Alan M. Rapoport, MD

Do you use nonpharmacologic approaches to treat your patients living with migraines? Which ones do you prefer?
I always like to start with nonpharmacologic approaches (also termed bio-behavioral approaches) with my patients. I talk to patients about sleep hygiene because if they don't sleep well, they're going to have more headaches. Most of my patients have issues with sleep and rarely feel refreshed in the morning. Most of them have middle insomnia; they wake up between 2 am and 4 am and cannot get back to sleep.

I also talk to my patients about eating properly. If patients don't eat on time or miss a meal, they often get headaches.  While timing is probably more critical, what they eat is important also. Poor diet can lead to decreased energy, and patients can become obese. Obesity impacts headache—especially migraine. I am not sure if there are any particularly good or bad foods for migraine patients, but in general, they should eat fewer fatty foods, fewer carbohydrates, more chicken, and fish than red meat, and a lot of fruits, vegetables, salads, nuts, and whole grains. A good trick is to limit the volume of each meal; do not go back for seconds and limit desserts and alcohol. 

Exercise is beneficial to decrease headaches, and the converse is even more true. Patients should start with low-impact, brief exercise like short walks and slowly build up to 20 minutes of cardio as tolerated, 3 to 5 times per week. Like poor diet choices, a sedentary lifestyle can lead to obesity and then not doing well with headaches and so on. 

What are your goals for treating your patients at the start of a migraine attack?

The goals for treating a migraine attack are to reduce the intensity of the pain quickly and, if possible, make the patient pain-free in ≤2 hours. We also try to reduce their most bothersome symptom, which is usually sensitivity to light or nausea, without causing any adverse effects from the treatment. Possibly as important, we want to get the patient back to functioning at work or at home, so they need no further treatment for that attack.

Unfortunately, many of the medicines we have available do cause adverse events, which are sometimes worse than the headache itself.  A patient can't continue to take a medication that causes significant side effects.

It is also critical to stop the headache quickly, as we don't want patients to take the prescribed acute care medicine and then, if they don’t feel like it’s working, proceed to take aspirin and then acetaminophen and then an anti-inflammatory tablet. The more medicine they take, the more likely they'll get medication overuse headache (MOH).  

MOH is not a great name, but it does imply that patients are taking one or many medications per week to stop their headaches, not realizing that this can worsen and prolong their headaches rather than helping them. They can also experience adverse events from taking so much medication. 

Finally, we want the patients to get rid of a headache so that they do not need to go to an emergency room, and we want to use medication that is cost effective and gets the patient functioning. Some medicines and devices are extremely expensive and not well covered by insurance companies but imagine the patient who takes a new medicine or uses a new device and gets better rapidly. If they hadn't done that, they may have lost a day or 2 of pay from missing work, or they might have gone to work and not done a very effective job because they were feeling miserable and couldn’t think or speak well. 

Do you prescribe triptans?

Definitely. The triptans first became available 30 years ago. There are 7 different triptans, and some work better for some patients than others. They come in tablets, injections, and nasal sprays. Sometimes patients need to try 2 or 3 different triptans to see which one is the most effective for them. If a patient has no success with tablets, there's a possibility that an injection or even a nasal spray would be more effective.
There are 2 triptans available as a nasal spray. I happen to like a triptan nasal spray called zolmitriptan, which usually works faster with fewer adverse events than the tablets.

There's also an injection of sumatriptan available, which is the fastest way to get relief from a triptan. Patients usually don't prefer it because it is an injection that they give themselves via an auto injector, and it may hurt and can be a bit complex to administer. There are definitely more adverse events when sumatriptan is given by injection, but because an injection can deliver very fast results that stop the headache reliably, some patients prefer it.

Triptans have been the mainstay treatment to stop an ongoing migraine attack for 30 years. We have always known there is some constriction of blood vessels and triptan-related side effects such as dizziness, drowsiness, and tingling sensations, so not every patient can take them. The newer medications that block calcitonin gene-related peptide (CGRP) do not constrict blood vessels and have fewer adverse events but cost a lot more if not covered by insurance.

