Headache & Migraine

Multiple studies clearly demonstrate triggers in episodic migraine, often related to change in homeostasis or environment, according to a recent investigation. Furthermore, many common migraine triggers are not easily modifiable, and avoiding triggers may not be realistic. However, healthy lifestyle choices such as exercise, adequate sleep, stress management, and eating regularly may prevent triggers and transformation to chronic migraine over time. Multiple migraine attack triggers have been established based on patient surveys, diary studies, and clinical trials. Key points include:

• Stress, menstrual cycle changes, weather changes, sleep disturbances, alcohol, and other foods are among the most common factors mentioned.
• Clinical studies have also verified that fasting, premenstrual periods in women, “letdown” after stress, and most likely low barometric pressures are migraine triggers.
• Premonitory symptoms such as neck pain, fatigue, and sensitivity to lights, sounds, or odors may mimic triggers.

Marmura MJ. Triggers, protectors, and predictors in episodic migraine. Curr Pain Headache Rep. 2018;22:81. doi:10.1007/s11916-018-0734-0.

Multiple studies clearly demonstrate triggers in episodic migraine, often related to change in homeostasis or environment, according to a recent investigation. Furthermore, many common migraine triggers are not easily modifiable, and avoiding triggers may not be realistic. However, healthy lifestyle choices such as exercise, adequate sleep, stress management, and eating regularly may prevent triggers and transformation to chronic migraine over time. Multiple migraine attack triggers have been established based on patient surveys, diary studies, and clinical trials. Key points include:

• Stress, menstrual cycle changes, weather changes, sleep disturbances, alcohol, and other foods are among the most common factors mentioned.
• Clinical studies have also verified that fasting, premenstrual periods in women, “letdown” after stress, and most likely low barometric pressures are migraine triggers.
• Premonitory symptoms such as neck pain, fatigue, and sensitivity to lights, sounds, or odors may mimic triggers.

Marmura MJ. Triggers, protectors, and predictors in episodic migraine. Curr Pain Headache Rep. 2018;22:81. doi:10.1007/s11916-018-0734-0.

Multiple studies clearly demonstrate triggers in episodic migraine, often related to change in homeostasis or environment, according to a recent investigation. Furthermore, many common migraine triggers are not easily modifiable, and avoiding triggers may not be realistic. However, healthy lifestyle choices such as exercise, adequate sleep, stress management, and eating regularly may prevent triggers and transformation to chronic migraine over time. Multiple migraine attack triggers have been established based on patient surveys, diary studies, and clinical trials. Key points include:

• Stress, menstrual cycle changes, weather changes, sleep disturbances, alcohol, and other foods are among the most common factors mentioned.
• Clinical studies have also verified that fasting, premenstrual periods in women, “letdown” after stress, and most likely low barometric pressures are migraine triggers.
• Premonitory symptoms such as neck pain, fatigue, and sensitivity to lights, sounds, or odors may mimic triggers.

Marmura MJ. Triggers, protectors, and predictors in episodic migraine. Curr Pain Headache Rep. 2018;22:81. doi:10.1007/s11916-018-0734-0.

A recent genome-wide association study (GWAS) provides new insights into the genetic basis of childhood migraine and allows for precision therapeutic development strategies targeting migraine patients of African-American ancestry. Researchers conducted a GWAS of 380 African-American children and 2129 ancestry-matched controls to identify variants associated with migraine. They then attempted to replicate their primary analysis in an independent cohort of 233 African-American patients and 4038 non-migraine control subjects. They found:

• Common variants at 5q33.1 are associated with migraine risk in African-American children.
• The association was validated in an independent study for an overall meta-analysis P-value of 3.81×10⁻¹⁰.
• eQTL (expression quantitative trait loci) analysis of the Genotype-Tissue Expression data also shows the genotypes of rs72793414 were strongly correlated with the mRNA expression levels of NMUR2 at 5q33.1.

Chang X, Pellegrino R, Garifallou, et al. Common variants at 5q33.1 predispose to migraine in African-American children. [Published online ahead of print September 28, 2018]. J Med Genet. doi:10.1136/jmedgenet-2018-105359.

A recent genome-wide association study (GWAS) provides new insights into the genetic basis of childhood migraine and allows for precision therapeutic development strategies targeting migraine patients of African-American ancestry. Researchers conducted a GWAS of 380 African-American children and 2129 ancestry-matched controls to identify variants associated with migraine. They then attempted to replicate their primary analysis in an independent cohort of 233 African-American patients and 4038 non-migraine control subjects. They found:

• Common variants at 5q33.1 are associated with migraine risk in African-American children.
• The association was validated in an independent study for an overall meta-analysis P-value of 3.81×10⁻¹⁰.
• eQTL (expression quantitative trait loci) analysis of the Genotype-Tissue Expression data also shows the genotypes of rs72793414 were strongly correlated with the mRNA expression levels of NMUR2 at 5q33.1.

Chang X, Pellegrino R, Garifallou, et al. Common variants at 5q33.1 predispose to migraine in African-American children. [Published online ahead of print September 28, 2018]. J Med Genet. doi:10.1136/jmedgenet-2018-105359.

A recent genome-wide association study (GWAS) provides new insights into the genetic basis of childhood migraine and allows for precision therapeutic development strategies targeting migraine patients of African-American ancestry. Researchers conducted a GWAS of 380 African-American children and 2129 ancestry-matched controls to identify variants associated with migraine. They then attempted to replicate their primary analysis in an independent cohort of 233 African-American patients and 4038 non-migraine control subjects. They found:

• Common variants at 5q33.1 are associated with migraine risk in African-American children.
• The association was validated in an independent study for an overall meta-analysis P-value of 3.81×10⁻¹⁰.
• eQTL (expression quantitative trait loci) analysis of the Genotype-Tissue Expression data also shows the genotypes of rs72793414 were strongly correlated with the mRNA expression levels of NMUR2 at 5q33.1.

Chang X, Pellegrino R, Garifallou, et al. Common variants at 5q33.1 predispose to migraine in African-American children. [Published online ahead of print September 28, 2018]. J Med Genet. doi:10.1136/jmedgenet-2018-105359.

The current diagnostic criteria for migraine outlined in the 3rd version of the International Classification of Headache Disorders (ICHD) are far more sensitive and specific than the clinical criteria proposed in 1962. This is according to a recent review that examines how the diagnostic criteria for migraine have evolved during the past 45 years and evaluates the strengths and weaknesses of the current diagnostic criteria promulgated by the ICHD. In future iterations, dividing episodic and chronic migraine into subtypes based on frequency (ie, low frequency vs high frequency; near-daily vs daily) potentially could assist in guiding clinical management. In addition, a better understanding of aura, vestibular migraine, migrainous infarction, and hemiplegic migraine likely will lead to more refined diagnostic criteria for those entities. As the pathophysiology of migraine is more fully elucidated and more sophisticated diagnostic technologies are developed (eg, the identification of biomarkers), the current diagnostic criteria for migraine will likely be further refined. Furthermore, the ICHD has allowed for more precise research study design in the field of headache medicine.

Tinsley A. Rothrock JF. What are we missing in the diagnostic criteria for migraine? Curr Pain Headache Rep. 2018;22:84. doi:10.1007/s11916-018-0733-1.

The current diagnostic criteria for migraine outlined in the 3rd version of the International Classification of Headache Disorders (ICHD) are far more sensitive and specific than the clinical criteria proposed in 1962. This is according to a recent review that examines how the diagnostic criteria for migraine have evolved during the past 45 years and evaluates the strengths and weaknesses of the current diagnostic criteria promulgated by the ICHD. In future iterations, dividing episodic and chronic migraine into subtypes based on frequency (ie, low frequency vs high frequency; near-daily vs daily) potentially could assist in guiding clinical management. In addition, a better understanding of aura, vestibular migraine, migrainous infarction, and hemiplegic migraine likely will lead to more refined diagnostic criteria for those entities. As the pathophysiology of migraine is more fully elucidated and more sophisticated diagnostic technologies are developed (eg, the identification of biomarkers), the current diagnostic criteria for migraine will likely be further refined. Furthermore, the ICHD has allowed for more precise research study design in the field of headache medicine.

