aggregation, which would make it another option.”
 

No unique risks at prescribed doses

The migraine indication originally started out narrower: Patients with both migraine and bleeding disorders. “But in talking with the FDA, they encouraged us to develop it for migraine,” Mr. Sippy said. The company is considering pursuing a third indication: menstrual pain co-occurring with migraine. Tremeau has not ruled out seeking an indication in patients with arthritis who cannot take other painkillers, whether opioids or NSAIDs.

Five years ago, when Tremeau first announced its plans to bring rofecoxib back – indeed the company was set up for that purpose and has only this and another COX-2 inhibitor in development – some experts warned that there is little to prevent the drug from being used off-label, whether in higher doses or for other diseases.

“That’s something else we’re seeking to solve in addition to going for younger populations,” said Mr. Sippy, who worked at Merck during the Vioxx crisis and later headed neurology at Sunovion before starting his own company.

“We’re going for the former middle dose as our high dose and now we know that you don’t want to take more than the prescribed amount. If it doesn’t work you get off it; you don’t want to dose-creep on it. That’s been a key insight: At the appropriate dose, this product has no unique risk relative to the drug class and potentially some unique benefits,” he said.
 

Risk versus benefit

Joseph Ross, MD, a health policy researcher at Yale University in New Haven, Conn., who in a 2018 editorial expressed concerns about rofecoxib’s revival, said in an email that he felt its use in migraine could be justified, with caveats.

During Vioxx’s original approval and time on the market, “there was a cardiovascular risk associated with use that was not being transparently and clearly reported to patients and clinicians,” Dr. Ross said.

“In terms of testing the product for use in patients with migraine – a population of generally younger patients at lower risk of cardiovascular disease – my only concern is that the risk is clearly communicated and that there is adequate postmarket safety surveillance,” he said. “If patients are making fully informed decisions, the potential benefit of the drug with respect to pain control may be worth the risks.”

Dr. Rapoport serves as an adviser for AbbVie, Amgen, Biohaven, Cala Health, Collegium Pharmaceutical, Satsuma, Teva, Theranica and Xoc; he is on the speakers bureau of AbbVie, Amgen, Biohaven, Impel, Lundbeck, and Teva. Dr. Ross disclosed research support from Johnson and Johnson, the Medical Device Innovation Consortium, and the Laura and John Arnold Foundation, along with government grants; he is also an expert witness in a lawsuit against Biogen.

In June, the Concord, Mass.–based company Tremeau Pharmaceuticals announced that the Food and Drug Administration was letting it proceed with a phase 3 clinical trial to test rofecoxib, the once-bestselling painkiller known as Vioxx, in patients with migraine.

The anti-inflammatory drug, a cyclooxygenase-2 (COX-2) inhibitor, received its first FDA approval in 1999 and became widely prescribed for arthritis and acute pain. In 2004 it was withdrawn by its manufacturer, Merck, after being shown to raise the risk of cardiovascular events.

In clinical trials and in real-world epidemiological studies, rofecoxib was associated with elevated heart attack, stroke, and related deaths; one 2005 study estimated that it had been responsible for some 38,000 excess deaths in the United States before being withdrawn. In 2007 Merck, beset with allegations that it had suppressed and mischaracterized rofecoxib’s safety data, paid out nearly $5 billion to settle thousands of lawsuits filed by patients and their families.

Shortly before its withdrawal, rofecoxib was approved for the treatment of migraine. Now, with its original patents expired, Tremeau hopes to gain approval for its reformulated version of the drug in both migraine and in hemophilia arthropathy, an indication for which it received an orphan drug designation in 2017 and the agency’s green light for trials in 2020.

Brad Sippy, Tremeau’s chief executive officer, said that his company chose the two indications in part because both patient populations have low cardiovascular risk. Migraine patients are generally younger than the arthritis populations formerly treated with rofecoxib and are unlikely to take the drug for more than a day or 2 at time, avoiding the risks associated with extended exposure.
 

A crowded market

The past several years have seen the emergence of a cornucopia of new migraine treatments, including monoclonal antibodies such as erenumab (Aimovig, Amgen), which help prevent attacks by blocking the vasodilator calcitonin gene-related peptide, or CGRP. In addition to the standard arsenal of triptans and nonsteroidal anti-inflammatory drugs for acute pain relief, migraine patients can now choose among serotonin-blocking agents such as lasmiditan (Reyvow, Eli Lilly), known as “ditans,” and small-molecule CGRP antagonists such as ubrogepant (Ubrelvy, Abbie), known as “gepants.” Some NSAIDs, including one COX inhibitor, have been formulated into rapidly absorbed powders or liquids for migraine.

Mr. Sippy said he sees a role for rofecoxib even in this crowded space. “Migraine as you know is a multimodal situation – few people say that only one drug works for them,” he said. “We think this is an option that would basically be like a high dose of ibuprofen,” but with less frequent dosing and lower gastrointestinal and platelet effects compared with ibuprofen and other NSAIDs.
 

An improved formulation

Rofecoxib “crosses the blood brain barrier very readily – better than other COX inhibitors on the market,” Mr. Sippy added. “It was well absorbed in its original formulation, and our product is even better absorbed than the original – we estimate it’s probably an hour quicker to [peak concentration].” In addition, he said, “our formulation is more efficient at delivering the drug so we don’t need as much active ingredient – our 17.5 milligrams gets you the same systemic exposure as 25 milligrams of the old product.”

A different mechanism of action

Neurologist Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews and professor of neurology at the University of California, Los Angeles, said that he was “cautiously optimistic” that “if used correctly and not too frequently, [rofecoxib] will find its niche in migraine treatment.”

“Patients liked Vioxx,” said Dr. Rapoport, past president of the International Headache Society. Even people currently on prevention “need to have an acute care drug handy.” While some patients on monoclonal antibodies have had success with gepants for acute care, “these both target the same pathway. It’s always nice to have options with a different mechanism of action.”

One of the arguments Tremeau has cited for reintroducing rofecoxib has been an urgent need for alternatives to opioid painkillers. Indeed some analysts have linked the demise of Vioxx with a subsequent increase in opioid prescribing.

Dr. Rapoport noted that he never prescribes opioids or butalbital, a barbiturate, for migraine, and that most headache specialists avoid them in clinical practice. But in the emergency setting, he said, patients receive them all too frequently.

Mr. Sippy said that opioid prescribing, while not unknown in migraine, was a bigger problem in hemophilic arthropathy, the first indication his company has pursued for rofecoxib. People with hemophilia “have a kind of arthritis that would respond well to an anti-inflammatory drug but they can’t take NSAIDs due to bleeding risk. This is why so many end up on opioids. Rofecoxib, as a COX-2 inhibitor, doesn’t have any effect on platelet aggregation, which would make it another option.”
 

No unique risks at prescribed doses

The migraine indication originally started out narrower: Patients with both migraine and bleeding disorders. “But in talking with the FDA, they encouraged us to develop it for migraine,” Mr. Sippy said. The company is considering pursuing a third indication: menstrual pain co-occurring with migraine. Tremeau has not ruled out seeking an indication in patients with arthritis who cannot take other painkillers, whether opioids or NSAIDs.

Five years ago, when Tremeau first announced its plans to bring rofecoxib back – indeed the company was set up for that purpose and has only this and another COX-2 inhibitor in development – some experts warned that there is little to prevent the drug from being used off-label, whether in higher doses or for other diseases.

“That’s something else we’re seeking to solve in addition to going for younger populations,” said Mr. Sippy, who worked at Merck during the Vioxx crisis and later headed neurology at Sunovion before starting his own company.

“We’re going for the former middle dose as our high dose and now we know that you don’t want to take more than the prescribed amount. If it doesn’t work you get off it; you don’t want to dose-creep on it. That’s been a key insight: At the appropriate dose, this product has no unique risk relative to the drug class and potentially some unique benefits,” he said.
 

Risk versus benefit

Joseph Ross, MD, a health policy researcher at Yale University in New Haven, Conn., who in a 2018 editorial expressed concerns about rofecoxib’s revival, said in an email that he felt its use in migraine could be justified, with caveats.

During Vioxx’s original approval and time on the market, “there was a cardiovascular risk associated with use that was not being transparently and clearly reported to patients and clinicians,” Dr. Ross said.

“In terms of testing the product for use in patients with migraine – a population of generally younger patients at lower risk of cardiovascular disease – my only concern is that the risk is clearly communicated and that there is adequate postmarket safety surveillance,” he said. “If patients are making fully informed decisions, the potential benefit of the drug with respect to pain control may be worth the risks.”

Dr. Rapoport serves as an adviser for AbbVie, Amgen, Biohaven, Cala Health, Collegium Pharmaceutical, Satsuma, Teva, Theranica and Xoc; he is on the speakers bureau of AbbVie, Amgen, Biohaven, Impel, Lundbeck, and Teva. Dr. Ross disclosed research support from Johnson and Johnson, the Medical Device Innovation Consortium, and the Laura and John Arnold Foundation, along with government grants; he is also an expert witness in a lawsuit against Biogen.

DENVER – In a debate over whether headache trials are representative of patients, one neurologist declared that they tend to leave out a variety of subjects with many types of headaches – the young, the old, the pregnant, and those without migraines, among others. But her counterpart defended migraine trials in particular, arguing that they’re evolving to become more valuable as researchers address their limitations.

At the core of the debate at the annual meeting of the American Headache Society were sharp divisions over how much the limitations of headache clinical trials matter. Both neurologists – Jan Brandes, MD, of Nashville (Tenn.) Neuroscience Group, and Amy Gelfand, MD, of the University of California at San Francisco, agree that they exist. But they diverged on how much they matter.
 

Exclusion/inclusion criteria are good

Dr. Brandes argued that randomized controlled trials “remain the single best study design,” and she said migraine headache trials have improved over the past couple of decades.

Eligibility criteria, for example, have expanded to allow patients with more subtypes of migraines to participate, she said. “Another change has been the establishment of guidelines or inclusion criteria that allow patients who have stable and treated hypertension, stable depression, and stable anxiety disorders that are controlled and treated and not interfering with the disease you’re studying.”

In essence, she said, “the exclusion/inclusion criteria are good.”

It’s also a positive change that longer patient-reported outcomes are included in trials, she said.
 

