Headache & Migraine

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

Editors’ note: For the April edition of Expert Perspectives, we asked 2 leading neurologists to present differing views on the use of calcitonin gene-related peptide  (CGRP) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class. To read a counterargument in which Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of CGRP mAbs, click here. 

Lawrence Robbins, MD is an associate professor of neurology at Chicago Medical School and is in private practice in Riverwoods, IL. 
Dr. Robbins discloses speaker’s bureau remuneration from AbbVie, Amgen, Biohaven, Impel NeuroPharma, Lundbeck, and Teva.

 
The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) were introduced in 2018 as efficacious with few adverse effects. Unfortunately, the phase 3 trials failed to indicate the considerable number of adverse effects that have since been identified. This is a common occurrence with new drugs and mAbs. 
 
There are few adverse events identified in the package insert (PI) for any of the 4 CGRP mAbs, but again that is not restricted to this class. Post-approval, it frequently takes time to piece together the true adverse effect profile. Reasons that phase 3 studies may miss adverse effects include 1) The studies are powered for efficacy but are not powered for adverse effects in terms of both the number of patients and the length of the study; 2) Studies do not use a checklist of likely adverse effects; and 3) Adverse effects become “disaggregated” (for example, 1 person states they have malaise, another tiredness, and another fatigue).                                                                
 
In the ensuing years since the launch of the CGRP mAbs, various lines of evidence pointed to the adverse effects attributed to these mAbs. These include the US Food and Drug Administration (FDA)/FDA Adverse Event Reporting System (FAERS) website, published studies, the collective experience of high prescribers, and filtered comments from patient chat boards. In addition, I have received hundreds of letters from providers and patients regarding serious adverse effects, which are detailed further in this article. 
 
As of March 2022, the FDA/FAERS website has listed approximately 50,000 adverse events in connection with the CGRP mAbs. The number of serious events (hospitalization or life-threatening issues) was about 7000. These large numbers, just 3.75 years after launch, are like those listed for onabotulinumtoxin A after 30 years! Most of the reports involve erenumab. This is because erenumab was approved first and is the most prescribed drug in this class. I do not believe it is more dangerous than the others. Considering that the vast majority of adverse events go unreported, these are staggering numbers. Regarding serious adverse events, only 1% to 10% are actually reported to the FDA. Nobody knows the true percentage of milder adverse events that are actually reported, but in my experience, it is extremely low.
 
Unfortunately, the FDA/FAERS website lists on only adverse events, not adverse effects, which are just as important to discuss. In my small practice I have observed 4 serious adverse effects in women I believe are attributable to CGRP mAbs. These include a cerebrovascular accident in a 21-year-old patient, a case of reversible cerebral vasoconstrictive syndrome in a 61-year-old patient, severe joint pain in a 66-year-old patient, and a constellation of symptoms that resembled multiple sclerosis in a 30-year-old patient. I have administered onabotulinumtoxinA to thousands of patients for 25 years, with no serious adverse effects.
 
There have been a number of post-approval articles, studies, and case reports published since the launch of the CGRP mAbs. Many “review” or “meta-analysis” articles tend to repeat the results of the pharma-sponsored studies. They typically characterize the CGRP mAbs as safe, with few adverse events. Long-term safety extension studies almost always conclude that the drug is safe. In my opinion, the results from these studies are not reliable because of their possible ties to phrama. 
 
Other studies tell a different tale. One observational study of erenumab concluded that adverse effects contributed to 33% of the discontinuations. Another study reported that 63.3% of patients taking mAbs described at least 1 adverse effect. A study of patients who had been prescribed erenumab indicated that 48% reported a non-serious adverse event after 3 months.  
 
Neurologists are generally unaware of the dangers posed by CGRP mAbs. In September 2021, I engaged in a debate on this topic during the International 15th World Congress on Controversies in Neurology (CONy). Prior to the debate, the audience members were polled. 94% believed the CGRP mAbs to be safe. After our debate, only 40% felt that these mAbs were safe. I think that the audience, primarily consisting of neurologists, was not informed as to the potential dangers of the CGRP mAbs.                                                        

                            
In our practice

For refractory patients, I do prescribe these CGRP mAbs. However, I feel they should only be prescribed after several other, safer options have failed. These include the natural approaches (butterbur, magnesium, riboflavin), several of the standard medications (amitriptyline, beta blockers, topiramate, valproate, angiotensin II receptor blockers), and onabotulinumtoxinA. Additionally, the newer gepants for prevention (rimegepant and atogepant) appear to be safer options than the CGRP mAbs, although we cannot say this definitively at this time.

In 2018, our clinic began a retrospective study that lasted until January 2020. We assessed 119 patients with chronic migraine who had been prescribed one of the CGRP mAbs. This study incorporated the use of a checklist of possible adverse effects. Each of these adverse effects had created a “signal.” We initially asked the patients, “Have you experienced any issues, problems, or side effects due to the CGRP monoclonal antibody?” The patients subsequently were interviewed and asked about each possible adverse effect included on the checklist. The patient and physician determined whether any adverse effect mentioned by the patient was due to the CGRP mAb. After discussing the checklist, 66% of the patients concluded they had experienced 1 additional adverse effect that they attributed to the CGRP mAb and had not originally disclosed in response to the initial question. Most of these patients identified more than 1 additional adverse effect through use of the checklist.  
 

Gathering data

To determine the true adverse event profile post-approval, we rely upon the input of high prescribers, who often can provide this necessary feedback. I have assessed input from headache provider chat boards, private correspondence with many providers, and discussions with colleagues at conferences. The opinions do vary, with some headache providers arguing that there are not that many adverse effects arising from the CGRP mAbs. Many others believe, as I do, that there are a large number of adverse events. In my observations, there is not a consensus among headache providers. 
 
The CGRP patient chat boards are another valuable line of evidence. I have screened 2800 comments from patients regarding adverse events. I filtered these down into 490 “highly believable” comments. Among those, the adverse events described align very well with our other lines of evidence. 
 
If we put all the post-approval lines of evidence together, we come up with the following list of “adverse effect signals” attribututed  to the CGRP mAbs. These include constipation (it may be severe; hence the warning in the erenumab PI), injection site reactions, joint pain, anxiety, muscle pain or cramps, hypertension or worsening hypertension (there is a warning in the erenumab PI), nausea (it may be severe; “area postrema syndrome” has occurred), rash, increased headache, fatigue, depression, insomnia, hair loss, tachycardia (and other cardiac arrhythmias), stroke, angina and myocardial infarction, weight gain or loss, irritability, and sexual dysfunction. There are also other adverse events. In his review of the CGRP mAbs, Thomas Moore, a leading expert in adverse events, cited the “sheer number of case reports, and it is likely that AEs of this migraine preventive were underestimated in the clinical trials.”   
 
This discussion has focused on short-term adverse events. We have no idea regarding long-term effects, but I suspect that we will encounter serious ones. Evolution has deemed CGRP to be vital for 450 million years. We ignore evolution at our peril. 
  
CGRP is a powerful vasodilator and protects our cardiovascular and cerebrovascular systems. CGRP resists the onset of hypertension. Wound and burn healing, as well as tissue repair, require CGRP. Bony metabolism and bone healing are partly dependent upon CGRP. CGRP protects from gastrointestinal (GI) ulcers and aids GI motility. CGRP mitigates the effects of sepsis. 
 
CGRP is also involved with flushing, thermoregulation, cold hypersensitivity, protecting the kidneys when under stress, helping regulate insulin release, and mediating the adrenal glucocorticoid response to acute stress (particularly in the mature fetus). Effects on the hypothalamic-pituitary-adrenal axis are worrisome but unknown. CGRP is important as a vasodilator during stress, and the CGRP mAbs have not yet been tested under stress.  

The CGRP mAbs have been terrific for many patients, and their efficacy is on par with onabotulinumtoxinA. However, in a short period of time we have witnessed a plethora of serious (and non-serious) adverse effects from short-term use. CGRP plays an important role in many physiologic processes. We have no idea as to the long-term consequences of blocking CGRP and we should proceed with caution.
 

Editors’ note: For the April edition of Expert Perspectives, we asked 2 leading neurologists to present differing views on the use of calcitonin gene-related peptide  (CGRP) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class. To read a counterargument in which Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of CGRP mAbs, click here. 

Lawrence Robbins, MD is an associate professor of neurology at Chicago Medical School and is in private practice in Riverwoods, IL. 
Dr. Robbins discloses speaker’s bureau remuneration from AbbVie, Amgen, Biohaven, Impel NeuroPharma, Lundbeck, and Teva.

 
The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) were introduced in 2018 as efficacious with few adverse effects. Unfortunately, the phase 3 trials failed to indicate the considerable number of adverse effects that have since been identified. This is a common occurrence with new drugs and mAbs. 
 
There are few adverse events identified in the package insert (PI) for any of the 4 CGRP mAbs, but again that is not restricted to this class. Post-approval, it frequently takes time to piece together the true adverse effect profile. Reasons that phase 3 studies may miss adverse effects include 1) The studies are powered for efficacy but are not powered for adverse effects in terms of both the number of patients and the length of the study; 2) Studies do not use a checklist of likely adverse effects; and 3) Adverse effects become “disaggregated” (for example, 1 person states they have malaise, another tiredness, and another fatigue).                                                                
 
In the ensuing years since the launch of the CGRP mAbs, various lines of evidence pointed to the adverse effects attributed to these mAbs. These include the US Food and Drug Administration (FDA)/FDA Adverse Event Reporting System (FAERS) website, published studies, the collective experience of high prescribers, and filtered comments from patient chat boards. In addition, I have received hundreds of letters from providers and patients regarding serious adverse effects, which are detailed further in this article. 
 
As of March 2022, the FDA/FAERS website has listed approximately 50,000 adverse events in connection with the CGRP mAbs. The number of serious events (hospitalization or life-threatening issues) was about 7000. These large numbers, just 3.75 years after launch, are like those listed for onabotulinumtoxin A after 30 years! Most of the reports involve erenumab. This is because erenumab was approved first and is the most prescribed drug in this class. I do not believe it is more dangerous than the others. Considering that the vast majority of adverse events go unreported, these are staggering numbers. Regarding serious adverse events, only 1% to 10% are actually reported to the FDA. Nobody knows the true percentage of milder adverse events that are actually reported, but in my experience, it is extremely low.
 
