Key clinical point: Quarterly and monthly dose regimens of fremanezumab effectively reduced the average monthly migraine days (MMD) vs. placebo in patients with difficult-to-treat migraine irrespective of country and continents.

Major finding: Reduction in MMD over 12 weeks was significantly higher with fremanezumab dose regimens vs. placebo in 3 top-recruiting countries including Czech Republic (least squares mean difference [LSMD]: quarterly, −1.9; monthly, −3.0), the United States (LSMD: quarterly, −3.7; monthly, −4.2), and Finland (LSMD: quarterly, −3.0; monthly, −3.9; P less than or equal to .01 for all).

Study details: Data come from an exploratory analysis of phase 3b FOCUS study including 838 patients with episodic or chronic migraine who had an inadequate response to 2-4 migraine preventive medication classes and were randomly allocated to either quarterly fremanezumab, monthly fremanezumab, or matched placebo.

Disclosures: The study was funded by Teva Pharmaceuticals. Some of the authors reported receiving research grants and/or personal compensation from multiple sources, including Teva Pharmaceuticals. Some of the authors declared being current/former employees of Teva Pharmaceuticals.

Source: Spierings ELH et al. J Headache Pain. 2021 Apr 16. doi: 10.1186/s10194-021-01232-8.

Key clinical point: Quarterly and monthly dose regimens of fremanezumab effectively reduced the average monthly migraine days (MMD) vs. placebo in patients with difficult-to-treat migraine irrespective of country and continents.

Major finding: Reduction in MMD over 12 weeks was significantly higher with fremanezumab dose regimens vs. placebo in 3 top-recruiting countries including Czech Republic (least squares mean difference [LSMD]: quarterly, −1.9; monthly, −3.0), the United States (LSMD: quarterly, −3.7; monthly, −4.2), and Finland (LSMD: quarterly, −3.0; monthly, −3.9; P less than or equal to .01 for all).

Study details: Data come from an exploratory analysis of phase 3b FOCUS study including 838 patients with episodic or chronic migraine who had an inadequate response to 2-4 migraine preventive medication classes and were randomly allocated to either quarterly fremanezumab, monthly fremanezumab, or matched placebo.

Disclosures: The study was funded by Teva Pharmaceuticals. Some of the authors reported receiving research grants and/or personal compensation from multiple sources, including Teva Pharmaceuticals. Some of the authors declared being current/former employees of Teva Pharmaceuticals.

Source: Spierings ELH et al. J Headache Pain. 2021 Apr 16. doi: 10.1186/s10194-021-01232-8.

Key clinical point: Quarterly and monthly dose regimens of fremanezumab effectively reduced the average monthly migraine days (MMD) vs. placebo in patients with difficult-to-treat migraine irrespective of country and continents.

Major finding: Reduction in MMD over 12 weeks was significantly higher with fremanezumab dose regimens vs. placebo in 3 top-recruiting countries including Czech Republic (least squares mean difference [LSMD]: quarterly, −1.9; monthly, −3.0), the United States (LSMD: quarterly, −3.7; monthly, −4.2), and Finland (LSMD: quarterly, −3.0; monthly, −3.9; P less than or equal to .01 for all).

Study details: Data come from an exploratory analysis of phase 3b FOCUS study including 838 patients with episodic or chronic migraine who had an inadequate response to 2-4 migraine preventive medication classes and were randomly allocated to either quarterly fremanezumab, monthly fremanezumab, or matched placebo.

Disclosures: The study was funded by Teva Pharmaceuticals. Some of the authors reported receiving research grants and/or personal compensation from multiple sources, including Teva Pharmaceuticals. Some of the authors declared being current/former employees of Teva Pharmaceuticals.

Source: Spierings ELH et al. J Headache Pain. 2021 Apr 16. doi: 10.1186/s10194-021-01232-8.

Key clinical point: In a predominantly refractory chronic migraine population, the initiation of erenumab reduced the frequency of monthly headache and migraine days and shortened the duration of headache/migraine attack.

Major finding: After erenumab initiation, mean headache/migraine days per month and mean headache/migraine duration per attack decreased by a mean of 5.6 days and 5.1 hours, respectively.

Study details: Findings are from a retrospective chart review of 1,034 patients with chronic migraine who were treated with erenumab for at least 3 consecutive months at 5 major headache centers in the U.S.A.

Disclosures: This study was supported by Amgen Inc (Thousand Oaks, CA). Some of the authors declared being employees of Analysis Group and Amgen Inc. Z Ahmed and A Blumenfeld served as consultants and on the advisory board for Amgen Inc. The other authors had no conflicts of interest.

Source: Faust E et al. Neurol Ther. 2021 Apr 15. doi: 10.1007/s40120-021-00245-4.

Key clinical point: In a predominantly refractory chronic migraine population, the initiation of erenumab reduced the frequency of monthly headache and migraine days and shortened the duration of headache/migraine attack.

Major finding: After erenumab initiation, mean headache/migraine days per month and mean headache/migraine duration per attack decreased by a mean of 5.6 days and 5.1 hours, respectively.

Study details: Findings are from a retrospective chart review of 1,034 patients with chronic migraine who were treated with erenumab for at least 3 consecutive months at 5 major headache centers in the U.S.A.

Disclosures: This study was supported by Amgen Inc (Thousand Oaks, CA). Some of the authors declared being employees of Analysis Group and Amgen Inc. Z Ahmed and A Blumenfeld served as consultants and on the advisory board for Amgen Inc. The other authors had no conflicts of interest.

Source: Faust E et al. Neurol Ther. 2021 Apr 15. doi: 10.1007/s40120-021-00245-4.

Key clinical point: In a predominantly refractory chronic migraine population, the initiation of erenumab reduced the frequency of monthly headache and migraine days and shortened the duration of headache/migraine attack.

Major finding: After erenumab initiation, mean headache/migraine days per month and mean headache/migraine duration per attack decreased by a mean of 5.6 days and 5.1 hours, respectively.

Study details: Findings are from a retrospective chart review of 1,034 patients with chronic migraine who were treated with erenumab for at least 3 consecutive months at 5 major headache centers in the U.S.A.

Disclosures: This study was supported by Amgen Inc (Thousand Oaks, CA). Some of the authors declared being employees of Analysis Group and Amgen Inc. Z Ahmed and A Blumenfeld served as consultants and on the advisory board for Amgen Inc. The other authors had no conflicts of interest.

Source: Faust E et al. Neurol Ther. 2021 Apr 15. doi: 10.1007/s40120-021-00245-4.

Key clinical point: Lasmiditan showed relatively better efficacy outcomes in migraine attacks when initiated at mild vs. moderate or severe pain.

Major finding: In GLADIATOR, a significantly greater proportion of patients treated with lasmiditan (200 mg) at mild vs. moderate or severe pain achieved 2-hour pain freedom (PF; both P less than .001) and 24-hour sustained PF (SPF; P less than .05). In SAMURAI and SPARTAN, numerically higher proportion of patients treated with lasmiditan (200 mg) at mild vs. moderate or severe pain achieved 2-hour PF (45.5% vs. 37.6% or 29.4%) and 24-hour SPF (31.8% vs. 22.7% or 15.0%).

Study details: Findings are from pooled analysis of phase 3 studies SAMURAI, SPARTAN, and GLADIATOR.

Disclosures: The work was funded by Eli Lilly and Company. Some of the authors declared serving as an advisory board member, speaker, and/or consultant and receiving advisory board fees, grant support, and/or consultant fees from multiple sources. Some of the authors declared being employees and stockholders of Eli Lilly and Company.

Source: Peres MFP et al. Curr Med Res Opin. 2021 Mar 31. doi: 10.1080/03007995.2021.1903846.

Key clinical point: Lasmiditan showed relatively better efficacy outcomes in migraine attacks when initiated at mild vs. moderate or severe pain.

Major finding: In GLADIATOR, a significantly greater proportion of patients treated with lasmiditan (200 mg) at mild vs. moderate or severe pain achieved 2-hour pain freedom (PF; both P less than .001) and 24-hour sustained PF (SPF; P less than .05). In SAMURAI and SPARTAN, numerically higher proportion of patients treated with lasmiditan (200 mg) at mild vs. moderate or severe pain achieved 2-hour PF (45.5% vs. 37.6% or 29.4%) and 24-hour SPF (31.8% vs. 22.7% or 15.0%).

Study details: Findings are from pooled analysis of phase 3 studies SAMURAI, SPARTAN, and GLADIATOR.

Disclosures: The work was funded by Eli Lilly and Company. Some of the authors declared serving as an advisory board member, speaker, and/or consultant and receiving advisory board fees, grant support, and/or consultant fees from multiple sources. Some of the authors declared being employees and stockholders of Eli Lilly and Company.

Source: Peres MFP et al. Curr Med Res Opin. 2021 Mar 31. doi: 10.1080/03007995.2021.1903846.

Key clinical point: Lasmiditan showed relatively better efficacy outcomes in migraine attacks when initiated at mild vs. moderate or severe pain.

Major finding: In GLADIATOR, a significantly greater proportion of patients treated with lasmiditan (200 mg) at mild vs. moderate or severe pain achieved 2-hour pain freedom (PF; both P less than .001) and 24-hour sustained PF (SPF; P less than .05). In SAMURAI and SPARTAN, numerically higher proportion of patients treated with lasmiditan (200 mg) at mild vs. moderate or severe pain achieved 2-hour PF (45.5% vs. 37.6% or 29.4%) and 24-hour SPF (31.8% vs. 22.7% or 15.0%).

Study details: Findings are from pooled analysis of phase 3 studies SAMURAI, SPARTAN, and GLADIATOR.