Exclusion/inclusion criteria are too restrictive

But Dr. Gelfand criticized the inclusion criteria in migraine trials, noting it includes “a lot of amazing complexity.” Trials often will limit participation to subjects aged 18-65, even though people have high rates of headaches, she said, and they frequently overrepresent men. Pregnant and lactating women are often omitted, too, even if a trial is examining a behavioral intervention. In some cases, lactating women may be breastfeeding for a year or two, she noted.

“The vast majority of births in the United States, 92%, are to females who are between the ages of 20 and 39. That is also the age range where migraine is most prevalent,” she said. Yes, certain new agents shouldn’t be tested for the first time in pregnant women because of the risk, she said, “but we need to grapple with the fact that migraine is affecting people who are also going to be pregnant and lactating.”

Many other criteria limit the subjects in headache trials, she said. The studies are “almost exclusively” of drugs for migraines, leaving out many people with other types such as adolescents with new persistent headaches. “Where are the trials for them?” she asked.

Other groups that are left out include those whose headaches that are due to a head injury, a viral infection such as COVID-19, or even vaccination against COVID-19, she said. “There are an infinite number of questions here that we are currently not even attempting to answer.”

Non-Whites are also poorly represented in trials, she said, and studies often don’t include data about non-Whites. “Race data exists. Where do we get off not even reporting it?”
 

Room for improvement

For her part, Dr. Brandes said less-common headache disorders are best studied in pragmatic trials until they can be better understood. “We need to understand pathophysiology better for some of these other disorders, particularly things like continuous headache and posttraumatic headache. Then we can begin to expand that.”

She added that randomized clinical trials are now underway regarding secondary headache related to COVID-19.

Dr. Brandes did not report disclosures. Dr. Gelfand had no disclosures.

DENVER – In a debate over whether headache trials are representative of patients, one neurologist declared that they tend to leave out a variety of subjects with many types of headaches – the young, the old, the pregnant, and those without migraines, among others. But her counterpart defended migraine trials in particular, arguing that they’re evolving to become more valuable as researchers address their limitations.

At the core of the debate at the annual meeting of the American Headache Society were sharp divisions over how much the limitations of headache clinical trials matter. Both neurologists – Jan Brandes, MD, of Nashville (Tenn.) Neuroscience Group, and Amy Gelfand, MD, of the University of California at San Francisco, agree that they exist. But they diverged on how much they matter.
 

Exclusion/inclusion criteria are good

Dr. Brandes argued that randomized controlled trials “remain the single best study design,” and she said migraine headache trials have improved over the past couple of decades.

Eligibility criteria, for example, have expanded to allow patients with more subtypes of migraines to participate, she said. “Another change has been the establishment of guidelines or inclusion criteria that allow patients who have stable and treated hypertension, stable depression, and stable anxiety disorders that are controlled and treated and not interfering with the disease you’re studying.”

In essence, she said, “the exclusion/inclusion criteria are good.”

It’s also a positive change that longer patient-reported outcomes are included in trials, she said.
 

Exclusion/inclusion criteria are too restrictive

But Dr. Gelfand criticized the inclusion criteria in migraine trials, noting it includes “a lot of amazing complexity.” Trials often will limit participation to subjects aged 18-65, even though people have high rates of headaches, she said, and they frequently overrepresent men. Pregnant and lactating women are often omitted, too, even if a trial is examining a behavioral intervention. In some cases, lactating women may be breastfeeding for a year or two, she noted.

“The vast majority of births in the United States, 92%, are to females who are between the ages of 20 and 39. That is also the age range where migraine is most prevalent,” she said. Yes, certain new agents shouldn’t be tested for the first time in pregnant women because of the risk, she said, “but we need to grapple with the fact that migraine is affecting people who are also going to be pregnant and lactating.”

Many other criteria limit the subjects in headache trials, she said. The studies are “almost exclusively” of drugs for migraines, leaving out many people with other types such as adolescents with new persistent headaches. “Where are the trials for them?” she asked.

Other groups that are left out include those whose headaches that are due to a head injury, a viral infection such as COVID-19, or even vaccination against COVID-19, she said. “There are an infinite number of questions here that we are currently not even attempting to answer.”

Non-Whites are also poorly represented in trials, she said, and studies often don’t include data about non-Whites. “Race data exists. Where do we get off not even reporting it?”
 

Room for improvement

For her part, Dr. Brandes said less-common headache disorders are best studied in pragmatic trials until they can be better understood. “We need to understand pathophysiology better for some of these other disorders, particularly things like continuous headache and posttraumatic headache. Then we can begin to expand that.”

She added that randomized clinical trials are now underway regarding secondary headache related to COVID-19.

Dr. Brandes did not report disclosures. Dr. Gelfand had no disclosures.

DENVER – In a debate over whether headache trials are representative of patients, one neurologist declared that they tend to leave out a variety of subjects with many types of headaches – the young, the old, the pregnant, and those without migraines, among others. But her counterpart defended migraine trials in particular, arguing that they’re evolving to become more valuable as researchers address their limitations.

At the core of the debate at the annual meeting of the American Headache Society were sharp divisions over how much the limitations of headache clinical trials matter. Both neurologists – Jan Brandes, MD, of Nashville (Tenn.) Neuroscience Group, and Amy Gelfand, MD, of the University of California at San Francisco, agree that they exist. But they diverged on how much they matter.
 

Exclusion/inclusion criteria are good

Dr. Brandes argued that randomized controlled trials “remain the single best study design,” and she said migraine headache trials have improved over the past couple of decades.

Eligibility criteria, for example, have expanded to allow patients with more subtypes of migraines to participate, she said. “Another change has been the establishment of guidelines or inclusion criteria that allow patients who have stable and treated hypertension, stable depression, and stable anxiety disorders that are controlled and treated and not interfering with the disease you’re studying.”

In essence, she said, “the exclusion/inclusion criteria are good.”

It’s also a positive change that longer patient-reported outcomes are included in trials, she said.
 

Exclusion/inclusion criteria are too restrictive

But Dr. Gelfand criticized the inclusion criteria in migraine trials, noting it includes “a lot of amazing complexity.” Trials often will limit participation to subjects aged 18-65, even though people have high rates of headaches, she said, and they frequently overrepresent men. Pregnant and lactating women are often omitted, too, even if a trial is examining a behavioral intervention. In some cases, lactating women may be breastfeeding for a year or two, she noted.

“The vast majority of births in the United States, 92%, are to females who are between the ages of 20 and 39. That is also the age range where migraine is most prevalent,” she said. Yes, certain new agents shouldn’t be tested for the first time in pregnant women because of the risk, she said, “but we need to grapple with the fact that migraine is affecting people who are also going to be pregnant and lactating.”

Many other criteria limit the subjects in headache trials, she said. The studies are “almost exclusively” of drugs for migraines, leaving out many people with other types such as adolescents with new persistent headaches. “Where are the trials for them?” she asked.

Other groups that are left out include those whose headaches that are due to a head injury, a viral infection such as COVID-19, or even vaccination against COVID-19, she said. “There are an infinite number of questions here that we are currently not even attempting to answer.”

Non-Whites are also poorly represented in trials, she said, and studies often don’t include data about non-Whites. “Race data exists. Where do we get off not even reporting it?”
 

Room for improvement

For her part, Dr. Brandes said less-common headache disorders are best studied in pragmatic trials until they can be better understood. “We need to understand pathophysiology better for some of these other disorders, particularly things like continuous headache and posttraumatic headache. Then we can begin to expand that.”

She added that randomized clinical trials are now underway regarding secondary headache related to COVID-19.

Dr. Brandes did not report disclosures. Dr. Gelfand had no disclosures.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

After an initial first dose of a CGRP mAb treatment, many patients ask whether a suboptimal response necessitates switching to another agent or whether a second (or third) dose should be given first. Eptinezumab is an intravenously administered mAb that is repeated every 12 weeks. Schim and colleagues present post hoc data for patients who initially had a minimally beneficial response to eptinezumab and received a second dose at week 13.
 

The authors define a suboptimal response as having less than a 50% decrease in monthly migraine days after 12 weeks. There were two pooled samples of patients—those who received 100 mg eptinezumab and those who received a 300 mg dose. Approximately 45% of patients in the pivotal trials of eptinezumab (PROMISE-1 and -2) were considered suboptimal responders, and 33%-37% of those suboptimal responders had a more than 50% decrease of their monthly migraine days after a second dose (week 24).
 

Further analysis determined predictive factors that favored a second dose response. The most prominent (and arguably most obvious) predictive factor was a favorable response after the first dose; the greater percent change in monthly migraine days after the first dose was proportional to the response after the second dose.Change in the Headache Impact Test (HIT-6) disability score after the first dose was also seen to be a strong predictive factor for improvement after the second dose.

When we discuss continuation of medications with our patients, especially when they have a suboptimal response, we should first keep in mind the degree of improvement that the patient initially had.There can be benefit from further treatment with the same medication; however, if the response truly was minimal, it may be better to consider another treatment option.

Practically every patient taking a preventive medication is taking at least one acute medication as well.Even the best preventive medication is not a guarantee that further exacerbations will not occur, and our patients will still need some acute treatment option even when their preventive medications are very effective. The study by Ambrosini and colleagues specifically shows how effective a preventive medication can be, specifically in allowing the patient to use fewer acute medications over time in a population of patients who have been resistant to two to four treatments.
 

Galcanezumab is a once-monthly mAb for the prevention of migraine.The authors of this study compared the acute use of medications for migraine in both the randomized and open-label stages of a study assessing treatment-refractory patients.A total of 462 patients were enrolled who were all resistant to two to four standard-of-care migraine-preventive medications that had been stopped either because of lack of efficacy or tolerance.The double-blind stage lasted 3 months; the open-label stage lasted another 3 months.
 

The treatment group was seen to use significantly fewer acute medications after just the first month and continued to improve through month 3.In the open-label phase, a similar improvement was noted in patients transitioning from placebo. In addition to acute medication use, emergency department use for migraine treatment was decreased significantly as well, by more than two thirds in month 3.

Migraine prevention will always remain the key ingredient for improvement for patients with higher frequencies of migraine, and adequate prevention will allow for the lower use of acute medications, and for less healthcare system use in general.
 

Most practitioners recommend migraine-specific medications for the acute treatment ofmigraine. Since the advent of sumatriptan, this has usually meant a triptan medication. However, a significant percentage of the population (up to 44% in one study) are either intolerant to, contraindicated for, or respond insufficiently to triptan medications. This can either be due to a strong triptan side effect (worsened nausea; tightness/soreness of the muscles of the chest, shoulders, and neck), having cardiovascular risk factors, or not responding adequately 2 hours after treatment.The study by Lipton and colleagues specifically assessed the efficacy of ubrogepant in this population.
 