Unfortunately, the FDA/FAERS website lists on only adverse events, not adverse effects, which are just as important to discuss. In my small practice I have observed 4 serious adverse effects in women I believe are attributable to CGRP mAbs. These include a cerebrovascular accident in a 21-year-old patient, a case of reversible cerebral vasoconstrictive syndrome in a 61-year-old patient, severe joint pain in a 66-year-old patient, and a constellation of symptoms that resembled multiple sclerosis in a 30-year-old patient. I have administered onabotulinumtoxinA to thousands of patients for 25 years, with no serious adverse effects.
 
There have been a number of post-approval articles, studies, and case reports published since the launch of the CGRP mAbs. Many “review” or “meta-analysis” articles tend to repeat the results of the pharma-sponsored studies. They typically characterize the CGRP mAbs as safe, with few adverse events. Long-term safety extension studies almost always conclude that the drug is safe. In my opinion, the results from these studies are not reliable because of their possible ties to phrama. 
 
Other studies tell a different tale. One observational study of erenumab concluded that adverse effects contributed to 33% of the discontinuations. Another study reported that 63.3% of patients taking mAbs described at least 1 adverse effect. A study of patients who had been prescribed erenumab indicated that 48% reported a non-serious adverse event after 3 months.  
 
Neurologists are generally unaware of the dangers posed by CGRP mAbs. In September 2021, I engaged in a debate on this topic during the International 15th World Congress on Controversies in Neurology (CONy). Prior to the debate, the audience members were polled. 94% believed the CGRP mAbs to be safe. After our debate, only 40% felt that these mAbs were safe. I think that the audience, primarily consisting of neurologists, was not informed as to the potential dangers of the CGRP mAbs.                                                        

                            
In our practice

For refractory patients, I do prescribe these CGRP mAbs. However, I feel they should only be prescribed after several other, safer options have failed. These include the natural approaches (butterbur, magnesium, riboflavin), several of the standard medications (amitriptyline, beta blockers, topiramate, valproate, angiotensin II receptor blockers), and onabotulinumtoxinA. Additionally, the newer gepants for prevention (rimegepant and atogepant) appear to be safer options than the CGRP mAbs, although we cannot say this definitively at this time.

In 2018, our clinic began a retrospective study that lasted until January 2020. We assessed 119 patients with chronic migraine who had been prescribed one of the CGRP mAbs. This study incorporated the use of a checklist of possible adverse effects. Each of these adverse effects had created a “signal.” We initially asked the patients, “Have you experienced any issues, problems, or side effects due to the CGRP monoclonal antibody?” The patients subsequently were interviewed and asked about each possible adverse effect included on the checklist. The patient and physician determined whether any adverse effect mentioned by the patient was due to the CGRP mAb. After discussing the checklist, 66% of the patients concluded they had experienced 1 additional adverse effect that they attributed to the CGRP mAb and had not originally disclosed in response to the initial question. Most of these patients identified more than 1 additional adverse effect through use of the checklist.  
 

Gathering data

To determine the true adverse event profile post-approval, we rely upon the input of high prescribers, who often can provide this necessary feedback. I have assessed input from headache provider chat boards, private correspondence with many providers, and discussions with colleagues at conferences. The opinions do vary, with some headache providers arguing that there are not that many adverse effects arising from the CGRP mAbs. Many others believe, as I do, that there are a large number of adverse events. In my observations, there is not a consensus among headache providers. 
 
The CGRP patient chat boards are another valuable line of evidence. I have screened 2800 comments from patients regarding adverse events. I filtered these down into 490 “highly believable” comments. Among those, the adverse events described align very well with our other lines of evidence. 
 
If we put all the post-approval lines of evidence together, we come up with the following list of “adverse effect signals” attribututed  to the CGRP mAbs. These include constipation (it may be severe; hence the warning in the erenumab PI), injection site reactions, joint pain, anxiety, muscle pain or cramps, hypertension or worsening hypertension (there is a warning in the erenumab PI), nausea (it may be severe; “area postrema syndrome” has occurred), rash, increased headache, fatigue, depression, insomnia, hair loss, tachycardia (and other cardiac arrhythmias), stroke, angina and myocardial infarction, weight gain or loss, irritability, and sexual dysfunction. There are also other adverse events. In his review of the CGRP mAbs, Thomas Moore, a leading expert in adverse events, cited the “sheer number of case reports, and it is likely that AEs of this migraine preventive were underestimated in the clinical trials.”   
 
This discussion has focused on short-term adverse events. We have no idea regarding long-term effects, but I suspect that we will encounter serious ones. Evolution has deemed CGRP to be vital for 450 million years. We ignore evolution at our peril. 
  
CGRP is a powerful vasodilator and protects our cardiovascular and cerebrovascular systems. CGRP resists the onset of hypertension. Wound and burn healing, as well as tissue repair, require CGRP. Bony metabolism and bone healing are partly dependent upon CGRP. CGRP protects from gastrointestinal (GI) ulcers and aids GI motility. CGRP mitigates the effects of sepsis. 
 
CGRP is also involved with flushing, thermoregulation, cold hypersensitivity, protecting the kidneys when under stress, helping regulate insulin release, and mediating the adrenal glucocorticoid response to acute stress (particularly in the mature fetus). Effects on the hypothalamic-pituitary-adrenal axis are worrisome but unknown. CGRP is important as a vasodilator during stress, and the CGRP mAbs have not yet been tested under stress.  

The CGRP mAbs have been terrific for many patients, and their efficacy is on par with onabotulinumtoxinA. However, in a short period of time we have witnessed a plethora of serious (and non-serious) adverse effects from short-term use. CGRP plays an important role in many physiologic processes. We have no idea as to the long-term consequences of blocking CGRP and we should proceed with caution.
 

Editors’ note: For the April edition of Expert Perspectives, we asked 2 leading neurologists to present differing views on the use of calcitonin gene-related peptide  (CGRP) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class. To read a counterargument in which Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of CGRP mAbs, click here. 

Lawrence Robbins, MD is an associate professor of neurology at Chicago Medical School and is in private practice in Riverwoods, IL. 
Dr. Robbins discloses speaker’s bureau remuneration from AbbVie, Amgen, Biohaven, Impel NeuroPharma, Lundbeck, and Teva.

 
The calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) were introduced in 2018 as efficacious with few adverse effects. Unfortunately, the phase 3 trials failed to indicate the considerable number of adverse effects that have since been identified. This is a common occurrence with new drugs and mAbs. 
 
There are few adverse events identified in the package insert (PI) for any of the 4 CGRP mAbs, but again that is not restricted to this class. Post-approval, it frequently takes time to piece together the true adverse effect profile. Reasons that phase 3 studies may miss adverse effects include 1) The studies are powered for efficacy but are not powered for adverse effects in terms of both the number of patients and the length of the study; 2) Studies do not use a checklist of likely adverse effects; and 3) Adverse effects become “disaggregated” (for example, 1 person states they have malaise, another tiredness, and another fatigue).                                                                
 
In the ensuing years since the launch of the CGRP mAbs, various lines of evidence pointed to the adverse effects attributed to these mAbs. These include the US Food and Drug Administration (FDA)/FDA Adverse Event Reporting System (FAERS) website, published studies, the collective experience of high prescribers, and filtered comments from patient chat boards. In addition, I have received hundreds of letters from providers and patients regarding serious adverse effects, which are detailed further in this article. 
 
As of March 2022, the FDA/FAERS website has listed approximately 50,000 adverse events in connection with the CGRP mAbs. The number of serious events (hospitalization or life-threatening issues) was about 7000. These large numbers, just 3.75 years after launch, are like those listed for onabotulinumtoxin A after 30 years! Most of the reports involve erenumab. This is because erenumab was approved first and is the most prescribed drug in this class. I do not believe it is more dangerous than the others. Considering that the vast majority of adverse events go unreported, these are staggering numbers. Regarding serious adverse events, only 1% to 10% are actually reported to the FDA. Nobody knows the true percentage of milder adverse events that are actually reported, but in my experience, it is extremely low.
 
Unfortunately, the FDA/FAERS website lists on only adverse events, not adverse effects, which are just as important to discuss. In my small practice I have observed 4 serious adverse effects in women I believe are attributable to CGRP mAbs. These include a cerebrovascular accident in a 21-year-old patient, a case of reversible cerebral vasoconstrictive syndrome in a 61-year-old patient, severe joint pain in a 66-year-old patient, and a constellation of symptoms that resembled multiple sclerosis in a 30-year-old patient. I have administered onabotulinumtoxinA to thousands of patients for 25 years, with no serious adverse effects.
 
There have been a number of post-approval articles, studies, and case reports published since the launch of the CGRP mAbs. Many “review” or “meta-analysis” articles tend to repeat the results of the pharma-sponsored studies. They typically characterize the CGRP mAbs as safe, with few adverse events. Long-term safety extension studies almost always conclude that the drug is safe. In my opinion, the results from these studies are not reliable because of their possible ties to phrama. 
 
Other studies tell a different tale. One observational study of erenumab concluded that adverse effects contributed to 33% of the discontinuations. Another study reported that 63.3% of patients taking mAbs described at least 1 adverse effect. A study of patients who had been prescribed erenumab indicated that 48% reported a non-serious adverse event after 3 months.  
 
Neurologists are generally unaware of the dangers posed by CGRP mAbs. In September 2021, I engaged in a debate on this topic during the International 15th World Congress on Controversies in Neurology (CONy). Prior to the debate, the audience members were polled. 94% believed the CGRP mAbs to be safe. After our debate, only 40% felt that these mAbs were safe. I think that the audience, primarily consisting of neurologists, was not informed as to the potential dangers of the CGRP mAbs.                                                        

                            
In our practice

For refractory patients, I do prescribe these CGRP mAbs. However, I feel they should only be prescribed after several other, safer options have failed. These include the natural approaches (butterbur, magnesium, riboflavin), several of the standard medications (amitriptyline, beta blockers, topiramate, valproate, angiotensin II receptor blockers), and onabotulinumtoxinA. Additionally, the newer gepants for prevention (rimegepant and atogepant) appear to be safer options than the CGRP mAbs, although we cannot say this definitively at this time.