Another newer, nontriptan nasal spray is dihydroergotamine (DHE) mesylate for acute care. It is one of the best medications to use if the patient’s migraine has been going on for 24 hours, as it tends to work well for a long-lasting headache. It also works for a long period, giving the patient a rest before their next attack. A nasal spray works faster than a tablet form, as the medication is absorbed from the nasal mucosa and does not have to make its way through the GI tract, then to the liver for metabolism, and finally, up to the brain before it begins to work. There can be some side effects in the nose such as discomfort or stuffiness, but if it works well, patients usually tolerate it. 

There's also a newer class of medicine called ditans. In a recent study, lasmiditan, which comes in a 50-mg and a 100-mg tablet for acute care of migraine, showed no vasoconstrictive effects, suggesting that ditans could be a safe option for patients living with chronic cardio- and cerebrovascular disease. Lasmiditan could be an alternative to triptans when they are contraindicated in patients with blood vessel disease, obesity, high blood pressure or cholesterol levels, or in nonresponsive patients. Lasmiditan does cause some dizziness and drowsiness, so patients cannot drive for 8 hours after taking it. However, it does have good efficacy.

When do you prescribe gepants?

Gepants are small-molecule CGRP receptor blockers. They are tablets that sit on the receptor, preventing the CGRP from docking on the receptor and increasing the headache during a migraine attack. There are 2 gepants that can be used to stop a headache that is just starting or in progress: ubrogepant and rimegepant. 

Ubrogepant is a regular tablet that is available in 50-mg or 100-mg strengths. If the first dose does not make a patient pain free, a second dose is recommended about 2 hours later. Rimegepant is a meltaway tablet and only comes in a 75-mg strength. It should be taken early in the attack, and usually the patient does not need further treatment that day. If they do, they need to switch to another treatment, as rimegepant should not be repeated that day. Rimegepant may be used for both acute care and prevention. It is the only tablet that can be used for both. 

Both drugs have been shown to provide pain freedom for about 20% of patients at 2 hours, which is statistically better than the patients that received the placebo. These drugs generally don’t cause many adverse events but can cause a little nausea or drowsiness in some patients. Ubrogepant has a few contraindications; patients on certain medications such as antibiotics or antifungals cannot take it. If a patient is not doing well on a triptan or should not be given a drug that constricts blood vessels, I often switch them to one of these gepants (if covered by insurance). Both drugs have a plan to let the patient try them at a low cost. 

How are the gepants used acutely?

Gepants are used just like a triptan. As soon as the patient has a migraine headache starting, they take either ubrogepant or rimegepant as quickly as possible. Some patients say they feel the gepant begin to work within an hour or less, and some patients say it doesn't work at all, so I have them try the other gepant. 

Gepants are probably a better option than triptans if the patient is >40 years because triptans can constrict blood vessels. Older patients, and certainly those who have any kind of cardiac or cerebral blood vessel issues or even peripheral blood vessel disease, should not be given triptans.

When do you consider using preventive treatment in migraine?

If a patient has ≥4 moderate-to-severe headache days a month, or fewer with severe disability, or does not respond to acute care medications or those drugs are contraindicated, I consider giving them preventive therapy for migraine. The goal is to decrease the number of migraine days per month and to decrease the intensity, duration, and disability of the attacks.

Which gepants can you use for prevention of migraine?

I discussed rimegepant as an acute care medication, but the same 75-mg meltaway tablet given every other day works preventively to decrease the number of headaches. I like it, as it has few adverse events—<3% of patients experience nausea and abdominal pain—and it can also be used to stop a headache on days the patient did not take a tablet.

Atogepant is a newer, US Food and Drug Administration (FDA)-approved gepant taken once daily by mouth for prevention of migraine, and it works to decrease headache days per month. It has more side effects than the other gepants, including constipation, drowsiness, and nausea. If a patient does not have many adverse events while taking it, it is a good migraine preventive. 

How do you feel about monoclonal antibodies that bind to CGRP or its receptor for migraine preventive treatment?