Disclosures: The work was funded by Eli Lilly and Company. Some of the authors declared serving as an advisory board member, speaker, and/or consultant and receiving advisory board fees, grant support, and/or consultant fees from multiple sources. Some of the authors declared being employees and stockholders of Eli Lilly and Company.

Source: Peres MFP et al. Curr Med Res Opin. 2021 Mar 31. doi: 10.1080/03007995.2021.1903846.

Key clinical point: The safety and efficacy of ubrogepant for acute treatment of migraine did not differ by the presence of cardiovascular risk factors.

Major finding: The efficacy of ubrogepant vs. placebo to achieve 2-hour pain freedom (P interaction = .1358) and absence of most bothersome migraine-associated symptom at 2 hours (P interaction = .7014) was comparable across cardiovascular risk categories. The adverse event profile of ubrogepant was similar across cardiovascular risk categories and to placebo.

Study details: This was a post hoc analysis that pooled data from ubrogepant 50 mg and placebo arms of phase 3 ACHIEVE I and II trials involving patients with migraine with or without aura. In the safety population, patients were categorized into moderate-high (n=311), low (n=920), and no (n=1,670) cardiovascular risk categories.

Disclosures: ACHIEVE I and II were funded by Allergan plc (prior to its acquisition by AbbVie). Some of the authors reported serving as advisory board members, speakers, consultants, and/or receiving honoraria from multiple sources. Three authors declared being full-time employees and stockholders of AbbVie.

Source: Hutchinson S et al. Cephalalgia. 2021 Apr 19. doi: 10.1177/03331024211000311.

Key clinical point: The safety and efficacy of ubrogepant for acute treatment of migraine did not differ by the presence of cardiovascular risk factors.

Major finding: The efficacy of ubrogepant vs. placebo to achieve 2-hour pain freedom (P interaction = .1358) and absence of most bothersome migraine-associated symptom at 2 hours (P interaction = .7014) was comparable across cardiovascular risk categories. The adverse event profile of ubrogepant was similar across cardiovascular risk categories and to placebo.

Study details: This was a post hoc analysis that pooled data from ubrogepant 50 mg and placebo arms of phase 3 ACHIEVE I and II trials involving patients with migraine with or without aura. In the safety population, patients were categorized into moderate-high (n=311), low (n=920), and no (n=1,670) cardiovascular risk categories.

Disclosures: ACHIEVE I and II were funded by Allergan plc (prior to its acquisition by AbbVie). Some of the authors reported serving as advisory board members, speakers, consultants, and/or receiving honoraria from multiple sources. Three authors declared being full-time employees and stockholders of AbbVie.

Source: Hutchinson S et al. Cephalalgia. 2021 Apr 19. doi: 10.1177/03331024211000311.

Key clinical point: The safety and efficacy of ubrogepant for acute treatment of migraine did not differ by the presence of cardiovascular risk factors.

Major finding: The efficacy of ubrogepant vs. placebo to achieve 2-hour pain freedom (P interaction = .1358) and absence of most bothersome migraine-associated symptom at 2 hours (P interaction = .7014) was comparable across cardiovascular risk categories. The adverse event profile of ubrogepant was similar across cardiovascular risk categories and to placebo.

Study details: This was a post hoc analysis that pooled data from ubrogepant 50 mg and placebo arms of phase 3 ACHIEVE I and II trials involving patients with migraine with or without aura. In the safety population, patients were categorized into moderate-high (n=311), low (n=920), and no (n=1,670) cardiovascular risk categories.

Disclosures: ACHIEVE I and II were funded by Allergan plc (prior to its acquisition by AbbVie). Some of the authors reported serving as advisory board members, speakers, consultants, and/or receiving honoraria from multiple sources. Three authors declared being full-time employees and stockholders of AbbVie.

Source: Hutchinson S et al. Cephalalgia. 2021 Apr 19. doi: 10.1177/03331024211000311.

Participants in the Alliance for Headache Disorders Advocacy session requested federal funding for headache research and treatment. While patients told their stories, a noted advocate said headache is “an eminently solvable problem, but the urgency is now.”

It is going to take more than a pandemic to stop key headache advocacy stakeholders from raising awareness of the devastating impact of migraine and cluster headache and to motivate Congress to act.

With COVID-19 still very much a part of our lives, the Alliance for Headache Disorders Advocacy (AHDA)—a nonprofit dedicated to advocating for equitable policies for people with headache disorders—moved forward with its annual Headache on the Hill advocacy day, which took place virtually for the first time via videoconferencing on March 23, 2021.

While participants missed the opportunity to travel to Washington to meet with key legislators face-to-face, optimists saw it as a chance to involve more patients, providers, researchers, and caregivers who otherwise would not be able to participate. Indeed, more were involved than ever before: 217 individuals from 47 states and 178 Congressional districts attended, meeting with influential lawmakers, including Senator Patrick Leahy (D-VT), chair of the Appropriations Committee; Senator Richard Shelby (R-AL), vice chair of the Appropriations Committee; Rep. Rose DeLauro (D-CT), chair of the House Committee on Appropriations; Senator Jon Tester (D-MT), chair of Senate Committee on Veterans’ Affairs; Senator Jerry Moran (R-KS), ranking member of the Senate Committee on Veterans’ Affairs; Senator Patty Murray (D-WA), chair of the Senate HELP Committee; and Senator Richard Burr (R-NC), ranking member of the Senate HELP Committee.

I have had the privilege of being a part of Headache on the Hill for 13 years and was pleased to participate in this year’s virtual event. Though the setting was different, our mission remained the same: to make our important legislative requests (“asks”) of as many offices in Congress as possible. This year, we had 2 asks that aim to improve headache research and access to treatment, especially for our Veterans:

• Increased research funding: The group requested that the National Institutes of Health (NIH) Helping to End Addiction Long-Term (HEAL) initiative focus on headache disorders to reduce disease burden and opioid prescribing. This would make more funding available for headache research.

• Improved treatment access: The group also asked Congress to fully fund Veterans Health Administration (VHA) Headache Disorders Centers of Excellence (HCoE), facilitating equitable access to care for disabled veterans. This would double the number of VA Centers of Excellence to treat headache disorders in our veterans.

Of course, getting results means more than simply asking. The request to our congresspeople and their staff is more likely to succeed if it is well-reasoned and backed by evidence; and the Headache on the Hill contingent delivered on these requirements.

Why Congress should direct HEAL to focus on headache disorders:

• Headache disorders are extraordinarily burdensome. As most of us know (but not all legislators are aware), 60 million Americans suffer from migraine headache; it is the second leading cause of disability lifetime in the world.¹ Additionally, cluster headache is thought to be the most severe type of pain humans can experience.²

• There is a critical need for more effective and safer treatments for headache disorders. Opioid use is known to worsen migraine frequency and severity for some and make medications for headache less effective.³ Guidelines uniformly recommend against treating migraine with opioids; yet somehow 10% of migraine sufferers actively use opioids,⁴ and nearly 60% receive opioids during visits to the emergency room.⁵

• NIH has underfunded research on headache disorders. NIH has not prioritized programs for headache disorders research despite the fact that since 2009, 17 appropriations report language statements have strongly urged NIH to do so.⁶ In fact, headache is the least-funded research area among the most burdensome diseases.^7,8 Instead, other important disorders were funded, even though Headache on the Hill advocacy arranged for the report language for headache.

• Statutory authority for the HEAL initiative calls for disease burden to be a “crucial consideration” in prioritizing research programs. Less than 1% of HEAL grants have been for headache disorders research.¹⁰ If disease burden was used as the only gauge for funding, NIH investment for migraine research would likely be 15 times higher than the roughly $20 million that has historically been allocated.⁹ We hope our work this year will get us where we need to be.

Why Congress should fully fund VHA Headache Disorders Centers of Excellence  

• Headache disorders are a major health issue for veterans. Some 350,000 Global War on Terror (GWOT) veterans have sustained traumatic brain injuries. Many of them experience headaches. In fact, research shows that half of these veterans reported 15 or more headache days per month 4 to 11 years after sustaining traumatic brain injury. Nine of every 10 veterans met the criteria for migraine.¹⁰ Moreover, 3 million GWOT veterans have been exposed to toxic open burn pits.¹¹ These individuals have been found to be twice as likely to experience functional limitations due to migraine than those who did not have burn pit duties.¹²

• Headache Centers of Excellence (HCoEs) work. In 2018, $10 million was appropriated to establish at least 5 HCoEs that provided 1) comprehensive direct patient specialized headache medicine care within the VHA; 2) consultation and referral specialized headache care centers within the VHA; 3) education and training of VHA healthcare providers in headache medicine; and 4) research to improve the quality of headache disorders care for veterans and civilians.¹³

• Fourteen sites now exist, and success continues to be demonstrated. Last year more than 400,000 veterans sought specialty care for headache disorders from the VHA.¹⁴ However, only half of these vets are within reasonable reach of a HCoE.

The asks

Armed with this evidence, we made specific asks of the House and Senate with respect to annual appropriations spending bills:

1. Legislators were asked to sign on to a letter or send their own letter to officials on the House and Senate Labor, Health and Human Services, Education, and Related Agencies appropriations subcommittees to allocate $50 million from the HEAL initiative for headache disorders research in fiscal year 2022.

2. Similarly, lawmakers were asked to sign onto a letter or send their own letter to members of the Military Construction and Veterans Affairs subcommittee to appropriate $25 million to fund a doubling of HCoEs from 14 to 28 to improve access to those seeking care for headache disorders.

