The goal of treating medication overuse headache is obvious: ceasing overuse of the medication in question in an effort to return to a headache pattern that is episodic and better managed. Although guidelines suggest withdrawal of the overused medication and initiating preventive treatment, there is debate about this approach versus withdrawal alone or preventive treatment without ceasing the overused medication. A recently published randomized trial from Carlsen and colleagues evaluated 3 treatment methods: 1) withdrawal plus preventive treatment; 2) preventive treatment only; and 3) withdrawal followed by optional preventive treatment 2 months after withdrawal. Investigators found all 3 approaches effective, but participants who underwent withdrawal plus preventive care saw their headache days reduced by 12.3 days, versus 9.9 days in the preventive-only group and 8.5 days in the withdrawal/optional preventive follow-up treatment contingent. No statistically significant differences were seen between the groups in terms of migraine days, days with short-term medication use, and headache pain intensity.

Particularly noteworthy was the finding that individuals treated with withdrawal plus preventive treatment were significantly more likely to achieve remission. Specifically, nearly 75% returned to experiencing episodic headache, compared with 60% in the preventive group and 42% in the withdrawal contingent. Nearly all (97%) of those on the withdrawal plus preventive regimen were cured of medication overuse headache, versus 90% (withdrawal) and 74% (preventive).

The bottom line: Individuals undergoing withdrawal plus preventive treatment were 30% more likely to be cured of medication overuse headache. Thus, it appears that detoxification is key.

Or is it?

On the one hand…

In studies, withdrawal from the offending medication is linked with substantial improvement in headache days. Additionally, individuals who previously responded poorly to preventive treatment fared better with such treatment after detoxification.

When treating medication overuse headache using the detoxification and preventive care approach, Sun-Edelstein and colleagues outline these important steps:

• Educate your patients and their family/caregivers about the detoxification process
• Wean patient off the offending medication with a goal of complete detoxification
• Initiate preventive medical therapy or behavioral/non-drug strategies
• Establish clear limits on acute medication intake
• Arrange for regular follow-up to minimize or prevent relapse

While on the other hand…

Even though guidelines recommend detoxification, there is data supporting the concept of initiating preventive treatment without detoxification. A randomized, double-blind, placebo-controlled trial by Mei and colleagues found that 100 mg per day of topiramate led to a significant reduction in headache days and average amount of acute medication intake, versus placebo. However, treatment completion rates were low, leading Sun-Edelstein and colleagues to surmise that topiramate without detoxification would probably not have had a high success rate in practice.

Meanwhile, onabotulinumtoxin A was found in the PREEMPT trials conducted by Dodick and colleagues to reduce the number of headache days, migraine days, and moderate/severe headache days, compared with placebo, at week 24. Disappointingly, researchers found that acute medication frequency was not reduced in the overall treatment group, but they did note a significant reduction in the subgroup that was taking triptans. Moreover, a follow-up analysis by Aurora and colleagues involving 32 weeks of open-label treatment with onabotulinumtoxin A following the 24-week randomized study revealed significant reductions in acute headache days at 56 weeks.

Using anti-CGRPs without acute medication withdrawal

More recently, strong evidence is emerging about the value of using anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies without acute medication withdrawal. The findings involve 4 anti-CGRP medications.

Erenumab: A subgroup analysis of a randomized, double-blind, placebo-controlled parallel-group trial by Tepper and colleagues showed that erenumab reduced frequency of migraine at 3 months in participants with chronic migraine and medication overuse. Patients receiving either 70 or 140 mg of erenumab saw their migraine frequency reduced by an average of 6.6 days, versus 3.5 days in the placebo group. 

Additionally, a significantly greater number of patients in the treatment groups stopped overusing medication, and did so early, which led to improved patient-reported outcomes. Acute migraine-specific medication treatment days were reduced by an average of 5.4 days in the 70 mg group, 4.9 days in the 140 mg contingent, and 2.9 days in those who received placebo.

Overall, consistent improvement in measures of impact, disability and health-related quality of life were seen in individuals’ treatment with erenumab.

Galcanezumab: A post-hoc analysis of pooled data from the phase 3 EVOLVE-1 and EVOLVE-2 studies, as well as the phase 3 REGAIN trial found that in participants with medication overuse, 120 mg and 240 mg doses of galcanezumab cut the number of average migraine days and decreased medication overuse. Average migraine days were lowered in EVOLVE participants by 6.26 days in the 120 mg group, 5.77 days in the 240 mg contingent, and 2.71 in those who received placebo. In REGAIN, these numbers were 4.78, 4.51, and 2.25, respectively. Average monthly medication use rates in EVOLVE were 6.2%, 7.9%, and 15.9%, respectively; in REGAIN they were 24.3%, 23.1%, and 40.6%, respectively.

Notably, though the study demonstrated galcanezumab’s efficacy in those with and without medication overuse, improvement was more pronounced in patients with medication overuse.

Fremanezumab: In an analysis by Silberstein and colleagues, significantly more patients who received quarterly or monthly injections of fremanezumab reported no medication overuse during the 3-month study, versus placebo. Specifically, 61% of participants who received monthly injections of fremanezumab and 55% of those who took quarterly injections reported no medication overuse. Among those receiving placebo, only 46% reverted to no overuse. The effect was seen as early as week 4. Additionally, among patients with medication overuse at baseline, the number of days with acute medication use was significantly lower in the treatment groups versus placebo—1.8 days lower in the quarterly group and 2.8 days in the monthly contingent.

A subsequent post-hoc analysis presented at the 2019 American Headache Society (AHS) Annual Scientific Meeting showed that the benefits were sustained over time and the medication was effective in difficult cases. Continued treatment with either quarterly or monthly dosing resulted in a reduced number of headache days, acute medication overuse headache, and headache-related disability, compared with baseline measures. Notably, about 6 in every 10 individuals with medication overuse at baseline who received fremanezumab reverted to no acute medication overuse at 6 months. This effect was maintained through 1 year of treatment.

Eptinezumab: In PROMISE-2, a post-hoc analysis of the phase 3 trials evaluating quarterly IV infusions of eptinezumab 100 mg and 300 mg, Lipton and colleagues reported that participants with chronic migraine and medication overuse experienced greater reductions in monthly migraine days during weeks 1 through 12, versus placebo (100 mg, 7.7 days; 300 mg, 8.2 days; placebo, 5.6 days). Benefits, seen as early as the day after dosing, were generally maintained or improved over 24 weeks.