In 2018, our clinic began a retrospective study that lasted until January 2020. We assessed 119 patients with chronic migraine who had been prescribed one of the CGRP mAbs. This study incorporated the use of a checklist of possible adverse effects. Each of these adverse effects had created a “signal.” We initially asked the patients, “Have you experienced any issues, problems, or side effects due to the CGRP monoclonal antibody?” The patients subsequently were interviewed and asked about each possible adverse effect included on the checklist. The patient and physician determined whether any adverse effect mentioned by the patient was due to the CGRP mAb. After discussing the checklist, 66% of the patients concluded they had experienced 1 additional adverse effect that they attributed to the CGRP mAb and had not originally disclosed in response to the initial question. Most of these patients identified more than 1 additional adverse effect through use of the checklist.  
 

Gathering data

To determine the true adverse event profile post-approval, we rely upon the input of high prescribers, who often can provide this necessary feedback. I have assessed input from headache provider chat boards, private correspondence with many providers, and discussions with colleagues at conferences. The opinions do vary, with some headache providers arguing that there are not that many adverse effects arising from the CGRP mAbs. Many others believe, as I do, that there are a large number of adverse events. In my observations, there is not a consensus among headache providers. 
 
The CGRP patient chat boards are another valuable line of evidence. I have screened 2800 comments from patients regarding adverse events. I filtered these down into 490 “highly believable” comments. Among those, the adverse events described align very well with our other lines of evidence. 
 
If we put all the post-approval lines of evidence together, we come up with the following list of “adverse effect signals” attribututed  to the CGRP mAbs. These include constipation (it may be severe; hence the warning in the erenumab PI), injection site reactions, joint pain, anxiety, muscle pain or cramps, hypertension or worsening hypertension (there is a warning in the erenumab PI), nausea (it may be severe; “area postrema syndrome” has occurred), rash, increased headache, fatigue, depression, insomnia, hair loss, tachycardia (and other cardiac arrhythmias), stroke, angina and myocardial infarction, weight gain or loss, irritability, and sexual dysfunction. There are also other adverse events. In his review of the CGRP mAbs, Thomas Moore, a leading expert in adverse events, cited the “sheer number of case reports, and it is likely that AEs of this migraine preventive were underestimated in the clinical trials.”   
 
This discussion has focused on short-term adverse events. We have no idea regarding long-term effects, but I suspect that we will encounter serious ones. Evolution has deemed CGRP to be vital for 450 million years. We ignore evolution at our peril. 
  
CGRP is a powerful vasodilator and protects our cardiovascular and cerebrovascular systems. CGRP resists the onset of hypertension. Wound and burn healing, as well as tissue repair, require CGRP. Bony metabolism and bone healing are partly dependent upon CGRP. CGRP protects from gastrointestinal (GI) ulcers and aids GI motility. CGRP mitigates the effects of sepsis. 
 
CGRP is also involved with flushing, thermoregulation, cold hypersensitivity, protecting the kidneys when under stress, helping regulate insulin release, and mediating the adrenal glucocorticoid response to acute stress (particularly in the mature fetus). Effects on the hypothalamic-pituitary-adrenal axis are worrisome but unknown. CGRP is important as a vasodilator during stress, and the CGRP mAbs have not yet been tested under stress.  

The CGRP mAbs have been terrific for many patients, and their efficacy is on par with onabotulinumtoxinA. However, in a short period of time we have witnessed a plethora of serious (and non-serious) adverse effects from short-term use. CGRP plays an important role in many physiologic processes. We have no idea as to the long-term consequences of blocking CGRP and we should proceed with caution.
 

Editors’ note: For the April edition of Expert Perspectives, we asked two leading neurologists to present differing views on the use of calcitonin gene-related peptide (CGRPs) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of the CGRP mAbs. To read a counter-argument in which Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class, click here.

Dr. Schim is Co-Director of The Headache Center of Southern California, The Neurology Center.  He is Board Member and past President of the Headache Consortium of the Pacific, Board Member and past President, American Heart Association San Diego, a Past President of the California Neurologic Society, and an active member of the American Academy of Neurology, American Stroke Association, and American Headache Society.

The identification of CGRP as a crucial pain signaling molecule in the trigeminal pathway, thereby establishing its link to migraine pain, has transformed care for patients with episodic and chronic migraine. Since 2018, the FDA has approved 4 monoclonal antibodies (mAbs) that either block the CGRP receptor or bind its ligand to prevent attachment to the receptor. 

These medications are helping patients with medication overuse headache (MOH) and chronic migraine; one study involving 139 patients showed that half the patients saw their headache days per month cut by half, and migraine days per month cut by 62%. In another small study, 23 patients (47%) with medication overuse headache reported having no MOH issues after 3 months. Most of these patients had a history of medication overuse, but no specific diagnosis of MOH.

In a survey, 277 physicians said that nearly half of their patients had resistant migraine, and 29% had refractory migraine. For these patients, the mAbs have helped restore some normalcy in their lives.  

But are these medications safe? Some clinicians posed this question even before the 2018 approval.

It is a valid question. The CGRP neuropeptide is a powerful dilator, establishing vascular homeostasis, organ development in utero, wound healing, and more. It is expressed in the peripheral and central nervous system and found abundantly in neurons and the unmyelinated A-fibers of the peripheral trigeminovascular system and trigeminal ganglion.

So, would blocking CGRP function in one area affect its function in another? So far, I have to say the answer is no. Neither the literature nor my observations say otherwise. 

Trials vs the real world

Finding an answer to this question takes more than reading clinical trials data. Participants in these trials do not necessarily represent the real world – no complicated morbidities, no pregnant or lactating women. And trial lengths are generally short.

Thus, it is important to assess the safety of these medications in the real world.  

In the trials of the subcutaneous mAbs, local injection site reactions were the most common adverse event. More specifically, erenumab showed increased incidence of constipation, and  post-marketing surveillance has revealed some risk of hypertension; pooled analysis from 4 trial phases showed that across treatment groups, 20 people out of 2443 began treatment for hypertension. Some patients enrolled in trials for atogepant, an oral small molecule CGRP receptor agonist, also reported constipation and nausea, suggesting that receptor blockade may result in a higher incidence of GI disturbance. In addition, these medicines on occasion have caused alopecia, fatigue, or achiness. 

Eptinezumab is administered intravenously, every 3 months, and thus does not have injection site reactions as a safety concern. In clinical trials, the most common adverse event was nasopharyngitis and hypersensitivity; Datta et al have provided a summary of safety and efficacy.

Raynaud’s and cluster headaches

A retrospective chart review study from the Mayo Clinic looking at individuals with Raynaud’s disease who were treated with CGRP antagonists showed that 5.3% of 169 patients had microvascular complications such as gangrene or autoimmune necrosis. There was no significant difference in demographic characteristics or rheumatologic history among those with Raynaud's who did or did not experience complications. In addition, microvascular complications of migraine therapies have preceded the use of CGRP modulators, as this has been documented in the past with other vasoactive substances such as ergots, triptans, and beta blockers. 

In a tolerability and safety study of galcanezumab in patients with chronic cluster headache, with up to 15 months of treatment, the most common treatment emergent adverse events were nasopharyngitis and injection site pain. In this population with 11% to 12% of individuals having baseline hypertension and nearly 63% currently using tobacco, less than 2.5% had any abnormalities on ECG.  

Vascular complications including pulmonary embolism, TIA, myocardial infarction, and atrial fibrillation have been reported but with no apparent relation between galcanezumab dosing and onset, with onset following the second to up to the eleventh monthly dose. 

Antidrug antibodies can also occur as a complication of exposure to therapeutic antibodies of this class and have been detected in up to 12% of individuals treated. This might lead to therapeutic failure but would not likely be a safety issue.

Anaphylaxis or serious hypersensitivity reactions are uncommon, and in general are the only contraindication to the use of these agents. 

Pregnancy registry information is just starting to become available. The number of reports on adverse drug reactions remains limited, and thus it is wise to avoid pregnancy and breastfeeding exposures as best as possible.

FAERS

The FDA adverse event reporting system (FAERS) database does contain reports on adverse events of approved medications. However, even the FDA website warns that the information provided regarding individual cases is unverified and wouldn’t establish causation, considering the confounding variables involved, and this information can be duplicated as well as incomplete. In addition, rates of occurrence cannot be established with reports, as the denominator of exposure is uncertain.  

With those caveats established, the most common reports in FAERS concern injection site reactions, more frequent migraine or headache, or drug ineffectiveness. While constipation has been the second most common AE for erenumab, it did not make the top 10 for fremanezumab or galcanezumab, and cardiovascular events have not ranked in the top 10 for any product. Reasons for discontinuing treatment included withdrawal by the patient (147 of 1,890 [8%]) and lack of efficacy (77 of 1,890 [4%]). 

As the reader can ascertain, different studies point out different reasons for discontinuing CGRP therapies. Other studies note that the most frequent reasons for discontinuation are lack of efficacy, constipation, and lack of insurance .

Conclusions

These medications have been well received; I believe. Fremanezumab, manufactured by Teva Pharmaceuticals, was approved in September 2018. According to Teva’s 2021 annual report, Ajovy, fremanezumab’s brand name, reached 21% market share in the US and 21% in Europe.

Aimovig, or erenumab, has been prescribed 620,000 times since its approval, according to the Novartis 2021 annual report. Galcanezumab, or Emgality, was approved in 2019, and had 65,300 prescriptions written in the since then. . Adherence to treatment has generally been very high in clinical practice, with the most common reason for a patient to switch being lack of effectiveness, rather than adverse events.

Of note, adverse events of other migraine therapeutics are not insignificant, and considering the pain that people with migraine endure, side effects must be hard to contend with for individuals to stop taking them. Case in point: A year before erenumab was approved, a study was published that looked at medical records for medication persistence in 8,700 chronic migraine patients, who all had been prescribed beta blockers, anti-seizure medications, or antidepressants. By 6 months, only 1 out of 4 patients were still taking the prescribed medicines. By 12 months, that  was down to 14%. And about one-third of patients who stopped treatment stayed untreated for at least a year. 