Stories from Americans nationwide

Headache on the Hill is about more than just presenting evidence and making requests. If that were the case, there is a pretty good chance that, before long, legislators would be looking at their watches, checking their smartphones, and flashing knowing glances at their aides in an effort to cut things short. However, humanizing the topic by sharing stories of the toll migraine and cluster headaches take on individuals is compelling testimony that hopefully will lead to meaningful action and positive outcomes. Here is a sampling of the stories told during and after the Headache on the Hill session:

• Rachel Koh and Ronetta Stokes: Koh registered for both the 2019 and 2020 Headache on the Hill sessions, only to be forced to cancel due to migraine attacks. But this year, according to the American Migraine Foundation, she was able to participate virtually and tell her representatives why increased funding was important for her, as well as veterans, including her father and uncle. Meanwhile, Stokes, a first-time participant, said she was struck by the conversations she had with legislators. Most knew someone with migraine, and some were sufferers themselves. “The more we share and spread the word, the sooner we can end the stigma,” Stokes told the American Migraine Foundation.

• Mia Maysack: Maysack wrote about her experience in a column for Pain News Network. “I live with both migraine disease and cluster headaches, which are called ‘suicide headaches’ for good reason,” she wrote. “There’s no limit to the chaos, interruption, inconvenience, and discomfort these conditions have caused in my life, requiring my full-time attention just to manage the symptoms. The difficult experiences I and countless others have faced in seeking, finding, and attempting different forms of treatment is why I continue to advocate—even when I don't feel up to it.” Maysack added that although it is relatively easy for her to receive a medication prescription for her condition, she’d like to see more consideration given to treatments such as water therapy, massage, oxygen, and mindful meditation.

• Chloe Vruno: Vruno, a 21-year-old college student, has suffered with migraine since the age of 15. “Some days are worse than others,” she noted in an article in her local newspaper, the Steuben County, IN Herald Republican. “Most days I have to push through a migraine to make it to class, but some days are so severe that I cannot make it to classes. On days I cannot make it, I use my accommodation for attendance flexibility, or now with COVID, I Zoom into class from my room.” Vruno wanted to make her representatives aware of these types of disruptions, a regular occurrence for migraine sufferers like her. This was her second Headache on the Hill event, and she found lawmakers whom she spoke with to be “extremely attentive, engaged, and excited.”

“A moral imperative”

Stories like these from regular individuals across the United States who suffer from headache disorders go a long way in convincing legislators to act. It also helps to tap into a celebrity’s endorsement when you can. Headache on the Hill did not disappoint in this regard, with Jon Stewart, the former host of The Daily Show, appearing as a special guest during a policy panel discussion on chronic headache disorders and toxic exposure. The session, which took place virtually as part of Headache on the Hill, featured Stewart, a national advocate for service personnel with toxic exposures, and Rep. Mark Takano (D-CA), who delivered the keynote address. The panel discussion included first responders, veterans, and clinicians.

Stewart summed up the sentiments of all Headache on the Hill stakeholders this way: “This is an eminently solvable problem, but the urgency is now. People will continue to suffer needlessly if we don’t get this done. It is a moral imperative that we pass a bill on presumption as soon as possible.”

I always enjoy going to Washington on cold days in February to be part of Headache on the Hill, and I hope we will be back in-person next year. We have tripled the number of attendees over the last 13 years and have a higher percentage of great patients and advocates now. I have to give a special thanks to Dr. Bob Shapiro, Professor of Neurology at the University of Vermont, who started and has guided this phenomenal effort over the years, to Dr. Chris Gottschalk, Professor of Neurology at Yale, who is gradually taking over the reins, and to Katie MacDonald who runs the entire show, even though she suffers from chronic migraine on a daily basis.

Participants in the Alliance for Headache Disorders Advocacy session requested federal funding for headache research and treatment. While patients told their stories, a noted advocate said headache is “an eminently solvable problem, but the urgency is now.”

It is going to take more than a pandemic to stop key headache advocacy stakeholders from raising awareness of the devastating impact of migraine and cluster headache and to motivate Congress to act.

With COVID-19 still very much a part of our lives, the Alliance for Headache Disorders Advocacy (AHDA)—a nonprofit dedicated to advocating for equitable policies for people with headache disorders—moved forward with its annual Headache on the Hill advocacy day, which took place virtually for the first time via videoconferencing on March 23, 2021.

While participants missed the opportunity to travel to Washington to meet with key legislators face-to-face, optimists saw it as a chance to involve more patients, providers, researchers, and caregivers who otherwise would not be able to participate. Indeed, more were involved than ever before: 217 individuals from 47 states and 178 Congressional districts attended, meeting with influential lawmakers, including Senator Patrick Leahy (D-VT), chair of the Appropriations Committee; Senator Richard Shelby (R-AL), vice chair of the Appropriations Committee; Rep. Rose DeLauro (D-CT), chair of the House Committee on Appropriations; Senator Jon Tester (D-MT), chair of Senate Committee on Veterans’ Affairs; Senator Jerry Moran (R-KS), ranking member of the Senate Committee on Veterans’ Affairs; Senator Patty Murray (D-WA), chair of the Senate HELP Committee; and Senator Richard Burr (R-NC), ranking member of the Senate HELP Committee.

I have had the privilege of being a part of Headache on the Hill for 13 years and was pleased to participate in this year’s virtual event. Though the setting was different, our mission remained the same: to make our important legislative requests (“asks”) of as many offices in Congress as possible. This year, we had 2 asks that aim to improve headache research and access to treatment, especially for our Veterans:

• Increased research funding: The group requested that the National Institutes of Health (NIH) Helping to End Addiction Long-Term (HEAL) initiative focus on headache disorders to reduce disease burden and opioid prescribing. This would make more funding available for headache research.

• Improved treatment access: The group also asked Congress to fully fund Veterans Health Administration (VHA) Headache Disorders Centers of Excellence (HCoE), facilitating equitable access to care for disabled veterans. This would double the number of VA Centers of Excellence to treat headache disorders in our veterans.

Of course, getting results means more than simply asking. The request to our congresspeople and their staff is more likely to succeed if it is well-reasoned and backed by evidence; and the Headache on the Hill contingent delivered on these requirements.

Why Congress should direct HEAL to focus on headache disorders:

• Headache disorders are extraordinarily burdensome. As most of us know (but not all legislators are aware), 60 million Americans suffer from migraine headache; it is the second leading cause of disability lifetime in the world.¹ Additionally, cluster headache is thought to be the most severe type of pain humans can experience.²

• There is a critical need for more effective and safer treatments for headache disorders. Opioid use is known to worsen migraine frequency and severity for some and make medications for headache less effective.³ Guidelines uniformly recommend against treating migraine with opioids; yet somehow 10% of migraine sufferers actively use opioids,⁴ and nearly 60% receive opioids during visits to the emergency room.⁵

• NIH has underfunded research on headache disorders. NIH has not prioritized programs for headache disorders research despite the fact that since 2009, 17 appropriations report language statements have strongly urged NIH to do so.⁶ In fact, headache is the least-funded research area among the most burdensome diseases.^7,8 Instead, other important disorders were funded, even though Headache on the Hill advocacy arranged for the report language for headache.

• Statutory authority for the HEAL initiative calls for disease burden to be a “crucial consideration” in prioritizing research programs. Less than 1% of HEAL grants have been for headache disorders research.¹⁰ If disease burden was used as the only gauge for funding, NIH investment for migraine research would likely be 15 times higher than the roughly $20 million that has historically been allocated.⁹ We hope our work this year will get us where we need to be.

Why Congress should fully fund VHA Headache Disorders Centers of Excellence  

• Headache disorders are a major health issue for veterans. Some 350,000 Global War on Terror (GWOT) veterans have sustained traumatic brain injuries. Many of them experience headaches. In fact, research shows that half of these veterans reported 15 or more headache days per month 4 to 11 years after sustaining traumatic brain injury. Nine of every 10 veterans met the criteria for migraine.¹⁰ Moreover, 3 million GWOT veterans have been exposed to toxic open burn pits.¹¹ These individuals have been found to be twice as likely to experience functional limitations due to migraine than those who did not have burn pit duties.¹²

• Headache Centers of Excellence (HCoEs) work. In 2018, $10 million was appropriated to establish at least 5 HCoEs that provided 1) comprehensive direct patient specialized headache medicine care within the VHA; 2) consultation and referral specialized headache care centers within the VHA; 3) education and training of VHA healthcare providers in headache medicine; and 4) research to improve the quality of headache disorders care for veterans and civilians.¹³

• Fourteen sites now exist, and success continues to be demonstrated. Last year more than 400,000 veterans sought specialty care for headache disorders from the VHA.¹⁴ However, only half of these vets are within reasonable reach of a HCoE.

The asks

Armed with this evidence, we made specific asks of the House and Senate with respect to annual appropriations spending bills:

1. Legislators were asked to sign on to a letter or send their own letter to officials on the House and Senate Labor, Health and Human Services, Education, and Related Agencies appropriations subcommittees to allocate $50 million from the HEAL initiative for headache disorders research in fiscal year 2022.

2. Similarly, lawmakers were asked to sign onto a letter or send their own letter to members of the Military Construction and Veterans Affairs subcommittee to appropriate $25 million to fund a doubling of HCoEs from 14 to 28 to improve access to those seeking care for headache disorders.

Stories from Americans nationwide

Headache on the Hill is about more than just presenting evidence and making requests. If that were the case, there is a pretty good chance that, before long, legislators would be looking at their watches, checking their smartphones, and flashing knowing glances at their aides in an effort to cut things short. However, humanizing the topic by sharing stories of the toll migraine and cluster headaches take on individuals is compelling testimony that hopefully will lead to meaningful action and positive outcomes. Here is a sampling of the stories told during and after the Headache on the Hill session:

• Rachel Koh and Ronetta Stokes: Koh registered for both the 2019 and 2020 Headache on the Hill sessions, only to be forced to cancel due to migraine attacks. But this year, according to the American Migraine Foundation, she was able to participate virtually and tell her representatives why increased funding was important for her, as well as veterans, including her father and uncle. Meanwhile, Stokes, a first-time participant, said she was struck by the conversations she had with legislators. Most knew someone with migraine, and some were sufferers themselves. “The more we share and spread the word, the sooner we can end the stigma,” Stokes told the American Migraine Foundation.