Tinsley A. Rothrock JF. What are we missing in the diagnostic criteria for migraine? Curr Pain Headache Rep. 2018;22:84. doi:10.1007/s11916-018-0733-1.

The current diagnostic criteria for migraine outlined in the 3rd version of the International Classification of Headache Disorders (ICHD) are far more sensitive and specific than the clinical criteria proposed in 1962. This is according to a recent review that examines how the diagnostic criteria for migraine have evolved during the past 45 years and evaluates the strengths and weaknesses of the current diagnostic criteria promulgated by the ICHD. In future iterations, dividing episodic and chronic migraine into subtypes based on frequency (ie, low frequency vs high frequency; near-daily vs daily) potentially could assist in guiding clinical management. In addition, a better understanding of aura, vestibular migraine, migrainous infarction, and hemiplegic migraine likely will lead to more refined diagnostic criteria for those entities. As the pathophysiology of migraine is more fully elucidated and more sophisticated diagnostic technologies are developed (eg, the identification of biomarkers), the current diagnostic criteria for migraine will likely be further refined. Furthermore, the ICHD has allowed for more precise research study design in the field of headache medicine.

Tinsley A. Rothrock JF. What are we missing in the diagnostic criteria for migraine? Curr Pain Headache Rep. 2018;22:84. doi:10.1007/s11916-018-0733-1.

Recent findings support the use of multimodal magnetic resonance (MR) imaging to distinguish migraine with aura from stroke and the simultaneous use of these MR imaging sequences to improve understanding of perfusion changes during migraine with aura. Hemiplegic migraine is a common cause of acute brain attack in pediatrics. MR imaging sequences useful in differentiating hemiplegic migraine from other entities include arterial spin-labeling, susceptibility-weighted imaging (SWI), magnetic resonance angiography (MRA), and diffusion-weighted imaging (DWI). Researchers evaluated 12 pediatric patients with acute hemiplegic migraine or migraine with aura who underwent MR imaging within 12 hours of symptom onset. Quantitative and qualitative analyses were performed on arterial spin-labeling, and qualitative analysis, on SWI and MRA sequences. They found:

• All 12 patients had normal DWI and abnormal arterial spin-labeling findings.
• Furthermore, a more rapid transition from hypoperfusion to rebound hyperperfusion was observed in 3 patients compared with prior reports.

Cobb-Pitstick KM, Munjal N, Safier R, Cummings DD, Zuccoli G. Time course of cerebral perfusion changes in children with migraine with aura mimicking stroke. Am J Neuroradiol.

2018;39(9):1751-1755. doi:10.3174/ajnr.A5693.

Recent findings support the use of multimodal magnetic resonance (MR) imaging to distinguish migraine with aura from stroke and the simultaneous use of these MR imaging sequences to improve understanding of perfusion changes during migraine with aura. Hemiplegic migraine is a common cause of acute brain attack in pediatrics. MR imaging sequences useful in differentiating hemiplegic migraine from other entities include arterial spin-labeling, susceptibility-weighted imaging (SWI), magnetic resonance angiography (MRA), and diffusion-weighted imaging (DWI). Researchers evaluated 12 pediatric patients with acute hemiplegic migraine or migraine with aura who underwent MR imaging within 12 hours of symptom onset. Quantitative and qualitative analyses were performed on arterial spin-labeling, and qualitative analysis, on SWI and MRA sequences. They found:

• All 12 patients had normal DWI and abnormal arterial spin-labeling findings.
• Furthermore, a more rapid transition from hypoperfusion to rebound hyperperfusion was observed in 3 patients compared with prior reports.

Cobb-Pitstick KM, Munjal N, Safier R, Cummings DD, Zuccoli G. Time course of cerebral perfusion changes in children with migraine with aura mimicking stroke. Am J Neuroradiol.

2018;39(9):1751-1755. doi:10.3174/ajnr.A5693.

Recent findings support the use of multimodal magnetic resonance (MR) imaging to distinguish migraine with aura from stroke and the simultaneous use of these MR imaging sequences to improve understanding of perfusion changes during migraine with aura. Hemiplegic migraine is a common cause of acute brain attack in pediatrics. MR imaging sequences useful in differentiating hemiplegic migraine from other entities include arterial spin-labeling, susceptibility-weighted imaging (SWI), magnetic resonance angiography (MRA), and diffusion-weighted imaging (DWI). Researchers evaluated 12 pediatric patients with acute hemiplegic migraine or migraine with aura who underwent MR imaging within 12 hours of symptom onset. Quantitative and qualitative analyses were performed on arterial spin-labeling, and qualitative analysis, on SWI and MRA sequences. They found:

• All 12 patients had normal DWI and abnormal arterial spin-labeling findings.
• Furthermore, a more rapid transition from hypoperfusion to rebound hyperperfusion was observed in 3 patients compared with prior reports.

Cobb-Pitstick KM, Munjal N, Safier R, Cummings DD, Zuccoli G. Time course of cerebral perfusion changes in children with migraine with aura mimicking stroke. Am J Neuroradiol.

2018;39(9):1751-1755. doi:10.3174/ajnr.A5693.

Emergency department (ED) visits for migraine are burdensome to patients and to the larger healthcare system and society, a recent study found. Furthermore, a substantial number of headache specialists are dissatisfied with the care their patients receive in the ED. Researchers

surveyed members of the American Headache Society (AHS) Emergency Department/Refractory/Inpatient (EDRI) Section to understand their practice regarding patients who call their office to be seen urgently, and to understand their communication with local EDs. There were 96 eligible AHS members, 50 of whom responded to questionnaires either by email or in person (52%).They found:

• Of total respondents, 59% reported giving rescue treatment to their patients to manage acute attacks.
• 54% reported using standard protocols for outpatients not responding to usual acute treatments.
• In the event of a request for urgent care, 12% of specialists reported bringing patients into the office most or all of the time, and 20% reported sending patients to the ED some or most of the time for headache management.
• 60% reported that their ED has a protocol for migraine management.

Minen MT, Ortega E, Lipton RB, Cowan R. American Headache Society survey about urgent and emergency management of headache patients. [Published online ahead of print September 12, 2018]. Headache. doi:10.1111/head.13387.

Emergency department (ED) visits for migraine are burdensome to patients and to the larger healthcare system and society, a recent study found. Furthermore, a substantial number of headache specialists are dissatisfied with the care their patients receive in the ED. Researchers

surveyed members of the American Headache Society (AHS) Emergency Department/Refractory/Inpatient (EDRI) Section to understand their practice regarding patients who call their office to be seen urgently, and to understand their communication with local EDs. There were 96 eligible AHS members, 50 of whom responded to questionnaires either by email or in person (52%).They found:

• Of total respondents, 59% reported giving rescue treatment to their patients to manage acute attacks.
• 54% reported using standard protocols for outpatients not responding to usual acute treatments.
• In the event of a request for urgent care, 12% of specialists reported bringing patients into the office most or all of the time, and 20% reported sending patients to the ED some or most of the time for headache management.
• 60% reported that their ED has a protocol for migraine management.

Minen MT, Ortega E, Lipton RB, Cowan R. American Headache Society survey about urgent and emergency management of headache patients. [Published online ahead of print September 12, 2018]. Headache. doi:10.1111/head.13387.

Emergency department (ED) visits for migraine are burdensome to patients and to the larger healthcare system and society, a recent study found. Furthermore, a substantial number of headache specialists are dissatisfied with the care their patients receive in the ED. Researchers

surveyed members of the American Headache Society (AHS) Emergency Department/Refractory/Inpatient (EDRI) Section to understand their practice regarding patients who call their office to be seen urgently, and to understand their communication with local EDs. There were 96 eligible AHS members, 50 of whom responded to questionnaires either by email or in person (52%).They found:

• Of total respondents, 59% reported giving rescue treatment to their patients to manage acute attacks.
• 54% reported using standard protocols for outpatients not responding to usual acute treatments.
• In the event of a request for urgent care, 12% of specialists reported bringing patients into the office most or all of the time, and 20% reported sending patients to the ED some or most of the time for headache management.
• 60% reported that their ED has a protocol for migraine management.

