Commentary: Novel Migraine Treatment Side Effects, November 2022

Calcitonin gene-related peptide (CGRP) antagonist medications are becoming more and more of a mainstay of both migraine prevention and acute treatment. Four CGRP monoclonal antibody medications and three oral CGRP antagonists are now available for prevention and acute treatment of migraine. When this class of medications was developed, many patients and providers were initially concerned regarding any potentially unanticipated long-term adverse events. The first CGRP antagonist medication, erenumab, was associated with constipation, and, although this has not been formally reported with other CGRP medications, there is some anecdotal evidence of gastrointestinal (GI) discomfort with both oral and other monoclonal antibody medications in this class. In 2021, erenumab was also reported to be associated with hypertension and a formal warning was issued for this.

Before CGRP was used for migraine prevention, it had been known to be a potent vasodilator. Although the randomized controlled trials (RCT) for all CGRP medications included a longitudinal review of blood pressure (BP) measures, none of those initial trials revealed an increased risk for hypertension or other cardiovascular events or concerns. Some of the initial trials even included patients at higher cardiovascular risk. Migraine itself is associated with an increased vascular risk; it is therefore extremely important to determine whether a potential treatment may be increasing this risk further.

In the study by de Vries and colleagues, all patients were started on either erenumab or fremanezumab and were included if they had a follow-up blood pressure measurement within 6 months. All patients had at least8 migraine days per month and had used four or more preventive medications. Patients taking erenumab were first started at 70 mg monthly and were optionally increased to 140 mg after 3 months. Fremanezumab was always given at a dose of 225 mg monthly (as opposed to 675 mg every 3 months). BP data were collected at baseline and followed up at every visit, with a maximum of 12 months of review. Patients were excluded if their baseline BP was measured while they were undergoing tapering an antihypertensive medication at the same time that they were starting the CGRP antagonist. Patients already treated for hypertension were included only if there were no changes to their hypertensive regimen.

Patients were also compared with a control group with a similar distribution in sex, age, and diagnosis, and who were not taking any migraine preventive medication that would affect their BP. Control group BP was also measured at least two different time points 1-3 months from baseline.

A total of 211 patients were enrolled: 109 in the erenumab group and 87 in the fremanezumab group. The erenumab group was also associated with an increase in both systolic BP (SBP) and diastolic BP (DBP) (SBP ≤ 9 mm Hg; DBP ≤ 6.3 mm Hg). The fremanezumab group had a lower increase in SBP (1 mm Hg) and no increase in DBP. Nine patients were started on antihypertensive medications, five of them after the baseline BP recording only. There was no change over time in the control group.

As noted, CGRP has a potent vasodilatory effect. Although not proven, a theory has been posited that CGRP receptor antagonist medications are somewhat more likely to lead to systemic adverse effects than are ligand-blocking medications. This may, at least in part, explain why erenumab appears to have more associated GI discomfort and constipation as well as a vascular effect with hypertension. In light of these findings, it is absolutely necessary for the additional CGRP medications to also be studied for these potential risk factors.

With the advent of novel acute treatments for migraine, many providers ask themselves what the potential risks and benefits are for each new class of drugs developed and approved over the past few years. Johnston and colleagues reviewed five recently published RCT to compare risk-benefit profiles for lasmiditan, rimegepant, and ubrogepant. Lasmiditan is the only medication in the ditan class, a serotonin (5HT-1F) receptor agonist medication approved for the acute treatment of migraine. Rimegepant and ubrogepant are oral CGRP antagonists.

Lasmiditan does have a potential risk for impairment while driving due to excessive sedation and dizziness; it is also more likely than the CGRP medications to lead to the development of medication overuse headache. The CGRP medications, however, are associated with a smaller responder rate for headache freedom at 2 hours. The investigators reviewed the data published in five RCT to develop a statistically based decision-making process that correlates with the number needed to treat vs the number needed to harm for all three of these medications. The number needed to treat is a statistically defined parameter that characterizes the number of patients that need to be treated with an intervention to achieve a positive event. The number needed to harm refers to an additional negative event relative to the reference treatment (placebo in the case of an RCT).

The reviewed studies compared multiple dosages of these medications. Efficacy outcomes were pain relief and pain freedom at 2 hours, sustained pain relief from 2 to 24 hours, and freedom from the most bothersome symptom at 2 hours. Safety outcomes were dizziness and nausea.