• Mia Maysack: Maysack wrote about her experience in a column for Pain News Network. “I live with both migraine disease and cluster headaches, which are called ‘suicide headaches’ for good reason,” she wrote. “There’s no limit to the chaos, interruption, inconvenience, and discomfort these conditions have caused in my life, requiring my full-time attention just to manage the symptoms. The difficult experiences I and countless others have faced in seeking, finding, and attempting different forms of treatment is why I continue to advocate—even when I don't feel up to it.” Maysack added that although it is relatively easy for her to receive a medication prescription for her condition, she’d like to see more consideration given to treatments such as water therapy, massage, oxygen, and mindful meditation.

• Chloe Vruno: Vruno, a 21-year-old college student, has suffered with migraine since the age of 15. “Some days are worse than others,” she noted in an article in her local newspaper, the Steuben County, IN Herald Republican. “Most days I have to push through a migraine to make it to class, but some days are so severe that I cannot make it to classes. On days I cannot make it, I use my accommodation for attendance flexibility, or now with COVID, I Zoom into class from my room.” Vruno wanted to make her representatives aware of these types of disruptions, a regular occurrence for migraine sufferers like her. This was her second Headache on the Hill event, and she found lawmakers whom she spoke with to be “extremely attentive, engaged, and excited.”

“A moral imperative”

Stories like these from regular individuals across the United States who suffer from headache disorders go a long way in convincing legislators to act. It also helps to tap into a celebrity’s endorsement when you can. Headache on the Hill did not disappoint in this regard, with Jon Stewart, the former host of The Daily Show, appearing as a special guest during a policy panel discussion on chronic headache disorders and toxic exposure. The session, which took place virtually as part of Headache on the Hill, featured Stewart, a national advocate for service personnel with toxic exposures, and Rep. Mark Takano (D-CA), who delivered the keynote address. The panel discussion included first responders, veterans, and clinicians.

Stewart summed up the sentiments of all Headache on the Hill stakeholders this way: “This is an eminently solvable problem, but the urgency is now. People will continue to suffer needlessly if we don’t get this done. It is a moral imperative that we pass a bill on presumption as soon as possible.”

I always enjoy going to Washington on cold days in February to be part of Headache on the Hill, and I hope we will be back in-person next year. We have tripled the number of attendees over the last 13 years and have a higher percentage of great patients and advocates now. I have to give a special thanks to Dr. Bob Shapiro, Professor of Neurology at the University of Vermont, who started and has guided this phenomenal effort over the years, to Dr. Chris Gottschalk, Professor of Neurology at Yale, who is gradually taking over the reins, and to Katie MacDonald who runs the entire show, even though she suffers from chronic migraine on a daily basis.

Participants in the Alliance for Headache Disorders Advocacy session requested federal funding for headache research and treatment. While patients told their stories, a noted advocate said headache is “an eminently solvable problem, but the urgency is now.”

It is going to take more than a pandemic to stop key headache advocacy stakeholders from raising awareness of the devastating impact of migraine and cluster headache and to motivate Congress to act.

With COVID-19 still very much a part of our lives, the Alliance for Headache Disorders Advocacy (AHDA)—a nonprofit dedicated to advocating for equitable policies for people with headache disorders—moved forward with its annual Headache on the Hill advocacy day, which took place virtually for the first time via videoconferencing on March 23, 2021.

While participants missed the opportunity to travel to Washington to meet with key legislators face-to-face, optimists saw it as a chance to involve more patients, providers, researchers, and caregivers who otherwise would not be able to participate. Indeed, more were involved than ever before: 217 individuals from 47 states and 178 Congressional districts attended, meeting with influential lawmakers, including Senator Patrick Leahy (D-VT), chair of the Appropriations Committee; Senator Richard Shelby (R-AL), vice chair of the Appropriations Committee; Rep. Rose DeLauro (D-CT), chair of the House Committee on Appropriations; Senator Jon Tester (D-MT), chair of Senate Committee on Veterans’ Affairs; Senator Jerry Moran (R-KS), ranking member of the Senate Committee on Veterans’ Affairs; Senator Patty Murray (D-WA), chair of the Senate HELP Committee; and Senator Richard Burr (R-NC), ranking member of the Senate HELP Committee.

I have had the privilege of being a part of Headache on the Hill for 13 years and was pleased to participate in this year’s virtual event. Though the setting was different, our mission remained the same: to make our important legislative requests (“asks”) of as many offices in Congress as possible. This year, we had 2 asks that aim to improve headache research and access to treatment, especially for our Veterans:

• Increased research funding: The group requested that the National Institutes of Health (NIH) Helping to End Addiction Long-Term (HEAL) initiative focus on headache disorders to reduce disease burden and opioid prescribing. This would make more funding available for headache research.

• Improved treatment access: The group also asked Congress to fully fund Veterans Health Administration (VHA) Headache Disorders Centers of Excellence (HCoE), facilitating equitable access to care for disabled veterans. This would double the number of VA Centers of Excellence to treat headache disorders in our veterans.

Of course, getting results means more than simply asking. The request to our congresspeople and their staff is more likely to succeed if it is well-reasoned and backed by evidence; and the Headache on the Hill contingent delivered on these requirements.

Why Congress should direct HEAL to focus on headache disorders:

• Headache disorders are extraordinarily burdensome. As most of us know (but not all legislators are aware), 60 million Americans suffer from migraine headache; it is the second leading cause of disability lifetime in the world.¹ Additionally, cluster headache is thought to be the most severe type of pain humans can experience.²

• There is a critical need for more effective and safer treatments for headache disorders. Opioid use is known to worsen migraine frequency and severity for some and make medications for headache less effective.³ Guidelines uniformly recommend against treating migraine with opioids; yet somehow 10% of migraine sufferers actively use opioids,⁴ and nearly 60% receive opioids during visits to the emergency room.⁵

• NIH has underfunded research on headache disorders. NIH has not prioritized programs for headache disorders research despite the fact that since 2009, 17 appropriations report language statements have strongly urged NIH to do so.⁶ In fact, headache is the least-funded research area among the most burdensome diseases.^7,8 Instead, other important disorders were funded, even though Headache on the Hill advocacy arranged for the report language for headache.

• Statutory authority for the HEAL initiative calls for disease burden to be a “crucial consideration” in prioritizing research programs. Less than 1% of HEAL grants have been for headache disorders research.¹⁰ If disease burden was used as the only gauge for funding, NIH investment for migraine research would likely be 15 times higher than the roughly $20 million that has historically been allocated.⁹ We hope our work this year will get us where we need to be.

Why Congress should fully fund VHA Headache Disorders Centers of Excellence  

• Headache disorders are a major health issue for veterans. Some 350,000 Global War on Terror (GWOT) veterans have sustained traumatic brain injuries. Many of them experience headaches. In fact, research shows that half of these veterans reported 15 or more headache days per month 4 to 11 years after sustaining traumatic brain injury. Nine of every 10 veterans met the criteria for migraine.¹⁰ Moreover, 3 million GWOT veterans have been exposed to toxic open burn pits.¹¹ These individuals have been found to be twice as likely to experience functional limitations due to migraine than those who did not have burn pit duties.¹²

• Headache Centers of Excellence (HCoEs) work. In 2018, $10 million was appropriated to establish at least 5 HCoEs that provided 1) comprehensive direct patient specialized headache medicine care within the VHA; 2) consultation and referral specialized headache care centers within the VHA; 3) education and training of VHA healthcare providers in headache medicine; and 4) research to improve the quality of headache disorders care for veterans and civilians.¹³

• Fourteen sites now exist, and success continues to be demonstrated. Last year more than 400,000 veterans sought specialty care for headache disorders from the VHA.¹⁴ However, only half of these vets are within reasonable reach of a HCoE.

The asks

Armed with this evidence, we made specific asks of the House and Senate with respect to annual appropriations spending bills:

1. Legislators were asked to sign on to a letter or send their own letter to officials on the House and Senate Labor, Health and Human Services, Education, and Related Agencies appropriations subcommittees to allocate $50 million from the HEAL initiative for headache disorders research in fiscal year 2022.

2. Similarly, lawmakers were asked to sign onto a letter or send their own letter to members of the Military Construction and Veterans Affairs subcommittee to appropriate $25 million to fund a doubling of HCoEs from 14 to 28 to improve access to those seeking care for headache disorders.

Stories from Americans nationwide

Headache on the Hill is about more than just presenting evidence and making requests. If that were the case, there is a pretty good chance that, before long, legislators would be looking at their watches, checking their smartphones, and flashing knowing glances at their aides in an effort to cut things short. However, humanizing the topic by sharing stories of the toll migraine and cluster headaches take on individuals is compelling testimony that hopefully will lead to meaningful action and positive outcomes. Here is a sampling of the stories told during and after the Headache on the Hill session:

• Rachel Koh and Ronetta Stokes: Koh registered for both the 2019 and 2020 Headache on the Hill sessions, only to be forced to cancel due to migraine attacks. But this year, according to the American Migraine Foundation, she was able to participate virtually and tell her representatives why increased funding was important for her, as well as veterans, including her father and uncle. Meanwhile, Stokes, a first-time participant, said she was struck by the conversations she had with legislators. Most knew someone with migraine, and some were sufferers themselves. “The more we share and spread the word, the sooner we can end the stigma,” Stokes told the American Migraine Foundation.

