Clinical Edge Journal Scan Commentary: Migraine January 2022

Ferrari et al¹provided information on an open label extension to the “LIBERTY” study which investigated the use of erenumab in subjects with episodic migraine that have failed multiple prior preventive medications. The initial Calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) studies excluded more refractory patients.  Most commercial insurances in the United States have a “step” policy that relates to use of these and other newer medications, meaning that the majority of patient in the US who receive these medications have previously tried other preventive medications. This raised the question whether migraine refractoriness is a negative predictive factor for erenumab.

This long-term open label study is more like the real-world use of erenumab, and as such the results are similar to what many practitioners are seeing in their clinical experience. Approximately 25% of subjects discontinued erenumab, mostly due to ineffectiveness. Adverse events were mild, and although erenumab has warnings for constipation and hypertension, this study did not show either as increasing over 2 years. Erenumab appeared to be tolerable over time. There were no newly noted safety signals in this study.

The efficacy of erenumab also appeared to be stable over time, without the development of tolerance to the medication. There is a slight decrease in the 50% responder rate at 2 years when these more refractory patients are compared to those that did not have multiple treatment failures. This study also looked at “functional parameters,” such as Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6), both of which were significantly improved over time.

Although there are some significant limitations in this study-primarily the fact that it is open label—this does give a more representative and real-world sample of patients who will be prescribed erenumab in the United States. Most practitioners will be glad to find that the long-term use of erenumab appears safe, and the efficacy remains stable, even in a more difficult-to-treat population.

A randomized controlled international study investigated the preventive use of occipital nerve blocks in migraine without aura.² The majority of the literature for the use of occipital nerve blocks is for acute treatment, and arguably the most significant study prior to this was Friedman et al³ investigating the use of this procedure in the emergency ward. Prior occipital nerve studies have been inconclusive, and although occipital nerve blocks are considered standard of care for specific conditions in most headache centers, reimbursement is usually very limited. Insurance companies have quoted prior preventive occipital nerve studies to justify non-coverage of these procedures, making access to them for many patients very limited.

Occipital nerve blocks are not performed uniformly, both regarding the medications used—some practitioners use no steroids, some use lidocaine and bupivocaine—and regarding the placement of the injections. In this a small cohort study, 55 subjects were divided into four groups for intervention—one of which was a control group of saline—and all were given one 2.5 mL injection at a point in between the occipital protuberance and the mastoid process bilaterally. Due to adverse events (alopecia and cutaneous atrophy) in two of the triamcinolone groups, recruitment was halted for those two groups. Patients were assessed based on headache duration, frequency, and severity over a 4-week course.

Compared to baseline all interventional groups had significantly decreased headache severity, which did return closer to baseline during the final week. Headache duration was decreased in the first 2 weeks post-injection. Headache frequency was seen to return to baseline at week 4, but prior to that the groups injected with lidocaine had a significant decrease in migraine frequency, with an average decrease in headache days.

Occipital nerve blocks are performed frequently for migraine, occipital neuralgia, cervicogenic headache, and many other conditions with noted tenderness over the occiput. As noted above, they are not performed uniformly—sometimes they are given for acute headache pain or status migranosus, and other times they are used in regular intervals for prevention. This data does finally show a preventive benefit with occipital nerve blocks, and this may allow for modifications in how occipital nerve blocks are currently performed. Based on this study, if given preventively, occipital nerve blocks should only contain topical anesthetics, not steroids, and should be performed on an every 2-3 week basis.

The limitations of this study are significant as well. This is a very small cohort, and the injections were performed in only one manner (one bilateral injection), whereas many practitioners will target the greater and lesser branches of the occipital nerve individually.  There were no exclusion criteria for subjects that already had occipital nerve blocks performed—those patients would be unblinded as there is a different sensation when injected with a topical anesthetic versus normal saline (normal saline does not cause burning subcutaneously).

These results should pave the way for further investigations in the use of occipital and other nerve blocks in the prevention of migraine. This should allow better access for our patients and the possibility of performing these procedures more uniformly in the future.

It can be challenging for many practitioners to determine which medication is ideal for individual situations. This is especially true when treating chronic migraine, where many potential complicating factors can influence positive to negative responses to treatment. The investigators here sought to determine which factors may potentially predict a positive response to galcanezumab.⁴

This is an observational study, where 156 subjects with a diagnosis of chronic migraine were enrolled. There was a 1-month run-in period where the following characteristics were collected: monthly headache days, monthly abortive medication intake, clinical features of migraine, and disability scores (MIDAS and HIT-6). These were tracked over a 3-month period after starting glacanezumab.