Minen MT, Ortega E, Lipton RB, Cowan R. American Headache Society survey about urgent and emergency management of headache patients. [Published online ahead of print September 12, 2018]. Headache. doi:10.1111/head.13387.

Researchers discovered 10.7% prevalence of migraines and synergism between female gender and stress on risk of migraine in a recent study, suggesting health interventions targeting women under stress may be beneficial. This analysis was based on data from 42,282 persons aged ≥12 years who participated in a 2013–2014 community health survey. A multivariate log-binomial model was used to calculate adjusted prevalence ratios for migraines associated with individual and joint exposures of female gender and stress. Researchers used relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S index) to measure additive interaction. They found:

• The adjusted prevalence ratios were 2.37 for female vs male, 1.63 for persons with high vs low levels of stress, and 3.38 for women with high stress vs men with low stress.
• The RERI estimate was 0.38, the AP estimate was 0.11, and the S index was 1.19.

Slatculescu AM, Chen Y. Synergism between female gender and high levels of daily stress associated with migraine headaches in Ontario, Canada. [Published online ahead of print August 28, 2018]. Neuroepidemiol. doi:10.1159/000492503.

Researchers discovered 10.7% prevalence of migraines and synergism between female gender and stress on risk of migraine in a recent study, suggesting health interventions targeting women under stress may be beneficial. This analysis was based on data from 42,282 persons aged ≥12 years who participated in a 2013–2014 community health survey. A multivariate log-binomial model was used to calculate adjusted prevalence ratios for migraines associated with individual and joint exposures of female gender and stress. Researchers used relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S index) to measure additive interaction. They found:

• The adjusted prevalence ratios were 2.37 for female vs male, 1.63 for persons with high vs low levels of stress, and 3.38 for women with high stress vs men with low stress.
• The RERI estimate was 0.38, the AP estimate was 0.11, and the S index was 1.19.

Slatculescu AM, Chen Y. Synergism between female gender and high levels of daily stress associated with migraine headaches in Ontario, Canada. [Published online ahead of print August 28, 2018]. Neuroepidemiol. doi:10.1159/000492503.

Researchers discovered 10.7% prevalence of migraines and synergism between female gender and stress on risk of migraine in a recent study, suggesting health interventions targeting women under stress may be beneficial. This analysis was based on data from 42,282 persons aged ≥12 years who participated in a 2013–2014 community health survey. A multivariate log-binomial model was used to calculate adjusted prevalence ratios for migraines associated with individual and joint exposures of female gender and stress. Researchers used relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S index) to measure additive interaction. They found:

• The adjusted prevalence ratios were 2.37 for female vs male, 1.63 for persons with high vs low levels of stress, and 3.38 for women with high stress vs men with low stress.
• The RERI estimate was 0.38, the AP estimate was 0.11, and the S index was 1.19.

Slatculescu AM, Chen Y. Synergism between female gender and high levels of daily stress associated with migraine headaches in Ontario, Canada. [Published online ahead of print August 28, 2018]. Neuroepidemiol. doi:10.1159/000492503.

ROCKVILLE, MD—The FDA has approved galcanezumab-gnlm (Emgality) for the preventive treatment of migraine in adults. Eli Lilly and Company manufactures the therapy. Emgality is the third calcitonin gene-related peptide (CGRP) antagonist to receive regulatory approval.

The approval is based on the results of three phase III clinical trials: EVOLVE-1, EVOLVE-2, and REGAIN. EVOLVE-1 and EVOLVE-2 were six-month, double-blind, placebo-controlled studies that included adults with episodic migraine. REGAIN was a three-month, double-blind, placebo-controlled study of adults with chronic migraine. The primary end point of all three trials was mean change from baseline in the number of monthly headache days.

In all trials, patients received either placebo, 120 mg of galcanezumab-gnlm after an initial loading dose of 240 mg, or 240 mg of galcanezumab-gnlm. In EVOLVE-1 and EVOLVE-2, people who received galcanezumab-gnlm had significantly fewer headache days per month than people who received placebo, and those who received galcanezumab-gnlm were also more likely to achieve a 50%, 75%, and 100% reduction in headache days.

In REGAIN, patients who received galcanezumab-gnlm experienced fewer monthly headache days than those who received placebo and were more likely to achieve a 50% reduction in headache days. There was no difference between groups in the likelihood of achieving a 75% or 100% reduction.

The recommended dosage, according to the label, is a monthly, 120-mg subcutaneous injection with an initial loading dose of 240 mg. The most common adverse event associated with galcanezumab-gnlm is injection-site reaction.

Galcanezumab-gnlm is under final review by the European Commission for approval in Europe.

—Lucas Franki

ROCKVILLE, MD—The FDA has approved galcanezumab-gnlm (Emgality) for the preventive treatment of migraine in adults. Eli Lilly and Company manufactures the therapy. Emgality is the third calcitonin gene-related peptide (CGRP) antagonist to receive regulatory approval.

The approval is based on the results of three phase III clinical trials: EVOLVE-1, EVOLVE-2, and REGAIN. EVOLVE-1 and EVOLVE-2 were six-month, double-blind, placebo-controlled studies that included adults with episodic migraine. REGAIN was a three-month, double-blind, placebo-controlled study of adults with chronic migraine. The primary end point of all three trials was mean change from baseline in the number of monthly headache days.

In all trials, patients received either placebo, 120 mg of galcanezumab-gnlm after an initial loading dose of 240 mg, or 240 mg of galcanezumab-gnlm. In EVOLVE-1 and EVOLVE-2, people who received galcanezumab-gnlm had significantly fewer headache days per month than people who received placebo, and those who received galcanezumab-gnlm were also more likely to achieve a 50%, 75%, and 100% reduction in headache days.

In REGAIN, patients who received galcanezumab-gnlm experienced fewer monthly headache days than those who received placebo and were more likely to achieve a 50% reduction in headache days. There was no difference between groups in the likelihood of achieving a 75% or 100% reduction.

The recommended dosage, according to the label, is a monthly, 120-mg subcutaneous injection with an initial loading dose of 240 mg. The most common adverse event associated with galcanezumab-gnlm is injection-site reaction.

Galcanezumab-gnlm is under final review by the European Commission for approval in Europe.

—Lucas Franki

ROCKVILLE, MD—The FDA has approved galcanezumab-gnlm (Emgality) for the preventive treatment of migraine in adults. Eli Lilly and Company manufactures the therapy. Emgality is the third calcitonin gene-related peptide (CGRP) antagonist to receive regulatory approval.

The approval is based on the results of three phase III clinical trials: EVOLVE-1, EVOLVE-2, and REGAIN. EVOLVE-1 and EVOLVE-2 were six-month, double-blind, placebo-controlled studies that included adults with episodic migraine. REGAIN was a three-month, double-blind, placebo-controlled study of adults with chronic migraine. The primary end point of all three trials was mean change from baseline in the number of monthly headache days.

In all trials, patients received either placebo, 120 mg of galcanezumab-gnlm after an initial loading dose of 240 mg, or 240 mg of galcanezumab-gnlm. In EVOLVE-1 and EVOLVE-2, people who received galcanezumab-gnlm had significantly fewer headache days per month than people who received placebo, and those who received galcanezumab-gnlm were also more likely to achieve a 50%, 75%, and 100% reduction in headache days.

In REGAIN, patients who received galcanezumab-gnlm experienced fewer monthly headache days than those who received placebo and were more likely to achieve a 50% reduction in headache days. There was no difference between groups in the likelihood of achieving a 75% or 100% reduction.

The recommended dosage, according to the label, is a monthly, 120-mg subcutaneous injection with an initial loading dose of 240 mg. The most common adverse event associated with galcanezumab-gnlm is injection-site reaction.

Galcanezumab-gnlm is under final review by the European Commission for approval in Europe.

—Lucas Franki

SAN FRANCISCO—A brief course of mindfulness training for patients with chronic migraine after their withdrawal from overuse of acute migraine medications proved as effective as prophylactic medication over the course of 12 months of follow-up, said Frank Andrasik, PhD, and colleagues at the 60th Annual Scientific Meeting of the American Headache Society.