The presumed reasons these patients stopped their medications: side effects and-or lack of efficacy. 

Migraine is a disabling disorder, for which the mAb class of medications has been highly beneficial for large numbers of patients, with far greater tolerability than prior oral preventives. While no treatments have absolute safety, the overall safety of this class of medications has been very high, leading to much improved clinical outcomes.

Editors’ note: For the April edition of Expert Perspectives, we asked two leading neurologists to present differing views on the use of calcitonin gene-related peptide (CGRPs) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of the CGRP mAbs. To read a counter-argument in which Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class, click here.

Dr. Schim is Co-Director of The Headache Center of Southern California, The Neurology Center.  He is Board Member and past President of the Headache Consortium of the Pacific, Board Member and past President, American Heart Association San Diego, a Past President of the California Neurologic Society, and an active member of the American Academy of Neurology, American Stroke Association, and American Headache Society.

The identification of CGRP as a crucial pain signaling molecule in the trigeminal pathway, thereby establishing its link to migraine pain, has transformed care for patients with episodic and chronic migraine. Since 2018, the FDA has approved 4 monoclonal antibodies (mAbs) that either block the CGRP receptor or bind its ligand to prevent attachment to the receptor. 

These medications are helping patients with medication overuse headache (MOH) and chronic migraine; one study involving 139 patients showed that half the patients saw their headache days per month cut by half, and migraine days per month cut by 62%. In another small study, 23 patients (47%) with medication overuse headache reported having no MOH issues after 3 months. Most of these patients had a history of medication overuse, but no specific diagnosis of MOH.

In a survey, 277 physicians said that nearly half of their patients had resistant migraine, and 29% had refractory migraine. For these patients, the mAbs have helped restore some normalcy in their lives.  

But are these medications safe? Some clinicians posed this question even before the 2018 approval.

It is a valid question. The CGRP neuropeptide is a powerful dilator, establishing vascular homeostasis, organ development in utero, wound healing, and more. It is expressed in the peripheral and central nervous system and found abundantly in neurons and the unmyelinated A-fibers of the peripheral trigeminovascular system and trigeminal ganglion.

So, would blocking CGRP function in one area affect its function in another? So far, I have to say the answer is no. Neither the literature nor my observations say otherwise. 

Trials vs the real world

Finding an answer to this question takes more than reading clinical trials data. Participants in these trials do not necessarily represent the real world – no complicated morbidities, no pregnant or lactating women. And trial lengths are generally short.

Thus, it is important to assess the safety of these medications in the real world.  

In the trials of the subcutaneous mAbs, local injection site reactions were the most common adverse event. More specifically, erenumab showed increased incidence of constipation, and  post-marketing surveillance has revealed some risk of hypertension; pooled analysis from 4 trial phases showed that across treatment groups, 20 people out of 2443 began treatment for hypertension. Some patients enrolled in trials for atogepant, an oral small molecule CGRP receptor agonist, also reported constipation and nausea, suggesting that receptor blockade may result in a higher incidence of GI disturbance. In addition, these medicines on occasion have caused alopecia, fatigue, or achiness. 

Eptinezumab is administered intravenously, every 3 months, and thus does not have injection site reactions as a safety concern. In clinical trials, the most common adverse event was nasopharyngitis and hypersensitivity; Datta et al have provided a summary of safety and efficacy.

Raynaud’s and cluster headaches

A retrospective chart review study from the Mayo Clinic looking at individuals with Raynaud’s disease who were treated with CGRP antagonists showed that 5.3% of 169 patients had microvascular complications such as gangrene or autoimmune necrosis. There was no significant difference in demographic characteristics or rheumatologic history among those with Raynaud's who did or did not experience complications. In addition, microvascular complications of migraine therapies have preceded the use of CGRP modulators, as this has been documented in the past with other vasoactive substances such as ergots, triptans, and beta blockers. 

In a tolerability and safety study of galcanezumab in patients with chronic cluster headache, with up to 15 months of treatment, the most common treatment emergent adverse events were nasopharyngitis and injection site pain. In this population with 11% to 12% of individuals having baseline hypertension and nearly 63% currently using tobacco, less than 2.5% had any abnormalities on ECG.  

Vascular complications including pulmonary embolism, TIA, myocardial infarction, and atrial fibrillation have been reported but with no apparent relation between galcanezumab dosing and onset, with onset following the second to up to the eleventh monthly dose. 

Antidrug antibodies can also occur as a complication of exposure to therapeutic antibodies of this class and have been detected in up to 12% of individuals treated. This might lead to therapeutic failure but would not likely be a safety issue.

Anaphylaxis or serious hypersensitivity reactions are uncommon, and in general are the only contraindication to the use of these agents. 

Pregnancy registry information is just starting to become available. The number of reports on adverse drug reactions remains limited, and thus it is wise to avoid pregnancy and breastfeeding exposures as best as possible.

FAERS

The FDA adverse event reporting system (FAERS) database does contain reports on adverse events of approved medications. However, even the FDA website warns that the information provided regarding individual cases is unverified and wouldn’t establish causation, considering the confounding variables involved, and this information can be duplicated as well as incomplete. In addition, rates of occurrence cannot be established with reports, as the denominator of exposure is uncertain.  

With those caveats established, the most common reports in FAERS concern injection site reactions, more frequent migraine or headache, or drug ineffectiveness. While constipation has been the second most common AE for erenumab, it did not make the top 10 for fremanezumab or galcanezumab, and cardiovascular events have not ranked in the top 10 for any product. Reasons for discontinuing treatment included withdrawal by the patient (147 of 1,890 [8%]) and lack of efficacy (77 of 1,890 [4%]). 

As the reader can ascertain, different studies point out different reasons for discontinuing CGRP therapies. Other studies note that the most frequent reasons for discontinuation are lack of efficacy, constipation, and lack of insurance .

Conclusions

These medications have been well received; I believe. Fremanezumab, manufactured by Teva Pharmaceuticals, was approved in September 2018. According to Teva’s 2021 annual report, Ajovy, fremanezumab’s brand name, reached 21% market share in the US and 21% in Europe.

Aimovig, or erenumab, has been prescribed 620,000 times since its approval, according to the Novartis 2021 annual report. Galcanezumab, or Emgality, was approved in 2019, and had 65,300 prescriptions written in the since then. . Adherence to treatment has generally been very high in clinical practice, with the most common reason for a patient to switch being lack of effectiveness, rather than adverse events.

Of note, adverse events of other migraine therapeutics are not insignificant, and considering the pain that people with migraine endure, side effects must be hard to contend with for individuals to stop taking them. Case in point: A year before erenumab was approved, a study was published that looked at medical records for medication persistence in 8,700 chronic migraine patients, who all had been prescribed beta blockers, anti-seizure medications, or antidepressants. By 6 months, only 1 out of 4 patients were still taking the prescribed medicines. By 12 months, that  was down to 14%. And about one-third of patients who stopped treatment stayed untreated for at least a year. 

The presumed reasons these patients stopped their medications: side effects and-or lack of efficacy. 

Migraine is a disabling disorder, for which the mAb class of medications has been highly beneficial for large numbers of patients, with far greater tolerability than prior oral preventives. While no treatments have absolute safety, the overall safety of this class of medications has been very high, leading to much improved clinical outcomes.

Editors’ note: For the April edition of Expert Perspectives, we asked two leading neurologists to present differing views on the use of calcitonin gene-related peptide (CGRPs) monoclonal antibodies (mAbs) for the treatment of migraine. Here, Jack D. Schim, MD, of the Neurology Center of Southern California, discusses the observed benefits of the CGRP mAbs. To read a counter-argument in which Lawrence Robbins, MD, of the Robbins Headache Clinic in Riverwoods, IL, discusses potential safety concerns associated with this drug class, click here.

Dr. Schim is Co-Director of The Headache Center of Southern California, The Neurology Center.  He is Board Member and past President of the Headache Consortium of the Pacific, Board Member and past President, American Heart Association San Diego, a Past President of the California Neurologic Society, and an active member of the American Academy of Neurology, American Stroke Association, and American Headache Society.

The identification of CGRP as a crucial pain signaling molecule in the trigeminal pathway, thereby establishing its link to migraine pain, has transformed care for patients with episodic and chronic migraine. Since 2018, the FDA has approved 4 monoclonal antibodies (mAbs) that either block the CGRP receptor or bind its ligand to prevent attachment to the receptor. 

These medications are helping patients with medication overuse headache (MOH) and chronic migraine; one study involving 139 patients showed that half the patients saw their headache days per month cut by half, and migraine days per month cut by 62%. In another small study, 23 patients (47%) with medication overuse headache reported having no MOH issues after 3 months. Most of these patients had a history of medication overuse, but no specific diagnosis of MOH.

In a survey, 277 physicians said that nearly half of their patients had resistant migraine, and 29% had refractory migraine. For these patients, the mAbs have helped restore some normalcy in their lives.  

But are these medications safe? Some clinicians posed this question even before the 2018 approval.

It is a valid question. The CGRP neuropeptide is a powerful dilator, establishing vascular homeostasis, organ development in utero, wound healing, and more. It is expressed in the peripheral and central nervous system and found abundantly in neurons and the unmyelinated A-fibers of the peripheral trigeminovascular system and trigeminal ganglion.

So, would blocking CGRP function in one area affect its function in another? So far, I have to say the answer is no. Neither the literature nor my observations say otherwise. 

Trials vs the real world

Finding an answer to this question takes more than reading clinical trials data. Participants in these trials do not necessarily represent the real world – no complicated morbidities, no pregnant or lactating women. And trial lengths are generally short.

Thus, it is important to assess the safety of these medications in the real world.  

In the trials of the subcutaneous mAbs, local injection site reactions were the most common adverse event. More specifically, erenumab showed increased incidence of constipation, and  post-marketing surveillance has revealed some risk of hypertension; pooled analysis from 4 trial phases showed that across treatment groups, 20 people out of 2443 began treatment for hypertension. Some patients enrolled in trials for atogepant, an oral small molecule CGRP receptor agonist, also reported constipation and nausea, suggesting that receptor blockade may result in a higher incidence of GI disturbance. In addition, these medicines on occasion have caused alopecia, fatigue, or achiness. 