Acute care medication use was reduced by about 50% in the treatment group versus roughly 25% in the placebo contingent. Most encouraging was the finding that about one-third of individuals in the treatment cohort experienced 6 months without medication overuse and below the chronic migraine diagnostic threshold; only 10% of patients who received placebo resolved in this way. Consistent improvement across patient-reported outcomes was also observed in the treatment group versus placebo.

While the studies involving topiramate, onabotulinumtoxin A, and the anti-CGRP monoclonal antibodies suggest that preventive treatment alone may effectively treat acute medical overuse and medication overuse headache, it is the data behind the anti-CGRP treatments that seem to be most compelling and causing conventional thinking to be challenged. These medications appear to be able to convert individuals with chronic migraine and medication overuse, out of overuse and back to episodic migraine. Moreover, results show they may be able to reduce acute medication use in episodic migraine, which reduces the risk of the headache sufferer transforming to chronic migraine. It is worth considering this approach in patients’ overuse acute care medication, as well as those in whom discontinuation may otherwise prove difficult without concurrent preventive treatment.

The emerging role of gepants

Availability of the so-called “gepants”—small molecule CGRP receptor agonists—is shedding additional light on management of medication overuse headache and pointing to the future. Gepants—which include ubrogepant, rimegepant, and atogepant—have been shown in early data to have a preventive effect when used regularly. Thus, it is much less likely that their use will lead to excess use and medication overuse headache.

Preclinical data demonstrated that continued use of ubrogepant does not appear to produce early or latent trigeminal sensory sensitization. Meanwhile, rimegepant, when used every other day, and as needed for acute treatment of migraine in individuals suffering from moderate-to-high frequency episodic migraine, resulted in reductions in monthly migraine days. The preventive effects appear to be rapid and sustained. And in a phase 3 trial, atogepant demonstrated efficacy at doses of 10 mg, 30 mg, and 60 mg twice a day, compared with placebo over 12 weeks.

It is important to note that the link between the gepants and medication overuse and medication overuse headache have not yet been studied. Still, it is encouraging to see that migraine frequency improves and medication use days are reduced when gepants are taken preventively. Thus, gepants could emerge as a preferred approach for acute or preventive treatment in individuals who have or are at risk of developing medication overuse headache.

The goal of treating medication overuse headache is obvious: ceasing overuse of the medication in question in an effort to return to a headache pattern that is episodic and better managed. Although guidelines suggest withdrawal of the overused medication and initiating preventive treatment, there is debate about this approach versus withdrawal alone or preventive treatment without ceasing the overused medication. A recently published randomized trial from Carlsen and colleagues evaluated 3 treatment methods: 1) withdrawal plus preventive treatment; 2) preventive treatment only; and 3) withdrawal followed by optional preventive treatment 2 months after withdrawal. Investigators found all 3 approaches effective, but participants who underwent withdrawal plus preventive care saw their headache days reduced by 12.3 days, versus 9.9 days in the preventive-only group and 8.5 days in the withdrawal/optional preventive follow-up treatment contingent. No statistically significant differences were seen between the groups in terms of migraine days, days with short-term medication use, and headache pain intensity.

Particularly noteworthy was the finding that individuals treated with withdrawal plus preventive treatment were significantly more likely to achieve remission. Specifically, nearly 75% returned to experiencing episodic headache, compared with 60% in the preventive group and 42% in the withdrawal contingent. Nearly all (97%) of those on the withdrawal plus preventive regimen were cured of medication overuse headache, versus 90% (withdrawal) and 74% (preventive).

The bottom line: Individuals undergoing withdrawal plus preventive treatment were 30% more likely to be cured of medication overuse headache. Thus, it appears that detoxification is key.

Or is it?

On the one hand…

In studies, withdrawal from the offending medication is linked with substantial improvement in headache days. Additionally, individuals who previously responded poorly to preventive treatment fared better with such treatment after detoxification.

When treating medication overuse headache using the detoxification and preventive care approach, Sun-Edelstein and colleagues outline these important steps:

• Educate your patients and their family/caregivers about the detoxification process
• Wean patient off the offending medication with a goal of complete detoxification
• Initiate preventive medical therapy or behavioral/non-drug strategies
• Establish clear limits on acute medication intake
• Arrange for regular follow-up to minimize or prevent relapse

While on the other hand…

Even though guidelines recommend detoxification, there is data supporting the concept of initiating preventive treatment without detoxification. A randomized, double-blind, placebo-controlled trial by Mei and colleagues found that 100 mg per day of topiramate led to a significant reduction in headache days and average amount of acute medication intake, versus placebo. However, treatment completion rates were low, leading Sun-Edelstein and colleagues to surmise that topiramate without detoxification would probably not have had a high success rate in practice.

Meanwhile, onabotulinumtoxin A was found in the PREEMPT trials conducted by Dodick and colleagues to reduce the number of headache days, migraine days, and moderate/severe headache days, compared with placebo, at week 24. Disappointingly, researchers found that acute medication frequency was not reduced in the overall treatment group, but they did note a significant reduction in the subgroup that was taking triptans. Moreover, a follow-up analysis by Aurora and colleagues involving 32 weeks of open-label treatment with onabotulinumtoxin A following the 24-week randomized study revealed significant reductions in acute headache days at 56 weeks.

Using anti-CGRPs without acute medication withdrawal

More recently, strong evidence is emerging about the value of using anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies without acute medication withdrawal. The findings involve 4 anti-CGRP medications.

Erenumab: A subgroup analysis of a randomized, double-blind, placebo-controlled parallel-group trial by Tepper and colleagues showed that erenumab reduced frequency of migraine at 3 months in participants with chronic migraine and medication overuse. Patients receiving either 70 or 140 mg of erenumab saw their migraine frequency reduced by an average of 6.6 days, versus 3.5 days in the placebo group. 

Additionally, a significantly greater number of patients in the treatment groups stopped overusing medication, and did so early, which led to improved patient-reported outcomes. Acute migraine-specific medication treatment days were reduced by an average of 5.4 days in the 70 mg group, 4.9 days in the 140 mg contingent, and 2.9 days in those who received placebo.

Overall, consistent improvement in measures of impact, disability and health-related quality of life were seen in individuals’ treatment with erenumab.

Galcanezumab: A post-hoc analysis of pooled data from the phase 3 EVOLVE-1 and EVOLVE-2 studies, as well as the phase 3 REGAIN trial found that in participants with medication overuse, 120 mg and 240 mg doses of galcanezumab cut the number of average migraine days and decreased medication overuse. Average migraine days were lowered in EVOLVE participants by 6.26 days in the 120 mg group, 5.77 days in the 240 mg contingent, and 2.71 in those who received placebo. In REGAIN, these numbers were 4.78, 4.51, and 2.25, respectively. Average monthly medication use rates in EVOLVE were 6.2%, 7.9%, and 15.9%, respectively; in REGAIN they were 24.3%, 23.1%, and 40.6%, respectively.