The number needed to treat was the lowest for 200 mg lasmiditan (twice the highest recommended acute dose), followed by 75 mg rimegepant. The number needed to harm was highest for 25 mg ubrogepant (half of the lowest recommended acute dose). Nausea was lowest for 75 mg rimegepant.

An individualized approach is always recommended when considering both preventive and acute treatments for migraine. It is definitely worth keeping these results in mind when discussing potential acute treatment options with patients. This is especially true when considering patients who may be more likely to experience either dizziness or nausea with other acute treatments. It is also worth individualizing a potential acute treatment when a patient experiences rapid-onset migraine symptoms. Further investigations into both acute and preventive treatments would enlighten and further individualize our clinical approaches.

Erenumab currently carries a prescriber warning for constipation. Although there has been some anecdotal evidence for constipation with other CGRP antagonists, this has never fully been investigated. Currently, the other CGRP medication options have fewer side effects and not all  are associated with constipation. Kudrow and colleagues sought to review the incidence of constipation, and GI motility in general, with both erenumab and galcanezumab. Their hypothesis was that a single dose of erenumab would be associated with delayed GI motility and a single dose of galcanezumab would not be.

This study was conducted as a multicenter trial with single-blinding. A total of 65 patients were enrolled and given either 140 mg erenumab or 240 mg galcanezumab (the loading dose). GI motility was measured via a wireless motility capsule at baseline before treatment and repeated at 2 weeks. This test is approved by the US Food and Drug Administration for evaluation of gastric transit time in patients with suspected gastroparesis and for evaluation of colonic transit time in patients with chronic idiopathic constipation. Patients with prior GI symptoms were excluded, as were patients taking a tricyclic antidepressant or a calcium-channel blocker, owing to known constipation with these agents.

The primary endpoint in this study was change from a baseline colonic transit time 2 weeks after injection with the CGRP monoclonal antibody. Secondary endpoints included change from baseline in whole-gut transit time, gastric emptying time, small-bowel transfer time, and combined small- and large-bowel transfer time. The Gastrointestinal Symptom Rating Scale (GSRS) was also used, evaluating abdominal pain, reflux, indigestion, constipation, and diarrhea based on a 7-point response, ranging from no discomfort to very severe discomfort.

The primary endpoint of baseline change in colonic transit time was not statistically significant between the groups: A mean change of 5.8 hours was noted for erenumab and 5.4 hours for galcanezumab. Most secondary endpoints were also not statistically significantly different between the two groups. Small-bowel transit time was  decreased in the galcanezumab group. When the patient-reported scales were reviewed, spontaneous bowel movements decreased significantly in the erenumab group, a finding that was not seen in the galcanezumab group and was statistically significant. The GSRS also showed a small but statistically significant change in the erenumab group.

This study does appear to show a significant difference in the two CGRP antagonist medications. The full side-effect profiles of the four CGRP monoclonal antibodies and three oral CGRP blocking medications available remain unknown. Further head-to-head comparisons will allow better differentiation of these options and better individualization of patient care.

Calcitonin gene-related peptide (CGRP) antagonist medications are becoming more and more of a mainstay of both migraine prevention and acute treatment. Four CGRP monoclonal antibody medications and three oral CGRP antagonists are now available for prevention and acute treatment of migraine. When this class of medications was developed, many patients and providers were initially concerned regarding any potentially unanticipated long-term adverse events. The first CGRP antagonist medication, erenumab, was associated with constipation, and, although this has not been formally reported with other CGRP medications, there is some anecdotal evidence of gastrointestinal (GI) discomfort with both oral and other monoclonal antibody medications in this class. In 2021, erenumab was also reported to be associated with hypertension and a formal warning was issued for this.

Before CGRP was used for migraine prevention, it had been known to be a potent vasodilator. Although the randomized controlled trials (RCT) for all CGRP medications included a longitudinal review of blood pressure (BP) measures, none of those initial trials revealed an increased risk for hypertension or other cardiovascular events or concerns. Some of the initial trials even included patients at higher cardiovascular risk. Migraine itself is associated with an increased vascular risk; it is therefore extremely important to determine whether a potential treatment may be increasing this risk further.