Eptinezumab is administered intravenously, every 3 months, and thus does not have injection site reactions as a safety concern. In clinical trials, the most common adverse event was nasopharyngitis and hypersensitivity; Datta et al have provided a summary of safety and efficacy.

Raynaud’s and cluster headaches

A retrospective chart review study from the Mayo Clinic looking at individuals with Raynaud’s disease who were treated with CGRP antagonists showed that 5.3% of 169 patients had microvascular complications such as gangrene or autoimmune necrosis. There was no significant difference in demographic characteristics or rheumatologic history among those with Raynaud's who did or did not experience complications. In addition, microvascular complications of migraine therapies have preceded the use of CGRP modulators, as this has been documented in the past with other vasoactive substances such as ergots, triptans, and beta blockers. 

In a tolerability and safety study of galcanezumab in patients with chronic cluster headache, with up to 15 months of treatment, the most common treatment emergent adverse events were nasopharyngitis and injection site pain. In this population with 11% to 12% of individuals having baseline hypertension and nearly 63% currently using tobacco, less than 2.5% had any abnormalities on ECG.  

Vascular complications including pulmonary embolism, TIA, myocardial infarction, and atrial fibrillation have been reported but with no apparent relation between galcanezumab dosing and onset, with onset following the second to up to the eleventh monthly dose. 

Antidrug antibodies can also occur as a complication of exposure to therapeutic antibodies of this class and have been detected in up to 12% of individuals treated. This might lead to therapeutic failure but would not likely be a safety issue.

Anaphylaxis or serious hypersensitivity reactions are uncommon, and in general are the only contraindication to the use of these agents. 

Pregnancy registry information is just starting to become available. The number of reports on adverse drug reactions remains limited, and thus it is wise to avoid pregnancy and breastfeeding exposures as best as possible.

FAERS

The FDA adverse event reporting system (FAERS) database does contain reports on adverse events of approved medications. However, even the FDA website warns that the information provided regarding individual cases is unverified and wouldn’t establish causation, considering the confounding variables involved, and this information can be duplicated as well as incomplete. In addition, rates of occurrence cannot be established with reports, as the denominator of exposure is uncertain.  

With those caveats established, the most common reports in FAERS concern injection site reactions, more frequent migraine or headache, or drug ineffectiveness. While constipation has been the second most common AE for erenumab, it did not make the top 10 for fremanezumab or galcanezumab, and cardiovascular events have not ranked in the top 10 for any product. Reasons for discontinuing treatment included withdrawal by the patient (147 of 1,890 [8%]) and lack of efficacy (77 of 1,890 [4%]). 

As the reader can ascertain, different studies point out different reasons for discontinuing CGRP therapies. Other studies note that the most frequent reasons for discontinuation are lack of efficacy, constipation, and lack of insurance .

Conclusions

These medications have been well received; I believe. Fremanezumab, manufactured by Teva Pharmaceuticals, was approved in September 2018. According to Teva’s 2021 annual report, Ajovy, fremanezumab’s brand name, reached 21% market share in the US and 21% in Europe.

Aimovig, or erenumab, has been prescribed 620,000 times since its approval, according to the Novartis 2021 annual report. Galcanezumab, or Emgality, was approved in 2019, and had 65,300 prescriptions written in the since then. . Adherence to treatment has generally been very high in clinical practice, with the most common reason for a patient to switch being lack of effectiveness, rather than adverse events.

Of note, adverse events of other migraine therapeutics are not insignificant, and considering the pain that people with migraine endure, side effects must be hard to contend with for individuals to stop taking them. Case in point: A year before erenumab was approved, a study was published that looked at medical records for medication persistence in 8,700 chronic migraine patients, who all had been prescribed beta blockers, anti-seizure medications, or antidepressants. By 6 months, only 1 out of 4 patients were still taking the prescribed medicines. By 12 months, that  was down to 14%. And about one-third of patients who stopped treatment stayed untreated for at least a year. 

The presumed reasons these patients stopped their medications: side effects and-or lack of efficacy. 

Migraine is a disabling disorder, for which the mAb class of medications has been highly beneficial for large numbers of patients, with far greater tolerability than prior oral preventives. While no treatments have absolute safety, the overall safety of this class of medications has been very high, leading to much improved clinical outcomes.

Cefaly is a commonly used nonprescription device that uses external trigeminal nerve stimulation (e-TNS) to either abort or prevent migraine attacks. The pivotal Cefaly study was published about 10 years ago, and Cefaly was the first US Food and Drug Administration–cleared neurostimulation device for headache. The initial acute data were gathered primarily in the hospital setting, and the investigators in the study by Kuruvilla and colleagues intended to replicate a more real-world scenario for the acute use of Cefaly.

This was a prospective, multicenter, sham-controlled study. Patients were enrolled if they developed migraine prior to age 50 years and experienced two to eight attacks per month of moderate to severe intensity. Patients were randomized to either Cefaly or a sham device. The Cefaly device itself has two setting: acute and preventive. For this study, the acute setting was used for 2 hours at a time during an acute attack (within the first 4 hours). The supraorbital and supratrochlear branches of trigeminal nerves bilaterally are stimulated with a continuous stimulation via a self-adhesive electrode. This has previously been shown to be safe and effective with the most common side effect noted to be skin irritation at the electrode site.

Patients collected data about their headaches in an e-diary and continued to treat for 2 months. The co-primary outcomes were headache freedom and resolution of most bothersome syndrome at 2 hours. Secondary outcomes were pain relief at 2 hours, resolution of any migraine-associated symptom at 2 hours after beginning e-TNS treatment, sustained pain freedom (defined as pain freedom at 2 hours and pain freedom at 24 hours without the use of antimigraine medication during those 24 hours), and use of a rescue medication between 2 and 24 hours after beginning an e-TNS session.

A total of 538 patients were enrolled. The percentage of patients with both freedom from pain and resolution of the most bothersome symptoms were statistically different in the intervention and sham groups. The secondary outcomes were also statistically improved in the device group, with the exception of use of rescue medications between 2 and 24 hours. The most common adverse events were forehead discomfort and paresthesia.

This study does show the effectiveness of Cefaly, especially when used for longer periods of time than had been previously recommended. The outcomes were all met with the exception of rescue medication use, and there is no contraindication to using any rescue medication while using the Cefaly device. Cefaly can be an excellent add-on for acute treatment, especially in patients that may need to use more than one intervention acutely for their migraine attacks.

Providers often discuss when to start medications but do not as often discuss when to stop medications. This is especially true for preventive medications for migraine. The best-case scenario is that a preventive medication is so effective that it is no longer necessary; but in other circumstances, preventive medications have to be stopped, for instance, during pregnancy planning. One concern especially when starting and stopping a monoclonal antibody (mAb) medication is the development of neutralizing antibodies to negate the effect of restarting the medication. This study was designed to determine whether restarting calcitonin gene-related peptide (CGRP)–mAb medications was still effective after having been previously stopped.

Raffaelli and colleagues managed a small (39 patients) open-label prospective study. Patients either had a diagnosis of episodic or chronic migraine and were initially given CGRP-mAbs for at least 8 months. They then stopped the therapy for at least 3 months and were restarted on the same mAb that they had initially used. They tracked their headache symptoms for 3 months after restarting therapy. If another treatment had been started in between, those patients were excluded.

The primary outcome was change in mean monthly migraine days between the last 4 weeks of treatment discontinuation and weeks 9-12 after restarting therapy. Secondary endpoints were the changes in mean monthly headache days across the other observation points and Headache Impact Test-6 (HIT-6) sum scores. Of the 39 patients enrolled, 16 were given erenumab, 15 galcanezumab, and 8 fremanezumab.

Mean migraine days and mean headache days were shown to have a statistically significant decrease after resumption of therapy. Restarting CGRP medications was not associated with other adverse events associated with these medications. This gives us evidence in favor of restarting the same CGRP medication when a patient's symptoms start to worsen after they have discontinued because of improvement or after pregnancy and breastfeeding.

The use of implanted devices for migraine treatment is considered somewhat controversial. Surgical interventions and implantations for migraine have not been well studied; however small case series have been published, and non-neurologists report anecdotally that these interventions can be helpful for refractory headache disorders. The study by Evans and colleagues reviewed via meta-analysis much of the prior data for nerve stimulation in migraine.

Studies included in this meta-analysis were English-language, peer-reviewed articles of prospective studies with patients over age 18 years for migraine diagnosed according to International Classification of Headache Disorders (ICHD) criteria. The devices were transcutaneous nerve stimulator devices in a single region of the head (occipital, supraorbital/supratrochlear areas) and enrolled a minimum of 10 patients in the treatment groups. A total of 14 studies were identified; 13 of the studies did report significant adverse events related to treatment.

Regarding migraine frequency, only four of the studies were considered comparable, investigating episodic migraine with 2-3 months of transcutaneous stimulation, and two were comparable in investigating chronic migraine. The episodic migraine studies had a pooled reduction by 2.8 days of migraine per month; chronic migraine was noted to be 2.97 days fewer per month. Three comparable studies for episodic migraine showed a pooled reduction in severity by 2.23 points after 3 months.

Occipital and other trigeminal branch stimulation implants are invasive and associated with risk, most prominently leading to migration and worsening headache and neck pain. This meta-analysis did reveal important pooled data, but it becomes less impressive when considering the published data for standard oral or injection therapies. The fact that there can be long-term worsening and adverse events with surgical implantation makes this choice a higher risk. Of note, there are now neurostimulation devices, such as Cefaly, that allow similar transcutaneous stimulation without the risk of surgery.

Cefaly is a commonly used nonprescription device that uses external trigeminal nerve stimulation (e-TNS) to either abort or prevent migraine attacks. The pivotal Cefaly study was published about 10 years ago, and Cefaly was the first US Food and Drug Administration–cleared neurostimulation device for headache. The initial acute data were gathered primarily in the hospital setting, and the investigators in the study by Kuruvilla and colleagues intended to replicate a more real-world scenario for the acute use of Cefaly.