Notably, though the study demonstrated galcanezumab’s efficacy in those with and without medication overuse, improvement was more pronounced in patients with medication overuse.

Fremanezumab: In an analysis by Silberstein and colleagues, significantly more patients who received quarterly or monthly injections of fremanezumab reported no medication overuse during the 3-month study, versus placebo. Specifically, 61% of participants who received monthly injections of fremanezumab and 55% of those who took quarterly injections reported no medication overuse. Among those receiving placebo, only 46% reverted to no overuse. The effect was seen as early as week 4. Additionally, among patients with medication overuse at baseline, the number of days with acute medication use was significantly lower in the treatment groups versus placebo—1.8 days lower in the quarterly group and 2.8 days in the monthly contingent.

A subsequent post-hoc analysis presented at the 2019 American Headache Society (AHS) Annual Scientific Meeting showed that the benefits were sustained over time and the medication was effective in difficult cases. Continued treatment with either quarterly or monthly dosing resulted in a reduced number of headache days, acute medication overuse headache, and headache-related disability, compared with baseline measures. Notably, about 6 in every 10 individuals with medication overuse at baseline who received fremanezumab reverted to no acute medication overuse at 6 months. This effect was maintained through 1 year of treatment.

Eptinezumab: In PROMISE-2, a post-hoc analysis of the phase 3 trials evaluating quarterly IV infusions of eptinezumab 100 mg and 300 mg, Lipton and colleagues reported that participants with chronic migraine and medication overuse experienced greater reductions in monthly migraine days during weeks 1 through 12, versus placebo (100 mg, 7.7 days; 300 mg, 8.2 days; placebo, 5.6 days). Benefits, seen as early as the day after dosing, were generally maintained or improved over 24 weeks.

Acute care medication use was reduced by about 50% in the treatment group versus roughly 25% in the placebo contingent. Most encouraging was the finding that about one-third of individuals in the treatment cohort experienced 6 months without medication overuse and below the chronic migraine diagnostic threshold; only 10% of patients who received placebo resolved in this way. Consistent improvement across patient-reported outcomes was also observed in the treatment group versus placebo.

While the studies involving topiramate, onabotulinumtoxin A, and the anti-CGRP monoclonal antibodies suggest that preventive treatment alone may effectively treat acute medical overuse and medication overuse headache, it is the data behind the anti-CGRP treatments that seem to be most compelling and causing conventional thinking to be challenged. These medications appear to be able to convert individuals with chronic migraine and medication overuse, out of overuse and back to episodic migraine. Moreover, results show they may be able to reduce acute medication use in episodic migraine, which reduces the risk of the headache sufferer transforming to chronic migraine. It is worth considering this approach in patients’ overuse acute care medication, as well as those in whom discontinuation may otherwise prove difficult without concurrent preventive treatment.

The emerging role of gepants

Availability of the so-called “gepants”—small molecule CGRP receptor agonists—is shedding additional light on management of medication overuse headache and pointing to the future. Gepants—which include ubrogepant, rimegepant, and atogepant—have been shown in early data to have a preventive effect when used regularly. Thus, it is much less likely that their use will lead to excess use and medication overuse headache.

Preclinical data demonstrated that continued use of ubrogepant does not appear to produce early or latent trigeminal sensory sensitization. Meanwhile, rimegepant, when used every other day, and as needed for acute treatment of migraine in individuals suffering from moderate-to-high frequency episodic migraine, resulted in reductions in monthly migraine days. The preventive effects appear to be rapid and sustained. And in a phase 3 trial, atogepant demonstrated efficacy at doses of 10 mg, 30 mg, and 60 mg twice a day, compared with placebo over 12 weeks.

It is important to note that the link between the gepants and medication overuse and medication overuse headache have not yet been studied. Still, it is encouraging to see that migraine frequency improves and medication use days are reduced when gepants are taken preventively. Thus, gepants could emerge as a preferred approach for acute or preventive treatment in individuals who have or are at risk of developing medication overuse headache.

The goal of treating medication overuse headache is obvious: ceasing overuse of the medication in question in an effort to return to a headache pattern that is episodic and better managed. Although guidelines suggest withdrawal of the overused medication and initiating preventive treatment, there is debate about this approach versus withdrawal alone or preventive treatment without ceasing the overused medication. A recently published randomized trial from Carlsen and colleagues evaluated 3 treatment methods: 1) withdrawal plus preventive treatment; 2) preventive treatment only; and 3) withdrawal followed by optional preventive treatment 2 months after withdrawal. Investigators found all 3 approaches effective, but participants who underwent withdrawal plus preventive care saw their headache days reduced by 12.3 days, versus 9.9 days in the preventive-only group and 8.5 days in the withdrawal/optional preventive follow-up treatment contingent. No statistically significant differences were seen between the groups in terms of migraine days, days with short-term medication use, and headache pain intensity.

Particularly noteworthy was the finding that individuals treated with withdrawal plus preventive treatment were significantly more likely to achieve remission. Specifically, nearly 75% returned to experiencing episodic headache, compared with 60% in the preventive group and 42% in the withdrawal contingent. Nearly all (97%) of those on the withdrawal plus preventive regimen were cured of medication overuse headache, versus 90% (withdrawal) and 74% (preventive).

The bottom line: Individuals undergoing withdrawal plus preventive treatment were 30% more likely to be cured of medication overuse headache. Thus, it appears that detoxification is key.

Or is it?

On the one hand…

In studies, withdrawal from the offending medication is linked with substantial improvement in headache days. Additionally, individuals who previously responded poorly to preventive treatment fared better with such treatment after detoxification.

When treating medication overuse headache using the detoxification and preventive care approach, Sun-Edelstein and colleagues outline these important steps:

• Educate your patients and their family/caregivers about the detoxification process
• Wean patient off the offending medication with a goal of complete detoxification
• Initiate preventive medical therapy or behavioral/non-drug strategies
• Establish clear limits on acute medication intake
• Arrange for regular follow-up to minimize or prevent relapse

While on the other hand…

Even though guidelines recommend detoxification, there is data supporting the concept of initiating preventive treatment without detoxification. A randomized, double-blind, placebo-controlled trial by Mei and colleagues found that 100 mg per day of topiramate led to a significant reduction in headache days and average amount of acute medication intake, versus placebo. However, treatment completion rates were low, leading Sun-Edelstein and colleagues to surmise that topiramate without detoxification would probably not have had a high success rate in practice.