Approximately 40% of subjects experienced a 50% reduction in headache frequency. The better responders had a lower body mass index, fewer previously failed preventive medications, unilateral headache pain, and previous good response to triptan use. Surprisingly, the presence of medication overuse was associated with persistent improvement at 3 months as well, with over 60% of subjects with medication overuse no longer overusing acute medications at 3 months.  

This study is helpful in identifying specific features that may allow a practitioner to better recommend CGRP mAb medications, such as galcanezumab. Chronic migraine can offer a challenge to even the best trained clinicians. Patients will often have multiple factors that have led to a conversion from episodic to chronic migraine, and a history of medication failures or intolerances. These patients are often referred specifically due to these challenges.

When deciding on a preventive medication for patients with chronic migraine, we often first consider which oral preventive medications may allow us to treat migraine in addition to another underlying issue—such as insomnia, depression, or hypertension. Although the oral class can improve other comorbidities, intolerance is significantly higher for most of these medications as well. The CGRP mAb class is somewhat more ideal for prevention of migraine; the focus when using this class is for migraine prevention alone, and the side effect profile is more tolerable for most patients. That said, if predictive factors were known a more individualized approach to migraine prevention would be possible.

The authors’ recognition of the factors associated with improvement in patients using glacanezumab allows this better individualization. Based on these results, patients with more unilateral pain, lower BMI, and good response to triptans could be recommended glacanuzumab with a great degree of confidence. This should be irrespective of even high frequency use of acute medications, as most of subjects in this study with medication overuse reverted after 3 months.

There is never a single ideal preventive or acute treatment for migraine in any population, however, recognizing factors that allow for an individualized approach improves the quality of life for our patients, and leaves them less disabled by migraine.

References

1. Ferrari MD et al. Two-year efficacy and safety of erenumab in participants with episodic migraine and 2–4 prior preventive treatment failures: results from the LIBERTY study. J Neurol Neurosurg Psychiatry. 2021(Nov 29).
2. Malekian N et al. Preventive effect of greater occipital nerve block on patients with episodic migraine: A randomized double‐blind placebo‐controlled clinical trial. Cephalalgia. 2021(Nov 17).
3. Friedman BW et al. A Randomized, Sham-Controlled Trial of Bilateral Greater Occipital Nerve Blocks With Bupivacaine for Acute Migraine Patients Refractory to Standard Emergency Department Treatment With Metoclopramide. Headache. 2018(Oct);58(9):1427-34. https://doi.org/10.1111/head.13395.
4. Vernieri F et al. Rapid response to galcanezumab and predictive factors in chronic migraine patients: A 3-month observational, longitudinal, cohort, multicenter, Italian real-life study. Eur J Neurol. 2021(Nov 26).

Ferrari et al¹provided information on an open label extension to the “LIBERTY” study which investigated the use of erenumab in subjects with episodic migraine that have failed multiple prior preventive medications. The initial Calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) studies excluded more refractory patients.  Most commercial insurances in the United States have a “step” policy that relates to use of these and other newer medications, meaning that the majority of patient in the US who receive these medications have previously tried other preventive medications. This raised the question whether migraine refractoriness is a negative predictive factor for erenumab.

This long-term open label study is more like the real-world use of erenumab, and as such the results are similar to what many practitioners are seeing in their clinical experience. Approximately 25% of subjects discontinued erenumab, mostly due to ineffectiveness. Adverse events were mild, and although erenumab has warnings for constipation and hypertension, this study did not show either as increasing over 2 years. Erenumab appeared to be tolerable over time. There were no newly noted safety signals in this study.

The efficacy of erenumab also appeared to be stable over time, without the development of tolerance to the medication. There is a slight decrease in the 50% responder rate at 2 years when these more refractory patients are compared to those that did not have multiple treatment failures. This study also looked at “functional parameters,” such as Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6), both of which were significantly improved over time.

Although there are some significant limitations in this study-primarily the fact that it is open label—this does give a more representative and real-world sample of patients who will be prescribed erenumab in the United States. Most practitioners will be glad to find that the long-term use of erenumab appears safe, and the efficacy remains stable, even in a more difficult-to-treat population.