Ubrogepant is a small-molecule CGRP antagonist for the acute treatment of migraine. Although somewhat controversial, most practitioners use ubrogepant in patients with some cardiovascular risk, a situation where they would be more likely to avoid the use of triptans.The study authors pooled post hoc data from the pivotal ubrogepant trials (ACHIEVE-1 and -2)to isolate patients with insufficient response to triptans, and their primary outcome was improvement in function 2 hours after medication dose.
 

Participants in the pivotal trials were separated into three groups: triptan responders, triptaninsufficient responders, and triptan-naive patients. Triptan response was defined as achieving pain freedom 2 hours after medication dose. Both those who had an insufficient response and those who no longer use the triptan owing to intolerance or contraindications were included in the group with insufficient triptan response. Function improvement was defined as the primary outcomeon the basis of a 4-point response scale (0 = no disability, 1 = mildly impaired, 2 = moderately impaired, 3 = severely impaired).In addition, patients were asked to report scores of satisfaction with the medication (yes or no) at 2 and 24 hours and their impression of overall change at 2 hours using a 7-point scale.
 

The population group of triptan insufficient responders (451 patients) had significant improvement in the primary outcome functional disability at 2, 4, and 7 hours after receipt of medications, but there was no statistical difference at 1 hour. This was similar when comparing those with intolerance to triptans, insufficient response to triptans, or contraindications for triptans. The secondary outcomes of satisfaction and global impression of change were also statistically improved in the insufficient-responders group. No additional tolerance issues or adverse events were noted in this group either.

It would certainly be worth considering the use of agepant acute medication, such as ubrogepant, in patients who are intolerant to or inadequately treated by triptan medications.There still is much to learn about cardiovascular risk and the use of CGRP antagonists, and although no adverse events were noted, more data may be necessary to widely prescribe this class in higher-risk patients.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

After an initial first dose of a CGRP mAb treatment, many patients ask whether a suboptimal response necessitates switching to another agent or whether a second (or third) dose should be given first. Eptinezumab is an intravenously administered mAb that is repeated every 12 weeks. Schim and colleagues present post hoc data for patients who initially had a minimally beneficial response to eptinezumab and received a second dose at week 13.
 

The authors define a suboptimal response as having less than a 50% decrease in monthly migraine days after 12 weeks. There were two pooled samples of patients—those who received 100 mg eptinezumab and those who received a 300 mg dose. Approximately 45% of patients in the pivotal trials of eptinezumab (PROMISE-1 and -2) were considered suboptimal responders, and 33%-37% of those suboptimal responders had a more than 50% decrease of their monthly migraine days after a second dose (week 24).
 

Further analysis determined predictive factors that favored a second dose response. The most prominent (and arguably most obvious) predictive factor was a favorable response after the first dose; the greater percent change in monthly migraine days after the first dose was proportional to the response after the second dose.Change in the Headache Impact Test (HIT-6) disability score after the first dose was also seen to be a strong predictive factor for improvement after the second dose.

When we discuss continuation of medications with our patients, especially when they have a suboptimal response, we should first keep in mind the degree of improvement that the patient initially had.There can be benefit from further treatment with the same medication; however, if the response truly was minimal, it may be better to consider another treatment option.

Practically every patient taking a preventive medication is taking at least one acute medication as well.Even the best preventive medication is not a guarantee that further exacerbations will not occur, and our patients will still need some acute treatment option even when their preventive medications are very effective. The study by Ambrosini and colleagues specifically shows how effective a preventive medication can be, specifically in allowing the patient to use fewer acute medications over time in a population of patients who have been resistant to two to four treatments.
 

Galcanezumab is a once-monthly mAb for the prevention of migraine.The authors of this study compared the acute use of medications for migraine in both the randomized and open-label stages of a study assessing treatment-refractory patients.A total of 462 patients were enrolled who were all resistant to two to four standard-of-care migraine-preventive medications that had been stopped either because of lack of efficacy or tolerance.The double-blind stage lasted 3 months; the open-label stage lasted another 3 months.
 

The treatment group was seen to use significantly fewer acute medications after just the first month and continued to improve through month 3.In the open-label phase, a similar improvement was noted in patients transitioning from placebo. In addition to acute medication use, emergency department use for migraine treatment was decreased significantly as well, by more than two thirds in month 3.

Migraine prevention will always remain the key ingredient for improvement for patients with higher frequencies of migraine, and adequate prevention will allow for the lower use of acute medications, and for less healthcare system use in general.
 

Most practitioners recommend migraine-specific medications for the acute treatment ofmigraine. Since the advent of sumatriptan, this has usually meant a triptan medication. However, a significant percentage of the population (up to 44% in one study) are either intolerant to, contraindicated for, or respond insufficiently to triptan medications. This can either be due to a strong triptan side effect (worsened nausea; tightness/soreness of the muscles of the chest, shoulders, and neck), having cardiovascular risk factors, or not responding adequately 2 hours after treatment.The study by Lipton and colleagues specifically assessed the efficacy of ubrogepant in this population.
 

Ubrogepant is a small-molecule CGRP antagonist for the acute treatment of migraine. Although somewhat controversial, most practitioners use ubrogepant in patients with some cardiovascular risk, a situation where they would be more likely to avoid the use of triptans.The study authors pooled post hoc data from the pivotal ubrogepant trials (ACHIEVE-1 and -2)to isolate patients with insufficient response to triptans, and their primary outcome was improvement in function 2 hours after medication dose.
 

Participants in the pivotal trials were separated into three groups: triptan responders, triptaninsufficient responders, and triptan-naive patients. Triptan response was defined as achieving pain freedom 2 hours after medication dose. Both those who had an insufficient response and those who no longer use the triptan owing to intolerance or contraindications were included in the group with insufficient triptan response. Function improvement was defined as the primary outcomeon the basis of a 4-point response scale (0 = no disability, 1 = mildly impaired, 2 = moderately impaired, 3 = severely impaired).In addition, patients were asked to report scores of satisfaction with the medication (yes or no) at 2 and 24 hours and their impression of overall change at 2 hours using a 7-point scale.
 

The population group of triptan insufficient responders (451 patients) had significant improvement in the primary outcome functional disability at 2, 4, and 7 hours after receipt of medications, but there was no statistical difference at 1 hour. This was similar when comparing those with intolerance to triptans, insufficient response to triptans, or contraindications for triptans. The secondary outcomes of satisfaction and global impression of change were also statistically improved in the insufficient-responders group. No additional tolerance issues or adverse events were noted in this group either.

It would certainly be worth considering the use of agepant acute medication, such as ubrogepant, in patients who are intolerant to or inadequately treated by triptan medications.There still is much to learn about cardiovascular risk and the use of CGRP antagonists, and although no adverse events were noted, more data may be necessary to widely prescribe this class in higher-risk patients.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

After an initial first dose of a CGRP mAb treatment, many patients ask whether a suboptimal response necessitates switching to another agent or whether a second (or third) dose should be given first. Eptinezumab is an intravenously administered mAb that is repeated every 12 weeks. Schim and colleagues present post hoc data for patients who initially had a minimally beneficial response to eptinezumab and received a second dose at week 13.
 

The authors define a suboptimal response as having less than a 50% decrease in monthly migraine days after 12 weeks. There were two pooled samples of patients—those who received 100 mg eptinezumab and those who received a 300 mg dose. Approximately 45% of patients in the pivotal trials of eptinezumab (PROMISE-1 and -2) were considered suboptimal responders, and 33%-37% of those suboptimal responders had a more than 50% decrease of their monthly migraine days after a second dose (week 24).
 

Further analysis determined predictive factors that favored a second dose response. The most prominent (and arguably most obvious) predictive factor was a favorable response after the first dose; the greater percent change in monthly migraine days after the first dose was proportional to the response after the second dose.Change in the Headache Impact Test (HIT-6) disability score after the first dose was also seen to be a strong predictive factor for improvement after the second dose.

When we discuss continuation of medications with our patients, especially when they have a suboptimal response, we should first keep in mind the degree of improvement that the patient initially had.There can be benefit from further treatment with the same medication; however, if the response truly was minimal, it may be better to consider another treatment option.

Practically every patient taking a preventive medication is taking at least one acute medication as well.Even the best preventive medication is not a guarantee that further exacerbations will not occur, and our patients will still need some acute treatment option even when their preventive medications are very effective. The study by Ambrosini and colleagues specifically shows how effective a preventive medication can be, specifically in allowing the patient to use fewer acute medications over time in a population of patients who have been resistant to two to four treatments.
 

Galcanezumab is a once-monthly mAb for the prevention of migraine.The authors of this study compared the acute use of medications for migraine in both the randomized and open-label stages of a study assessing treatment-refractory patients.A total of 462 patients were enrolled who were all resistant to two to four standard-of-care migraine-preventive medications that had been stopped either because of lack of efficacy or tolerance.The double-blind stage lasted 3 months; the open-label stage lasted another 3 months.
 

The treatment group was seen to use significantly fewer acute medications after just the first month and continued to improve through month 3.In the open-label phase, a similar improvement was noted in patients transitioning from placebo. In addition to acute medication use, emergency department use for migraine treatment was decreased significantly as well, by more than two thirds in month 3.

Migraine prevention will always remain the key ingredient for improvement for patients with higher frequencies of migraine, and adequate prevention will allow for the lower use of acute medications, and for less healthcare system use in general.
 

Most practitioners recommend migraine-specific medications for the acute treatment ofmigraine. Since the advent of sumatriptan, this has usually meant a triptan medication. However, a significant percentage of the population (up to 44% in one study) are either intolerant to, contraindicated for, or respond insufficiently to triptan medications. This can either be due to a strong triptan side effect (worsened nausea; tightness/soreness of the muscles of the chest, shoulders, and neck), having cardiovascular risk factors, or not responding adequately 2 hours after treatment.The study by Lipton and colleagues specifically assessed the efficacy of ubrogepant in this population.
 

Ubrogepant is a small-molecule CGRP antagonist for the acute treatment of migraine. Although somewhat controversial, most practitioners use ubrogepant in patients with some cardiovascular risk, a situation where they would be more likely to avoid the use of triptans.The study authors pooled post hoc data from the pivotal ubrogepant trials (ACHIEVE-1 and -2)to isolate patients with insufficient response to triptans, and their primary outcome was improvement in function 2 hours after medication dose.
 