“The effects of mindfulness by and large rivaled those of medication alone. Although [it was]not specifically assessed, patients commented that mindfulness did not have side effects and promoted greater involvement and adherence,” said Dr. Andrasik, Professor and Chair of the Department of Psychology and Director of the Center for Behavioral Medicine at the University of Memphis.

He noted that his study, which was published in the Journal of Headache Pain, is best considered exploratory because of its small size and nonrandomized design.

After five days of structured acute medication withdrawal in an outpatient day hospital setting, study participants were treated with either pharmacologic prophylaxis for migraine—most often using botulinum toxin—or a brief course in mindfulness training entailing six once-weekly 45-minute sessions plus home practice for seven to 10 minutes per day. “While this study design does not rise to level one randomized trial evidence, it does reflect real-world clinical practice, where patients often have a big say in choosing their treatment plan,” Dr. Andrasik observed.

At baseline, all 44 patients met diagnostic criteria for chronic migraine with associated acute medication overuse. They averaged 20.5 headache days per month, with 18.4 days of acute migraine medication use. At three, six, and 12 months of follow-up, the 22 patients in the mindfulness group averaged 8.3, 10.4, and 12.4 headache days per month, while the 22 on pharmacologic prophylaxis averaged 8.8, 11, and 8.6 headache days per month. Both groups averaged similar seven- to 10-day reductions in days of acute migraine medication use per month.

Using the widely accepted end point of at least a 50% reduction in headache days per month, 50% of the mindfulness-only group and 52.6% of the prophylactic medication-only group met that standard at 12 months of follow-up. Moreover, at 12 months, 65% of the mindfulness therapy group and 73.7% of the preventive medication group no longer met diagnostic criteria for chronic migraine.

The mindfulness protocol used in the study was based upon the popular mindfulness-based stress reduction program developed by Jon Kabat-Zinn, PhD, and colleagues in the mid 1980s.

Scores on the Migraine Disability Assessment (MIDAS) measure and the Beck Depression Inventory improved significantly and to a similar extent from baseline in both groups. In contrast, scores on the State-Trait Anxiety Inventory did not change significantly in either study arm.

Mindfulness for Migraine Is Still Emerging

Dr. Andrasik and session chair Elizabeth K. Seng, PhD, cautioned that despite solid evidence of efficacy for mindfulness training in the treatment of depression and several chronic pain disorders, mindfulness for treatment of migraine is still in its infancy. Large randomized, controlled clinical trials are ongoing or in the planning stages, and no results are available.

Dr. Seng, a Research Assistant Professor at Albert Einstein College of Medicine in New York, described mindfulness and acceptance as “third-wave” behavioral treatments for migraine. The first-wave therapies focused on fostering behavioral changes to reduce perceived stress to avoid triggering migraine attacks. Second-wave therapies involved interactions aimed at helping patients reframe maladaptive automatic thoughts to reduce stress stemming from the daily hassles of life.

“The focus in the first- and second-wave therapies is, ‘Change something and your life will be better. Change your behaviors, clean up your act, change your thoughts because your thoughts are not helping you, and thereby reduce stress and reduce migraine.’ These mindfulness therapies are incredibly different from that,” she explained.

Third-wave therapies are not directed toward changing daily stress or automatic thoughts; instead, they seek to change the patient’s relationship to them such that they no longer create barriers to engaging in life activities that the patient finds nourishing and meaningful. It is a matter of creating a willingness to experience pain to achieve worthwhile objectives, Dr. Seng explained.

Measuring Success

It is unclear that a reduction in migraine days—the traditional yardstick for therapeutic efficacy in migraine research—is the right primary outcome measure for third-wave therapies, according to the psychologist. “So far, our evidence would suggest that mindfulness-based therapies do not reduce migraine days as much as other behavioral treatments, but what they are doing is increasing migraine-related quality of life and reducing migraine-related disability to the same or possibly larger extent than our other behavioral treatments,” Dr. Seng said. “Maybe what these third-wave therapies are actually doing is impacting our cognitive and emotional functioning, and even if patients still experience similar levels of headache frequency, their reaction to those headache days no longer leads to suffering. That could be a clinically relevant outcome.”

Dr. Seng plans to formally study mindfulness therapies in a subgroup of migraine patients with high levels of depression. They might respond especially well, she hypothesized, since mindfulness was originally developed as a treatment for severe depression. “Patients who are depressed have a hard time overcoming barriers to engaging in nourishing life activities, and when they have a headache day, it is even worse. That is one of the things that is leading them to have migraine-related disability,” she said.

Dr. Andrasik, whose study was supported by the European Commission and an Italian research foundation, reported having no financial conflicts of interest regarding his presentation. Dr. Seng reported serving as a consultant to GlaxoSmithKline.

—Bruce Jancin

Suggested Reading

Grazzi L, Sansone E, Raggi A, et al. Mindfulness and pharmacological prophylaxis after withdrawal from medication overuse in patients with chronic migraine: an effectiveness trial with a one-year follow-up. J Headache Pain. 2017;18(1):15.

Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med. 1985;8(2):163-190.

SAN FRANCISCO—A brief course of mindfulness training for patients with chronic migraine after their withdrawal from overuse of acute migraine medications proved as effective as prophylactic medication over the course of 12 months of follow-up, said Frank Andrasik, PhD, and colleagues at the 60th Annual Scientific Meeting of the American Headache Society.

“The effects of mindfulness by and large rivaled those of medication alone. Although [it was]not specifically assessed, patients commented that mindfulness did not have side effects and promoted greater involvement and adherence,” said Dr. Andrasik, Professor and Chair of the Department of Psychology and Director of the Center for Behavioral Medicine at the University of Memphis.

He noted that his study, which was published in the Journal of Headache Pain, is best considered exploratory because of its small size and nonrandomized design.

After five days of structured acute medication withdrawal in an outpatient day hospital setting, study participants were treated with either pharmacologic prophylaxis for migraine—most often using botulinum toxin—or a brief course in mindfulness training entailing six once-weekly 45-minute sessions plus home practice for seven to 10 minutes per day. “While this study design does not rise to level one randomized trial evidence, it does reflect real-world clinical practice, where patients often have a big say in choosing their treatment plan,” Dr. Andrasik observed.

At baseline, all 44 patients met diagnostic criteria for chronic migraine with associated acute medication overuse. They averaged 20.5 headache days per month, with 18.4 days of acute migraine medication use. At three, six, and 12 months of follow-up, the 22 patients in the mindfulness group averaged 8.3, 10.4, and 12.4 headache days per month, while the 22 on pharmacologic prophylaxis averaged 8.8, 11, and 8.6 headache days per month. Both groups averaged similar seven- to 10-day reductions in days of acute migraine medication use per month.

Using the widely accepted end point of at least a 50% reduction in headache days per month, 50% of the mindfulness-only group and 52.6% of the prophylactic medication-only group met that standard at 12 months of follow-up. Moreover, at 12 months, 65% of the mindfulness therapy group and 73.7% of the preventive medication group no longer met diagnostic criteria for chronic migraine.

The mindfulness protocol used in the study was based upon the popular mindfulness-based stress reduction program developed by Jon Kabat-Zinn, PhD, and colleagues in the mid 1980s.

Scores on the Migraine Disability Assessment (MIDAS) measure and the Beck Depression Inventory improved significantly and to a similar extent from baseline in both groups. In contrast, scores on the State-Trait Anxiety Inventory did not change significantly in either study arm.

Mindfulness for Migraine Is Still Emerging

Dr. Andrasik and session chair Elizabeth K. Seng, PhD, cautioned that despite solid evidence of efficacy for mindfulness training in the treatment of depression and several chronic pain disorders, mindfulness for treatment of migraine is still in its infancy. Large randomized, controlled clinical trials are ongoing or in the planning stages, and no results are available.

Dr. Seng, a Research Assistant Professor at Albert Einstein College of Medicine in New York, described mindfulness and acceptance as “third-wave” behavioral treatments for migraine. The first-wave therapies focused on fostering behavioral changes to reduce perceived stress to avoid triggering migraine attacks. Second-wave therapies involved interactions aimed at helping patients reframe maladaptive automatic thoughts to reduce stress stemming from the daily hassles of life.