• Mia Maysack: Maysack wrote about her experience in a column for Pain News Network. “I live with both migraine disease and cluster headaches, which are called ‘suicide headaches’ for good reason,” she wrote. “There’s no limit to the chaos, interruption, inconvenience, and discomfort these conditions have caused in my life, requiring my full-time attention just to manage the symptoms. The difficult experiences I and countless others have faced in seeking, finding, and attempting different forms of treatment is why I continue to advocate—even when I don't feel up to it.” Maysack added that although it is relatively easy for her to receive a medication prescription for her condition, she’d like to see more consideration given to treatments such as water therapy, massage, oxygen, and mindful meditation.

• Chloe Vruno: Vruno, a 21-year-old college student, has suffered with migraine since the age of 15. “Some days are worse than others,” she noted in an article in her local newspaper, the Steuben County, IN Herald Republican. “Most days I have to push through a migraine to make it to class, but some days are so severe that I cannot make it to classes. On days I cannot make it, I use my accommodation for attendance flexibility, or now with COVID, I Zoom into class from my room.” Vruno wanted to make her representatives aware of these types of disruptions, a regular occurrence for migraine sufferers like her. This was her second Headache on the Hill event, and she found lawmakers whom she spoke with to be “extremely attentive, engaged, and excited.”

“A moral imperative”

Stories like these from regular individuals across the United States who suffer from headache disorders go a long way in convincing legislators to act. It also helps to tap into a celebrity’s endorsement when you can. Headache on the Hill did not disappoint in this regard, with Jon Stewart, the former host of The Daily Show, appearing as a special guest during a policy panel discussion on chronic headache disorders and toxic exposure. The session, which took place virtually as part of Headache on the Hill, featured Stewart, a national advocate for service personnel with toxic exposures, and Rep. Mark Takano (D-CA), who delivered the keynote address. The panel discussion included first responders, veterans, and clinicians.

Stewart summed up the sentiments of all Headache on the Hill stakeholders this way: “This is an eminently solvable problem, but the urgency is now. People will continue to suffer needlessly if we don’t get this done. It is a moral imperative that we pass a bill on presumption as soon as possible.”

I always enjoy going to Washington on cold days in February to be part of Headache on the Hill, and I hope we will be back in-person next year. We have tripled the number of attendees over the last 13 years and have a higher percentage of great patients and advocates now. I have to give a special thanks to Dr. Bob Shapiro, Professor of Neurology at the University of Vermont, who started and has guided this phenomenal effort over the years, to Dr. Chris Gottschalk, Professor of Neurology at Yale, who is gradually taking over the reins, and to Katie MacDonald who runs the entire show, even though she suffers from chronic migraine on a daily basis.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Key clinical point: Eptinezumab, particularly at a dosage of 300 mg, has significant efficacy and an acceptable safety profile for treatment of migraine.

Major finding: Eptinezumab significantly reduced the mean monthly migraine days (MMDs) compared with placebo at week 12 at a dosage of 30 mg (change in MMDs, −0.29; P = .0001), 100 mg (change in MMDs, −0.31; P less than .00001), and 300 mg (change in MMDs, −0.41; P less than .00001). Treatment-emergent adverse events were not significantly different between eptinezumab and placebo.

Study details: This was a meta-analysis of 4 randomized controlled trials including 2,739 patients with migraine.

Disclosures: This work was supported by the Suzhou Health Talents Training Project. The authors declared no competing interests.

Source: Yan Z et al. J Headache Pain. 2021 Mar 6. doi: 10.1186/s10194-021-01220-y.

Key clinical point: Eptinezumab, particularly at a dosage of 300 mg, has significant efficacy and an acceptable safety profile for treatment of migraine.

Major finding: Eptinezumab significantly reduced the mean monthly migraine days (MMDs) compared with placebo at week 12 at a dosage of 30 mg (change in MMDs, −0.29; P = .0001), 100 mg (change in MMDs, −0.31; P less than .00001), and 300 mg (change in MMDs, −0.41; P less than .00001). Treatment-emergent adverse events were not significantly different between eptinezumab and placebo.

Study details: This was a meta-analysis of 4 randomized controlled trials including 2,739 patients with migraine.

Disclosures: This work was supported by the Suzhou Health Talents Training Project. The authors declared no competing interests.

Source: Yan Z et al. J Headache Pain. 2021 Mar 6. doi: 10.1186/s10194-021-01220-y.

Key clinical point: Eptinezumab, particularly at a dosage of 300 mg, has significant efficacy and an acceptable safety profile for treatment of migraine.

Major finding: Eptinezumab significantly reduced the mean monthly migraine days (MMDs) compared with placebo at week 12 at a dosage of 30 mg (change in MMDs, −0.29; P = .0001), 100 mg (change in MMDs, −0.31; P less than .00001), and 300 mg (change in MMDs, −0.41; P less than .00001). Treatment-emergent adverse events were not significantly different between eptinezumab and placebo.

Study details: This was a meta-analysis of 4 randomized controlled trials including 2,739 patients with migraine.

Disclosures: This work was supported by the Suzhou Health Talents Training Project. The authors declared no competing interests.

Source: Yan Z et al. J Headache Pain. 2021 Mar 6. doi: 10.1186/s10194-021-01220-y.

Key clinical point: Components of nonpharmacological interventions are effective for treatment of pediatric migraine.

Major finding: Short-term self-administered treatments (standardized mean difference [SMD], 1.44; 95% confidence interval [95% CI], 0.26-2.62), biofeedback (SMD, 1.41; 95% CI, 0.64-2.17), relaxation (SMD, 1.38; 95% CI, 0.61-2.14), and psychological treatments (SMD, 1.36; 95% CI, 0.15-2.57) were more effective than the waiting list, with findings being similar for long-term treatments.

Study details: A network meta-analysis of 12 randomized clinical trials that evaluated nonpharmacological treatments for pediatric migraine in 576 children and adolescents with episodic migraine.

Disclosures: The study was supported in part by the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment. The authors reported no potential conflicts of interest.

Source: Koechlin H et al. Pediatrics. 2021 Mar 9. doi: 10.1542/peds.2019-4107.

Key clinical point: Components of nonpharmacological interventions are effective for treatment of pediatric migraine.

Major finding: Short-term self-administered treatments (standardized mean difference [SMD], 1.44; 95% confidence interval [95% CI], 0.26-2.62), biofeedback (SMD, 1.41; 95% CI, 0.64-2.17), relaxation (SMD, 1.38; 95% CI, 0.61-2.14), and psychological treatments (SMD, 1.36; 95% CI, 0.15-2.57) were more effective than the waiting list, with findings being similar for long-term treatments.

Study details: A network meta-analysis of 12 randomized clinical trials that evaluated nonpharmacological treatments for pediatric migraine in 576 children and adolescents with episodic migraine.

Disclosures: The study was supported in part by the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment. The authors reported no potential conflicts of interest.

Source: Koechlin H et al. Pediatrics. 2021 Mar 9. doi: 10.1542/peds.2019-4107.

Key clinical point: Components of nonpharmacological interventions are effective for treatment of pediatric migraine.

Major finding: Short-term self-administered treatments (standardized mean difference [SMD], 1.44; 95% confidence interval [95% CI], 0.26-2.62), biofeedback (SMD, 1.41; 95% CI, 0.64-2.17), relaxation (SMD, 1.38; 95% CI, 0.61-2.14), and psychological treatments (SMD, 1.36; 95% CI, 0.15-2.57) were more effective than the waiting list, with findings being similar for long-term treatments.

Study details: A network meta-analysis of 12 randomized clinical trials that evaluated nonpharmacological treatments for pediatric migraine in 576 children and adolescents with episodic migraine.

Disclosures: The study was supported in part by the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment. The authors reported no potential conflicts of interest.

Source: Koechlin H et al. Pediatrics. 2021 Mar 9. doi: 10.1542/peds.2019-4107.

Patients with neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) seem to benefit from rituximab (Rituxan) therapy, according to data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR).

Indeed, the percentage of patients with active disease, as scored by the BILAG-2004 index or SLEDAI-2K (SLE Disease Activity Index 2000), fell significantly (P < .0001) when comparing pre- and postrituximab treatment scores. There was also a reduction in the dose of oral steroids used.

Interestingly, the use of concomitant cyclophosphamide might enhance the level of improvement seen in some patients, Trixy David, MBBS, reported during an abstract session at the British Society for Rheumatology annual conference.

“Larger-scale studies are warranted to establish the effectiveness of rituximab alone, or in combination with cyclophosphamide, in the treatment neuropsychiatric lupus,” said Dr. David, a clinical research fellow at the University of Manchester (England) and specialist registrar in rheumatology at the Manchester University National Health Service Foundation Trust.

Neil Basu, MBChB, PhD, who chaired the virtual session, called the findings “enlightening” and “descriptive.”

The study “provides some interesting data, which should be tested in a robust, randomized clinical trial,” he agreed, and not that clinicians should now start using rituximab for their NPSLE cases.

Dr. Basu, who is a clinical senior lecturer in rheumatology and honorary consultant rheumatologist at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, added: “It is really important that we do these studies to help support a rationale for such a trial, which are obviously very expensive and require strong evidence before we go down that track. I think these data have really been quite enlightening in that respect.”

Rationale for rituximab in neuropsychiatric lupus

Managing patients with NPSLE remains an area of substantial unmet need. According to a recent review in Rheumatology, “there is a dearth of controlled clinical trials to guide management” and “therapeutic options include symptomatic, antithrombotic, and immunosuppressive agents that are supported by observational cohort studies.”