Before the gepants became available, 4 different pharmaceutical companies were making monoclonal antibodies (mAbs) that bind to either CGRP or its receptor. This class of medication can be quite effective for most patients needing migraine prevention, as these medications last for a long time if the patient keeps taking it. 

Antibodies, when injected, continue to work for 1 to 3 months, making them perfect for migraine prevention, but they must be given either by the patient using an autoinjector with a tiny needle or by intravenous (IV) infusion in a hospital or office. They tend to be quite effective and have few adverse events.  

The first one to come out was erenumab, then frenanezumab, and galcanezumab. The newest one is eptinezumab, given by IV infusion over 30 minutes. Erenumab is the only mAb that sits on the receptor to prevent the CGRP from docking on the receptor, and it's the only one that seems to cause adverse events such as constipation and increased blood pressure in some patients. Eptinezumab is the only drug in this category given by IV infusion; patients must come to the office to receive the injection every 3 months. Even though eptinezumab is a powerful drug, I find that patients generally don't like coming in for IV treatment. I reserve it for when a patient has failed several other preventive treatments. The other 3 drugs (erenumab, fremanezumab, galcanezumab) are subcutaneous injections that the patient can self-administer at home. Fremanezumab can be taken once a month or once every 3 months, depending on the dose prescribed. 

What migraine devices do you like to prescribe?

The device that I tend to have my patients use is called Nerivio®; it has been cleared by the FDA for acute treatment of migraine in patients ≥12 years. An article was just published in the journal Headache on its use in prevention of migraine. The company expects the FDA to clear it very soon for prevention when used for 45 minutes every other day.

Nerivio® is an electrical stimulator that is placed on the upper arm like a blood pressure cuff. It is battery-powered and links to an app on a smartphone. I have my patients turn it up slowly to a higher gain, and when they feel a slight discomfort, they lower down until they do not feel it. That's where I recommend that they keep it for 45 minutes of treatment, starting at the beginning of a migraine attack. 

Nerivio® also has a behavioral medicine program incorporated into the smartphone app that lasts for 25 minutes. While the patient is receiving the 45 minutes of electrical stimulation, they are also being guided through relaxation techniques to help ease the headache. The company has done a controlled study comparing the efficacy of Nerivio® with and without the behavioral treatment and found that the 2 together are more effective than Nerivio® alone. 

The early double-blind studies of this device, as sent to the FDA for clearance, have excellent efficacy data with very few adverse events. Thus, it is used by many patients. The company has arranged a lower cost for the first month of treatment so a patient can see whether the device is effective.

There's also a device called Relivion®, which is worn like a tiara on the head to stimulate 4 nerves above the eyebrows that are part of the trigeminal system and 2 in the back of the head that affect the occipital nerves.

One of the earliest devices to launch is the gammaCore vagal nerve stimulator. It is handheld and controlled by the patient. It is placed on the front and side of the neck in the region of the vagal nerve. For acute care of migraine, the patient stimulates for 2 minutes and then waits several minutes before repeating 2 minutes of treatment. If you want to prescribe it for the prevention of migraine, a patient could do this sequence twice per day. It has been approved for acute care and prevention of migraine and, along with other medication for cluster headaches, it is easy to use and approved for almost any kind of headache. Unfortunately, it is extremely expensive for patients and is not covered well by insurance unless the patient is a veteran or goes to a Veterans Health Administration hospital for care. 

There are a few other devices that also work for migraine. Most electrical stimulation devices are costly, but we do hope that insurance companies will begin to cover them soon. Most devices cause few adverse events, have few contraindications, and will be used more as they become more affordable.

Can you summarize migraine treatment for us in one paragraph?

No, but I will try. We have many acute care treatments for migraine that are effective. Some, such as the triptans, do constrict blood vessels, and certain patients should not be taking medications that affect blood vessels. Some medications cause certain side effects or take too long to work, and we have other options for those patients. If a patient has ≥4 headache days per month or fewer associated with a lot of disability, we need to consider prevention. We have older preventives such as beta blockers and epilepsy medications, which are less expensive and can work but usually have many side effects. Now we have 4 mAbs that bind to CGRP or its receptor, which work well for a month or more with few adverse events. We also have 2 oral gepants for prevention. When you add in several devices, I have so many options for my patients today that I am a lucky neurologist, and my patients are even luckier!