This was a prospective, multicenter, sham-controlled study. Patients were enrolled if they developed migraine prior to age 50 years and experienced two to eight attacks per month of moderate to severe intensity. Patients were randomized to either Cefaly or a sham device. The Cefaly device itself has two setting: acute and preventive. For this study, the acute setting was used for 2 hours at a time during an acute attack (within the first 4 hours). The supraorbital and supratrochlear branches of trigeminal nerves bilaterally are stimulated with a continuous stimulation via a self-adhesive electrode. This has previously been shown to be safe and effective with the most common side effect noted to be skin irritation at the electrode site.

Patients collected data about their headaches in an e-diary and continued to treat for 2 months. The co-primary outcomes were headache freedom and resolution of most bothersome syndrome at 2 hours. Secondary outcomes were pain relief at 2 hours, resolution of any migraine-associated symptom at 2 hours after beginning e-TNS treatment, sustained pain freedom (defined as pain freedom at 2 hours and pain freedom at 24 hours without the use of antimigraine medication during those 24 hours), and use of a rescue medication between 2 and 24 hours after beginning an e-TNS session.

A total of 538 patients were enrolled. The percentage of patients with both freedom from pain and resolution of the most bothersome symptoms were statistically different in the intervention and sham groups. The secondary outcomes were also statistically improved in the device group, with the exception of use of rescue medications between 2 and 24 hours. The most common adverse events were forehead discomfort and paresthesia.

This study does show the effectiveness of Cefaly, especially when used for longer periods of time than had been previously recommended. The outcomes were all met with the exception of rescue medication use, and there is no contraindication to using any rescue medication while using the Cefaly device. Cefaly can be an excellent add-on for acute treatment, especially in patients that may need to use more than one intervention acutely for their migraine attacks.

Providers often discuss when to start medications but do not as often discuss when to stop medications. This is especially true for preventive medications for migraine. The best-case scenario is that a preventive medication is so effective that it is no longer necessary; but in other circumstances, preventive medications have to be stopped, for instance, during pregnancy planning. One concern especially when starting and stopping a monoclonal antibody (mAb) medication is the development of neutralizing antibodies to negate the effect of restarting the medication. This study was designed to determine whether restarting calcitonin gene-related peptide (CGRP)–mAb medications was still effective after having been previously stopped.

Raffaelli and colleagues managed a small (39 patients) open-label prospective study. Patients either had a diagnosis of episodic or chronic migraine and were initially given CGRP-mAbs for at least 8 months. They then stopped the therapy for at least 3 months and were restarted on the same mAb that they had initially used. They tracked their headache symptoms for 3 months after restarting therapy. If another treatment had been started in between, those patients were excluded.

The primary outcome was change in mean monthly migraine days between the last 4 weeks of treatment discontinuation and weeks 9-12 after restarting therapy. Secondary endpoints were the changes in mean monthly headache days across the other observation points and Headache Impact Test-6 (HIT-6) sum scores. Of the 39 patients enrolled, 16 were given erenumab, 15 galcanezumab, and 8 fremanezumab.

Mean migraine days and mean headache days were shown to have a statistically significant decrease after resumption of therapy. Restarting CGRP medications was not associated with other adverse events associated with these medications. This gives us evidence in favor of restarting the same CGRP medication when a patient's symptoms start to worsen after they have discontinued because of improvement or after pregnancy and breastfeeding.

The use of implanted devices for migraine treatment is considered somewhat controversial. Surgical interventions and implantations for migraine have not been well studied; however small case series have been published, and non-neurologists report anecdotally that these interventions can be helpful for refractory headache disorders. The study by Evans and colleagues reviewed via meta-analysis much of the prior data for nerve stimulation in migraine.

Studies included in this meta-analysis were English-language, peer-reviewed articles of prospective studies with patients over age 18 years for migraine diagnosed according to International Classification of Headache Disorders (ICHD) criteria. The devices were transcutaneous nerve stimulator devices in a single region of the head (occipital, supraorbital/supratrochlear areas) and enrolled a minimum of 10 patients in the treatment groups. A total of 14 studies were identified; 13 of the studies did report significant adverse events related to treatment.

Regarding migraine frequency, only four of the studies were considered comparable, investigating episodic migraine with 2-3 months of transcutaneous stimulation, and two were comparable in investigating chronic migraine. The episodic migraine studies had a pooled reduction by 2.8 days of migraine per month; chronic migraine was noted to be 2.97 days fewer per month. Three comparable studies for episodic migraine showed a pooled reduction in severity by 2.23 points after 3 months.

Occipital and other trigeminal branch stimulation implants are invasive and associated with risk, most prominently leading to migration and worsening headache and neck pain. This meta-analysis did reveal important pooled data, but it becomes less impressive when considering the published data for standard oral or injection therapies. The fact that there can be long-term worsening and adverse events with surgical implantation makes this choice a higher risk. Of note, there are now neurostimulation devices, such as Cefaly, that allow similar transcutaneous stimulation without the risk of surgery.

Cefaly is a commonly used nonprescription device that uses external trigeminal nerve stimulation (e-TNS) to either abort or prevent migraine attacks. The pivotal Cefaly study was published about 10 years ago, and Cefaly was the first US Food and Drug Administration–cleared neurostimulation device for headache. The initial acute data were gathered primarily in the hospital setting, and the investigators in the study by Kuruvilla and colleagues intended to replicate a more real-world scenario for the acute use of Cefaly.

This was a prospective, multicenter, sham-controlled study. Patients were enrolled if they developed migraine prior to age 50 years and experienced two to eight attacks per month of moderate to severe intensity. Patients were randomized to either Cefaly or a sham device. The Cefaly device itself has two setting: acute and preventive. For this study, the acute setting was used for 2 hours at a time during an acute attack (within the first 4 hours). The supraorbital and supratrochlear branches of trigeminal nerves bilaterally are stimulated with a continuous stimulation via a self-adhesive electrode. This has previously been shown to be safe and effective with the most common side effect noted to be skin irritation at the electrode site.

Patients collected data about their headaches in an e-diary and continued to treat for 2 months. The co-primary outcomes were headache freedom and resolution of most bothersome syndrome at 2 hours. Secondary outcomes were pain relief at 2 hours, resolution of any migraine-associated symptom at 2 hours after beginning e-TNS treatment, sustained pain freedom (defined as pain freedom at 2 hours and pain freedom at 24 hours without the use of antimigraine medication during those 24 hours), and use of a rescue medication between 2 and 24 hours after beginning an e-TNS session.

A total of 538 patients were enrolled. The percentage of patients with both freedom from pain and resolution of the most bothersome symptoms were statistically different in the intervention and sham groups. The secondary outcomes were also statistically improved in the device group, with the exception of use of rescue medications between 2 and 24 hours. The most common adverse events were forehead discomfort and paresthesia.

This study does show the effectiveness of Cefaly, especially when used for longer periods of time than had been previously recommended. The outcomes were all met with the exception of rescue medication use, and there is no contraindication to using any rescue medication while using the Cefaly device. Cefaly can be an excellent add-on for acute treatment, especially in patients that may need to use more than one intervention acutely for their migraine attacks.

Providers often discuss when to start medications but do not as often discuss when to stop medications. This is especially true for preventive medications for migraine. The best-case scenario is that a preventive medication is so effective that it is no longer necessary; but in other circumstances, preventive medications have to be stopped, for instance, during pregnancy planning. One concern especially when starting and stopping a monoclonal antibody (mAb) medication is the development of neutralizing antibodies to negate the effect of restarting the medication. This study was designed to determine whether restarting calcitonin gene-related peptide (CGRP)–mAb medications was still effective after having been previously stopped.

Raffaelli and colleagues managed a small (39 patients) open-label prospective study. Patients either had a diagnosis of episodic or chronic migraine and were initially given CGRP-mAbs for at least 8 months. They then stopped the therapy for at least 3 months and were restarted on the same mAb that they had initially used. They tracked their headache symptoms for 3 months after restarting therapy. If another treatment had been started in between, those patients were excluded.

The primary outcome was change in mean monthly migraine days between the last 4 weeks of treatment discontinuation and weeks 9-12 after restarting therapy. Secondary endpoints were the changes in mean monthly headache days across the other observation points and Headache Impact Test-6 (HIT-6) sum scores. Of the 39 patients enrolled, 16 were given erenumab, 15 galcanezumab, and 8 fremanezumab.

Mean migraine days and mean headache days were shown to have a statistically significant decrease after resumption of therapy. Restarting CGRP medications was not associated with other adverse events associated with these medications. This gives us evidence in favor of restarting the same CGRP medication when a patient's symptoms start to worsen after they have discontinued because of improvement or after pregnancy and breastfeeding.

The use of implanted devices for migraine treatment is considered somewhat controversial. Surgical interventions and implantations for migraine have not been well studied; however small case series have been published, and non-neurologists report anecdotally that these interventions can be helpful for refractory headache disorders. The study by Evans and colleagues reviewed via meta-analysis much of the prior data for nerve stimulation in migraine.

Studies included in this meta-analysis were English-language, peer-reviewed articles of prospective studies with patients over age 18 years for migraine diagnosed according to International Classification of Headache Disorders (ICHD) criteria. The devices were transcutaneous nerve stimulator devices in a single region of the head (occipital, supraorbital/supratrochlear areas) and enrolled a minimum of 10 patients in the treatment groups. A total of 14 studies were identified; 13 of the studies did report significant adverse events related to treatment.

Regarding migraine frequency, only four of the studies were considered comparable, investigating episodic migraine with 2-3 months of transcutaneous stimulation, and two were comparable in investigating chronic migraine. The episodic migraine studies had a pooled reduction by 2.8 days of migraine per month; chronic migraine was noted to be 2.97 days fewer per month. Three comparable studies for episodic migraine showed a pooled reduction in severity by 2.23 points after 3 months.