Participants in the pivotal trials were separated into three groups: triptan responders, triptaninsufficient responders, and triptan-naive patients. Triptan response was defined as achieving pain freedom 2 hours after medication dose. Both those who had an insufficient response and those who no longer use the triptan owing to intolerance or contraindications were included in the group with insufficient triptan response. Function improvement was defined as the primary outcomeon the basis of a 4-point response scale (0 = no disability, 1 = mildly impaired, 2 = moderately impaired, 3 = severely impaired).In addition, patients were asked to report scores of satisfaction with the medication (yes or no) at 2 and 24 hours and their impression of overall change at 2 hours using a 7-point scale.
 

The population group of triptan insufficient responders (451 patients) had significant improvement in the primary outcome functional disability at 2, 4, and 7 hours after receipt of medications, but there was no statistical difference at 1 hour. This was similar when comparing those with intolerance to triptans, insufficient response to triptans, or contraindications for triptans. The secondary outcomes of satisfaction and global impression of change were also statistically improved in the insufficient-responders group. No additional tolerance issues or adverse events were noted in this group either.

It would certainly be worth considering the use of agepant acute medication, such as ubrogepant, in patients who are intolerant to or inadequately treated by triptan medications.There still is much to learn about cardiovascular risk and the use of CGRP antagonists, and although no adverse events were noted, more data may be necessary to widely prescribe this class in higher-risk patients.

Cognitive-behavioral therapies (CBTs) can provide relief from comorbid, persistent posttraumatic headache and posttraumatic stress disorder, new research suggests.

Results from a randomized clinical trial of almost 200 military veterans showed that, compared with usual care, CBT for headache led to significant improvement in both headache disability and PTSD symptoms. Cognitive-processing therapy (CPT) also led to significant improvement in PTSD symptoms, but it did not improve headache disability.

Lead author Donald McGeary, PhD, department of rehabilitation medicine, the University of Texas Health Science Center,San Antonio, noted the improvements shown in headache disability after CBT were likely caused by its building of patients’ confidence that they could control or manage their headaches themselves.

That sense of control was key to helping patients “get their lives back. If you can improve a person’s belief that they can control their headache, they function better,” Dr. McGeary said in a news release.

The findings were published online in JAMA Neurology.
 

Signature wounds

Both mild traumatic brain injury (TBI) and PTSD are signature wounds of post-9/11 military conflicts. The two conditions commonly occur together and can harm quality of life and functioning, the investigators noted. Following mild TBI, many veterans experience persistent posttraumatic headache, which often co-occurs with PTSD.

To gauge the impact of CBTs for this patient population, researchers recruited 193 post-9/11 combat veterans (mean age, 39.7 years) with clinically significant PTSD symptoms and posttraumatic headache that had persisted more than 3 months after TBI. Of these, 167 were men.

All participants were receiving care at the Polytrauma Rehabilitation Center of the South Texas Veterans Health Care System in Houston.

They were randomly allocated to undergo 8 sessions of manualized CBT for headache, 12 sessions of manualized CPT for PTSD, or usual headache treatment.

CBT for headache uses CBT concepts to reduce headache disability and improve mood – and includes key components, such as relaxation, setting goals for activities patients want to resume, and planning for those situations.

CPT is a leading psychotherapy for PTSD. It teaches patients how to evaluate and change upsetting and maladaptive thoughts related to their trauma. The idea is that, by changing thoughts, patients can change the way they feel.

Treatment as usual was consistent with multidisciplinary treatment in a large Veterans Affairs multiple-trauma center and could include pharmacotherapies, physical and occupational therapies, pain medications, acupuncture, and massage.

The coprimary outcomes were headache-related disability on the six-item Headache Impact Test (HIT-6) and PTSD symptom severity on the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PCL-5), assessed from end of treatment to 6 months post treatment.

At baseline, all participants reported severe headache-related disability (mean HIT-6 score, 65.8 points) and severe PTSD symptoms (mean PCL-5 score, 48.4 points).
 

Significant improvement

Compared with usual care, CBT for headache led to significant improvement in headache disability (posttreatment mean change in HIT-6 score, –3.4 points; P < .01) and PTSD symptoms (posttreatment change in PCL-5, –6.5 points; P = .04).

CPT also led to significant improvement in PTSD symptoms (8.9 points lower on the PCL-5 after treatment; P = .01), but it had only a modest effect on headache disability (1.4 points lower after treatment; P = .21).

“This was a surprise,” Dr. McGeary said. “If theories about PTSD driving posttraumatic headache are correct, you’d expect CPT to help both PTSD and headache. Our findings call that into question.”

Despite improvements in headache disability, CBT for headache did not significantly reduce headache frequency or intensity.

The researchers are now hoping to replicate their findings in a larger trial at multiple military and VA sites around the United States.

“We need more women, more racial and ethnic diversity, veterans as well as active military of different branches with varying comorbidities in different geographic regions attached to different hospitals and medical systems, because we’re comparing to usual care,” Dr. McGeary said.
 

A step forward

Commenting on the study, retired Col. Elspeth Cameron Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, said she was “pleased” to see that this study was conducted and that she was pleased with the results.

“It’s been 20 years since 9/11, and wars are pretty much forgotten, but people are still suffering from the effects of traumatic brain injury and posttraumatic stress disorder. These are not conditions that go away quickly or lightly. They do take work,” said Dr. Ritchie, who was not involved with the research.

Finding therapies besides medication that are helpful is “good and is a step forward. The more alternatives we have, the better,” she concluded.

The study was supported in part by the Department of Defense and the Department of Veterans Affairs. Dr. McGeary and Dr. Ritchie have reported no relevant financial relationships.

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

Cognitive-behavioral therapies (CBTs) can provide relief from comorbid, persistent posttraumatic headache and posttraumatic stress disorder, new research suggests.

Results from a randomized clinical trial of almost 200 military veterans showed that, compared with usual care, CBT for headache led to significant improvement in both headache disability and PTSD symptoms. Cognitive-processing therapy (CPT) also led to significant improvement in PTSD symptoms, but it did not improve headache disability.

Lead author Donald McGeary, PhD, department of rehabilitation medicine, the University of Texas Health Science Center,San Antonio, noted the improvements shown in headache disability after CBT were likely caused by its building of patients’ confidence that they could control or manage their headaches themselves.

That sense of control was key to helping patients “get their lives back. If you can improve a person’s belief that they can control their headache, they function better,” Dr. McGeary said in a news release.

The findings were published online in JAMA Neurology.
 

Signature wounds

Both mild traumatic brain injury (TBI) and PTSD are signature wounds of post-9/11 military conflicts. The two conditions commonly occur together and can harm quality of life and functioning, the investigators noted. Following mild TBI, many veterans experience persistent posttraumatic headache, which often co-occurs with PTSD.

To gauge the impact of CBTs for this patient population, researchers recruited 193 post-9/11 combat veterans (mean age, 39.7 years) with clinically significant PTSD symptoms and posttraumatic headache that had persisted more than 3 months after TBI. Of these, 167 were men.

All participants were receiving care at the Polytrauma Rehabilitation Center of the South Texas Veterans Health Care System in Houston.

They were randomly allocated to undergo 8 sessions of manualized CBT for headache, 12 sessions of manualized CPT for PTSD, or usual headache treatment.

CBT for headache uses CBT concepts to reduce headache disability and improve mood – and includes key components, such as relaxation, setting goals for activities patients want to resume, and planning for those situations.

CPT is a leading psychotherapy for PTSD. It teaches patients how to evaluate and change upsetting and maladaptive thoughts related to their trauma. The idea is that, by changing thoughts, patients can change the way they feel.

Treatment as usual was consistent with multidisciplinary treatment in a large Veterans Affairs multiple-trauma center and could include pharmacotherapies, physical and occupational therapies, pain medications, acupuncture, and massage.

The coprimary outcomes were headache-related disability on the six-item Headache Impact Test (HIT-6) and PTSD symptom severity on the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PCL-5), assessed from end of treatment to 6 months post treatment.

At baseline, all participants reported severe headache-related disability (mean HIT-6 score, 65.8 points) and severe PTSD symptoms (mean PCL-5 score, 48.4 points).
 

Significant improvement

Compared with usual care, CBT for headache led to significant improvement in headache disability (posttreatment mean change in HIT-6 score, –3.4 points; P < .01) and PTSD symptoms (posttreatment change in PCL-5, –6.5 points; P = .04).

CPT also led to significant improvement in PTSD symptoms (8.9 points lower on the PCL-5 after treatment; P = .01), but it had only a modest effect on headache disability (1.4 points lower after treatment; P = .21).

“This was a surprise,” Dr. McGeary said. “If theories about PTSD driving posttraumatic headache are correct, you’d expect CPT to help both PTSD and headache. Our findings call that into question.”

Despite improvements in headache disability, CBT for headache did not significantly reduce headache frequency or intensity.

The researchers are now hoping to replicate their findings in a larger trial at multiple military and VA sites around the United States.

“We need more women, more racial and ethnic diversity, veterans as well as active military of different branches with varying comorbidities in different geographic regions attached to different hospitals and medical systems, because we’re comparing to usual care,” Dr. McGeary said.
 

A step forward

Commenting on the study, retired Col. Elspeth Cameron Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, said she was “pleased” to see that this study was conducted and that she was pleased with the results.

“It’s been 20 years since 9/11, and wars are pretty much forgotten, but people are still suffering from the effects of traumatic brain injury and posttraumatic stress disorder. These are not conditions that go away quickly or lightly. They do take work,” said Dr. Ritchie, who was not involved with the research.

Finding therapies besides medication that are helpful is “good and is a step forward. The more alternatives we have, the better,” she concluded.

The study was supported in part by the Department of Defense and the Department of Veterans Affairs. Dr. McGeary and Dr. Ritchie have reported no relevant financial relationships.

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

Cognitive-behavioral therapies (CBTs) can provide relief from comorbid, persistent posttraumatic headache and posttraumatic stress disorder, new research suggests.

Results from a randomized clinical trial of almost 200 military veterans showed that, compared with usual care, CBT for headache led to significant improvement in both headache disability and PTSD symptoms. Cognitive-processing therapy (CPT) also led to significant improvement in PTSD symptoms, but it did not improve headache disability.

Lead author Donald McGeary, PhD, department of rehabilitation medicine, the University of Texas Health Science Center,San Antonio, noted the improvements shown in headache disability after CBT were likely caused by its building of patients’ confidence that they could control or manage their headaches themselves.