A randomized controlled international study investigated the preventive use of occipital nerve blocks in migraine without aura.² The majority of the literature for the use of occipital nerve blocks is for acute treatment, and arguably the most significant study prior to this was Friedman et al³ investigating the use of this procedure in the emergency ward. Prior occipital nerve studies have been inconclusive, and although occipital nerve blocks are considered standard of care for specific conditions in most headache centers, reimbursement is usually very limited. Insurance companies have quoted prior preventive occipital nerve studies to justify non-coverage of these procedures, making access to them for many patients very limited.

Occipital nerve blocks are not performed uniformly, both regarding the medications used—some practitioners use no steroids, some use lidocaine and bupivocaine—and regarding the placement of the injections. In this a small cohort study, 55 subjects were divided into four groups for intervention—one of which was a control group of saline—and all were given one 2.5 mL injection at a point in between the occipital protuberance and the mastoid process bilaterally. Due to adverse events (alopecia and cutaneous atrophy) in two of the triamcinolone groups, recruitment was halted for those two groups. Patients were assessed based on headache duration, frequency, and severity over a 4-week course.

Compared to baseline all interventional groups had significantly decreased headache severity, which did return closer to baseline during the final week. Headache duration was decreased in the first 2 weeks post-injection. Headache frequency was seen to return to baseline at week 4, but prior to that the groups injected with lidocaine had a significant decrease in migraine frequency, with an average decrease in headache days.

Occipital nerve blocks are performed frequently for migraine, occipital neuralgia, cervicogenic headache, and many other conditions with noted tenderness over the occiput. As noted above, they are not performed uniformly—sometimes they are given for acute headache pain or status migranosus, and other times they are used in regular intervals for prevention. This data does finally show a preventive benefit with occipital nerve blocks, and this may allow for modifications in how occipital nerve blocks are currently performed. Based on this study, if given preventively, occipital nerve blocks should only contain topical anesthetics, not steroids, and should be performed on an every 2-3 week basis.

The limitations of this study are significant as well. This is a very small cohort, and the injections were performed in only one manner (one bilateral injection), whereas many practitioners will target the greater and lesser branches of the occipital nerve individually.  There were no exclusion criteria for subjects that already had occipital nerve blocks performed—those patients would be unblinded as there is a different sensation when injected with a topical anesthetic versus normal saline (normal saline does not cause burning subcutaneously).

These results should pave the way for further investigations in the use of occipital and other nerve blocks in the prevention of migraine. This should allow better access for our patients and the possibility of performing these procedures more uniformly in the future.

It can be challenging for many practitioners to determine which medication is ideal for individual situations. This is especially true when treating chronic migraine, where many potential complicating factors can influence positive to negative responses to treatment. The investigators here sought to determine which factors may potentially predict a positive response to galcanezumab.⁴

This is an observational study, where 156 subjects with a diagnosis of chronic migraine were enrolled. There was a 1-month run-in period where the following characteristics were collected: monthly headache days, monthly abortive medication intake, clinical features of migraine, and disability scores (MIDAS and HIT-6). These were tracked over a 3-month period after starting glacanezumab.

Approximately 40% of subjects experienced a 50% reduction in headache frequency. The better responders had a lower body mass index, fewer previously failed preventive medications, unilateral headache pain, and previous good response to triptan use. Surprisingly, the presence of medication overuse was associated with persistent improvement at 3 months as well, with over 60% of subjects with medication overuse no longer overusing acute medications at 3 months.  

This study is helpful in identifying specific features that may allow a practitioner to better recommend CGRP mAb medications, such as galcanezumab. Chronic migraine can offer a challenge to even the best trained clinicians. Patients will often have multiple factors that have led to a conversion from episodic to chronic migraine, and a history of medication failures or intolerances. These patients are often referred specifically due to these challenges.

When deciding on a preventive medication for patients with chronic migraine, we often first consider which oral preventive medications may allow us to treat migraine in addition to another underlying issue—such as insomnia, depression, or hypertension. Although the oral class can improve other comorbidities, intolerance is significantly higher for most of these medications as well. The CGRP mAb class is somewhat more ideal for prevention of migraine; the focus when using this class is for migraine prevention alone, and the side effect profile is more tolerable for most patients. That said, if predictive factors were known a more individualized approach to migraine prevention would be possible.