Despite being seen in at least half of all patients with SLE, neuropsychiatric disease “is not very well studied in patients with lupus, as a lot of large-scale trials tend to exclude patients with active neurological disease,” Dr. David said.

Although it is unclear why neuropsychiatric disease occurs in SLE, it could be “as a result of vascular injury or disruption of the blood brain barrier, thereby allowing the passive diffusion of autoantibodies and cytokines across through the cerebral spinal fluid, thereby generating a proinflammatory response,” Dr. David suggested.

“We know B cells are involved in the pathogenesis of lupus, and rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells and mediates transient B-cell depletion,” she said. Notably, there have been some small studies suggesting that rituximab may be effective in neuropsychiatric lupus, and it is currently widely used to treat refractory lupus in the United Kingdom.
 

About the BILAG-BR and results

“Our aim was to describe the baseline characteristics and short-term effectiveness of rituximab in patients treated for neuropsychiatric lupus within the BILAG-BR,” Dr. David explained.

Started in 2009, the BILAG-BR now contains information on more than 1,400 individuals with SLE who have been recruited at 62 centers in the United Kingdom. Its purpose is to evaluate the long-term safety and effectiveness of biologic drugs versus standard immunosuppressive therapy such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine. To date, 1,229 patients have been treated with biologics, of whom 1,056 have received rituximab.

A total of 74 rituximab-treated patients were identified as having active neuropsychiatric disease, making this “the largest prospective observational cohort to date, to our knowledge,” Dr. David said.

The median age of patients was 45.5 years, the majority was female (82%) and White (74%). The median disease duration was 11.5 years.

A total of 96% had multiple organ involvement and not just neuropsychiatric disease, and 91% were positive for antineutrophil antibodies.

The top six neuropsychiatric manifestations were cognitive dysfunction and lupus headache (both affecting 27.5% of patients); acute confessional state or mononeuropathy (each seen in 10% of patients); and seizure disorder and polyneuropathy, seen in a respective 8.6% and 8.7% of patients. These findings are in line with a 2011 meta-analysis, Dr. David pointed out.

BILAG-2004 scores before and after rituximab treatment were available for 50 patients. The number of patients with a BILAG A score dropped from 24 (48%) at baseline to 7 (14%) after treatment with rituximab, and the number with a BILAG B score declined from 26 (52%) at baseline to 4 (8%) after rituximab (both P < .0001).

There was also a reduction following rituximab treatment in the percentage of patients categorized as having mainly central nervous system disease (70% vs. 11%), peripheral nervous system disease (19% vs. 6%), or both (11% vs. 8%).

Total SLEDAI-2K scores were also reduced following rituximab treatment, from a median of 12 at baseline to 2 (P < .0001).

Pre- and postrituximab oral prednisolone doses were a median of 15 mg and 10 mg (P = .009).

Limitations

“Our data are from a real-world setting of patients who had active neuropsychiatric disease and were treated with rituximab,” Dr. David said. There are of course many limitations that go hand in hand with observational studies.

“There was the issue of missing data,” Dr. David said. It was difficult or not possible to determine what doses of steroids patients were taking after rituximab therapy, particularly in terms of intravenous steroids, and what doses of any other concomitant disease-modifying therapy might have been around the time that patients initiated or stopped rituximab treatment.

“These could have acted as potential confounders,” she acknowledged.

Dr. Basu noted: “My major haziness from it is the uncertainty of knowing why these patients improved. Yes, they had rituximab, but I’m sure also that they probably received high doses of steroids if they had quite severe CNS lupus which was categorized as a BILAG-A or a B.”

Patients may also be given methylprednisolone when clinicians are really concerned, he continued, and “as was quite clearly pointed out,” there was quite a lot of missing data from a steroid perspective.

Dr. David and coinvestigators reported having no conflicts of interest. The BILAG-BR is supported by funding from Lupus UK, GlaxoSmithKline, and Roche. Dr. Basu did not state having any disclosures.

Patients with neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) seem to benefit from rituximab (Rituxan) therapy, according to data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR).

Indeed, the percentage of patients with active disease, as scored by the BILAG-2004 index or SLEDAI-2K (SLE Disease Activity Index 2000), fell significantly (P < .0001) when comparing pre- and postrituximab treatment scores. There was also a reduction in the dose of oral steroids used.

Interestingly, the use of concomitant cyclophosphamide might enhance the level of improvement seen in some patients, Trixy David, MBBS, reported during an abstract session at the British Society for Rheumatology annual conference.

“Larger-scale studies are warranted to establish the effectiveness of rituximab alone, or in combination with cyclophosphamide, in the treatment neuropsychiatric lupus,” said Dr. David, a clinical research fellow at the University of Manchester (England) and specialist registrar in rheumatology at the Manchester University National Health Service Foundation Trust.

Neil Basu, MBChB, PhD, who chaired the virtual session, called the findings “enlightening” and “descriptive.”

The study “provides some interesting data, which should be tested in a robust, randomized clinical trial,” he agreed, and not that clinicians should now start using rituximab for their NPSLE cases.

Dr. Basu, who is a clinical senior lecturer in rheumatology and honorary consultant rheumatologist at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, added: “It is really important that we do these studies to help support a rationale for such a trial, which are obviously very expensive and require strong evidence before we go down that track. I think these data have really been quite enlightening in that respect.”

Rationale for rituximab in neuropsychiatric lupus

Managing patients with NPSLE remains an area of substantial unmet need. According to a recent review in Rheumatology, “there is a dearth of controlled clinical trials to guide management” and “therapeutic options include symptomatic, antithrombotic, and immunosuppressive agents that are supported by observational cohort studies.”

Despite being seen in at least half of all patients with SLE, neuropsychiatric disease “is not very well studied in patients with lupus, as a lot of large-scale trials tend to exclude patients with active neurological disease,” Dr. David said.

Although it is unclear why neuropsychiatric disease occurs in SLE, it could be “as a result of vascular injury or disruption of the blood brain barrier, thereby allowing the passive diffusion of autoantibodies and cytokines across through the cerebral spinal fluid, thereby generating a proinflammatory response,” Dr. David suggested.

“We know B cells are involved in the pathogenesis of lupus, and rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells and mediates transient B-cell depletion,” she said. Notably, there have been some small studies suggesting that rituximab may be effective in neuropsychiatric lupus, and it is currently widely used to treat refractory lupus in the United Kingdom.
 

About the BILAG-BR and results

“Our aim was to describe the baseline characteristics and short-term effectiveness of rituximab in patients treated for neuropsychiatric lupus within the BILAG-BR,” Dr. David explained.

Started in 2009, the BILAG-BR now contains information on more than 1,400 individuals with SLE who have been recruited at 62 centers in the United Kingdom. Its purpose is to evaluate the long-term safety and effectiveness of biologic drugs versus standard immunosuppressive therapy such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine. To date, 1,229 patients have been treated with biologics, of whom 1,056 have received rituximab.

A total of 74 rituximab-treated patients were identified as having active neuropsychiatric disease, making this “the largest prospective observational cohort to date, to our knowledge,” Dr. David said.

The median age of patients was 45.5 years, the majority was female (82%) and White (74%). The median disease duration was 11.5 years.

A total of 96% had multiple organ involvement and not just neuropsychiatric disease, and 91% were positive for antineutrophil antibodies.

The top six neuropsychiatric manifestations were cognitive dysfunction and lupus headache (both affecting 27.5% of patients); acute confessional state or mononeuropathy (each seen in 10% of patients); and seizure disorder and polyneuropathy, seen in a respective 8.6% and 8.7% of patients. These findings are in line with a 2011 meta-analysis, Dr. David pointed out.

BILAG-2004 scores before and after rituximab treatment were available for 50 patients. The number of patients with a BILAG A score dropped from 24 (48%) at baseline to 7 (14%) after treatment with rituximab, and the number with a BILAG B score declined from 26 (52%) at baseline to 4 (8%) after rituximab (both P < .0001).

There was also a reduction following rituximab treatment in the percentage of patients categorized as having mainly central nervous system disease (70% vs. 11%), peripheral nervous system disease (19% vs. 6%), or both (11% vs. 8%).

Total SLEDAI-2K scores were also reduced following rituximab treatment, from a median of 12 at baseline to 2 (P < .0001).

Pre- and postrituximab oral prednisolone doses were a median of 15 mg and 10 mg (P = .009).

Limitations

“Our data are from a real-world setting of patients who had active neuropsychiatric disease and were treated with rituximab,” Dr. David said. There are of course many limitations that go hand in hand with observational studies.

“There was the issue of missing data,” Dr. David said. It was difficult or not possible to determine what doses of steroids patients were taking after rituximab therapy, particularly in terms of intravenous steroids, and what doses of any other concomitant disease-modifying therapy might have been around the time that patients initiated or stopped rituximab treatment.

“These could have acted as potential confounders,” she acknowledged.

Dr. Basu noted: “My major haziness from it is the uncertainty of knowing why these patients improved. Yes, they had rituximab, but I’m sure also that they probably received high doses of steroids if they had quite severe CNS lupus which was categorized as a BILAG-A or a B.”

Patients may also be given methylprednisolone when clinicians are really concerned, he continued, and “as was quite clearly pointed out,” there was quite a lot of missing data from a steroid perspective.

Dr. David and coinvestigators reported having no conflicts of interest. The BILAG-BR is supported by funding from Lupus UK, GlaxoSmithKline, and Roche. Dr. Basu did not state having any disclosures.

Patients with neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) seem to benefit from rituximab (Rituxan) therapy, according to data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR).

Indeed, the percentage of patients with active disease, as scored by the BILAG-2004 index or SLEDAI-2K (SLE Disease Activity Index 2000), fell significantly (P < .0001) when comparing pre- and postrituximab treatment scores. There was also a reduction in the dose of oral steroids used.