“The focus in the first- and second-wave therapies is, ‘Change something and your life will be better. Change your behaviors, clean up your act, change your thoughts because your thoughts are not helping you, and thereby reduce stress and reduce migraine.’ These mindfulness therapies are incredibly different from that,” she explained.

Third-wave therapies are not directed toward changing daily stress or automatic thoughts; instead, they seek to change the patient’s relationship to them such that they no longer create barriers to engaging in life activities that the patient finds nourishing and meaningful. It is a matter of creating a willingness to experience pain to achieve worthwhile objectives, Dr. Seng explained.

Measuring Success

It is unclear that a reduction in migraine days—the traditional yardstick for therapeutic efficacy in migraine research—is the right primary outcome measure for third-wave therapies, according to the psychologist. “So far, our evidence would suggest that mindfulness-based therapies do not reduce migraine days as much as other behavioral treatments, but what they are doing is increasing migraine-related quality of life and reducing migraine-related disability to the same or possibly larger extent than our other behavioral treatments,” Dr. Seng said. “Maybe what these third-wave therapies are actually doing is impacting our cognitive and emotional functioning, and even if patients still experience similar levels of headache frequency, their reaction to those headache days no longer leads to suffering. That could be a clinically relevant outcome.”

Dr. Seng plans to formally study mindfulness therapies in a subgroup of migraine patients with high levels of depression. They might respond especially well, she hypothesized, since mindfulness was originally developed as a treatment for severe depression. “Patients who are depressed have a hard time overcoming barriers to engaging in nourishing life activities, and when they have a headache day, it is even worse. That is one of the things that is leading them to have migraine-related disability,” she said.

Dr. Andrasik, whose study was supported by the European Commission and an Italian research foundation, reported having no financial conflicts of interest regarding his presentation. Dr. Seng reported serving as a consultant to GlaxoSmithKline.

—Bruce Jancin

Suggested Reading

Grazzi L, Sansone E, Raggi A, et al. Mindfulness and pharmacological prophylaxis after withdrawal from medication overuse in patients with chronic migraine: an effectiveness trial with a one-year follow-up. J Headache Pain. 2017;18(1):15.

Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med. 1985;8(2):163-190.

SAN FRANCISCO—A brief course of mindfulness training for patients with chronic migraine after their withdrawal from overuse of acute migraine medications proved as effective as prophylactic medication over the course of 12 months of follow-up, said Frank Andrasik, PhD, and colleagues at the 60th Annual Scientific Meeting of the American Headache Society.

“The effects of mindfulness by and large rivaled those of medication alone. Although [it was]not specifically assessed, patients commented that mindfulness did not have side effects and promoted greater involvement and adherence,” said Dr. Andrasik, Professor and Chair of the Department of Psychology and Director of the Center for Behavioral Medicine at the University of Memphis.

He noted that his study, which was published in the Journal of Headache Pain, is best considered exploratory because of its small size and nonrandomized design.

After five days of structured acute medication withdrawal in an outpatient day hospital setting, study participants were treated with either pharmacologic prophylaxis for migraine—most often using botulinum toxin—or a brief course in mindfulness training entailing six once-weekly 45-minute sessions plus home practice for seven to 10 minutes per day. “While this study design does not rise to level one randomized trial evidence, it does reflect real-world clinical practice, where patients often have a big say in choosing their treatment plan,” Dr. Andrasik observed.

At baseline, all 44 patients met diagnostic criteria for chronic migraine with associated acute medication overuse. They averaged 20.5 headache days per month, with 18.4 days of acute migraine medication use. At three, six, and 12 months of follow-up, the 22 patients in the mindfulness group averaged 8.3, 10.4, and 12.4 headache days per month, while the 22 on pharmacologic prophylaxis averaged 8.8, 11, and 8.6 headache days per month. Both groups averaged similar seven- to 10-day reductions in days of acute migraine medication use per month.

Using the widely accepted end point of at least a 50% reduction in headache days per month, 50% of the mindfulness-only group and 52.6% of the prophylactic medication-only group met that standard at 12 months of follow-up. Moreover, at 12 months, 65% of the mindfulness therapy group and 73.7% of the preventive medication group no longer met diagnostic criteria for chronic migraine.

The mindfulness protocol used in the study was based upon the popular mindfulness-based stress reduction program developed by Jon Kabat-Zinn, PhD, and colleagues in the mid 1980s.

Scores on the Migraine Disability Assessment (MIDAS) measure and the Beck Depression Inventory improved significantly and to a similar extent from baseline in both groups. In contrast, scores on the State-Trait Anxiety Inventory did not change significantly in either study arm.

Mindfulness for Migraine Is Still Emerging

Dr. Andrasik and session chair Elizabeth K. Seng, PhD, cautioned that despite solid evidence of efficacy for mindfulness training in the treatment of depression and several chronic pain disorders, mindfulness for treatment of migraine is still in its infancy. Large randomized, controlled clinical trials are ongoing or in the planning stages, and no results are available.

Dr. Seng, a Research Assistant Professor at Albert Einstein College of Medicine in New York, described mindfulness and acceptance as “third-wave” behavioral treatments for migraine. The first-wave therapies focused on fostering behavioral changes to reduce perceived stress to avoid triggering migraine attacks. Second-wave therapies involved interactions aimed at helping patients reframe maladaptive automatic thoughts to reduce stress stemming from the daily hassles of life.

“The focus in the first- and second-wave therapies is, ‘Change something and your life will be better. Change your behaviors, clean up your act, change your thoughts because your thoughts are not helping you, and thereby reduce stress and reduce migraine.’ These mindfulness therapies are incredibly different from that,” she explained.

Third-wave therapies are not directed toward changing daily stress or automatic thoughts; instead, they seek to change the patient’s relationship to them such that they no longer create barriers to engaging in life activities that the patient finds nourishing and meaningful. It is a matter of creating a willingness to experience pain to achieve worthwhile objectives, Dr. Seng explained.

Measuring Success

It is unclear that a reduction in migraine days—the traditional yardstick for therapeutic efficacy in migraine research—is the right primary outcome measure for third-wave therapies, according to the psychologist. “So far, our evidence would suggest that mindfulness-based therapies do not reduce migraine days as much as other behavioral treatments, but what they are doing is increasing migraine-related quality of life and reducing migraine-related disability to the same or possibly larger extent than our other behavioral treatments,” Dr. Seng said. “Maybe what these third-wave therapies are actually doing is impacting our cognitive and emotional functioning, and even if patients still experience similar levels of headache frequency, their reaction to those headache days no longer leads to suffering. That could be a clinically relevant outcome.”

Dr. Seng plans to formally study mindfulness therapies in a subgroup of migraine patients with high levels of depression. They might respond especially well, she hypothesized, since mindfulness was originally developed as a treatment for severe depression. “Patients who are depressed have a hard time overcoming barriers to engaging in nourishing life activities, and when they have a headache day, it is even worse. That is one of the things that is leading them to have migraine-related disability,” she said.

Dr. Andrasik, whose study was supported by the European Commission and an Italian research foundation, reported having no financial conflicts of interest regarding his presentation. Dr. Seng reported serving as a consultant to GlaxoSmithKline.

—Bruce Jancin

Suggested Reading

Grazzi L, Sansone E, Raggi A, et al. Mindfulness and pharmacological prophylaxis after withdrawal from medication overuse in patients with chronic migraine: an effectiveness trial with a one-year follow-up. J Headache Pain. 2017;18(1):15.

Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the self-regulation of chronic pain. J Behav Med. 1985;8(2):163-190.

Neurology Reviews recently shared two poll questions with our Facebook followers about treatment medication overuse headache (MOH). I was very interested to see the results of our poll. While the number of responses was somewhat low, we do get some sense of what respondents are saying. In this commentary, I will first tell you my perspective on the answers and then we will see what some other headache specialists say about the answers to these questions.

Poll Results:
 

Can MOH be treated with preventive medications without detoxification?

33 votes

YES, 39%

NO, 61%

Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor) without detoxification?

26 votes

YES, 38%

NO, 62%

My Commentary:

Let me explain in more detail my thoughts on the first question, “Can MOH be treated with preventive medications without detoxification?”