That sense of control was key to helping patients “get their lives back. If you can improve a person’s belief that they can control their headache, they function better,” Dr. McGeary said in a news release.

The findings were published online in JAMA Neurology.
 

Signature wounds

Both mild traumatic brain injury (TBI) and PTSD are signature wounds of post-9/11 military conflicts. The two conditions commonly occur together and can harm quality of life and functioning, the investigators noted. Following mild TBI, many veterans experience persistent posttraumatic headache, which often co-occurs with PTSD.

To gauge the impact of CBTs for this patient population, researchers recruited 193 post-9/11 combat veterans (mean age, 39.7 years) with clinically significant PTSD symptoms and posttraumatic headache that had persisted more than 3 months after TBI. Of these, 167 were men.

All participants were receiving care at the Polytrauma Rehabilitation Center of the South Texas Veterans Health Care System in Houston.

They were randomly allocated to undergo 8 sessions of manualized CBT for headache, 12 sessions of manualized CPT for PTSD, or usual headache treatment.

CBT for headache uses CBT concepts to reduce headache disability and improve mood – and includes key components, such as relaxation, setting goals for activities patients want to resume, and planning for those situations.

CPT is a leading psychotherapy for PTSD. It teaches patients how to evaluate and change upsetting and maladaptive thoughts related to their trauma. The idea is that, by changing thoughts, patients can change the way they feel.

Treatment as usual was consistent with multidisciplinary treatment in a large Veterans Affairs multiple-trauma center and could include pharmacotherapies, physical and occupational therapies, pain medications, acupuncture, and massage.

The coprimary outcomes were headache-related disability on the six-item Headache Impact Test (HIT-6) and PTSD symptom severity on the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PCL-5), assessed from end of treatment to 6 months post treatment.

At baseline, all participants reported severe headache-related disability (mean HIT-6 score, 65.8 points) and severe PTSD symptoms (mean PCL-5 score, 48.4 points).
 

Significant improvement

Compared with usual care, CBT for headache led to significant improvement in headache disability (posttreatment mean change in HIT-6 score, –3.4 points; P < .01) and PTSD symptoms (posttreatment change in PCL-5, –6.5 points; P = .04).

CPT also led to significant improvement in PTSD symptoms (8.9 points lower on the PCL-5 after treatment; P = .01), but it had only a modest effect on headache disability (1.4 points lower after treatment; P = .21).

“This was a surprise,” Dr. McGeary said. “If theories about PTSD driving posttraumatic headache are correct, you’d expect CPT to help both PTSD and headache. Our findings call that into question.”

Despite improvements in headache disability, CBT for headache did not significantly reduce headache frequency or intensity.

The researchers are now hoping to replicate their findings in a larger trial at multiple military and VA sites around the United States.

“We need more women, more racial and ethnic diversity, veterans as well as active military of different branches with varying comorbidities in different geographic regions attached to different hospitals and medical systems, because we’re comparing to usual care,” Dr. McGeary said.
 

A step forward

Commenting on the study, retired Col. Elspeth Cameron Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, said she was “pleased” to see that this study was conducted and that she was pleased with the results.

“It’s been 20 years since 9/11, and wars are pretty much forgotten, but people are still suffering from the effects of traumatic brain injury and posttraumatic stress disorder. These are not conditions that go away quickly or lightly. They do take work,” said Dr. Ritchie, who was not involved with the research.

Finding therapies besides medication that are helpful is “good and is a step forward. The more alternatives we have, the better,” she concluded.

The study was supported in part by the Department of Defense and the Department of Veterans Affairs. Dr. McGeary and Dr. Ritchie have reported no relevant financial relationships.

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

Children and adolescents with migraine are about twice as likely to have an anxiety or depressive disorder as those without migraine, results from a new review and meta-analysis suggest.

“This is compelling, high-level evidence showing there’s this established comorbidity between migraine and anxiety and depressive symptoms and disorders in this age group,” co-investigator Serena L. Orr, MD, a pediatric neurologist and headache specialist at Alberta Children’s Hospital and assistant professor in the department of pediatrics, University of Calgary (Alta.), told this news organization.

The results “should compel every clinician who is seeing a child or adolescent with migraine to screen for anxiety and depression and to manage that if it’s present. That should be the standard of care with this level of evidence,” Dr. Orr said.

The findings were presented at the American Headache Society (AHS) Annual Meeting 2022.
 

Incidence divergence

Previous studies have suggested that 10%-20% of children and adolescents will experience migraine at some point before adulthood, with the prevalence increasing after puberty.

While the female-to-male ratio is about 1:1 before puberty, there is a “big divergence in incidence curves” afterward – with the female-to-male ratio reaching 2-3:1 in adulthood, Dr. Orr noted. Experts believe hormones drive this divergence, she said, noting that male adults with migraine have lower testosterone levels than male adults without migraine.

Dr. Orr and her colleagues were keen to investigate the relationship between child migraine and anxiety symptoms and disorders, as well as between child migraine and depression symptoms and disorders. They searched the literature for related case-control, cross-sectional, and cohort studies with participants of ages up to 18 years.

The researchers selected 80 studies to include in the review. Most of the studies were carried out in the past 30 to 40 years and were in English and other languages. Both community-based and clinical studies were included.

Of the total, 73 studies reported on the association between the exposures and migraine, and 51 were amenable to quantitative pooling.

Results from a meta-analysis that included 16 studies that compared children and adolescents who had migraine with their healthy peers showed a significant association between migraine and anxiety symptoms (standardized mean difference, 1.13; 95% confidence interval, 0.64-1.63; P < .0001).

Compared with children who did not have migraine, those with migraine had almost twice the odds of an anxiety disorder in 15 studies (odds ratio, 1.93; 95% CI, 1.49-2.50; P < .0001).

In addition, there was an association between migraine and depressive symptoms in 17 relevant studies (SMD, 0.67; 95% CI, 0.46-0.87; P < .0001). Participants with versus without migraine also had higher odds of depressive disorders in 18 studies (OR, 2.01; 95% CI, 1.46-2.78; P < .0001).

Effect sizes were similar between community-based and clinic studies. Dr. Orr said it is important to note that the analysis wasn’t restricted to studies with “just kids with really high disease burden who are going to naturally be more predisposed to psychiatric comorbidity.”
 

‘Shocking’ lack of research

The researchers were also interested in determining whether having migraine along with anxiety or depression symptoms or disorders could affect headache-specific outcomes and whether such patients’ conditions would be more refractory to treatment. However, these outcomes were “all over the place” in the 18 relevant studies, Dr. Orr reported.

“Some looked at headache frequency, some at disability, some at school functioning; so, we were not able to put them into a meta-analysis,” she said.

Only two studies examined whether anxiety or depression earlier in childhood predisposes to subsequent migraine, so that issue is still unresolved, Dr. Orr added.

The investigators also assessed whether outcomes with migraine are similar to those with other headache types, such as tension-type headaches. “We did not find a difference at the symptom or disorder level, but there were fewer of those studies” – and these, too, were heterogeneous, said Dr. Orr.

The researchers did not find any studies of the association between migraine and trauma, which Dr. Orr said was “shocking.”

“In the broader pediatric chronic-pain literature, there’s research showing that having a trauma or stress-related disorder is associated with more chronic pain and worse chronic pain outcomes, but we could not find a study that specifically looked at that question in migraine,” she added.

Emerging evidence suggests there may be a bidirectional relationship between migraine and anxiety/depression, at least in adults. Dr. Orr said having these symptoms appears to raise the risk for migraine, but whether that’s environmental or driven by shared genetics isn’t clear.

Experiencing chronic pain may also predispose individuals to anxiety and depression, “but we need more studies on this.”

In addition to screening children with migraine for anxiety and depression, clinicians should advocate for better access to mental health resources for patients with these comorbidities, Dr. Orr noted.

She added that a limitation of the review was that 82.5% of the studies reported unadjusted associations and that 26.3% of the studies were of low quality.
 

High-level evidence

Sara Pavitt, MD, chief of the Pediatric Headache Program and assistant professor in the department of neurology, the University of Texas at Austin, said the investigators “should be applauded” for providing “high-level evidence” to better understand the relationship between migraine and anxiety and depression in pediatric patients.

Such information has been “lacking” for this patient population, said Dr. Pavitt, who was not involved with the research.

She noted that screening kids for mood disorders is challenging, given the relatively few pediatric mental health care providers. A referral for a psychiatric follow-up can mean a 9- to 12-month wait – or even longer for children who do not have insurance or use Medicare.

“Providers need to have more incentives to care for patients with Medicare or lack of insurance – these patients are often excluded from practices because reimbursement is so poor,” Dr. Pavitt said.

Additional pediatric studies are needed to understand how other mental health disorders, such as panic disorder, phobias, and posttraumatic stress disorder, may be related to migraine, she added.

The study received no outside funding. Dr. Orr has received grants from the Canadian Institutes of Health Research and royalties from Cambridge University Press for book publication, and she is on editorial boards of Headache, Neurology, and the American Migraine Foundation. Dr. Pavitt serves on an advisory board for Theranica, which produces a neuromodulation device for acute migraine treatment, although this is not directly relevant to this review.

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

Children and adolescents with migraine are about twice as likely to have an anxiety or depressive disorder as those without migraine, results from a new review and meta-analysis suggest.

“This is compelling, high-level evidence showing there’s this established comorbidity between migraine and anxiety and depressive symptoms and disorders in this age group,” co-investigator Serena L. Orr, MD, a pediatric neurologist and headache specialist at Alberta Children’s Hospital and assistant professor in the department of pediatrics, University of Calgary (Alta.), told this news organization.

The results “should compel every clinician who is seeing a child or adolescent with migraine to screen for anxiety and depression and to manage that if it’s present. That should be the standard of care with this level of evidence,” Dr. Orr said.

The findings were presented at the American Headache Society (AHS) Annual Meeting 2022.
 

Incidence divergence

Previous studies have suggested that 10%-20% of children and adolescents will experience migraine at some point before adulthood, with the prevalence increasing after puberty.

While the female-to-male ratio is about 1:1 before puberty, there is a “big divergence in incidence curves” afterward – with the female-to-male ratio reaching 2-3:1 in adulthood, Dr. Orr noted. Experts believe hormones drive this divergence, she said, noting that male adults with migraine have lower testosterone levels than male adults without migraine.

Dr. Orr and her colleagues were keen to investigate the relationship between child migraine and anxiety symptoms and disorders, as well as between child migraine and depression symptoms and disorders. They searched the literature for related case-control, cross-sectional, and cohort studies with participants of ages up to 18 years.