Interestingly, the use of concomitant cyclophosphamide might enhance the level of improvement seen in some patients, Trixy David, MBBS, reported during an abstract session at the British Society for Rheumatology annual conference.

“Larger-scale studies are warranted to establish the effectiveness of rituximab alone, or in combination with cyclophosphamide, in the treatment neuropsychiatric lupus,” said Dr. David, a clinical research fellow at the University of Manchester (England) and specialist registrar in rheumatology at the Manchester University National Health Service Foundation Trust.

Neil Basu, MBChB, PhD, who chaired the virtual session, called the findings “enlightening” and “descriptive.”

The study “provides some interesting data, which should be tested in a robust, randomized clinical trial,” he agreed, and not that clinicians should now start using rituximab for their NPSLE cases.

Dr. Basu, who is a clinical senior lecturer in rheumatology and honorary consultant rheumatologist at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, added: “It is really important that we do these studies to help support a rationale for such a trial, which are obviously very expensive and require strong evidence before we go down that track. I think these data have really been quite enlightening in that respect.”

Rationale for rituximab in neuropsychiatric lupus

Managing patients with NPSLE remains an area of substantial unmet need. According to a recent review in Rheumatology, “there is a dearth of controlled clinical trials to guide management” and “therapeutic options include symptomatic, antithrombotic, and immunosuppressive agents that are supported by observational cohort studies.”

Despite being seen in at least half of all patients with SLE, neuropsychiatric disease “is not very well studied in patients with lupus, as a lot of large-scale trials tend to exclude patients with active neurological disease,” Dr. David said.

Although it is unclear why neuropsychiatric disease occurs in SLE, it could be “as a result of vascular injury or disruption of the blood brain barrier, thereby allowing the passive diffusion of autoantibodies and cytokines across through the cerebral spinal fluid, thereby generating a proinflammatory response,” Dr. David suggested.

“We know B cells are involved in the pathogenesis of lupus, and rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells and mediates transient B-cell depletion,” she said. Notably, there have been some small studies suggesting that rituximab may be effective in neuropsychiatric lupus, and it is currently widely used to treat refractory lupus in the United Kingdom.
 

About the BILAG-BR and results

“Our aim was to describe the baseline characteristics and short-term effectiveness of rituximab in patients treated for neuropsychiatric lupus within the BILAG-BR,” Dr. David explained.

Started in 2009, the BILAG-BR now contains information on more than 1,400 individuals with SLE who have been recruited at 62 centers in the United Kingdom. Its purpose is to evaluate the long-term safety and effectiveness of biologic drugs versus standard immunosuppressive therapy such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine. To date, 1,229 patients have been treated with biologics, of whom 1,056 have received rituximab.

A total of 74 rituximab-treated patients were identified as having active neuropsychiatric disease, making this “the largest prospective observational cohort to date, to our knowledge,” Dr. David said.

The median age of patients was 45.5 years, the majority was female (82%) and White (74%). The median disease duration was 11.5 years.

A total of 96% had multiple organ involvement and not just neuropsychiatric disease, and 91% were positive for antineutrophil antibodies.

The top six neuropsychiatric manifestations were cognitive dysfunction and lupus headache (both affecting 27.5% of patients); acute confessional state or mononeuropathy (each seen in 10% of patients); and seizure disorder and polyneuropathy, seen in a respective 8.6% and 8.7% of patients. These findings are in line with a 2011 meta-analysis, Dr. David pointed out.

BILAG-2004 scores before and after rituximab treatment were available for 50 patients. The number of patients with a BILAG A score dropped from 24 (48%) at baseline to 7 (14%) after treatment with rituximab, and the number with a BILAG B score declined from 26 (52%) at baseline to 4 (8%) after rituximab (both P < .0001).

There was also a reduction following rituximab treatment in the percentage of patients categorized as having mainly central nervous system disease (70% vs. 11%), peripheral nervous system disease (19% vs. 6%), or both (11% vs. 8%).

Total SLEDAI-2K scores were also reduced following rituximab treatment, from a median of 12 at baseline to 2 (P < .0001).

Pre- and postrituximab oral prednisolone doses were a median of 15 mg and 10 mg (P = .009).

Limitations

“Our data are from a real-world setting of patients who had active neuropsychiatric disease and were treated with rituximab,” Dr. David said. There are of course many limitations that go hand in hand with observational studies.

“There was the issue of missing data,” Dr. David said. It was difficult or not possible to determine what doses of steroids patients were taking after rituximab therapy, particularly in terms of intravenous steroids, and what doses of any other concomitant disease-modifying therapy might have been around the time that patients initiated or stopped rituximab treatment.

“These could have acted as potential confounders,” she acknowledged.

Dr. Basu noted: “My major haziness from it is the uncertainty of knowing why these patients improved. Yes, they had rituximab, but I’m sure also that they probably received high doses of steroids if they had quite severe CNS lupus which was categorized as a BILAG-A or a B.”

Patients may also be given methylprednisolone when clinicians are really concerned, he continued, and “as was quite clearly pointed out,” there was quite a lot of missing data from a steroid perspective.

Dr. David and coinvestigators reported having no conflicts of interest. The BILAG-BR is supported by funding from Lupus UK, GlaxoSmithKline, and Roche. Dr. Basu did not state having any disclosures.

Intranasal zavegepant, a third-generation calcitonin gene-related peptide (CGRP) receptor agonist, is effective and well tolerated in the treatment of acute migraine, new research shows. In a randomized dose-ranging, placebo-controlled, phase 2/3 trial, investigators found both the 10- and 20-mg doses of the drug were associated with pain freedom in more than 20% of patients and alleviated the most bothersome symptom, defined as photophobia, phonophobia, or nausea, in more than 40% of patients.

Most adverse events associated with zavegepant were mild or moderate. The drug is not associated with liver toxicity.

Three doses

Zavegepant is the only intranasal CGRP receptor antagonist undergoing late-stage development for the acute treatment of migraine. A previous single ascending dose study suggested the drug provided systemic exposure and had potentially therapeutic effects.

The study included participants age 18 years or older who had a diagnosis of migraine for at least 1 year, had two to eight migraine attacks of moderate or severe intensity and fewer than 15 monthly headache days over the previous 3 months.

The investigators randomly assigned participants in this phase 2/3 trial to placebo or a 5-mg, 10-mg, or 20-mg dose of intranasal zavegepant. Participants treated a single attack of moderate to severe pain with their assigned treatment.

The study’s two primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after dosing.

The investigators randomly assigned 1,673 participants to treatment. Of this group, 1,588 treated an attack with study medication. The researchers also included 1,581 participants in the modified intention-to-treat population. Of this group, 387 received the 5-mg dose, 391 received the 10-mg dose, 402 received the 20-mg dose, and 401 received placebo.
 

Pain freedom

The population’s median age was approximately 41 years, 86% of participants were female, and 14% were taking preventive migraine medication. Participants’ mean number of moderate or severe attacks per month was 4.9 overall. The most common most bothersome symptom was photophobia.

The researchers observed a difference in outcome between the active and placebo arms as early as 15 minutes post-dose, but this difference was not statistically significant. At 2 hours, the rate of pain freedom was 15.5% in the placebo group, 22.5% in the 10-mg group (P = .0113), and 23.1% in the 20-mg group (P = .0055). The result for the 5-mg group (19.6%) was not significantly different from that of the placebo group.

The rate of freedom from the most bothersome symptom was 33.7% in the placebo group, 41.9% in the 10-mg group (P = .0155), and 42.5% in the 20-mg group (P = .0094). For this endpoint as well, the result of the 5-mg group (39%) was not significantly different from that among controls.

The most common adverse events were dysgeusia (impaired sense of taste) and nasal discomfort. The rate of dysgeusia ranged from 13.5% to 16.1% in the zavegepant groups, compared with 3.5% among controls. The rate of nasal discomfort ranged from 1.3% to 5.2% in the zavegepant groups, compared with 0.2% among controls. The investigators concluded that intranasal zavegepant had a favorable safety profile.
 

‘Exciting potential addition’

Commenting on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said: “Zavegepant is an exciting potential addition to rimegepant for the acute care of migraine.”

Many patients like the orally dissolving tablet formulation of rimegepant (Nurtec), but some have nausea and do not absorb oral preparations well, said Dr. Rapoport, who is editor-in-chief of Neurology Reviews and a past president of the International Headache Society. “So, it makes sense to have a gepant, which is not a vasoconstrictor and has few adverse events, developed as a nasal spray.” Nasal preparations often work more quickly than oral preparations, he added.

Other intranasal treatments available for migraine include dihydroergotamine (Migranal), zolmitriptan (Zomig), sumatriptan (Imitrex), and ketorolac (Sprix). It is not possible to compare zavegepant with these medications, or with other CGRP receptor antagonists, because they have not been studied in head-to-head trials, said Dr. Rapoport, who was not involved in the study but has previously consulted for Biohaven Pharmaceuticals, the drug’s manufacturer.

“I would predict a nasal spray would work somewhat faster and better in some patients with nausea or poor absorption, so I would be happy to have it approved and available.”

The current study uses endpoints typically prescribed by the U.S. Food and Drug Administration and includes a large sample size, said Dr. Rapoport.

“During the informed consent [stage], the patients in this trial would be told that there is a 3-in-4 chance that they would be getting an active drug versus placebo, and that often increases the placebo response,” he added. “In this trial, a placebo response of 15.5% is slightly high, but not atypical,” he added.

This study raises the question of whether other acute-care migraine medications should be studied as nasal preparations. “I think the answer is yes,” said Dr. Rapoport. “Fast-acting, effective nasal preparations that are easy to use and cause few adverse events [are] what we need.”