If a patient had the diagnosis of MOH – meaning 15 or more headache days per month for at least 3 months, with use of stronger medications (triptans, ergots, opiates, butalbital-containing medications) for 10 days per month or milder treatment (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) for 15 days per month – can they improve by being put on a traditional preventive medication without intentionally reducing their overused acute medications by a detoxification protocol ordered by a doctor or nurse?

Only 39% of our audience said yes. Yet some studies have shown that patients placed on onabotulinumtoxinA or topiramate might improve without them going through a detoxification of the overused medications. As a physician, I would suggest simultaneously decreasing in their acute medications. I think in some cases this approach creates additional improvement and makes the patient feel better. It would be better for their quality of life, as well as for their kidneys and possibly even their brains.

Here are my thoughts on the second question, “Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor), without detoxification?”

If a patient has MOH, can you expect them to improve after being placed on 1 of the 4 monoclonal antibodies to CGRP ligand or its receptor – all of which are either recently approved or currently in development – without suggesting that they decrease their overused acute care medications? Note that erenumab (Aimovig-aaoe) has been approved by the FDA and marketed as of the time of this writing; we expect 2 more products to be approved very soon.

Almost an identical percentage of our audience (38%) said yes. There is evidence in published clinical trials that those patients given these new medications did about as well with or without the presence of MOH, and both groups did better than the placebo patients. Note that most trials prohibited overuse of opiates and butalbital.

I am a firm believer of detoxifying patients from their overused over-the-counter (OTC) or prescription medications. I believe that opiates and butalbital-containing medications, when overused, are worse for patients than OTCs, NSAIDs, ergot and triptans, but all of these can cause MOH. There are many studies showing that both inpatient and outpatient detoxification alone can really help. However, it is difficult to detoxify patients and some refuse to try this approach.

So, what should we do as physicians? If a patient has MOH, I educate them, try to detoxify them slowly on an outpatient basis, and if I feel it will help, start them on a preventive medication, even before the detoxification begins so they can reach therapeutic levels. In the future, will I use one of the standard preventives, approved or off-label, for migraine prevention (beta blockers, topiramate and other anticonvulsants, antidepressants, angiotensin receptor blockers, onabotulinumtoxinA and others)? It remains to be seen. I am leaning towards the anti CGRP ligand and receptor monoclonal antibodies and preventive small molecule oral CGRP receptor blockers. While that might be enough to start with, I will continue explaining to my patients why they should actively begin a slow detoxification.

Let us see what some headache specialists said about both questions.

Robert Cowan, MD, FAAN:

There have been studies that show migraine can improve without the discontinuation of medication overuse. But that is not what the question asks. The question as posed is whether MOH can be treated with a preventive medication without detoxification. Since the diagnosis of MOH has, in the past, required the cessation of overuse leading to an improvement in the underlying headache, then technically, the answer would be “no.” But that being said, there is ample evidence that the number of headache days/months and other measures of headache can, in fact, improve with the introduction of a preventive, along with other measures such as lifestyle modification. The other ambiguity in the question has to do with what is meant by “detoxification.” Is this a hospital-based detox, or is a gradual decrease in the offending medicine in combination with the addition of a preventive, still considered “detoxification?” Also, does the response imply a sequential relationship between the detoxification and initiation of the preventive? Without further clarification, this response ratio to the question is very difficult to interpret.

There is animal data that suggests acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and anti-CGRP antibodies may be useful for the MOH (Cephalalgia. 2017;37(6):560-570. doi: 10.1177/0333102416650702). While there are no published CGRP antibody studies that did not exclude MOH patients to my knowledge, an abstract by Silberstein et al at the recent AHS Scientific Meeting reported decreased use of overused medication with fremanazumab (Headache. 2018;58(S2):76-78).

Ira Turner, MD

There is clear data to suggest that it is not necessary to detoxify these patients before starting preventive therapy. This is true for the older and newer medications. In fact, not only do these preventive therapies still work in the presence of medication overuse, but they also help to reduce medication overuse. The one caveat that must be mentioned is that this may not apply to opiate overuse. Opiate over-users were excluded from these studies.

While it is of course our goal to reduce and stop acute medication overuse, it should not be done at the expense of delaying preventive therapy. In fact, it is desirable to do both simultaneously. This applies to oral preventive medications, botulinum toxin and CGRP monoclonal antibodies.

In view of this well-established data, it was quite surprising to me to see the results of the 2 polls cited. It seems as if we still have a lot of educating to do regarding migraine prevention in general and with medication overuse in migraine in particular.

Stewart Tepper, MD

Dr. Tepper did not have time to comment, but suggested we show you an abstract presented at the recent AHS meeting. It shows that erenumab-aaoe helps patients with MOH who have not been detoxified (Headache. 2018;58(S2):160-162).

###

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, MD

Editor-in-Chief

Migraine Resource Center

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA

Los Angeles, California

Neurology Reviews recently shared two poll questions with our Facebook followers about treatment medication overuse headache (MOH). I was very interested to see the results of our poll. While the number of responses was somewhat low, we do get some sense of what respondents are saying. In this commentary, I will first tell you my perspective on the answers and then we will see what some other headache specialists say about the answers to these questions.

Poll Results:
 

Can MOH be treated with preventive medications without detoxification?

33 votes

YES, 39%

NO, 61%

Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor) without detoxification?

26 votes

YES, 38%

NO, 62%

My Commentary:

Let me explain in more detail my thoughts on the first question, “Can MOH be treated with preventive medications without detoxification?”

If a patient had the diagnosis of MOH – meaning 15 or more headache days per month for at least 3 months, with use of stronger medications (triptans, ergots, opiates, butalbital-containing medications) for 10 days per month or milder treatment (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) for 15 days per month – can they improve by being put on a traditional preventive medication without intentionally reducing their overused acute medications by a detoxification protocol ordered by a doctor or nurse?

Only 39% of our audience said yes. Yet some studies have shown that patients placed on onabotulinumtoxinA or topiramate might improve without them going through a detoxification of the overused medications. As a physician, I would suggest simultaneously decreasing in their acute medications. I think in some cases this approach creates additional improvement and makes the patient feel better. It would be better for their quality of life, as well as for their kidneys and possibly even their brains.

Here are my thoughts on the second question, “Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor), without detoxification?”

If a patient has MOH, can you expect them to improve after being placed on 1 of the 4 monoclonal antibodies to CGRP ligand or its receptor – all of which are either recently approved or currently in development – without suggesting that they decrease their overused acute care medications? Note that erenumab (Aimovig-aaoe) has been approved by the FDA and marketed as of the time of this writing; we expect 2 more products to be approved very soon.

Almost an identical percentage of our audience (38%) said yes. There is evidence in published clinical trials that those patients given these new medications did about as well with or without the presence of MOH, and both groups did better than the placebo patients. Note that most trials prohibited overuse of opiates and butalbital.

I am a firm believer of detoxifying patients from their overused over-the-counter (OTC) or prescription medications. I believe that opiates and butalbital-containing medications, when overused, are worse for patients than OTCs, NSAIDs, ergot and triptans, but all of these can cause MOH. There are many studies showing that both inpatient and outpatient detoxification alone can really help. However, it is difficult to detoxify patients and some refuse to try this approach.

So, what should we do as physicians? If a patient has MOH, I educate them, try to detoxify them slowly on an outpatient basis, and if I feel it will help, start them on a preventive medication, even before the detoxification begins so they can reach therapeutic levels. In the future, will I use one of the standard preventives, approved or off-label, for migraine prevention (beta blockers, topiramate and other anticonvulsants, antidepressants, angiotensin receptor blockers, onabotulinumtoxinA and others)? It remains to be seen. I am leaning towards the anti CGRP ligand and receptor monoclonal antibodies and preventive small molecule oral CGRP receptor blockers. While that might be enough to start with, I will continue explaining to my patients why they should actively begin a slow detoxification.

Let us see what some headache specialists said about both questions.