Occipital and other trigeminal branch stimulation implants are invasive and associated with risk, most prominently leading to migration and worsening headache and neck pain. This meta-analysis did reveal important pooled data, but it becomes less impressive when considering the published data for standard oral or injection therapies. The fact that there can be long-term worsening and adverse events with surgical implantation makes this choice a higher risk. Of note, there are now neurostimulation devices, such as Cefaly, that allow similar transcutaneous stimulation without the risk of surgery.

Key clinical point: Patients with chronic migraine (CM) or episodic migraine (EM) show a clinically significant improvement in headache characteristics after prophylactic transcutaneous nerve stimulation.

Major finding: Transcutaneous nerve stimulation reduced the headache frequency (mean monthly headache days) by 2.81 (95% CI 2.18-3.43) days in EM and by 2.97 (95% CI 1.66-4.28) days in CM and the pain severity by 2.23 (95% CI 1.64-2.81) pain scale points in EM.

Study details: The data come from a meta-analysis of 14 studies that included 995 patients with EM or CM treated with transcutaneous stimulation of a single nerve.

Disclosures: The study received no financial support. The authors declared no conflicts of interest.

Source: Evans AG et al. Outcomes of transcutaneous nerve stimulation for migraine headaches: a systematic review and meta-analysis. J Neurol. 2022 (Mar 16). Doi: 10.1007/s00415-022-11059-1

Key clinical point: Patients with chronic migraine (CM) or episodic migraine (EM) show a clinically significant improvement in headache characteristics after prophylactic transcutaneous nerve stimulation.

Major finding: Transcutaneous nerve stimulation reduced the headache frequency (mean monthly headache days) by 2.81 (95% CI 2.18-3.43) days in EM and by 2.97 (95% CI 1.66-4.28) days in CM and the pain severity by 2.23 (95% CI 1.64-2.81) pain scale points in EM.

Study details: The data come from a meta-analysis of 14 studies that included 995 patients with EM or CM treated with transcutaneous stimulation of a single nerve.

Disclosures: The study received no financial support. The authors declared no conflicts of interest.

Source: Evans AG et al. Outcomes of transcutaneous nerve stimulation for migraine headaches: a systematic review and meta-analysis. J Neurol. 2022 (Mar 16). Doi: 10.1007/s00415-022-11059-1

Key clinical point: Patients with chronic migraine (CM) or episodic migraine (EM) show a clinically significant improvement in headache characteristics after prophylactic transcutaneous nerve stimulation.

Major finding: Transcutaneous nerve stimulation reduced the headache frequency (mean monthly headache days) by 2.81 (95% CI 2.18-3.43) days in EM and by 2.97 (95% CI 1.66-4.28) days in CM and the pain severity by 2.23 (95% CI 1.64-2.81) pain scale points in EM.

Study details: The data come from a meta-analysis of 14 studies that included 995 patients with EM or CM treated with transcutaneous stimulation of a single nerve.

Disclosures: The study received no financial support. The authors declared no conflicts of interest.

Source: Evans AG et al. Outcomes of transcutaneous nerve stimulation for migraine headaches: a systematic review and meta-analysis. J Neurol. 2022 (Mar 16). Doi: 10.1007/s00415-022-11059-1

Key clinical point: Fremanezumab is effective and well-tolerated in real-life patients with difficult-to-treat high-frequency episodic migraine (HFEM) or chronic migraine (CM).

Major finding: At week 12, fremanezumab significantly decreased monthly migraine days (−4.6 days; P < .05) in patients with HFEM and monthly headache days (−9.4 days; P < .001) in patients with CM. The rate of treatment-emergent adverse events, graded mild and transient, was only 5.7%.

Study details: This was a multicenter, prospective, real-life study including 53 patients with HFEM (8-14 days/month) or CM who had multiple therapeutic failures and received subcutaneous fremanezumab (225 mg monthly or 675 mg quarterly) for 12 weeks.

Disclosures: The study was partially sponsored by the Italian Ministry of Health (Ricerca Corrente). Some authors declared receiving travel grants or honoraria for advisory boards, speaker panels, consultation, or clinical investigation studies from various sources. M Filippi is the Editor-in-Chief of the Journal of Neurology.

Source: Barbanti P et al. Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week, multicenter, real-life, cohort study (the FRIEND study). J Headache Pain. 2022;23:46 (Apr 9). Doi: 10.1186/s10194-022-01396-x

Key clinical point: Fremanezumab is effective and well-tolerated in real-life patients with difficult-to-treat high-frequency episodic migraine (HFEM) or chronic migraine (CM).

Major finding: At week 12, fremanezumab significantly decreased monthly migraine days (−4.6 days; P < .05) in patients with HFEM and monthly headache days (−9.4 days; P < .001) in patients with CM. The rate of treatment-emergent adverse events, graded mild and transient, was only 5.7%.

Study details: This was a multicenter, prospective, real-life study including 53 patients with HFEM (8-14 days/month) or CM who had multiple therapeutic failures and received subcutaneous fremanezumab (225 mg monthly or 675 mg quarterly) for 12 weeks.

Disclosures: The study was partially sponsored by the Italian Ministry of Health (Ricerca Corrente). Some authors declared receiving travel grants or honoraria for advisory boards, speaker panels, consultation, or clinical investigation studies from various sources. M Filippi is the Editor-in-Chief of the Journal of Neurology.

Source: Barbanti P et al. Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week, multicenter, real-life, cohort study (the FRIEND study). J Headache Pain. 2022;23:46 (Apr 9). Doi: 10.1186/s10194-022-01396-x

Key clinical point: Fremanezumab is effective and well-tolerated in real-life patients with difficult-to-treat high-frequency episodic migraine (HFEM) or chronic migraine (CM).

Major finding: At week 12, fremanezumab significantly decreased monthly migraine days (−4.6 days; P < .05) in patients with HFEM and monthly headache days (−9.4 days; P < .001) in patients with CM. The rate of treatment-emergent adverse events, graded mild and transient, was only 5.7%.

Study details: This was a multicenter, prospective, real-life study including 53 patients with HFEM (8-14 days/month) or CM who had multiple therapeutic failures and received subcutaneous fremanezumab (225 mg monthly or 675 mg quarterly) for 12 weeks.

Disclosures: The study was partially sponsored by the Italian Ministry of Health (Ricerca Corrente). Some authors declared receiving travel grants or honoraria for advisory boards, speaker panels, consultation, or clinical investigation studies from various sources. M Filippi is the Editor-in-Chief of the Journal of Neurology.

Source: Barbanti P et al. Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week, multicenter, real-life, cohort study (the FRIEND study). J Headache Pain. 2022;23:46 (Apr 9). Doi: 10.1186/s10194-022-01396-x

Key clinical point: Patients with migraine show higher treatment adherence and persistence to calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAb), specifically to galcanezumab, over standard-of-care (SOC) migraine preventive treatments.

Major finding: At 12 months of follow-up, CGRP mAb vs. SOC initiators had significantly higher mean adherence (proportion of days covered: 55.1% vs. 35.2%; P < .001) and persistence (212.5 vs. 131.9 days; P < .001). Similarly, galcanezumab vs. SOC initiators showed significantly higher adherence (63.7% vs. 33.7%; P < .001) and persistence (252.3 vs. 127.3 days; P < .001).

Study details: This retrospective, observational, claims database study created two separate 1:1 propensity-score-matched cohorts of adult patients with migraine initiating SOC or a CGRP mAb (n = 3082 pairs) and SOC or galcanezumab (n = 421 pairs).

Disclosures: The study was funded by Eli Lilly and Company. All authors declared being current/former employees or minor shareholders of Eli Lilly or a company contracted by Eli Lilly.

Source: Varnado OJ et al. Treatment patterns for calcitonin gene-related peptide monoclonal antibodies including galcanezumab versus conventional preventive treatments for migraine: A retrospective us claims study, Patient Prefer Adherence. 2022;16:821-839 (Mar 29). Doi: 10.2147/PPA.S346660

Key clinical point: Patients with migraine show higher treatment adherence and persistence to calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAb), specifically to galcanezumab, over standard-of-care (SOC) migraine preventive treatments.

Major finding: At 12 months of follow-up, CGRP mAb vs. SOC initiators had significantly higher mean adherence (proportion of days covered: 55.1% vs. 35.2%; P < .001) and persistence (212.5 vs. 131.9 days; P < .001). Similarly, galcanezumab vs. SOC initiators showed significantly higher adherence (63.7% vs. 33.7%; P < .001) and persistence (252.3 vs. 127.3 days; P < .001).

Study details: This retrospective, observational, claims database study created two separate 1:1 propensity-score-matched cohorts of adult patients with migraine initiating SOC or a CGRP mAb (n = 3082 pairs) and SOC or galcanezumab (n = 421 pairs).

Disclosures: The study was funded by Eli Lilly and Company. All authors declared being current/former employees or minor shareholders of Eli Lilly or a company contracted by Eli Lilly.

Source: Varnado OJ et al. Treatment patterns for calcitonin gene-related peptide monoclonal antibodies including galcanezumab versus conventional preventive treatments for migraine: A retrospective us claims study, Patient Prefer Adherence. 2022;16:821-839 (Mar 29). Doi: 10.2147/PPA.S346660

Key clinical point: Patients with migraine show higher treatment adherence and persistence to calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAb), specifically to galcanezumab, over standard-of-care (SOC) migraine preventive treatments.

Major finding: At 12 months of follow-up, CGRP mAb vs. SOC initiators had significantly higher mean adherence (proportion of days covered: 55.1% vs. 35.2%; P < .001) and persistence (212.5 vs. 131.9 days; P < .001). Similarly, galcanezumab vs. SOC initiators showed significantly higher adherence (63.7% vs. 33.7%; P < .001) and persistence (252.3 vs. 127.3 days; P < .001).

Study details: This retrospective, observational, claims database study created two separate 1:1 propensity-score-matched cohorts of adult patients with migraine initiating SOC or a CGRP mAb (n = 3082 pairs) and SOC or galcanezumab (n = 421 pairs).

Disclosures: The study was funded by Eli Lilly and Company. All authors declared being current/former employees or minor shareholders of Eli Lilly or a company contracted by Eli Lilly.