The authors’ recognition of the factors associated with improvement in patients using glacanezumab allows this better individualization. Based on these results, patients with more unilateral pain, lower BMI, and good response to triptans could be recommended glacanuzumab with a great degree of confidence. This should be irrespective of even high frequency use of acute medications, as most of subjects in this study with medication overuse reverted after 3 months.

There is never a single ideal preventive or acute treatment for migraine in any population, however, recognizing factors that allow for an individualized approach improves the quality of life for our patients, and leaves them less disabled by migraine.

References

1. Ferrari MD et al. Two-year efficacy and safety of erenumab in participants with episodic migraine and 2–4 prior preventive treatment failures: results from the LIBERTY study. J Neurol Neurosurg Psychiatry. 2021(Nov 29).
2. Malekian N et al. Preventive effect of greater occipital nerve block on patients with episodic migraine: A randomized double‐blind placebo‐controlled clinical trial. Cephalalgia. 2021(Nov 17).
3. Friedman BW et al. A Randomized, Sham-Controlled Trial of Bilateral Greater Occipital Nerve Blocks With Bupivacaine for Acute Migraine Patients Refractory to Standard Emergency Department Treatment With Metoclopramide. Headache. 2018(Oct);58(9):1427-34. https://doi.org/10.1111/head.13395.
4. Vernieri F et al. Rapid response to galcanezumab and predictive factors in chronic migraine patients: A 3-month observational, longitudinal, cohort, multicenter, Italian real-life study. Eur J Neurol. 2021(Nov 26).

Ferrari et al¹provided information on an open label extension to the “LIBERTY” study which investigated the use of erenumab in subjects with episodic migraine that have failed multiple prior preventive medications. The initial Calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) studies excluded more refractory patients.  Most commercial insurances in the United States have a “step” policy that relates to use of these and other newer medications, meaning that the majority of patient in the US who receive these medications have previously tried other preventive medications. This raised the question whether migraine refractoriness is a negative predictive factor for erenumab.

This long-term open label study is more like the real-world use of erenumab, and as such the results are similar to what many practitioners are seeing in their clinical experience. Approximately 25% of subjects discontinued erenumab, mostly due to ineffectiveness. Adverse events were mild, and although erenumab has warnings for constipation and hypertension, this study did not show either as increasing over 2 years. Erenumab appeared to be tolerable over time. There were no newly noted safety signals in this study.

The efficacy of erenumab also appeared to be stable over time, without the development of tolerance to the medication. There is a slight decrease in the 50% responder rate at 2 years when these more refractory patients are compared to those that did not have multiple treatment failures. This study also looked at “functional parameters,” such as Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6), both of which were significantly improved over time.

Although there are some significant limitations in this study-primarily the fact that it is open label—this does give a more representative and real-world sample of patients who will be prescribed erenumab in the United States. Most practitioners will be glad to find that the long-term use of erenumab appears safe, and the efficacy remains stable, even in a more difficult-to-treat population.

A randomized controlled international study investigated the preventive use of occipital nerve blocks in migraine without aura.² The majority of the literature for the use of occipital nerve blocks is for acute treatment, and arguably the most significant study prior to this was Friedman et al³ investigating the use of this procedure in the emergency ward. Prior occipital nerve studies have been inconclusive, and although occipital nerve blocks are considered standard of care for specific conditions in most headache centers, reimbursement is usually very limited. Insurance companies have quoted prior preventive occipital nerve studies to justify non-coverage of these procedures, making access to them for many patients very limited.

Occipital nerve blocks are not performed uniformly, both regarding the medications used—some practitioners use no steroids, some use lidocaine and bupivocaine—and regarding the placement of the injections. In this a small cohort study, 55 subjects were divided into four groups for intervention—one of which was a control group of saline—and all were given one 2.5 mL injection at a point in between the occipital protuberance and the mastoid process bilaterally. Due to adverse events (alopecia and cutaneous atrophy) in two of the triamcinolone groups, recruitment was halted for those two groups. Patients were assessed based on headache duration, frequency, and severity over a 4-week course.

Compared to baseline all interventional groups had significantly decreased headache severity, which did return closer to baseline during the final week. Headache duration was decreased in the first 2 weeks post-injection. Headache frequency was seen to return to baseline at week 4, but prior to that the groups injected with lidocaine had a significant decrease in migraine frequency, with an average decrease in headache days.