Robert Cowan, MD, FAAN:

There have been studies that show migraine can improve without the discontinuation of medication overuse. But that is not what the question asks. The question as posed is whether MOH can be treated with a preventive medication without detoxification. Since the diagnosis of MOH has, in the past, required the cessation of overuse leading to an improvement in the underlying headache, then technically, the answer would be “no.” But that being said, there is ample evidence that the number of headache days/months and other measures of headache can, in fact, improve with the introduction of a preventive, along with other measures such as lifestyle modification. The other ambiguity in the question has to do with what is meant by “detoxification.” Is this a hospital-based detox, or is a gradual decrease in the offending medicine in combination with the addition of a preventive, still considered “detoxification?” Also, does the response imply a sequential relationship between the detoxification and initiation of the preventive? Without further clarification, this response ratio to the question is very difficult to interpret.

There is animal data that suggests acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and anti-CGRP antibodies may be useful for the MOH (Cephalalgia. 2017;37(6):560-570. doi: 10.1177/0333102416650702). While there are no published CGRP antibody studies that did not exclude MOH patients to my knowledge, an abstract by Silberstein et al at the recent AHS Scientific Meeting reported decreased use of overused medication with fremanazumab (Headache. 2018;58(S2):76-78).

Ira Turner, MD

There is clear data to suggest that it is not necessary to detoxify these patients before starting preventive therapy. This is true for the older and newer medications. In fact, not only do these preventive therapies still work in the presence of medication overuse, but they also help to reduce medication overuse. The one caveat that must be mentioned is that this may not apply to opiate overuse. Opiate over-users were excluded from these studies.

While it is of course our goal to reduce and stop acute medication overuse, it should not be done at the expense of delaying preventive therapy. In fact, it is desirable to do both simultaneously. This applies to oral preventive medications, botulinum toxin and CGRP monoclonal antibodies.

In view of this well-established data, it was quite surprising to me to see the results of the 2 polls cited. It seems as if we still have a lot of educating to do regarding migraine prevention in general and with medication overuse in migraine in particular.

Stewart Tepper, MD

Dr. Tepper did not have time to comment, but suggested we show you an abstract presented at the recent AHS meeting. It shows that erenumab-aaoe helps patients with MOH who have not been detoxified (Headache. 2018;58(S2):160-162).

###

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, MD

Editor-in-Chief

Migraine Resource Center

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA

Los Angeles, California

Neurology Reviews recently shared two poll questions with our Facebook followers about treatment medication overuse headache (MOH). I was very interested to see the results of our poll. While the number of responses was somewhat low, we do get some sense of what respondents are saying. In this commentary, I will first tell you my perspective on the answers and then we will see what some other headache specialists say about the answers to these questions.

Poll Results:
 

Can MOH be treated with preventive medications without detoxification?

33 votes

YES, 39%

NO, 61%

Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor) without detoxification?

26 votes

YES, 38%

NO, 62%

My Commentary:

Let me explain in more detail my thoughts on the first question, “Can MOH be treated with preventive medications without detoxification?”

If a patient had the diagnosis of MOH – meaning 15 or more headache days per month for at least 3 months, with use of stronger medications (triptans, ergots, opiates, butalbital-containing medications) for 10 days per month or milder treatment (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) for 15 days per month – can they improve by being put on a traditional preventive medication without intentionally reducing their overused acute medications by a detoxification protocol ordered by a doctor or nurse?

Only 39% of our audience said yes. Yet some studies have shown that patients placed on onabotulinumtoxinA or topiramate might improve without them going through a detoxification of the overused medications. As a physician, I would suggest simultaneously decreasing in their acute medications. I think in some cases this approach creates additional improvement and makes the patient feel better. It would be better for their quality of life, as well as for their kidneys and possibly even their brains.

Here are my thoughts on the second question, “Can MOH be treated with the new preventive medications (the monoclonal antibodies to CGRP ligand or receptor), without detoxification?”

If a patient has MOH, can you expect them to improve after being placed on 1 of the 4 monoclonal antibodies to CGRP ligand or its receptor – all of which are either recently approved or currently in development – without suggesting that they decrease their overused acute care medications? Note that erenumab (Aimovig-aaoe) has been approved by the FDA and marketed as of the time of this writing; we expect 2 more products to be approved very soon.

Almost an identical percentage of our audience (38%) said yes. There is evidence in published clinical trials that those patients given these new medications did about as well with or without the presence of MOH, and both groups did better than the placebo patients. Note that most trials prohibited overuse of opiates and butalbital.

I am a firm believer of detoxifying patients from their overused over-the-counter (OTC) or prescription medications. I believe that opiates and butalbital-containing medications, when overused, are worse for patients than OTCs, NSAIDs, ergot and triptans, but all of these can cause MOH. There are many studies showing that both inpatient and outpatient detoxification alone can really help. However, it is difficult to detoxify patients and some refuse to try this approach.

So, what should we do as physicians? If a patient has MOH, I educate them, try to detoxify them slowly on an outpatient basis, and if I feel it will help, start them on a preventive medication, even before the detoxification begins so they can reach therapeutic levels. In the future, will I use one of the standard preventives, approved or off-label, for migraine prevention (beta blockers, topiramate and other anticonvulsants, antidepressants, angiotensin receptor blockers, onabotulinumtoxinA and others)? It remains to be seen. I am leaning towards the anti CGRP ligand and receptor monoclonal antibodies and preventive small molecule oral CGRP receptor blockers. While that might be enough to start with, I will continue explaining to my patients why they should actively begin a slow detoxification.

Let us see what some headache specialists said about both questions.

Robert Cowan, MD, FAAN:

There have been studies that show migraine can improve without the discontinuation of medication overuse. But that is not what the question asks. The question as posed is whether MOH can be treated with a preventive medication without detoxification. Since the diagnosis of MOH has, in the past, required the cessation of overuse leading to an improvement in the underlying headache, then technically, the answer would be “no.” But that being said, there is ample evidence that the number of headache days/months and other measures of headache can, in fact, improve with the introduction of a preventive, along with other measures such as lifestyle modification. The other ambiguity in the question has to do with what is meant by “detoxification.” Is this a hospital-based detox, or is a gradual decrease in the offending medicine in combination with the addition of a preventive, still considered “detoxification?” Also, does the response imply a sequential relationship between the detoxification and initiation of the preventive? Without further clarification, this response ratio to the question is very difficult to interpret.

There is animal data that suggests acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and anti-CGRP antibodies may be useful for the MOH (Cephalalgia. 2017;37(6):560-570. doi: 10.1177/0333102416650702). While there are no published CGRP antibody studies that did not exclude MOH patients to my knowledge, an abstract by Silberstein et al at the recent AHS Scientific Meeting reported decreased use of overused medication with fremanazumab (Headache. 2018;58(S2):76-78).

Ira Turner, MD

There is clear data to suggest that it is not necessary to detoxify these patients before starting preventive therapy. This is true for the older and newer medications. In fact, not only do these preventive therapies still work in the presence of medication overuse, but they also help to reduce medication overuse. The one caveat that must be mentioned is that this may not apply to opiate overuse. Opiate over-users were excluded from these studies.

While it is of course our goal to reduce and stop acute medication overuse, it should not be done at the expense of delaying preventive therapy. In fact, it is desirable to do both simultaneously. This applies to oral preventive medications, botulinum toxin and CGRP monoclonal antibodies.

In view of this well-established data, it was quite surprising to me to see the results of the 2 polls cited. It seems as if we still have a lot of educating to do regarding migraine prevention in general and with medication overuse in migraine in particular.

Stewart Tepper, MD

Dr. Tepper did not have time to comment, but suggested we show you an abstract presented at the recent AHS meeting. It shows that erenumab-aaoe helps patients with MOH who have not been detoxified (Headache. 2018;58(S2):160-162).

###

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, MD

Editor-in-Chief

Migraine Resource Center

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA

Los Angeles, California

Fremanezumab increases the number of headache-free days with normal function for patients with episodic or chronic migraine, according to post hoc analyses published online ahead of print August 17 in Neurology. Fremanezumab appears to improve all measures of function in patients with episodic migraine, and some measures in patients with chronic migraine.

“The results should be considered exploratory,” said Juliana VanderPluym, MD, a neurologist at Mayo Clinic in Phoenix, and colleagues. “Further research is needed to confirm these preliminary findings and to understand the factors contributing to perceived functional status on headache-free days.”