Meanwhile, onabotulinumtoxin A was found in the PREEMPT trials conducted by Dodick and colleagues to reduce the number of headache days, migraine days, and moderate/severe headache days, compared with placebo, at week 24. Disappointingly, researchers found that acute medication frequency was not reduced in the overall treatment group, but they did note a significant reduction in the subgroup that was taking triptans. Moreover, a follow-up analysis by Aurora and colleagues involving 32 weeks of open-label treatment with onabotulinumtoxin A following the 24-week randomized study revealed significant reductions in acute headache days at 56 weeks.

Using anti-CGRPs without acute medication withdrawal

More recently, strong evidence is emerging about the value of using anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies without acute medication withdrawal. The findings involve 4 anti-CGRP medications.

Erenumab: A subgroup analysis of a randomized, double-blind, placebo-controlled parallel-group trial by Tepper and colleagues showed that erenumab reduced frequency of migraine at 3 months in participants with chronic migraine and medication overuse. Patients receiving either 70 or 140 mg of erenumab saw their migraine frequency reduced by an average of 6.6 days, versus 3.5 days in the placebo group. 

Additionally, a significantly greater number of patients in the treatment groups stopped overusing medication, and did so early, which led to improved patient-reported outcomes. Acute migraine-specific medication treatment days were reduced by an average of 5.4 days in the 70 mg group, 4.9 days in the 140 mg contingent, and 2.9 days in those who received placebo.

Overall, consistent improvement in measures of impact, disability and health-related quality of life were seen in individuals’ treatment with erenumab.

Galcanezumab: A post-hoc analysis of pooled data from the phase 3 EVOLVE-1 and EVOLVE-2 studies, as well as the phase 3 REGAIN trial found that in participants with medication overuse, 120 mg and 240 mg doses of galcanezumab cut the number of average migraine days and decreased medication overuse. Average migraine days were lowered in EVOLVE participants by 6.26 days in the 120 mg group, 5.77 days in the 240 mg contingent, and 2.71 in those who received placebo. In REGAIN, these numbers were 4.78, 4.51, and 2.25, respectively. Average monthly medication use rates in EVOLVE were 6.2%, 7.9%, and 15.9%, respectively; in REGAIN they were 24.3%, 23.1%, and 40.6%, respectively.

Notably, though the study demonstrated galcanezumab’s efficacy in those with and without medication overuse, improvement was more pronounced in patients with medication overuse.

Fremanezumab: In an analysis by Silberstein and colleagues, significantly more patients who received quarterly or monthly injections of fremanezumab reported no medication overuse during the 3-month study, versus placebo. Specifically, 61% of participants who received monthly injections of fremanezumab and 55% of those who took quarterly injections reported no medication overuse. Among those receiving placebo, only 46% reverted to no overuse. The effect was seen as early as week 4. Additionally, among patients with medication overuse at baseline, the number of days with acute medication use was significantly lower in the treatment groups versus placebo—1.8 days lower in the quarterly group and 2.8 days in the monthly contingent.

A subsequent post-hoc analysis presented at the 2019 American Headache Society (AHS) Annual Scientific Meeting showed that the benefits were sustained over time and the medication was effective in difficult cases. Continued treatment with either quarterly or monthly dosing resulted in a reduced number of headache days, acute medication overuse headache, and headache-related disability, compared with baseline measures. Notably, about 6 in every 10 individuals with medication overuse at baseline who received fremanezumab reverted to no acute medication overuse at 6 months. This effect was maintained through 1 year of treatment.

Eptinezumab: In PROMISE-2, a post-hoc analysis of the phase 3 trials evaluating quarterly IV infusions of eptinezumab 100 mg and 300 mg, Lipton and colleagues reported that participants with chronic migraine and medication overuse experienced greater reductions in monthly migraine days during weeks 1 through 12, versus placebo (100 mg, 7.7 days; 300 mg, 8.2 days; placebo, 5.6 days). Benefits, seen as early as the day after dosing, were generally maintained or improved over 24 weeks.

Acute care medication use was reduced by about 50% in the treatment group versus roughly 25% in the placebo contingent. Most encouraging was the finding that about one-third of individuals in the treatment cohort experienced 6 months without medication overuse and below the chronic migraine diagnostic threshold; only 10% of patients who received placebo resolved in this way. Consistent improvement across patient-reported outcomes was also observed in the treatment group versus placebo.

While the studies involving topiramate, onabotulinumtoxin A, and the anti-CGRP monoclonal antibodies suggest that preventive treatment alone may effectively treat acute medical overuse and medication overuse headache, it is the data behind the anti-CGRP treatments that seem to be most compelling and causing conventional thinking to be challenged. These medications appear to be able to convert individuals with chronic migraine and medication overuse, out of overuse and back to episodic migraine. Moreover, results show they may be able to reduce acute medication use in episodic migraine, which reduces the risk of the headache sufferer transforming to chronic migraine. It is worth considering this approach in patients’ overuse acute care medication, as well as those in whom discontinuation may otherwise prove difficult without concurrent preventive treatment.

The emerging role of gepants

Availability of the so-called “gepants”—small molecule CGRP receptor agonists—is shedding additional light on management of medication overuse headache and pointing to the future. Gepants—which include ubrogepant, rimegepant, and atogepant—have been shown in early data to have a preventive effect when used regularly. Thus, it is much less likely that their use will lead to excess use and medication overuse headache.

Preclinical data demonstrated that continued use of ubrogepant does not appear to produce early or latent trigeminal sensory sensitization. Meanwhile, rimegepant, when used every other day, and as needed for acute treatment of migraine in individuals suffering from moderate-to-high frequency episodic migraine, resulted in reductions in monthly migraine days. The preventive effects appear to be rapid and sustained. And in a phase 3 trial, atogepant demonstrated efficacy at doses of 10 mg, 30 mg, and 60 mg twice a day, compared with placebo over 12 weeks.

It is important to note that the link between the gepants and medication overuse and medication overuse headache have not yet been studied. Still, it is encouraging to see that migraine frequency improves and medication use days are reduced when gepants are taken preventively. Thus, gepants could emerge as a preferred approach for acute or preventive treatment in individuals who have or are at risk of developing medication overuse headache.

Key clinical point: Erenumab significantly reduced acute medication use and health care resource utilization (HCRU) among patients with migraine in a real-world setting in the U.S.A.