The researchers selected 80 studies to include in the review. Most of the studies were carried out in the past 30 to 40 years and were in English and other languages. Both community-based and clinical studies were included.

Of the total, 73 studies reported on the association between the exposures and migraine, and 51 were amenable to quantitative pooling.

Results from a meta-analysis that included 16 studies that compared children and adolescents who had migraine with their healthy peers showed a significant association between migraine and anxiety symptoms (standardized mean difference, 1.13; 95% confidence interval, 0.64-1.63; P < .0001).

Compared with children who did not have migraine, those with migraine had almost twice the odds of an anxiety disorder in 15 studies (odds ratio, 1.93; 95% CI, 1.49-2.50; P < .0001).

In addition, there was an association between migraine and depressive symptoms in 17 relevant studies (SMD, 0.67; 95% CI, 0.46-0.87; P < .0001). Participants with versus without migraine also had higher odds of depressive disorders in 18 studies (OR, 2.01; 95% CI, 1.46-2.78; P < .0001).

Effect sizes were similar between community-based and clinic studies. Dr. Orr said it is important to note that the analysis wasn’t restricted to studies with “just kids with really high disease burden who are going to naturally be more predisposed to psychiatric comorbidity.”
 

‘Shocking’ lack of research

The researchers were also interested in determining whether having migraine along with anxiety or depression symptoms or disorders could affect headache-specific outcomes and whether such patients’ conditions would be more refractory to treatment. However, these outcomes were “all over the place” in the 18 relevant studies, Dr. Orr reported.

“Some looked at headache frequency, some at disability, some at school functioning; so, we were not able to put them into a meta-analysis,” she said.

Only two studies examined whether anxiety or depression earlier in childhood predisposes to subsequent migraine, so that issue is still unresolved, Dr. Orr added.

The investigators also assessed whether outcomes with migraine are similar to those with other headache types, such as tension-type headaches. “We did not find a difference at the symptom or disorder level, but there were fewer of those studies” – and these, too, were heterogeneous, said Dr. Orr.

The researchers did not find any studies of the association between migraine and trauma, which Dr. Orr said was “shocking.”

“In the broader pediatric chronic-pain literature, there’s research showing that having a trauma or stress-related disorder is associated with more chronic pain and worse chronic pain outcomes, but we could not find a study that specifically looked at that question in migraine,” she added.

Emerging evidence suggests there may be a bidirectional relationship between migraine and anxiety/depression, at least in adults. Dr. Orr said having these symptoms appears to raise the risk for migraine, but whether that’s environmental or driven by shared genetics isn’t clear.

Experiencing chronic pain may also predispose individuals to anxiety and depression, “but we need more studies on this.”

In addition to screening children with migraine for anxiety and depression, clinicians should advocate for better access to mental health resources for patients with these comorbidities, Dr. Orr noted.

She added that a limitation of the review was that 82.5% of the studies reported unadjusted associations and that 26.3% of the studies were of low quality.
 

High-level evidence

Sara Pavitt, MD, chief of the Pediatric Headache Program and assistant professor in the department of neurology, the University of Texas at Austin, said the investigators “should be applauded” for providing “high-level evidence” to better understand the relationship between migraine and anxiety and depression in pediatric patients.

Such information has been “lacking” for this patient population, said Dr. Pavitt, who was not involved with the research.

She noted that screening kids for mood disorders is challenging, given the relatively few pediatric mental health care providers. A referral for a psychiatric follow-up can mean a 9- to 12-month wait – or even longer for children who do not have insurance or use Medicare.

“Providers need to have more incentives to care for patients with Medicare or lack of insurance – these patients are often excluded from practices because reimbursement is so poor,” Dr. Pavitt said.

Additional pediatric studies are needed to understand how other mental health disorders, such as panic disorder, phobias, and posttraumatic stress disorder, may be related to migraine, she added.

The study received no outside funding. Dr. Orr has received grants from the Canadian Institutes of Health Research and royalties from Cambridge University Press for book publication, and she is on editorial boards of Headache, Neurology, and the American Migraine Foundation. Dr. Pavitt serves on an advisory board for Theranica, which produces a neuromodulation device for acute migraine treatment, although this is not directly relevant to this review.

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

Children and adolescents with migraine are about twice as likely to have an anxiety or depressive disorder as those without migraine, results from a new review and meta-analysis suggest.

“This is compelling, high-level evidence showing there’s this established comorbidity between migraine and anxiety and depressive symptoms and disorders in this age group,” co-investigator Serena L. Orr, MD, a pediatric neurologist and headache specialist at Alberta Children’s Hospital and assistant professor in the department of pediatrics, University of Calgary (Alta.), told this news organization.

The results “should compel every clinician who is seeing a child or adolescent with migraine to screen for anxiety and depression and to manage that if it’s present. That should be the standard of care with this level of evidence,” Dr. Orr said.

The findings were presented at the American Headache Society (AHS) Annual Meeting 2022.
 

Incidence divergence

Previous studies have suggested that 10%-20% of children and adolescents will experience migraine at some point before adulthood, with the prevalence increasing after puberty.

While the female-to-male ratio is about 1:1 before puberty, there is a “big divergence in incidence curves” afterward – with the female-to-male ratio reaching 2-3:1 in adulthood, Dr. Orr noted. Experts believe hormones drive this divergence, she said, noting that male adults with migraine have lower testosterone levels than male adults without migraine.

Dr. Orr and her colleagues were keen to investigate the relationship between child migraine and anxiety symptoms and disorders, as well as between child migraine and depression symptoms and disorders. They searched the literature for related case-control, cross-sectional, and cohort studies with participants of ages up to 18 years.

The researchers selected 80 studies to include in the review. Most of the studies were carried out in the past 30 to 40 years and were in English and other languages. Both community-based and clinical studies were included.

Of the total, 73 studies reported on the association between the exposures and migraine, and 51 were amenable to quantitative pooling.

Results from a meta-analysis that included 16 studies that compared children and adolescents who had migraine with their healthy peers showed a significant association between migraine and anxiety symptoms (standardized mean difference, 1.13; 95% confidence interval, 0.64-1.63; P < .0001).

Compared with children who did not have migraine, those with migraine had almost twice the odds of an anxiety disorder in 15 studies (odds ratio, 1.93; 95% CI, 1.49-2.50; P < .0001).

In addition, there was an association between migraine and depressive symptoms in 17 relevant studies (SMD, 0.67; 95% CI, 0.46-0.87; P < .0001). Participants with versus without migraine also had higher odds of depressive disorders in 18 studies (OR, 2.01; 95% CI, 1.46-2.78; P < .0001).

Effect sizes were similar between community-based and clinic studies. Dr. Orr said it is important to note that the analysis wasn’t restricted to studies with “just kids with really high disease burden who are going to naturally be more predisposed to psychiatric comorbidity.”
 

‘Shocking’ lack of research

The researchers were also interested in determining whether having migraine along with anxiety or depression symptoms or disorders could affect headache-specific outcomes and whether such patients’ conditions would be more refractory to treatment. However, these outcomes were “all over the place” in the 18 relevant studies, Dr. Orr reported.

“Some looked at headache frequency, some at disability, some at school functioning; so, we were not able to put them into a meta-analysis,” she said.

Only two studies examined whether anxiety or depression earlier in childhood predisposes to subsequent migraine, so that issue is still unresolved, Dr. Orr added.

The investigators also assessed whether outcomes with migraine are similar to those with other headache types, such as tension-type headaches. “We did not find a difference at the symptom or disorder level, but there were fewer of those studies” – and these, too, were heterogeneous, said Dr. Orr.

The researchers did not find any studies of the association between migraine and trauma, which Dr. Orr said was “shocking.”

“In the broader pediatric chronic-pain literature, there’s research showing that having a trauma or stress-related disorder is associated with more chronic pain and worse chronic pain outcomes, but we could not find a study that specifically looked at that question in migraine,” she added.

Emerging evidence suggests there may be a bidirectional relationship between migraine and anxiety/depression, at least in adults. Dr. Orr said having these symptoms appears to raise the risk for migraine, but whether that’s environmental or driven by shared genetics isn’t clear.

Experiencing chronic pain may also predispose individuals to anxiety and depression, “but we need more studies on this.”

In addition to screening children with migraine for anxiety and depression, clinicians should advocate for better access to mental health resources for patients with these comorbidities, Dr. Orr noted.

She added that a limitation of the review was that 82.5% of the studies reported unadjusted associations and that 26.3% of the studies were of low quality.
 

High-level evidence

Sara Pavitt, MD, chief of the Pediatric Headache Program and assistant professor in the department of neurology, the University of Texas at Austin, said the investigators “should be applauded” for providing “high-level evidence” to better understand the relationship between migraine and anxiety and depression in pediatric patients.

Such information has been “lacking” for this patient population, said Dr. Pavitt, who was not involved with the research.

She noted that screening kids for mood disorders is challenging, given the relatively few pediatric mental health care providers. A referral for a psychiatric follow-up can mean a 9- to 12-month wait – or even longer for children who do not have insurance or use Medicare.

“Providers need to have more incentives to care for patients with Medicare or lack of insurance – these patients are often excluded from practices because reimbursement is so poor,” Dr. Pavitt said.

Additional pediatric studies are needed to understand how other mental health disorders, such as panic disorder, phobias, and posttraumatic stress disorder, may be related to migraine, she added.

The study received no outside funding. Dr. Orr has received grants from the Canadian Institutes of Health Research and royalties from Cambridge University Press for book publication, and she is on editorial boards of Headache, Neurology, and the American Migraine Foundation. Dr. Pavitt serves on an advisory board for Theranica, which produces a neuromodulation device for acute migraine treatment, although this is not directly relevant to this review.

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

A new tool can help streamline diagnosis and treatment of migraine in the primary care setting, research suggests.

Early results from a small pilot study showed that the tool, essentially a medical record “best-practice alert,” reduces specialist referrals and MRI studies.

The idea behind the tool is to give primary care physicians “fingertip access” to prompts on patients’ electronic health record, leading to best migraine management and treatment, said coinvestigator, Scott M. Friedenberg, MD, vice chair of clinical practice, Geisinger Medical Center, Danville, Pa.

When clinicians enter a headache diagnosis into a patient’s EHR, a pop-up asks a handful of questions and “prompts them with the right medications so if they just click a button, they can order the medications straight away,” Dr. Friedenberg said.

