Clinical Edge Journal Scan Commentary: Migraine April 2022

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.