Major finding: The mean number of claims (rate ratio [RR], 0.77) and number of patients using acute medication (both P less than .0001) significantly declined in 6 months postinitiation of erenumab. Similarly, 6-month HCRU of migraine-specific office visits (RR, 0.77) and all-cause office visits (RR, 0.92) decreased significantly (both P less than .0001).

Study details: Data come from a retrospective, exploratory analysis of 3,171 adult patients with migraine who initiated erenumab and had at least 3 doses in the 6 months post-index period.

Disclosures: The study was supported by Novartis Pharma AG. SJ Tepper reported serving as a consultant and/or on advisory boards, receiving grants, and CME honoraria from multiple sources. Some of the authors declared being employees and shareholders of Novartis.

Source: Tepper SJ et al. J Headache Pain. 2021 Apr 19. doi: 10.1186/s10194-021-01238-2.

Key clinical point: Erenumab significantly reduced acute medication use and health care resource utilization (HCRU) among patients with migraine in a real-world setting in the U.S.A.

Major finding: The mean number of claims (rate ratio [RR], 0.77) and number of patients using acute medication (both P less than .0001) significantly declined in 6 months postinitiation of erenumab. Similarly, 6-month HCRU of migraine-specific office visits (RR, 0.77) and all-cause office visits (RR, 0.92) decreased significantly (both P less than .0001).

Study details: Data come from a retrospective, exploratory analysis of 3,171 adult patients with migraine who initiated erenumab and had at least 3 doses in the 6 months post-index period.

Disclosures: The study was supported by Novartis Pharma AG. SJ Tepper reported serving as a consultant and/or on advisory boards, receiving grants, and CME honoraria from multiple sources. Some of the authors declared being employees and shareholders of Novartis.

Source: Tepper SJ et al. J Headache Pain. 2021 Apr 19. doi: 10.1186/s10194-021-01238-2.

Key clinical point: Erenumab significantly reduced acute medication use and health care resource utilization (HCRU) among patients with migraine in a real-world setting in the U.S.A.

Major finding: The mean number of claims (rate ratio [RR], 0.77) and number of patients using acute medication (both P less than .0001) significantly declined in 6 months postinitiation of erenumab. Similarly, 6-month HCRU of migraine-specific office visits (RR, 0.77) and all-cause office visits (RR, 0.92) decreased significantly (both P less than .0001).

Study details: Data come from a retrospective, exploratory analysis of 3,171 adult patients with migraine who initiated erenumab and had at least 3 doses in the 6 months post-index period.

Disclosures: The study was supported by Novartis Pharma AG. SJ Tepper reported serving as a consultant and/or on advisory boards, receiving grants, and CME honoraria from multiple sources. Some of the authors declared being employees and shareholders of Novartis.

Source: Tepper SJ et al. J Headache Pain. 2021 Apr 19. doi: 10.1186/s10194-021-01238-2.

Key clinical point: In patients with migraine, most calcitonin gene-related peptide (CGRP) monoclonal antibodies were similarly effective; however, galcanezumab was more likely to cause treatment-emerging adverse events (TEAEs).

Major finding: Fremanezumab vs. placebo had the highest probability to reduce monthly migraine days (mean difference [MD], −2.19; 95% credible interval [95% CrI], −3.15 to −1.25) followed by galcanezumab (MD, −2.10; 95% CrI, −2.76 to −1.45), erenumab (MD, −1.61; 95% CrI, −2.40 to −0.84), and eptinezumab (MD, −1.43; 95% CrI, −2.59 to −0.36). However, galcanezumab was more likely to cause TEAEs (relative risk, 1.11; 95% CrI, 1.01-1.22).

Study details: Findings are from a systematic review and network meta-analysis of 18 randomized clinical trials involving 8,926 patients with migraine.

Disclosures: No information on funding was available. The authors had no commercial or financial disclosures.

Source: Wang X et al. Front Pharmacol. 2021 Mar 25. doi: 10.3389/fphar.2021.649143.

Key clinical point: In patients with migraine, most calcitonin gene-related peptide (CGRP) monoclonal antibodies were similarly effective; however, galcanezumab was more likely to cause treatment-emerging adverse events (TEAEs).

Major finding: Fremanezumab vs. placebo had the highest probability to reduce monthly migraine days (mean difference [MD], −2.19; 95% credible interval [95% CrI], −3.15 to −1.25) followed by galcanezumab (MD, −2.10; 95% CrI, −2.76 to −1.45), erenumab (MD, −1.61; 95% CrI, −2.40 to −0.84), and eptinezumab (MD, −1.43; 95% CrI, −2.59 to −0.36). However, galcanezumab was more likely to cause TEAEs (relative risk, 1.11; 95% CrI, 1.01-1.22).

Study details: Findings are from a systematic review and network meta-analysis of 18 randomized clinical trials involving 8,926 patients with migraine.

Disclosures: No information on funding was available. The authors had no commercial or financial disclosures.

Source: Wang X et al. Front Pharmacol. 2021 Mar 25. doi: 10.3389/fphar.2021.649143.

Key clinical point: In patients with migraine, most calcitonin gene-related peptide (CGRP) monoclonal antibodies were similarly effective; however, galcanezumab was more likely to cause treatment-emerging adverse events (TEAEs).

Major finding: Fremanezumab vs. placebo had the highest probability to reduce monthly migraine days (mean difference [MD], −2.19; 95% credible interval [95% CrI], −3.15 to −1.25) followed by galcanezumab (MD, −2.10; 95% CrI, −2.76 to −1.45), erenumab (MD, −1.61; 95% CrI, −2.40 to −0.84), and eptinezumab (MD, −1.43; 95% CrI, −2.59 to −0.36). However, galcanezumab was more likely to cause TEAEs (relative risk, 1.11; 95% CrI, 1.01-1.22).

Study details: Findings are from a systematic review and network meta-analysis of 18 randomized clinical trials involving 8,926 patients with migraine.

Disclosures: No information on funding was available. The authors had no commercial or financial disclosures.

Source: Wang X et al. Front Pharmacol. 2021 Mar 25. doi: 10.3389/fphar.2021.649143.

Race and socioeconomic status can hinder and delay patient access to migraine treatment and result in poorer outcomes, according to a study published in the April issue of Headache. People of African descent and Latinx ethnicity tend to fare worse than other people of color and their White counterparts.