Examining Two Phase II Trials

Fremanezumab is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). Dr. VanderPluym and colleagues analyzed data from randomized, double-blind phase II trials of the therapy for prevention of high-frequency episodic migraine (ie, eight to 14 headache days per month) and chronic migraine. Patients with high-frequency episodic migraine received placebo or monthly subcutaneous fremanezumab injections of 225 mg or 675 mg. Patients with chronic migraine received placebo or an initial 675-mg fremanezumab dose followed by monthly subcutaneous injections of 225 mg or 900 mg. The treatment period was three months.

Participants entered information into an electronic diary daily. Questions about functional performance elicited information about “work/school/household chore performance” and “concentration/mental fatigue.” For the former category, patients recorded their performance as normal, less than 50% impaired, or at least 50% impaired. For the latter category, patients recorded how much time they had spent working more slowly, finding it difficult to concentrate, and feeling tired or drained.

Fremanezumab Improved Concentration

In the high-frequency episodic migraine study, patients who received fremanezumab had a greater increase in headache-free days with normal concentration and normal performance at work, school, and home, compared with controls.

In the study of chronic migraine, the 900-mg dose was associated with consistent improvements in function on headache-free days. Patients with chronic migraine in the 225-mg dose group had increases compared with controls in the number of headache-free days in which they performed household chores normally and had no time with difficulty concentrating. The 225-mg group had minimal changes in the number of headache-free days in which work/study and household chore performance was impaired by 50% or more, as well as in in time with difficulty concentrating, but its results were better than those of controls.

“One could postulate that patients had more headache-free days with normal functional performance simply because they had more headache-free days on fremanezumab,” said Dr. VanderPluym. “With increased headache-free days, patients may have had reduced interictal anxiety and thus reduced avoidance behavior and lifestyle compromise, allowing them to function normally.”

Patients receiving fremanezumab significantly reduced their intake of acute medications, compared with controls. This reduction likely decreased the number of side effects associated with acute medications and could have contributed to better functional performance, said the authors.

A limitation of the analysis is that the assessment of function was not based on standardized questionnaires such as the Headache Impact Test-6 or the Migraine-Specific Quality of Life Questionnaire.

—Erik Greb

Suggested Reading

VanderPluym J, Dodick DW, Lipton RB, et al. Fremanezumab for preventive treatment of migraine: functional status on headache-free days. Neurology. 2018 Aug 17 [Epub ahead of print].

Fremanezumab increases the number of headache-free days with normal function for patients with episodic or chronic migraine, according to post hoc analyses published online ahead of print August 17 in Neurology. Fremanezumab appears to improve all measures of function in patients with episodic migraine, and some measures in patients with chronic migraine.

“The results should be considered exploratory,” said Juliana VanderPluym, MD, a neurologist at Mayo Clinic in Phoenix, and colleagues. “Further research is needed to confirm these preliminary findings and to understand the factors contributing to perceived functional status on headache-free days.”

Examining Two Phase II Trials

Fremanezumab is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). Dr. VanderPluym and colleagues analyzed data from randomized, double-blind phase II trials of the therapy for prevention of high-frequency episodic migraine (ie, eight to 14 headache days per month) and chronic migraine. Patients with high-frequency episodic migraine received placebo or monthly subcutaneous fremanezumab injections of 225 mg or 675 mg. Patients with chronic migraine received placebo or an initial 675-mg fremanezumab dose followed by monthly subcutaneous injections of 225 mg or 900 mg. The treatment period was three months.

Participants entered information into an electronic diary daily. Questions about functional performance elicited information about “work/school/household chore performance” and “concentration/mental fatigue.” For the former category, patients recorded their performance as normal, less than 50% impaired, or at least 50% impaired. For the latter category, patients recorded how much time they had spent working more slowly, finding it difficult to concentrate, and feeling tired or drained.

Fremanezumab Improved Concentration

In the high-frequency episodic migraine study, patients who received fremanezumab had a greater increase in headache-free days with normal concentration and normal performance at work, school, and home, compared with controls.

In the study of chronic migraine, the 900-mg dose was associated with consistent improvements in function on headache-free days. Patients with chronic migraine in the 225-mg dose group had increases compared with controls in the number of headache-free days in which they performed household chores normally and had no time with difficulty concentrating. The 225-mg group had minimal changes in the number of headache-free days in which work/study and household chore performance was impaired by 50% or more, as well as in in time with difficulty concentrating, but its results were better than those of controls.

“One could postulate that patients had more headache-free days with normal functional performance simply because they had more headache-free days on fremanezumab,” said Dr. VanderPluym. “With increased headache-free days, patients may have had reduced interictal anxiety and thus reduced avoidance behavior and lifestyle compromise, allowing them to function normally.”

Patients receiving fremanezumab significantly reduced their intake of acute medications, compared with controls. This reduction likely decreased the number of side effects associated with acute medications and could have contributed to better functional performance, said the authors.

A limitation of the analysis is that the assessment of function was not based on standardized questionnaires such as the Headache Impact Test-6 or the Migraine-Specific Quality of Life Questionnaire.

—Erik Greb

Suggested Reading

VanderPluym J, Dodick DW, Lipton RB, et al. Fremanezumab for preventive treatment of migraine: functional status on headache-free days. Neurology. 2018 Aug 17 [Epub ahead of print].

Fremanezumab increases the number of headache-free days with normal function for patients with episodic or chronic migraine, according to post hoc analyses published online ahead of print August 17 in Neurology. Fremanezumab appears to improve all measures of function in patients with episodic migraine, and some measures in patients with chronic migraine.

“The results should be considered exploratory,” said Juliana VanderPluym, MD, a neurologist at Mayo Clinic in Phoenix, and colleagues. “Further research is needed to confirm these preliminary findings and to understand the factors contributing to perceived functional status on headache-free days.”

Examining Two Phase II Trials

Fremanezumab is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). Dr. VanderPluym and colleagues analyzed data from randomized, double-blind phase II trials of the therapy for prevention of high-frequency episodic migraine (ie, eight to 14 headache days per month) and chronic migraine. Patients with high-frequency episodic migraine received placebo or monthly subcutaneous fremanezumab injections of 225 mg or 675 mg. Patients with chronic migraine received placebo or an initial 675-mg fremanezumab dose followed by monthly subcutaneous injections of 225 mg or 900 mg. The treatment period was three months.

Participants entered information into an electronic diary daily. Questions about functional performance elicited information about “work/school/household chore performance” and “concentration/mental fatigue.” For the former category, patients recorded their performance as normal, less than 50% impaired, or at least 50% impaired. For the latter category, patients recorded how much time they had spent working more slowly, finding it difficult to concentrate, and feeling tired or drained.

Fremanezumab Improved Concentration

In the high-frequency episodic migraine study, patients who received fremanezumab had a greater increase in headache-free days with normal concentration and normal performance at work, school, and home, compared with controls.

In the study of chronic migraine, the 900-mg dose was associated with consistent improvements in function on headache-free days. Patients with chronic migraine in the 225-mg dose group had increases compared with controls in the number of headache-free days in which they performed household chores normally and had no time with difficulty concentrating. The 225-mg group had minimal changes in the number of headache-free days in which work/study and household chore performance was impaired by 50% or more, as well as in in time with difficulty concentrating, but its results were better than those of controls.

“One could postulate that patients had more headache-free days with normal functional performance simply because they had more headache-free days on fremanezumab,” said Dr. VanderPluym. “With increased headache-free days, patients may have had reduced interictal anxiety and thus reduced avoidance behavior and lifestyle compromise, allowing them to function normally.”

Patients receiving fremanezumab significantly reduced their intake of acute medications, compared with controls. This reduction likely decreased the number of side effects associated with acute medications and could have contributed to better functional performance, said the authors.

A limitation of the analysis is that the assessment of function was not based on standardized questionnaires such as the Headache Impact Test-6 or the Migraine-Specific Quality of Life Questionnaire.

—Erik Greb

Suggested Reading

VanderPluym J, Dodick DW, Lipton RB, et al. Fremanezumab for preventive treatment of migraine: functional status on headache-free days. Neurology. 2018 Aug 17 [Epub ahead of print].