Occipital nerve blocks are performed frequently for migraine, occipital neuralgia, cervicogenic headache, and many other conditions with noted tenderness over the occiput. As noted above, they are not performed uniformly—sometimes they are given for acute headache pain or status migranosus, and other times they are used in regular intervals for prevention. This data does finally show a preventive benefit with occipital nerve blocks, and this may allow for modifications in how occipital nerve blocks are currently performed. Based on this study, if given preventively, occipital nerve blocks should only contain topical anesthetics, not steroids, and should be performed on an every 2-3 week basis.

The limitations of this study are significant as well. This is a very small cohort, and the injections were performed in only one manner (one bilateral injection), whereas many practitioners will target the greater and lesser branches of the occipital nerve individually.  There were no exclusion criteria for subjects that already had occipital nerve blocks performed—those patients would be unblinded as there is a different sensation when injected with a topical anesthetic versus normal saline (normal saline does not cause burning subcutaneously).

These results should pave the way for further investigations in the use of occipital and other nerve blocks in the prevention of migraine. This should allow better access for our patients and the possibility of performing these procedures more uniformly in the future.

It can be challenging for many practitioners to determine which medication is ideal for individual situations. This is especially true when treating chronic migraine, where many potential complicating factors can influence positive to negative responses to treatment. The investigators here sought to determine which factors may potentially predict a positive response to galcanezumab.⁴

This is an observational study, where 156 subjects with a diagnosis of chronic migraine were enrolled. There was a 1-month run-in period where the following characteristics were collected: monthly headache days, monthly abortive medication intake, clinical features of migraine, and disability scores (MIDAS and HIT-6). These were tracked over a 3-month period after starting glacanezumab.

Approximately 40% of subjects experienced a 50% reduction in headache frequency. The better responders had a lower body mass index, fewer previously failed preventive medications, unilateral headache pain, and previous good response to triptan use. Surprisingly, the presence of medication overuse was associated with persistent improvement at 3 months as well, with over 60% of subjects with medication overuse no longer overusing acute medications at 3 months.  

This study is helpful in identifying specific features that may allow a practitioner to better recommend CGRP mAb medications, such as galcanezumab. Chronic migraine can offer a challenge to even the best trained clinicians. Patients will often have multiple factors that have led to a conversion from episodic to chronic migraine, and a history of medication failures or intolerances. These patients are often referred specifically due to these challenges.

When deciding on a preventive medication for patients with chronic migraine, we often first consider which oral preventive medications may allow us to treat migraine in addition to another underlying issue—such as insomnia, depression, or hypertension. Although the oral class can improve other comorbidities, intolerance is significantly higher for most of these medications as well. The CGRP mAb class is somewhat more ideal for prevention of migraine; the focus when using this class is for migraine prevention alone, and the side effect profile is more tolerable for most patients. That said, if predictive factors were known a more individualized approach to migraine prevention would be possible.

The authors’ recognition of the factors associated with improvement in patients using glacanezumab allows this better individualization. Based on these results, patients with more unilateral pain, lower BMI, and good response to triptans could be recommended glacanuzumab with a great degree of confidence. This should be irrespective of even high frequency use of acute medications, as most of subjects in this study with medication overuse reverted after 3 months.

There is never a single ideal preventive or acute treatment for migraine in any population, however, recognizing factors that allow for an individualized approach improves the quality of life for our patients, and leaves them less disabled by migraine.

References

1. Ferrari MD et al. Two-year efficacy and safety of erenumab in participants with episodic migraine and 2–4 prior preventive treatment failures: results from the LIBERTY study. J Neurol Neurosurg Psychiatry. 2021(Nov 29).
2. Malekian N et al. Preventive effect of greater occipital nerve block on patients with episodic migraine: A randomized double‐blind placebo‐controlled clinical trial. Cephalalgia. 2021(Nov 17).
3. Friedman BW et al. A Randomized, Sham-Controlled Trial of Bilateral Greater Occipital Nerve Blocks With Bupivacaine for Acute Migraine Patients Refractory to Standard Emergency Department Treatment With Metoclopramide. Headache. 2018(Oct);58(9):1427-34. https://doi.org/10.1111/head.13395.
4. Vernieri F et al. Rapid response to galcanezumab and predictive factors in chronic migraine patients: A 3-month observational, longitudinal, cohort, multicenter, Italian real-life study. Eur J Neurol. 2021(Nov 26).