“It should be shocking to neurologists and other clinicians who care for migraine patients how few are able to successfully traverse the barriers to achieve an accurate diagnosis and proper, evidence-based, acute and preventative treatment,” commented Peter McAllister, MD, medical director at the New England Institute for Neurology and Headache and chief medical officer for clinical research at Ki Clinical Research in Stamford, Conn. Dr. McAllister was not involved in this study.
 

Assessing barriers to care

Researchers designed the study with the primary objective of estimating the number of patients with migraines with unmet clinical needs and who were impacted by four preidentified barriers to care. To evaluate their objective, researchers conducted a longitudinal, Internet-based survey known as the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. They collected data over 1 year examining a cohort of patients that mimicked the diverse demographics of the U.S. population. Researchers conducted longitudinal assessments every 3 months for 15 months, incorporating cross-sectional analyses that surveyed health care use, family burden, and comorbidities or endophenotypes.

Eligible enrollees were 18 years of age or older.

Researchers identified four barriers that hindered patient outcomes, and they served as the primary outcomes of the studies. They were:

• Health care provider consultations. Investigators used study participants’ responses to the following question during their interactions with their health care providers to help evaluate the quality of their consultation experience: “What type of doctor is currently managing your headaches?” Researchers included data from patients whose practitioners fit the description of those they deemed best suited to address ongoing headache challenges. These medical professionals included general practitioners, family physicians, internal medicine doctors, nurse practitioners, physician assistants, neurologists, pain specialists, headache specialists, and obstetrician-gynecologists.
• Diagnosis. Carefully evaluating patients’ responses to a series of questions helped researchers gauge the accuracy of diagnosis. Questions included: “Have you ever been diagnosed by a doctor or other health professional with any of the following types of headaches?” Respondents were also given a list of options that provided additional context around their headaches and were encouraged to select all appropriate responses. The list included a fictional response option of “citrene headache” to determine incorrect responses. For this study, researchers deemed it necessary to recognize a chronic migraine diagnosis to ensure that patients received appropriate treatment.
• Minimally appropriate pharmacologic treatment. Researchers used the following question to determine whether patients’ chronic migraine and episodic migraine were being managed with the least amount of pharmacological treatment necessary. “Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches when you have them?” Researchers defined “minimally appropriate acute pharmacologic treatment” as the use of any prescription nonsteroidal anti-inflammatory drug (NSAID), triptan, ergotamine derivative, or isometheptene.
• Avoidance of medication overuse. The study authors pointed out the sometimes nebulous process of characterizing the appropriate use of preventative medication in patients with episodic migraines as “not straightforward” for some patients because not all patients require preventive treatment. Study participants were required to report having received any form of preventative therapy, defined as pharmacological therapies approved by guidelines and supported by data. Such therapies included various antiseizure medication, antidepressants (for example, doxepin, venlafaxine, duloxetine, amitriptyline, imipramine, nortriptyline, and desvenlafaxine), antihypertensives, and toxin injections. Treatments such as behavioral and neuromodulatory therapies were excluded from the list.

According to lead author Dawn C. Buse, PhD, of the department of neurology at Albert Einstein College of Medicine, New York, acute medication overuse provides an important modifiable target for intervention and recommends that clinicians use the opportunity to optimize migraine care by reducing the patients’ reliance on acute therapies. Taking such initiatives to decrease medication overuse is especially important in communities of color, who are more likely to overuse medications for migraines.

Patients with higher income levels were more likely to overcome each barrier. People of African, African American, or multiracial descent were more prone to overuse of medications to manage their migraines.

Of the 489,537 respondents invited to participate in the CaMEO study, 16,879 qualified for inclusion. Slightly more than half of the respondents (n = 9,184 [54.7%]) had a migraine-related disability (MIDAS) score of 6 or greater – an indicator of disability that is least mild in nature. Most patients who had episodic migraines or chronic migraines (86.2%) had some form of health insurance coverage (n = 9.184; 84.1%; P = .048). Of those patients who were insured, 7,930 patients experienced episodic migraine (86.3%) and the remainder had chronic migraine (n = 1,254; 13.7%). Higher-income patients were more likely to traverse barriers to care. While patients of African descent had higher consultation rates, they also had higher rates of acute medication overuse.

Patients with chronic migraine were more likely to be older than patients with episodic migraine (41.0 vs. 39.6 years; P = .0001) and female (83.0% vs. 79.0%; P = .001), and White (84.5% vs. 79.1%; P < .001). Similarly, patients with chronic migraine were more likely to have a higher mean body mass index (29.8 kg/m² vs. 28.9 kg/m²; P < .001) and lower rates of full- or part-time employment (56.8% vs. 67.1%; P < .001), and were less likely to have a 4-year degree (64.8 vs. 55.6; P < .001) and annual household incomes below $75,000 (72.6% vs. 64.6%; P < .001). Approximately three-quarters of the patients with episodic migraine (75.7%; 1655/2187) and one-third of patients with chronic migraine (32.8%; 168/512) received accurate diagnoses.

The data uncovered an association with acute medication overuse. Among current consulters who had received an accurate diagnosis and minimally adequate treatment, medication overuse rates were highest among those reporting two or more races (53%) and Blacks and African Americans (45%) and lowest among Whites (33%) and those categorized as “other” race (32%). Ethnic and cultural differences in headache literacy may contribute to differences in medication overuse. 
 

Strategies to improve outcomes

Both Dr. Buse and Dr. McAllister see the value advocacy and education offer in helping to improve outcomes in marginalized communities and other groups negatively impacted by various barriers.

“Patient advocacy and outreach are key here, especially in those traditionally underrepresented in the migraine space, such as men, people of color, blue-collar workers, etc.,” Dr. McAllister noted.

Dr. Buse emphasized the importance of education for patients and health care professionals alike. “A large percentage of people who meet criteria for migraine in the U.S. do not seek care or possibly even know that they have migraines,” Dr. Buse said. “This finding underscores the importance of public health education about migraine as well as well as providing migraine support, education, and resources to health care professionals on the front lines.”

Other strategies recommended by Dr, Buse to ease the impact of barriers include encouraging patient discussion, setting up time for follow-up appointments and education, referring patients for neurological and other specialty consults when warranted, reviewing essential lifestyle habits for migraine management, and creating personalized, mutually agreed-upon treatment plans.

Dr. Buse has received support and honoraria from AbbVie, Amgen, Avanir, Biohaven, Eli Lilly, and Promius.

Race and socioeconomic status can hinder and delay patient access to migraine treatment and result in poorer outcomes, according to a study published in the April issue of Headache. People of African descent and Latinx ethnicity tend to fare worse than other people of color and their White counterparts.