Biohaven Pharmaceuticals sponsored the study. Dr. Lipton has been a consultant for Biohaven, has conducted studies funded by the company, and has stock in the company. Dr. Rapoport has consulted and spoken for Biohaven, but did not participate in the current study.

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

Intranasal zavegepant, a third-generation calcitonin gene-related peptide (CGRP) receptor agonist, is effective and well tolerated in the treatment of acute migraine, new research shows. In a randomized dose-ranging, placebo-controlled, phase 2/3 trial, investigators found both the 10- and 20-mg doses of the drug were associated with pain freedom in more than 20% of patients and alleviated the most bothersome symptom, defined as photophobia, phonophobia, or nausea, in more than 40% of patients.

Most adverse events associated with zavegepant were mild or moderate. The drug is not associated with liver toxicity.

Three doses

Zavegepant is the only intranasal CGRP receptor antagonist undergoing late-stage development for the acute treatment of migraine. A previous single ascending dose study suggested the drug provided systemic exposure and had potentially therapeutic effects.

The study included participants age 18 years or older who had a diagnosis of migraine for at least 1 year, had two to eight migraine attacks of moderate or severe intensity and fewer than 15 monthly headache days over the previous 3 months.

The investigators randomly assigned participants in this phase 2/3 trial to placebo or a 5-mg, 10-mg, or 20-mg dose of intranasal zavegepant. Participants treated a single attack of moderate to severe pain with their assigned treatment.

The study’s two primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after dosing.

The investigators randomly assigned 1,673 participants to treatment. Of this group, 1,588 treated an attack with study medication. The researchers also included 1,581 participants in the modified intention-to-treat population. Of this group, 387 received the 5-mg dose, 391 received the 10-mg dose, 402 received the 20-mg dose, and 401 received placebo.
 

Pain freedom

The population’s median age was approximately 41 years, 86% of participants were female, and 14% were taking preventive migraine medication. Participants’ mean number of moderate or severe attacks per month was 4.9 overall. The most common most bothersome symptom was photophobia.

The researchers observed a difference in outcome between the active and placebo arms as early as 15 minutes post-dose, but this difference was not statistically significant. At 2 hours, the rate of pain freedom was 15.5% in the placebo group, 22.5% in the 10-mg group (P = .0113), and 23.1% in the 20-mg group (P = .0055). The result for the 5-mg group (19.6%) was not significantly different from that of the placebo group.

The rate of freedom from the most bothersome symptom was 33.7% in the placebo group, 41.9% in the 10-mg group (P = .0155), and 42.5% in the 20-mg group (P = .0094). For this endpoint as well, the result of the 5-mg group (39%) was not significantly different from that among controls.

The most common adverse events were dysgeusia (impaired sense of taste) and nasal discomfort. The rate of dysgeusia ranged from 13.5% to 16.1% in the zavegepant groups, compared with 3.5% among controls. The rate of nasal discomfort ranged from 1.3% to 5.2% in the zavegepant groups, compared with 0.2% among controls. The investigators concluded that intranasal zavegepant had a favorable safety profile.
 

‘Exciting potential addition’

Commenting on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said: “Zavegepant is an exciting potential addition to rimegepant for the acute care of migraine.”

Many patients like the orally dissolving tablet formulation of rimegepant (Nurtec), but some have nausea and do not absorb oral preparations well, said Dr. Rapoport, who is editor-in-chief of Neurology Reviews and a past president of the International Headache Society. “So, it makes sense to have a gepant, which is not a vasoconstrictor and has few adverse events, developed as a nasal spray.” Nasal preparations often work more quickly than oral preparations, he added.

Other intranasal treatments available for migraine include dihydroergotamine (Migranal), zolmitriptan (Zomig), sumatriptan (Imitrex), and ketorolac (Sprix). It is not possible to compare zavegepant with these medications, or with other CGRP receptor antagonists, because they have not been studied in head-to-head trials, said Dr. Rapoport, who was not involved in the study but has previously consulted for Biohaven Pharmaceuticals, the drug’s manufacturer.

“I would predict a nasal spray would work somewhat faster and better in some patients with nausea or poor absorption, so I would be happy to have it approved and available.”

The current study uses endpoints typically prescribed by the U.S. Food and Drug Administration and includes a large sample size, said Dr. Rapoport.

“During the informed consent [stage], the patients in this trial would be told that there is a 3-in-4 chance that they would be getting an active drug versus placebo, and that often increases the placebo response,” he added. “In this trial, a placebo response of 15.5% is slightly high, but not atypical,” he added.

This study raises the question of whether other acute-care migraine medications should be studied as nasal preparations. “I think the answer is yes,” said Dr. Rapoport. “Fast-acting, effective nasal preparations that are easy to use and cause few adverse events [are] what we need.”

Biohaven Pharmaceuticals sponsored the study. Dr. Lipton has been a consultant for Biohaven, has conducted studies funded by the company, and has stock in the company. Dr. Rapoport has consulted and spoken for Biohaven, but did not participate in the current study.

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

Intranasal zavegepant, a third-generation calcitonin gene-related peptide (CGRP) receptor agonist, is effective and well tolerated in the treatment of acute migraine, new research shows. In a randomized dose-ranging, placebo-controlled, phase 2/3 trial, investigators found both the 10- and 20-mg doses of the drug were associated with pain freedom in more than 20% of patients and alleviated the most bothersome symptom, defined as photophobia, phonophobia, or nausea, in more than 40% of patients.

Most adverse events associated with zavegepant were mild or moderate. The drug is not associated with liver toxicity.

Three doses

Zavegepant is the only intranasal CGRP receptor antagonist undergoing late-stage development for the acute treatment of migraine. A previous single ascending dose study suggested the drug provided systemic exposure and had potentially therapeutic effects.

The study included participants age 18 years or older who had a diagnosis of migraine for at least 1 year, had two to eight migraine attacks of moderate or severe intensity and fewer than 15 monthly headache days over the previous 3 months.

The investigators randomly assigned participants in this phase 2/3 trial to placebo or a 5-mg, 10-mg, or 20-mg dose of intranasal zavegepant. Participants treated a single attack of moderate to severe pain with their assigned treatment.

The study’s two primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after dosing.

The investigators randomly assigned 1,673 participants to treatment. Of this group, 1,588 treated an attack with study medication. The researchers also included 1,581 participants in the modified intention-to-treat population. Of this group, 387 received the 5-mg dose, 391 received the 10-mg dose, 402 received the 20-mg dose, and 401 received placebo.
 

Pain freedom

The population’s median age was approximately 41 years, 86% of participants were female, and 14% were taking preventive migraine medication. Participants’ mean number of moderate or severe attacks per month was 4.9 overall. The most common most bothersome symptom was photophobia.

The researchers observed a difference in outcome between the active and placebo arms as early as 15 minutes post-dose, but this difference was not statistically significant. At 2 hours, the rate of pain freedom was 15.5% in the placebo group, 22.5% in the 10-mg group (P = .0113), and 23.1% in the 20-mg group (P = .0055). The result for the 5-mg group (19.6%) was not significantly different from that of the placebo group.

The rate of freedom from the most bothersome symptom was 33.7% in the placebo group, 41.9% in the 10-mg group (P = .0155), and 42.5% in the 20-mg group (P = .0094). For this endpoint as well, the result of the 5-mg group (39%) was not significantly different from that among controls.

The most common adverse events were dysgeusia (impaired sense of taste) and nasal discomfort. The rate of dysgeusia ranged from 13.5% to 16.1% in the zavegepant groups, compared with 3.5% among controls. The rate of nasal discomfort ranged from 1.3% to 5.2% in the zavegepant groups, compared with 0.2% among controls. The investigators concluded that intranasal zavegepant had a favorable safety profile.
 

‘Exciting potential addition’

Commenting on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said: “Zavegepant is an exciting potential addition to rimegepant for the acute care of migraine.”

Many patients like the orally dissolving tablet formulation of rimegepant (Nurtec), but some have nausea and do not absorb oral preparations well, said Dr. Rapoport, who is editor-in-chief of Neurology Reviews and a past president of the International Headache Society. “So, it makes sense to have a gepant, which is not a vasoconstrictor and has few adverse events, developed as a nasal spray.” Nasal preparations often work more quickly than oral preparations, he added.

Other intranasal treatments available for migraine include dihydroergotamine (Migranal), zolmitriptan (Zomig), sumatriptan (Imitrex), and ketorolac (Sprix). It is not possible to compare zavegepant with these medications, or with other CGRP receptor antagonists, because they have not been studied in head-to-head trials, said Dr. Rapoport, who was not involved in the study but has previously consulted for Biohaven Pharmaceuticals, the drug’s manufacturer.

“I would predict a nasal spray would work somewhat faster and better in some patients with nausea or poor absorption, so I would be happy to have it approved and available.”

The current study uses endpoints typically prescribed by the U.S. Food and Drug Administration and includes a large sample size, said Dr. Rapoport.

“During the informed consent [stage], the patients in this trial would be told that there is a 3-in-4 chance that they would be getting an active drug versus placebo, and that often increases the placebo response,” he added. “In this trial, a placebo response of 15.5% is slightly high, but not atypical,” he added.

This study raises the question of whether other acute-care migraine medications should be studied as nasal preparations. “I think the answer is yes,” said Dr. Rapoport. “Fast-acting, effective nasal preparations that are easy to use and cause few adverse events [are] what we need.”

Biohaven Pharmaceuticals sponsored the study. Dr. Lipton has been a consultant for Biohaven, has conducted studies funded by the company, and has stock in the company. Dr. Rapoport has consulted and spoken for Biohaven, but did not participate in the current study.

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