The findings were presented at the annual meeting of the American Headache Society.
 

Fewer referrals, MRI testing

Researchers reviewed charts for 693 general neurology referrals. About 20% of the patients were referred for headache. In about 80% of these cases, the final diagnosis was migraine and/or chronic daily headache.

The physicians had documented criteria for identifying migraine, such as sensitivity to light, nausea, and missed social activity or work, in fewer than 1% of cases. There’s roughly an 80% chance that if a headache meets two of these three criteria, it is a migraine, Dr. Friedenberg noted.

About 60% of the participants with headache were referred with no treatment trial. About 20% were referred after having tried two medicines, and 30% were referred after trying one medicine.

“In many cases, we’re being asked to evaluate people with primary headache or uncomplicated headache that has not been treated,” said Dr. Friedenberg.

The investigators developed the tool, and its most recent iteration was tested by 10 physicians at two sites for 3 months. These doctors did not receive education on headache, they were just taught how to use the tool.

Results showed that referrals for neurology consults dropped 77% and MRI ordering dropped 35% after use of the tool. This translated into a savings of $192,000.

However, using the tool didn’t significantly affect prescribing habits of the physicians.
 

Migraine frequently undertreated

“When you drill it down, the only thing that changed were medications they were comfortable with, so they increased steroids and nonsteroidal prescribing, but preventives didn’t change, narcotics didn’t change, and CGRP [calcitonin gene-related peptide] inhibitors didn’t change,” Dr. Friedenberg said.

Although believing patients are “not bad enough to treat” might help explain why clinicians did not change prescribing habits, the reality is that many patients have migraine and should be treated, he added.

Dr. Friedenberg pointed out that previous research suggests that 60% or more of patients with a primary headache or migraine are undertreated.

The tool should increase awareness about, and comfort level with, diagnosing and treating migraine among primary care doctors, he noted. “We hope it will make it easier for them to do the right thing and have neurology as a readily available partner,” said Dr. Friedenberg.

“Primary care doctors are incredibly busy and incredibly pressured, and anything you can do to help facilitate that is a positive,” he added.

The researchers now plan to train pharmacists to comanage headache along with primary care doctors, as is done, for example, for patients with diabetes. This should result in a reduction in physician burden, said Dr. Friedenberg.

The next step is to conduct a larger study at the 38 sites in the Geisinger health complex. Half the sites will use the new tool, and the other half will continue to use their current headache management process.

“The study will compare everything from MRI ordering to neurology referrals and prescribing, how often patients go to the emergency department, how often they have a clinic visit, whether the provider is satisfied with the tool, and if the patient’s headaches are getting better,” Dr. Friedenberg said.
 

Lessons for clinical practice

Jessica Ailani, MD, director at MedStar Georgetown Headache Center and associate professor in the department of neurology at Georgetown University, cochaired the session in which the research was presented and called the project “really fantastic.”

The study offers “many lessons” for clinical practice and showed that the tool was effective in improving diagnosis of migraine, said Dr. Ailani, who is also secretary of the American Headache Society.

“There’s a long wait time to see specialists, and most migraine can be diagnosed and basic management can be done by primary care physicians,” she said.

“The next step would be to work on a way to improve prescriptions of migraine-specific treatments,” she added.

Dr. Ailani noted that the AHS would be keen to find ways to engage in “collaborative work” with the investigators.

The investigators and Dr. Ailani reported no relevant financial relationships.

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

A new tool can help streamline diagnosis and treatment of migraine in the primary care setting, research suggests.

Early results from a small pilot study showed that the tool, essentially a medical record “best-practice alert,” reduces specialist referrals and MRI studies.

The idea behind the tool is to give primary care physicians “fingertip access” to prompts on patients’ electronic health record, leading to best migraine management and treatment, said coinvestigator, Scott M. Friedenberg, MD, vice chair of clinical practice, Geisinger Medical Center, Danville, Pa.

When clinicians enter a headache diagnosis into a patient’s EHR, a pop-up asks a handful of questions and “prompts them with the right medications so if they just click a button, they can order the medications straight away,” Dr. Friedenberg said.

The findings were presented at the annual meeting of the American Headache Society.
 

Fewer referrals, MRI testing

Researchers reviewed charts for 693 general neurology referrals. About 20% of the patients were referred for headache. In about 80% of these cases, the final diagnosis was migraine and/or chronic daily headache.

The physicians had documented criteria for identifying migraine, such as sensitivity to light, nausea, and missed social activity or work, in fewer than 1% of cases. There’s roughly an 80% chance that if a headache meets two of these three criteria, it is a migraine, Dr. Friedenberg noted.

About 60% of the participants with headache were referred with no treatment trial. About 20% were referred after having tried two medicines, and 30% were referred after trying one medicine.

“In many cases, we’re being asked to evaluate people with primary headache or uncomplicated headache that has not been treated,” said Dr. Friedenberg.

The investigators developed the tool, and its most recent iteration was tested by 10 physicians at two sites for 3 months. These doctors did not receive education on headache, they were just taught how to use the tool.

Results showed that referrals for neurology consults dropped 77% and MRI ordering dropped 35% after use of the tool. This translated into a savings of $192,000.

However, using the tool didn’t significantly affect prescribing habits of the physicians.
 

Migraine frequently undertreated

“When you drill it down, the only thing that changed were medications they were comfortable with, so they increased steroids and nonsteroidal prescribing, but preventives didn’t change, narcotics didn’t change, and CGRP [calcitonin gene-related peptide] inhibitors didn’t change,” Dr. Friedenberg said.

Although believing patients are “not bad enough to treat” might help explain why clinicians did not change prescribing habits, the reality is that many patients have migraine and should be treated, he added.

Dr. Friedenberg pointed out that previous research suggests that 60% or more of patients with a primary headache or migraine are undertreated.

The tool should increase awareness about, and comfort level with, diagnosing and treating migraine among primary care doctors, he noted. “We hope it will make it easier for them to do the right thing and have neurology as a readily available partner,” said Dr. Friedenberg.

“Primary care doctors are incredibly busy and incredibly pressured, and anything you can do to help facilitate that is a positive,” he added.

The researchers now plan to train pharmacists to comanage headache along with primary care doctors, as is done, for example, for patients with diabetes. This should result in a reduction in physician burden, said Dr. Friedenberg.

The next step is to conduct a larger study at the 38 sites in the Geisinger health complex. Half the sites will use the new tool, and the other half will continue to use their current headache management process.

“The study will compare everything from MRI ordering to neurology referrals and prescribing, how often patients go to the emergency department, how often they have a clinic visit, whether the provider is satisfied with the tool, and if the patient’s headaches are getting better,” Dr. Friedenberg said.
 

Lessons for clinical practice

Jessica Ailani, MD, director at MedStar Georgetown Headache Center and associate professor in the department of neurology at Georgetown University, cochaired the session in which the research was presented and called the project “really fantastic.”

The study offers “many lessons” for clinical practice and showed that the tool was effective in improving diagnosis of migraine, said Dr. Ailani, who is also secretary of the American Headache Society.

“There’s a long wait time to see specialists, and most migraine can be diagnosed and basic management can be done by primary care physicians,” she said.

“The next step would be to work on a way to improve prescriptions of migraine-specific treatments,” she added.

Dr. Ailani noted that the AHS would be keen to find ways to engage in “collaborative work” with the investigators.

The investigators and Dr. Ailani reported no relevant financial relationships.

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

A new tool can help streamline diagnosis and treatment of migraine in the primary care setting, research suggests.

Early results from a small pilot study showed that the tool, essentially a medical record “best-practice alert,” reduces specialist referrals and MRI studies.

The idea behind the tool is to give primary care physicians “fingertip access” to prompts on patients’ electronic health record, leading to best migraine management and treatment, said coinvestigator, Scott M. Friedenberg, MD, vice chair of clinical practice, Geisinger Medical Center, Danville, Pa.

When clinicians enter a headache diagnosis into a patient’s EHR, a pop-up asks a handful of questions and “prompts them with the right medications so if they just click a button, they can order the medications straight away,” Dr. Friedenberg said.

The findings were presented at the annual meeting of the American Headache Society.
 

Fewer referrals, MRI testing

Researchers reviewed charts for 693 general neurology referrals. About 20% of the patients were referred for headache. In about 80% of these cases, the final diagnosis was migraine and/or chronic daily headache.

The physicians had documented criteria for identifying migraine, such as sensitivity to light, nausea, and missed social activity or work, in fewer than 1% of cases. There’s roughly an 80% chance that if a headache meets two of these three criteria, it is a migraine, Dr. Friedenberg noted.

About 60% of the participants with headache were referred with no treatment trial. About 20% were referred after having tried two medicines, and 30% were referred after trying one medicine.

“In many cases, we’re being asked to evaluate people with primary headache or uncomplicated headache that has not been treated,” said Dr. Friedenberg.

The investigators developed the tool, and its most recent iteration was tested by 10 physicians at two sites for 3 months. These doctors did not receive education on headache, they were just taught how to use the tool.

Results showed that referrals for neurology consults dropped 77% and MRI ordering dropped 35% after use of the tool. This translated into a savings of $192,000.

However, using the tool didn’t significantly affect prescribing habits of the physicians.
 

Migraine frequently undertreated

“When you drill it down, the only thing that changed were medications they were comfortable with, so they increased steroids and nonsteroidal prescribing, but preventives didn’t change, narcotics didn’t change, and CGRP [calcitonin gene-related peptide] inhibitors didn’t change,” Dr. Friedenberg said.

Although believing patients are “not bad enough to treat” might help explain why clinicians did not change prescribing habits, the reality is that many patients have migraine and should be treated, he added.

Dr. Friedenberg pointed out that previous research suggests that 60% or more of patients with a primary headache or migraine are undertreated.

The tool should increase awareness about, and comfort level with, diagnosing and treating migraine among primary care doctors, he noted. “We hope it will make it easier for them to do the right thing and have neurology as a readily available partner,” said Dr. Friedenberg.

“Primary care doctors are incredibly busy and incredibly pressured, and anything you can do to help facilitate that is a positive,” he added.

The researchers now plan to train pharmacists to comanage headache along with primary care doctors, as is done, for example, for patients with diabetes. This should result in a reduction in physician burden, said Dr. Friedenberg.

The next step is to conduct a larger study at the 38 sites in the Geisinger health complex. Half the sites will use the new tool, and the other half will continue to use their current headache management process.