In the study by de Vries and colleagues, all patients were started on either erenumab or fremanezumab and were included if they had a follow-up blood pressure measurement within 6 months. All patients had at least8 migraine days per month and had used four or more preventive medications. Patients taking erenumab were first started at 70 mg monthly and were optionally increased to 140 mg after 3 months. Fremanezumab was always given at a dose of 225 mg monthly (as opposed to 675 mg every 3 months). BP data were collected at baseline and followed up at every visit, with a maximum of 12 months of review. Patients were excluded if their baseline BP was measured while they were undergoing tapering an antihypertensive medication at the same time that they were starting the CGRP antagonist. Patients already treated for hypertension were included only if there were no changes to their hypertensive regimen.

Patients were also compared with a control group with a similar distribution in sex, age, and diagnosis, and who were not taking any migraine preventive medication that would affect their BP. Control group BP was also measured at least two different time points 1-3 months from baseline.

A total of 211 patients were enrolled: 109 in the erenumab group and 87 in the fremanezumab group. The erenumab group was also associated with an increase in both systolic BP (SBP) and diastolic BP (DBP) (SBP ≤ 9 mm Hg; DBP ≤ 6.3 mm Hg). The fremanezumab group had a lower increase in SBP (1 mm Hg) and no increase in DBP. Nine patients were started on antihypertensive medications, five of them after the baseline BP recording only. There was no change over time in the control group.

As noted, CGRP has a potent vasodilatory effect. Although not proven, a theory has been posited that CGRP receptor antagonist medications are somewhat more likely to lead to systemic adverse effects than are ligand-blocking medications. This may, at least in part, explain why erenumab appears to have more associated GI discomfort and constipation as well as a vascular effect with hypertension. In light of these findings, it is absolutely necessary for the additional CGRP medications to also be studied for these potential risk factors.

With the advent of novel acute treatments for migraine, many providers ask themselves what the potential risks and benefits are for each new class of drugs developed and approved over the past few years. Johnston and colleagues reviewed five recently published RCT to compare risk-benefit profiles for lasmiditan, rimegepant, and ubrogepant. Lasmiditan is the only medication in the ditan class, a serotonin (5HT-1F) receptor agonist medication approved for the acute treatment of migraine. Rimegepant and ubrogepant are oral CGRP antagonists.

Lasmiditan does have a potential risk for impairment while driving due to excessive sedation and dizziness; it is also more likely than the CGRP medications to lead to the development of medication overuse headache. The CGRP medications, however, are associated with a smaller responder rate for headache freedom at 2 hours. The investigators reviewed the data published in five RCT to develop a statistically based decision-making process that correlates with the number needed to treat vs the number needed to harm for all three of these medications. The number needed to treat is a statistically defined parameter that characterizes the number of patients that need to be treated with an intervention to achieve a positive event. The number needed to harm refers to an additional negative event relative to the reference treatment (placebo in the case of an RCT).

The reviewed studies compared multiple dosages of these medications. Efficacy outcomes were pain relief and pain freedom at 2 hours, sustained pain relief from 2 to 24 hours, and freedom from the most bothersome symptom at 2 hours. Safety outcomes were dizziness and nausea.

The number needed to treat was the lowest for 200 mg lasmiditan (twice the highest recommended acute dose), followed by 75 mg rimegepant. The number needed to harm was highest for 25 mg ubrogepant (half of the lowest recommended acute dose). Nausea was lowest for 75 mg rimegepant.

An individualized approach is always recommended when considering both preventive and acute treatments for migraine. It is definitely worth keeping these results in mind when discussing potential acute treatment options with patients. This is especially true when considering patients who may be more likely to experience either dizziness or nausea with other acute treatments. It is also worth individualizing a potential acute treatment when a patient experiences rapid-onset migraine symptoms. Further investigations into both acute and preventive treatments would enlighten and further individualize our clinical approaches.

Erenumab currently carries a prescriber warning for constipation. Although there has been some anecdotal evidence for constipation with other CGRP antagonists, this has never fully been investigated. Currently, the other CGRP medication options have fewer side effects and not all  are associated with constipation. Kudrow and colleagues sought to review the incidence of constipation, and GI motility in general, with both erenumab and galcanezumab. Their hypothesis was that a single dose of erenumab would be associated with delayed GI motility and a single dose of galcanezumab would not be.

This study was conducted as a multicenter trial with single-blinding. A total of 65 patients were enrolled and given either 140 mg erenumab or 240 mg galcanezumab (the loading dose). GI motility was measured via a wireless motility capsule at baseline before treatment and repeated at 2 weeks. This test is approved by the US Food and Drug Administration for evaluation of gastric transit time in patients with suspected gastroparesis and for evaluation of colonic transit time in patients with chronic idiopathic constipation. Patients with prior GI symptoms were excluded, as were patients taking a tricyclic antidepressant or a calcium-channel blocker, owing to known constipation with these agents.