“It should be shocking to neurologists and other clinicians who care for migraine patients how few are able to successfully traverse the barriers to achieve an accurate diagnosis and proper, evidence-based, acute and preventative treatment,” commented Peter McAllister, MD, medical director at the New England Institute for Neurology and Headache and chief medical officer for clinical research at Ki Clinical Research in Stamford, Conn. Dr. McAllister was not involved in this study.
 

Assessing barriers to care

Researchers designed the study with the primary objective of estimating the number of patients with migraines with unmet clinical needs and who were impacted by four preidentified barriers to care. To evaluate their objective, researchers conducted a longitudinal, Internet-based survey known as the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. They collected data over 1 year examining a cohort of patients that mimicked the diverse demographics of the U.S. population. Researchers conducted longitudinal assessments every 3 months for 15 months, incorporating cross-sectional analyses that surveyed health care use, family burden, and comorbidities or endophenotypes.

Eligible enrollees were 18 years of age or older.

Researchers identified four barriers that hindered patient outcomes, and they served as the primary outcomes of the studies. They were:

• Health care provider consultations. Investigators used study participants’ responses to the following question during their interactions with their health care providers to help evaluate the quality of their consultation experience: “What type of doctor is currently managing your headaches?” Researchers included data from patients whose practitioners fit the description of those they deemed best suited to address ongoing headache challenges. These medical professionals included general practitioners, family physicians, internal medicine doctors, nurse practitioners, physician assistants, neurologists, pain specialists, headache specialists, and obstetrician-gynecologists.
• Diagnosis. Carefully evaluating patients’ responses to a series of questions helped researchers gauge the accuracy of diagnosis. Questions included: “Have you ever been diagnosed by a doctor or other health professional with any of the following types of headaches?” Respondents were also given a list of options that provided additional context around their headaches and were encouraged to select all appropriate responses. The list included a fictional response option of “citrene headache” to determine incorrect responses. For this study, researchers deemed it necessary to recognize a chronic migraine diagnosis to ensure that patients received appropriate treatment.
• Minimally appropriate pharmacologic treatment. Researchers used the following question to determine whether patients’ chronic migraine and episodic migraine were being managed with the least amount of pharmacological treatment necessary. “Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches when you have them?” Researchers defined “minimally appropriate acute pharmacologic treatment” as the use of any prescription nonsteroidal anti-inflammatory drug (NSAID), triptan, ergotamine derivative, or isometheptene.
• Avoidance of medication overuse. The study authors pointed out the sometimes nebulous process of characterizing the appropriate use of preventative medication in patients with episodic migraines as “not straightforward” for some patients because not all patients require preventive treatment. Study participants were required to report having received any form of preventative therapy, defined as pharmacological therapies approved by guidelines and supported by data. Such therapies included various antiseizure medication, antidepressants (for example, doxepin, venlafaxine, duloxetine, amitriptyline, imipramine, nortriptyline, and desvenlafaxine), antihypertensives, and toxin injections. Treatments such as behavioral and neuromodulatory therapies were excluded from the list.

According to lead author Dawn C. Buse, PhD, of the department of neurology at Albert Einstein College of Medicine, New York, acute medication overuse provides an important modifiable target for intervention and recommends that clinicians use the opportunity to optimize migraine care by reducing the patients’ reliance on acute therapies. Taking such initiatives to decrease medication overuse is especially important in communities of color, who are more likely to overuse medications for migraines.

Patients with higher income levels were more likely to overcome each barrier. People of African, African American, or multiracial descent were more prone to overuse of medications to manage their migraines.

Of the 489,537 respondents invited to participate in the CaMEO study, 16,879 qualified for inclusion. Slightly more than half of the respondents (n = 9,184 [54.7%]) had a migraine-related disability (MIDAS) score of 6 or greater – an indicator of disability that is least mild in nature. Most patients who had episodic migraines or chronic migraines (86.2%) had some form of health insurance coverage (n = 9.184; 84.1%; P = .048). Of those patients who were insured, 7,930 patients experienced episodic migraine (86.3%) and the remainder had chronic migraine (n = 1,254; 13.7%). Higher-income patients were more likely to traverse barriers to care. While patients of African descent had higher consultation rates, they also had higher rates of acute medication overuse.

Patients with chronic migraine were more likely to be older than patients with episodic migraine (41.0 vs. 39.6 years; P = .0001) and female (83.0% vs. 79.0%; P = .001), and White (84.5% vs. 79.1%; P < .001). Similarly, patients with chronic migraine were more likely to have a higher mean body mass index (29.8 kg/m² vs. 28.9 kg/m²; P < .001) and lower rates of full- or part-time employment (56.8% vs. 67.1%; P < .001), and were less likely to have a 4-year degree (64.8 vs. 55.6; P < .001) and annual household incomes below $75,000 (72.6% vs. 64.6%; P < .001). Approximately three-quarters of the patients with episodic migraine (75.7%; 1655/2187) and one-third of patients with chronic migraine (32.8%; 168/512) received accurate diagnoses.

The data uncovered an association with acute medication overuse. Among current consulters who had received an accurate diagnosis and minimally adequate treatment, medication overuse rates were highest among those reporting two or more races (53%) and Blacks and African Americans (45%) and lowest among Whites (33%) and those categorized as “other” race (32%). Ethnic and cultural differences in headache literacy may contribute to differences in medication overuse. 
 

Strategies to improve outcomes

Both Dr. Buse and Dr. McAllister see the value advocacy and education offer in helping to improve outcomes in marginalized communities and other groups negatively impacted by various barriers.

“Patient advocacy and outreach are key here, especially in those traditionally underrepresented in the migraine space, such as men, people of color, blue-collar workers, etc.,” Dr. McAllister noted.

Dr. Buse emphasized the importance of education for patients and health care professionals alike. “A large percentage of people who meet criteria for migraine in the U.S. do not seek care or possibly even know that they have migraines,” Dr. Buse said. “This finding underscores the importance of public health education about migraine as well as well as providing migraine support, education, and resources to health care professionals on the front lines.”

Other strategies recommended by Dr, Buse to ease the impact of barriers include encouraging patient discussion, setting up time for follow-up appointments and education, referring patients for neurological and other specialty consults when warranted, reviewing essential lifestyle habits for migraine management, and creating personalized, mutually agreed-upon treatment plans.

Dr. Buse has received support and honoraria from AbbVie, Amgen, Avanir, Biohaven, Eli Lilly, and Promius.

Race and socioeconomic status can hinder and delay patient access to migraine treatment and result in poorer outcomes, according to a study published in the April issue of Headache. People of African descent and Latinx ethnicity tend to fare worse than other people of color and their White counterparts.