Source: Varnado OJ et al. Treatment patterns for calcitonin gene-related peptide monoclonal antibodies including galcanezumab versus conventional preventive treatments for migraine: A retrospective us claims study, Patient Prefer Adherence. 2022;16:821-839 (Mar 29). Doi: 10.2147/PPA.S346660

Key clinical point: Real-time ultrasound-guided stellate ganglion block (SGB) can effectively ameliorate migraine pain and disability without causing any serious complications, thus improving the quality of life of patients.

Major finding: After 3 months of SGB administration, the numerical rating scale score decreased from 7.0 to 2.0 (P < .01), Migraine Disability Assessment Scale total score from 14.0 to 7.0 (P < .001), and analgesic use frequency from 6.2 ± 2.8 to 1.9 ± 1.8. No serious complications were observed.

Study details: The study enrolled 81 patients aged >18 years with migraine who received SGB on the affected side with 0.15% ropivacaine weekly 4 times.

Disclosures: The study was sponsored by a grant from the Shanghai Municipal Health Commission. The authors reported no conflicts of interest.

Source: Hou J et al. Real-time ultrasound-guided stellate ganglion block for migraine: an observational study. BMC Anesthesiol. 2022;22:78 (Mar 24). Doi: 10.1186/s12871-022-01622-8

Key clinical point: Real-time ultrasound-guided stellate ganglion block (SGB) can effectively ameliorate migraine pain and disability without causing any serious complications, thus improving the quality of life of patients.

Major finding: After 3 months of SGB administration, the numerical rating scale score decreased from 7.0 to 2.0 (P < .01), Migraine Disability Assessment Scale total score from 14.0 to 7.0 (P < .001), and analgesic use frequency from 6.2 ± 2.8 to 1.9 ± 1.8. No serious complications were observed.

Study details: The study enrolled 81 patients aged >18 years with migraine who received SGB on the affected side with 0.15% ropivacaine weekly 4 times.

Disclosures: The study was sponsored by a grant from the Shanghai Municipal Health Commission. The authors reported no conflicts of interest.

Source: Hou J et al. Real-time ultrasound-guided stellate ganglion block for migraine: an observational study. BMC Anesthesiol. 2022;22:78 (Mar 24). Doi: 10.1186/s12871-022-01622-8

Key clinical point: Real-time ultrasound-guided stellate ganglion block (SGB) can effectively ameliorate migraine pain and disability without causing any serious complications, thus improving the quality of life of patients.

Major finding: After 3 months of SGB administration, the numerical rating scale score decreased from 7.0 to 2.0 (P < .01), Migraine Disability Assessment Scale total score from 14.0 to 7.0 (P < .001), and analgesic use frequency from 6.2 ± 2.8 to 1.9 ± 1.8. No serious complications were observed.

Study details: The study enrolled 81 patients aged >18 years with migraine who received SGB on the affected side with 0.15% ropivacaine weekly 4 times.

Disclosures: The study was sponsored by a grant from the Shanghai Municipal Health Commission. The authors reported no conflicts of interest.

Source: Hou J et al. Real-time ultrasound-guided stellate ganglion block for migraine: an observational study. BMC Anesthesiol. 2022;22:78 (Mar 24). Doi: 10.1186/s12871-022-01622-8

Key clinical point: Migraine frequency decreases significantly in most patients with migraine on resuming preventive treatment with the same calcitonin gene-related peptide-receptor (CGRP-[R]) monoclonal antibody (mAb) after a 3-month drug holiday.

Major finding: After 9-12 weeks of therapy resumption, monthly migraine days reduced significantly (−4.5 days, P < .001) and attained a level comparable with that in the 4-week period before therapy discontinuation (P > .999).

Study details: Findings are from a longitudinal cohort study including 39 patients with episodic or chronic migraine who restarted treatment with erenumab (n = 16) or galcanezumab/fremanezumab (n = 23) after a 3-month drug holiday following the first treatment cycle with the same CGRP(-R) mAb.

Disclosures: This study did not receive any financial support. Some authors declared serving on the advisory board of or receiving consulting, speaker, or personal fees from various sources.

Source: Raffaelli B et al. Resumption of migraine preventive treatment with CGRP(-receptor) antibodies after a 3-month drug holiday: A real-world experience. J Headache Pain. 2022;23:40 (Mar 30). Doi:  10.1186/s10194-022-01417-9

Key clinical point: Migraine frequency decreases significantly in most patients with migraine on resuming preventive treatment with the same calcitonin gene-related peptide-receptor (CGRP-[R]) monoclonal antibody (mAb) after a 3-month drug holiday.

Major finding: After 9-12 weeks of therapy resumption, monthly migraine days reduced significantly (−4.5 days, P < .001) and attained a level comparable with that in the 4-week period before therapy discontinuation (P > .999).

Study details: Findings are from a longitudinal cohort study including 39 patients with episodic or chronic migraine who restarted treatment with erenumab (n = 16) or galcanezumab/fremanezumab (n = 23) after a 3-month drug holiday following the first treatment cycle with the same CGRP(-R) mAb.

Disclosures: This study did not receive any financial support. Some authors declared serving on the advisory board of or receiving consulting, speaker, or personal fees from various sources.

Source: Raffaelli B et al. Resumption of migraine preventive treatment with CGRP(-receptor) antibodies after a 3-month drug holiday: A real-world experience. J Headache Pain. 2022;23:40 (Mar 30). Doi:  10.1186/s10194-022-01417-9

Key clinical point: Migraine frequency decreases significantly in most patients with migraine on resuming preventive treatment with the same calcitonin gene-related peptide-receptor (CGRP-[R]) monoclonal antibody (mAb) after a 3-month drug holiday.

Major finding: After 9-12 weeks of therapy resumption, monthly migraine days reduced significantly (−4.5 days, P < .001) and attained a level comparable with that in the 4-week period before therapy discontinuation (P > .999).

Study details: Findings are from a longitudinal cohort study including 39 patients with episodic or chronic migraine who restarted treatment with erenumab (n = 16) or galcanezumab/fremanezumab (n = 23) after a 3-month drug holiday following the first treatment cycle with the same CGRP(-R) mAb.

Disclosures: This study did not receive any financial support. Some authors declared serving on the advisory board of or receiving consulting, speaker, or personal fees from various sources.

Source: Raffaelli B et al. Resumption of migraine preventive treatment with CGRP(-receptor) antibodies after a 3-month drug holiday: A real-world experience. J Headache Pain. 2022;23:40 (Mar 30). Doi:  10.1186/s10194-022-01417-9

Key clinical point: Topiramate in combination with monthly injections of greater occipital nerve block (GONB) is better at decreasing monthly migraine days (MMD) in chronic migraine (CM) than topiramate monotherapy at month 3 and is equally well tolerated.

Major finding: At month 3, greater reductions in MMD were observed in patients receiving topiramate and GONB with lidocaine+methylprednisolone (−9.6 vs. −7.3 days; P = .003) and topiramate and GONB with only lidocaine (−10.1 vs. −7.3 days; P < .001) compared with patients receiving topiramate monotherapy. Tolerability between the groups was comparable.

Study details: Findings are from a parallel group, three-arm study including 125 adult patients with CM who were randomly assigned to receive topiramate alone (n = 41), topiramate and GONB with lidocaine+methylprednisolone in month 1 followed by monthly lidocaine injections (n = 44), or topiramate and GONB with monthly lidocaine injections (n = 40) for 3 months.

Disclosures: The study received no financial support. The authors declared no conflicts of interest.

Source: Chowdhury D et al. Efficacy and tolerability of combination treatment of topiramate and greater occipital nerve block versus topiramate monotherapy for the preventive treatment of chronic migraine: A randomized controlled trial. Cephalalgia. 2022 (Mar 8). Doi: 10.1177/03331024221082077

Key clinical point: Topiramate in combination with monthly injections of greater occipital nerve block (GONB) is better at decreasing monthly migraine days (MMD) in chronic migraine (CM) than topiramate monotherapy at month 3 and is equally well tolerated.

Major finding: At month 3, greater reductions in MMD were observed in patients receiving topiramate and GONB with lidocaine+methylprednisolone (−9.6 vs. −7.3 days; P = .003) and topiramate and GONB with only lidocaine (−10.1 vs. −7.3 days; P < .001) compared with patients receiving topiramate monotherapy. Tolerability between the groups was comparable.

Study details: Findings are from a parallel group, three-arm study including 125 adult patients with CM who were randomly assigned to receive topiramate alone (n = 41), topiramate and GONB with lidocaine+methylprednisolone in month 1 followed by monthly lidocaine injections (n = 44), or topiramate and GONB with monthly lidocaine injections (n = 40) for 3 months.

Disclosures: The study received no financial support. The authors declared no conflicts of interest.

Source: Chowdhury D et al. Efficacy and tolerability of combination treatment of topiramate and greater occipital nerve block versus topiramate monotherapy for the preventive treatment of chronic migraine: A randomized controlled trial. Cephalalgia. 2022 (Mar 8). Doi: 10.1177/03331024221082077

Key clinical point: Topiramate in combination with monthly injections of greater occipital nerve block (GONB) is better at decreasing monthly migraine days (MMD) in chronic migraine (CM) than topiramate monotherapy at month 3 and is equally well tolerated.

Major finding: At month 3, greater reductions in MMD were observed in patients receiving topiramate and GONB with lidocaine+methylprednisolone (−9.6 vs. −7.3 days; P = .003) and topiramate and GONB with only lidocaine (−10.1 vs. −7.3 days; P < .001) compared with patients receiving topiramate monotherapy. Tolerability between the groups was comparable.

Study details: Findings are from a parallel group, three-arm study including 125 adult patients with CM who were randomly assigned to receive topiramate alone (n = 41), topiramate and GONB with lidocaine+methylprednisolone in month 1 followed by monthly lidocaine injections (n = 44), or topiramate and GONB with monthly lidocaine injections (n = 40) for 3 months.

Disclosures: The study received no financial support. The authors declared no conflicts of interest.

Source: Chowdhury D et al. Efficacy and tolerability of combination treatment of topiramate and greater occipital nerve block versus topiramate monotherapy for the preventive treatment of chronic migraine: A randomized controlled trial. Cephalalgia. 2022 (Mar 8). Doi: 10.1177/03331024221082077