The primary endpoint in this study was change from a baseline colonic transit time 2 weeks after injection with the CGRP monoclonal antibody. Secondary endpoints included change from baseline in whole-gut transit time, gastric emptying time, small-bowel transfer time, and combined small- and large-bowel transfer time. The Gastrointestinal Symptom Rating Scale (GSRS) was also used, evaluating abdominal pain, reflux, indigestion, constipation, and diarrhea based on a 7-point response, ranging from no discomfort to very severe discomfort.

The primary endpoint of baseline change in colonic transit time was not statistically significant between the groups: A mean change of 5.8 hours was noted for erenumab and 5.4 hours for galcanezumab. Most secondary endpoints were also not statistically significantly different between the two groups. Small-bowel transit time was  decreased in the galcanezumab group. When the patient-reported scales were reviewed, spontaneous bowel movements decreased significantly in the erenumab group, a finding that was not seen in the galcanezumab group and was statistically significant. The GSRS also showed a small but statistically significant change in the erenumab group.

This study does appear to show a significant difference in the two CGRP antagonist medications. The full side-effect profiles of the four CGRP monoclonal antibodies and three oral CGRP blocking medications available remain unknown. Further head-to-head comparisons will allow better differentiation of these options and better individualization of patient care.

Calcitonin gene-related peptide (CGRP) antagonist medications are becoming more and more of a mainstay of both migraine prevention and acute treatment. Four CGRP monoclonal antibody medications and three oral CGRP antagonists are now available for prevention and acute treatment of migraine. When this class of medications was developed, many patients and providers were initially concerned regarding any potentially unanticipated long-term adverse events. The first CGRP antagonist medication, erenumab, was associated with constipation, and, although this has not been formally reported with other CGRP medications, there is some anecdotal evidence of gastrointestinal (GI) discomfort with both oral and other monoclonal antibody medications in this class. In 2021, erenumab was also reported to be associated with hypertension and a formal warning was issued for this.

Before CGRP was used for migraine prevention, it had been known to be a potent vasodilator. Although the randomized controlled trials (RCT) for all CGRP medications included a longitudinal review of blood pressure (BP) measures, none of those initial trials revealed an increased risk for hypertension or other cardiovascular events or concerns. Some of the initial trials even included patients at higher cardiovascular risk. Migraine itself is associated with an increased vascular risk; it is therefore extremely important to determine whether a potential treatment may be increasing this risk further.

In the study by de Vries and colleagues, all patients were started on either erenumab or fremanezumab and were included if they had a follow-up blood pressure measurement within 6 months. All patients had at least8 migraine days per month and had used four or more preventive medications. Patients taking erenumab were first started at 70 mg monthly and were optionally increased to 140 mg after 3 months. Fremanezumab was always given at a dose of 225 mg monthly (as opposed to 675 mg every 3 months). BP data were collected at baseline and followed up at every visit, with a maximum of 12 months of review. Patients were excluded if their baseline BP was measured while they were undergoing tapering an antihypertensive medication at the same time that they were starting the CGRP antagonist. Patients already treated for hypertension were included only if there were no changes to their hypertensive regimen.

Patients were also compared with a control group with a similar distribution in sex, age, and diagnosis, and who were not taking any migraine preventive medication that would affect their BP. Control group BP was also measured at least two different time points 1-3 months from baseline.

A total of 211 patients were enrolled: 109 in the erenumab group and 87 in the fremanezumab group. The erenumab group was also associated with an increase in both systolic BP (SBP) and diastolic BP (DBP) (SBP ≤ 9 mm Hg; DBP ≤ 6.3 mm Hg). The fremanezumab group had a lower increase in SBP (1 mm Hg) and no increase in DBP. Nine patients were started on antihypertensive medications, five of them after the baseline BP recording only. There was no change over time in the control group.

As noted, CGRP has a potent vasodilatory effect. Although not proven, a theory has been posited that CGRP receptor antagonist medications are somewhat more likely to lead to systemic adverse effects than are ligand-blocking medications. This may, at least in part, explain why erenumab appears to have more associated GI discomfort and constipation as well as a vascular effect with hypertension. In light of these findings, it is absolutely necessary for the additional CGRP medications to also be studied for these potential risk factors.