“The study will compare everything from MRI ordering to neurology referrals and prescribing, how often patients go to the emergency department, how often they have a clinic visit, whether the provider is satisfied with the tool, and if the patient’s headaches are getting better,” Dr. Friedenberg said.
 

Lessons for clinical practice

Jessica Ailani, MD, director at MedStar Georgetown Headache Center and associate professor in the department of neurology at Georgetown University, cochaired the session in which the research was presented and called the project “really fantastic.”

The study offers “many lessons” for clinical practice and showed that the tool was effective in improving diagnosis of migraine, said Dr. Ailani, who is also secretary of the American Headache Society.

“There’s a long wait time to see specialists, and most migraine can be diagnosed and basic management can be done by primary care physicians,” she said.

“The next step would be to work on a way to improve prescriptions of migraine-specific treatments,” she added.

Dr. Ailani noted that the AHS would be keen to find ways to engage in “collaborative work” with the investigators.

The investigators and Dr. Ailani reported no relevant financial relationships.

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

Key clinical point: Severe migraine without aura increased the long-term risk for atrial fibrillation (AF) by 16%-21% in both men and women. The risk for future AF was highest in women with severe migraine with aura but not significant in male counterparts.

Major finding: Men (adjusted hazard ratio [aHR] 1.21; 95% CI 1.12-1.31) and women (aHR 1.16; 95% CI 1.09-1.22) with severe migraine without aura had a modest but significantly higher risk for AF. The risk was most prominent in women with severe migraine with aura (aHR 1.48; 95% CI 1.18-1.85), but was not significant in men.

Study details: Findings are from a large-scale population-based study including 4,020,488 participants without AF, of which 4986 and 105,029 had migraine with and without aura, respectively.

Disclosures: This study was supported by a Korea Medical Device Development Fund grant funded by the Korea Government. E-K Choi and GYH Lip reported receiving research grants or speaking fees or serving as consultants or speakers for various sources.

Source: Rhee T-M et al. Type and severity of migraine determines risk of atrial fibrillation in women. Front Cardiovasc Med. 2022;9:910225 (May 31). Doi: 10.3389/fcvm.2022.910225

Key clinical point: Severe migraine without aura increased the long-term risk for atrial fibrillation (AF) by 16%-21% in both men and women. The risk for future AF was highest in women with severe migraine with aura but not significant in male counterparts.

Major finding: Men (adjusted hazard ratio [aHR] 1.21; 95% CI 1.12-1.31) and women (aHR 1.16; 95% CI 1.09-1.22) with severe migraine without aura had a modest but significantly higher risk for AF. The risk was most prominent in women with severe migraine with aura (aHR 1.48; 95% CI 1.18-1.85), but was not significant in men.

Study details: Findings are from a large-scale population-based study including 4,020,488 participants without AF, of which 4986 and 105,029 had migraine with and without aura, respectively.

Disclosures: This study was supported by a Korea Medical Device Development Fund grant funded by the Korea Government. E-K Choi and GYH Lip reported receiving research grants or speaking fees or serving as consultants or speakers for various sources.

Source: Rhee T-M et al. Type and severity of migraine determines risk of atrial fibrillation in women. Front Cardiovasc Med. 2022;9:910225 (May 31). Doi: 10.3389/fcvm.2022.910225

Key clinical point: Severe migraine without aura increased the long-term risk for atrial fibrillation (AF) by 16%-21% in both men and women. The risk for future AF was highest in women with severe migraine with aura but not significant in male counterparts.

Major finding: Men (adjusted hazard ratio [aHR] 1.21; 95% CI 1.12-1.31) and women (aHR 1.16; 95% CI 1.09-1.22) with severe migraine without aura had a modest but significantly higher risk for AF. The risk was most prominent in women with severe migraine with aura (aHR 1.48; 95% CI 1.18-1.85), but was not significant in men.

Study details: Findings are from a large-scale population-based study including 4,020,488 participants without AF, of which 4986 and 105,029 had migraine with and without aura, respectively.

Disclosures: This study was supported by a Korea Medical Device Development Fund grant funded by the Korea Government. E-K Choi and GYH Lip reported receiving research grants or speaking fees or serving as consultants or speakers for various sources.

Source: Rhee T-M et al. Type and severity of migraine determines risk of atrial fibrillation in women. Front Cardiovasc Med. 2022;9:910225 (May 31). Doi: 10.3389/fcvm.2022.910225

Key clinical point: A higher proportion of patients with migraine treated with atogepant vs. placebo showed a significant reduction in the monthly migraine days (MMD) during the 12 weeks of treatment.

Major finding: At 12 weeks, ≥50% reduction in the mean MMD was achieved by a significantly higher proportion of patients receiving 10 mg (55.6%), 30 mg (58.7%), or 60 mg (60.8%) atogepant compared with placebo (29.0%; all P < .001), with findings being similar for ≥25%, ≥75%, and 100% reduction in mean MMD. The incidence of treatment-emergent adverse events was similar among the treatment groups.

Study details: This was a secondary analysis of the ADVANCE trial including 873 patients with a ≥1-year history of migraine with or without aura who were randomly assigned to receive atogepant (10, 30, or 60 mg; n = 659) or placebo (n = 214).

Disclosures: This study was sponsored by Allergan. Some authors declared receiving speaking fees, consulting fees, personal fees, research grants, or royalties or owing stocks or stock options in various sources, including Allergan/AbbVie.

Source: Lipton RB et al. Rates of response to atogepant for migraine prophylaxis among adults:

A secondary analysis of a randomized clinical trial. JAMA Netw Open. 2022;5(6):e2215499 Jun 8). Doi:  10.1001/jamanetworkopen.2022.15499

Key clinical point: A higher proportion of patients with migraine treated with atogepant vs. placebo showed a significant reduction in the monthly migraine days (MMD) during the 12 weeks of treatment.

Major finding: At 12 weeks, ≥50% reduction in the mean MMD was achieved by a significantly higher proportion of patients receiving 10 mg (55.6%), 30 mg (58.7%), or 60 mg (60.8%) atogepant compared with placebo (29.0%; all P < .001), with findings being similar for ≥25%, ≥75%, and 100% reduction in mean MMD. The incidence of treatment-emergent adverse events was similar among the treatment groups.

Study details: This was a secondary analysis of the ADVANCE trial including 873 patients with a ≥1-year history of migraine with or without aura who were randomly assigned to receive atogepant (10, 30, or 60 mg; n = 659) or placebo (n = 214).

Disclosures: This study was sponsored by Allergan. Some authors declared receiving speaking fees, consulting fees, personal fees, research grants, or royalties or owing stocks or stock options in various sources, including Allergan/AbbVie.

Source: Lipton RB et al. Rates of response to atogepant for migraine prophylaxis among adults:

A secondary analysis of a randomized clinical trial. JAMA Netw Open. 2022;5(6):e2215499 Jun 8). Doi:  10.1001/jamanetworkopen.2022.15499

Key clinical point: A higher proportion of patients with migraine treated with atogepant vs. placebo showed a significant reduction in the monthly migraine days (MMD) during the 12 weeks of treatment.

Major finding: At 12 weeks, ≥50% reduction in the mean MMD was achieved by a significantly higher proportion of patients receiving 10 mg (55.6%), 30 mg (58.7%), or 60 mg (60.8%) atogepant compared with placebo (29.0%; all P < .001), with findings being similar for ≥25%, ≥75%, and 100% reduction in mean MMD. The incidence of treatment-emergent adverse events was similar among the treatment groups.

Study details: This was a secondary analysis of the ADVANCE trial including 873 patients with a ≥1-year history of migraine with or without aura who were randomly assigned to receive atogepant (10, 30, or 60 mg; n = 659) or placebo (n = 214).

Disclosures: This study was sponsored by Allergan. Some authors declared receiving speaking fees, consulting fees, personal fees, research grants, or royalties or owing stocks or stock options in various sources, including Allergan/AbbVie.

Source: Lipton RB et al. Rates of response to atogepant for migraine prophylaxis among adults:

A secondary analysis of a randomized clinical trial. JAMA Netw Open. 2022;5(6):e2215499 Jun 8). Doi:  10.1001/jamanetworkopen.2022.15499

Key clinical point: Migraine was significantly associated with fetal-type posterior cerebral artery (PCA) status in patients with ischemic stroke.

Major finding: Fetal-type PCA status was independently associated with migraine (adjusted odds ratio [aOR] 2.06; P = .005). The other factors independently associated with migraine were hypertension (aOR 1.97; P = .011), female gender (aOR 2.03; P = .017) and National Institutes of Health Stroke Scale score at admission (aOR 1.08; P = .018).

Study details: This cross-sectional study included 750 patients aged ≥18 years with ischemic stroke, of which 11.3% had migraine history.

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

Source: Zhang Y et al. The association between migraine and fetal-type posterior cerebral artery in patients with ischemic stroke. Cerebrovasc Dis. 2022 (May 13). Doi: 10.1159/000524616

Key clinical point: Migraine was significantly associated with fetal-type posterior cerebral artery (PCA) status in patients with ischemic stroke.

Major finding: Fetal-type PCA status was independently associated with migraine (adjusted odds ratio [aOR] 2.06; P = .005). The other factors independently associated with migraine were hypertension (aOR 1.97; P = .011), female gender (aOR 2.03; P = .017) and National Institutes of Health Stroke Scale score at admission (aOR 1.08; P = .018).

Study details: This cross-sectional study included 750 patients aged ≥18 years with ischemic stroke, of which 11.3% had migraine history.

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

Source: Zhang Y et al. The association between migraine and fetal-type posterior cerebral artery in patients with ischemic stroke. Cerebrovasc Dis. 2022 (May 13). Doi: 10.1159/000524616

Key clinical point: Migraine was significantly associated with fetal-type posterior cerebral artery (PCA) status in patients with ischemic stroke.

Major finding: Fetal-type PCA status was independently associated with migraine (adjusted odds ratio [aOR] 2.06; P = .005). The other factors independently associated with migraine were hypertension (aOR 1.97; P = .011), female gender (aOR 2.03; P = .017) and National Institutes of Health Stroke Scale score at admission (aOR 1.08; P = .018).

Study details: This cross-sectional study included 750 patients aged ≥18 years with ischemic stroke, of which 11.3% had migraine history.

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

Source: Zhang Y et al. The association between migraine and fetal-type posterior cerebral artery in patients with ischemic stroke. Cerebrovasc Dis. 2022 (May 13). Doi: 10.1159/000524616