“It should be shocking to neurologists and other clinicians who care for migraine patients how few are able to successfully traverse the barriers to achieve an accurate diagnosis and proper, evidence-based, acute and preventative treatment,” commented Peter McAllister, MD, medical director at the New England Institute for Neurology and Headache and chief medical officer for clinical research at Ki Clinical Research in Stamford, Conn. Dr. McAllister was not involved in this study.
 

Assessing barriers to care

Researchers designed the study with the primary objective of estimating the number of patients with migraines with unmet clinical needs and who were impacted by four preidentified barriers to care. To evaluate their objective, researchers conducted a longitudinal, Internet-based survey known as the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. They collected data over 1 year examining a cohort of patients that mimicked the diverse demographics of the U.S. population. Researchers conducted longitudinal assessments every 3 months for 15 months, incorporating cross-sectional analyses that surveyed health care use, family burden, and comorbidities or endophenotypes.

Eligible enrollees were 18 years of age or older.

Researchers identified four barriers that hindered patient outcomes, and they served as the primary outcomes of the studies. They were:

• Health care provider consultations. Investigators used study participants’ responses to the following question during their interactions with their health care providers to help evaluate the quality of their consultation experience: “What type of doctor is currently managing your headaches?” Researchers included data from patients whose practitioners fit the description of those they deemed best suited to address ongoing headache challenges. These medical professionals included general practitioners, family physicians, internal medicine doctors, nurse practitioners, physician assistants, neurologists, pain specialists, headache specialists, and obstetrician-gynecologists.
• Diagnosis. Carefully evaluating patients’ responses to a series of questions helped researchers gauge the accuracy of diagnosis. Questions included: “Have you ever been diagnosed by a doctor or other health professional with any of the following types of headaches?” Respondents were also given a list of options that provided additional context around their headaches and were encouraged to select all appropriate responses. The list included a fictional response option of “citrene headache” to determine incorrect responses. For this study, researchers deemed it necessary to recognize a chronic migraine diagnosis to ensure that patients received appropriate treatment.
• Minimally appropriate pharmacologic treatment. Researchers used the following question to determine whether patients’ chronic migraine and episodic migraine were being managed with the least amount of pharmacological treatment necessary. “Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches when you have them?” Researchers defined “minimally appropriate acute pharmacologic treatment” as the use of any prescription nonsteroidal anti-inflammatory drug (NSAID), triptan, ergotamine derivative, or isometheptene.
• Avoidance of medication overuse. The study authors pointed out the sometimes nebulous process of characterizing the appropriate use of preventative medication in patients with episodic migraines as “not straightforward” for some patients because not all patients require preventive treatment. Study participants were required to report having received any form of preventative therapy, defined as pharmacological therapies approved by guidelines and supported by data. Such therapies included various antiseizure medication, antidepressants (for example, doxepin, venlafaxine, duloxetine, amitriptyline, imipramine, nortriptyline, and desvenlafaxine), antihypertensives, and toxin injections. Treatments such as behavioral and neuromodulatory therapies were excluded from the list.

According to lead author Dawn C. Buse, PhD, of the department of neurology at Albert Einstein College of Medicine, New York, acute medication overuse provides an important modifiable target for intervention and recommends that clinicians use the opportunity to optimize migraine care by reducing the patients’ reliance on acute therapies. Taking such initiatives to decrease medication overuse is especially important in communities of color, who are more likely to overuse medications for migraines.

Patients with higher income levels were more likely to overcome each barrier. People of African, African American, or multiracial descent were more prone to overuse of medications to manage their migraines.

Of the 489,537 respondents invited to participate in the CaMEO study, 16,879 qualified for inclusion. Slightly more than half of the respondents (n = 9,184 [54.7%]) had a migraine-related disability (MIDAS) score of 6 or greater – an indicator of disability that is least mild in nature. Most patients who had episodic migraines or chronic migraines (86.2%) had some form of health insurance coverage (n = 9.184; 84.1%; P = .048). Of those patients who were insured, 7,930 patients experienced episodic migraine (86.3%) and the remainder had chronic migraine (n = 1,254; 13.7%). Higher-income patients were more likely to traverse barriers to care. While patients of African descent had higher consultation rates, they also had higher rates of acute medication overuse.

Patients with chronic migraine were more likely to be older than patients with episodic migraine (41.0 vs. 39.6 years; P = .0001) and female (83.0% vs. 79.0%; P = .001), and White (84.5% vs. 79.1%; P < .001). Similarly, patients with chronic migraine were more likely to have a higher mean body mass index (29.8 kg/m² vs. 28.9 kg/m²; P < .001) and lower rates of full- or part-time employment (56.8% vs. 67.1%; P < .001), and were less likely to have a 4-year degree (64.8 vs. 55.6; P < .001) and annual household incomes below $75,000 (72.6% vs. 64.6%; P < .001). Approximately three-quarters of the patients with episodic migraine (75.7%; 1655/2187) and one-third of patients with chronic migraine (32.8%; 168/512) received accurate diagnoses.

The data uncovered an association with acute medication overuse. Among current consulters who had received an accurate diagnosis and minimally adequate treatment, medication overuse rates were highest among those reporting two or more races (53%) and Blacks and African Americans (45%) and lowest among Whites (33%) and those categorized as “other” race (32%). Ethnic and cultural differences in headache literacy may contribute to differences in medication overuse. 
 

Strategies to improve outcomes

Both Dr. Buse and Dr. McAllister see the value advocacy and education offer in helping to improve outcomes in marginalized communities and other groups negatively impacted by various barriers.

“Patient advocacy and outreach are key here, especially in those traditionally underrepresented in the migraine space, such as men, people of color, blue-collar workers, etc.,” Dr. McAllister noted.

Dr. Buse emphasized the importance of education for patients and health care professionals alike. “A large percentage of people who meet criteria for migraine in the U.S. do not seek care or possibly even know that they have migraines,” Dr. Buse said. “This finding underscores the importance of public health education about migraine as well as well as providing migraine support, education, and resources to health care professionals on the front lines.”

Other strategies recommended by Dr, Buse to ease the impact of barriers include encouraging patient discussion, setting up time for follow-up appointments and education, referring patients for neurological and other specialty consults when warranted, reviewing essential lifestyle habits for migraine management, and creating personalized, mutually agreed-upon treatment plans.

Dr. Buse has received support and honoraria from AbbVie, Amgen, Avanir, Biohaven, Eli Lilly, and Promius.

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.