With the advent of novel acute treatments for migraine, many providers ask themselves what the potential risks and benefits are for each new class of drugs developed and approved over the past few years. Johnston and colleagues reviewed five recently published RCT to compare risk-benefit profiles for lasmiditan, rimegepant, and ubrogepant. Lasmiditan is the only medication in the ditan class, a serotonin (5HT-1F) receptor agonist medication approved for the acute treatment of migraine. Rimegepant and ubrogepant are oral CGRP antagonists.

Lasmiditan does have a potential risk for impairment while driving due to excessive sedation and dizziness; it is also more likely than the CGRP medications to lead to the development of medication overuse headache. The CGRP medications, however, are associated with a smaller responder rate for headache freedom at 2 hours. The investigators reviewed the data published in five RCT to develop a statistically based decision-making process that correlates with the number needed to treat vs the number needed to harm for all three of these medications. The number needed to treat is a statistically defined parameter that characterizes the number of patients that need to be treated with an intervention to achieve a positive event. The number needed to harm refers to an additional negative event relative to the reference treatment (placebo in the case of an RCT).

The reviewed studies compared multiple dosages of these medications. Efficacy outcomes were pain relief and pain freedom at 2 hours, sustained pain relief from 2 to 24 hours, and freedom from the most bothersome symptom at 2 hours. Safety outcomes were dizziness and nausea.

The number needed to treat was the lowest for 200 mg lasmiditan (twice the highest recommended acute dose), followed by 75 mg rimegepant. The number needed to harm was highest for 25 mg ubrogepant (half of the lowest recommended acute dose). Nausea was lowest for 75 mg rimegepant.

An individualized approach is always recommended when considering both preventive and acute treatments for migraine. It is definitely worth keeping these results in mind when discussing potential acute treatment options with patients. This is especially true when considering patients who may be more likely to experience either dizziness or nausea with other acute treatments. It is also worth individualizing a potential acute treatment when a patient experiences rapid-onset migraine symptoms. Further investigations into both acute and preventive treatments would enlighten and further individualize our clinical approaches.

Erenumab currently carries a prescriber warning for constipation. Although there has been some anecdotal evidence for constipation with other CGRP antagonists, this has never fully been investigated. Currently, the other CGRP medication options have fewer side effects and not all  are associated with constipation. Kudrow and colleagues sought to review the incidence of constipation, and GI motility in general, with both erenumab and galcanezumab. Their hypothesis was that a single dose of erenumab would be associated with delayed GI motility and a single dose of galcanezumab would not be.

This study was conducted as a multicenter trial with single-blinding. A total of 65 patients were enrolled and given either 140 mg erenumab or 240 mg galcanezumab (the loading dose). GI motility was measured via a wireless motility capsule at baseline before treatment and repeated at 2 weeks. This test is approved by the US Food and Drug Administration for evaluation of gastric transit time in patients with suspected gastroparesis and for evaluation of colonic transit time in patients with chronic idiopathic constipation. Patients with prior GI symptoms were excluded, as were patients taking a tricyclic antidepressant or a calcium-channel blocker, owing to known constipation with these agents.

The primary endpoint in this study was change from a baseline colonic transit time 2 weeks after injection with the CGRP monoclonal antibody. Secondary endpoints included change from baseline in whole-gut transit time, gastric emptying time, small-bowel transfer time, and combined small- and large-bowel transfer time. The Gastrointestinal Symptom Rating Scale (GSRS) was also used, evaluating abdominal pain, reflux, indigestion, constipation, and diarrhea based on a 7-point response, ranging from no discomfort to very severe discomfort.

The primary endpoint of baseline change in colonic transit time was not statistically significant between the groups: A mean change of 5.8 hours was noted for erenumab and 5.4 hours for galcanezumab. Most secondary endpoints were also not statistically significantly different between the two groups. Small-bowel transit time was  decreased in the galcanezumab group. When the patient-reported scales were reviewed, spontaneous bowel movements decreased significantly in the erenumab group, a finding that was not seen in the galcanezumab group and was statistically significant. The GSRS also showed a small but statistically significant change in the erenumab group.

This study does appear to show a significant difference in the two CGRP antagonist medications. The full side-effect profiles of the four CGRP monoclonal antibodies and three oral CGRP blocking medications available remain unknown. Further head-to-head comparisons will allow better differentiation of these options and better individualization of patient care.