Do you use nonpharmacologic approaches to treat your patients living with migraines? Which ones do you prefer?
I always like to start with nonpharmacologic approaches (also termed bio-behavioral approaches) with my patients. I talk to patients about sleep hygiene because if they don't sleep well, they're going to have more headaches. Most of my patients have issues with sleep and rarely feel refreshed in the morning. Most of them have middle insomnia; they wake up between 2 am and 4 am and cannot get back to sleep.

I also talk to my patients about eating properly. If patients don't eat on time or miss a meal, they often get headaches.  While timing is probably more critical, what they eat is important also. Poor diet can lead to decreased energy, and patients can become obese. Obesity impacts headache—especially migraine. I am not sure if there are any particularly good or bad foods for migraine patients, but in general, they should eat fewer fatty foods, fewer carbohydrates, more chicken, and fish than red meat, and a lot of fruits, vegetables, salads, nuts, and whole grains. A good trick is to limit the volume of each meal; do not go back for seconds and limit desserts and alcohol. 

Exercise is beneficial to decrease headaches, and the converse is even more true. Patients should start with low-impact, brief exercise like short walks and slowly build up to 20 minutes of cardio as tolerated, 3 to 5 times per week. Like poor diet choices, a sedentary lifestyle can lead to obesity and then not doing well with headaches and so on. 

What are your goals for treating your patients at the start of a migraine attack?

The goals for treating a migraine attack are to reduce the intensity of the pain quickly and, if possible, make the patient pain-free in ≤2 hours. We also try to reduce their most bothersome symptom, which is usually sensitivity to light or nausea, without causing any adverse effects from the treatment. Possibly as important, we want to get the patient back to functioning at work or at home, so they need no further treatment for that attack.

Unfortunately, many of the medicines we have available do cause adverse events, which are sometimes worse than the headache itself.  A patient can't continue to take a medication that causes significant side effects.

It is also critical to stop the headache quickly, as we don't want patients to take the prescribed acute care medicine and then, if they don’t feel like it’s working, proceed to take aspirin and then acetaminophen and then an anti-inflammatory tablet. The more medicine they take, the more likely they'll get medication overuse headache (MOH).  

MOH is not a great name, but it does imply that patients are taking one or many medications per week to stop their headaches, not realizing that this can worsen and prolong their headaches rather than helping them. They can also experience adverse events from taking so much medication. 

Finally, we want the patients to get rid of a headache so that they do not need to go to an emergency room, and we want to use medication that is cost effective and gets the patient functioning. Some medicines and devices are extremely expensive and not well covered by insurance companies but imagine the patient who takes a new medicine or uses a new device and gets better rapidly. If they hadn't done that, they may have lost a day or 2 of pay from missing work, or they might have gone to work and not done a very effective job because they were feeling miserable and couldn’t think or speak well. 

Do you prescribe triptans?

Definitely. The triptans first became available 30 years ago. There are 7 different triptans, and some work better for some patients than others. They come in tablets, injections, and nasal sprays. Sometimes patients need to try 2 or 3 different triptans to see which one is the most effective for them. If a patient has no success with tablets, there's a possibility that an injection or even a nasal spray would be more effective.
There are 2 triptans available as a nasal spray. I happen to like a triptan nasal spray called zolmitriptan, which usually works faster with fewer adverse events than the tablets.

There's also an injection of sumatriptan available, which is the fastest way to get relief from a triptan. Patients usually don't prefer it because it is an injection that they give themselves via an auto injector, and it may hurt and can be a bit complex to administer. There are definitely more adverse events when sumatriptan is given by injection, but because an injection can deliver very fast results that stop the headache reliably, some patients prefer it.

Triptans have been the mainstay treatment to stop an ongoing migraine attack for 30 years. We have always known there is some constriction of blood vessels and triptan-related side effects such as dizziness, drowsiness, and tingling sensations, so not every patient can take them. The newer medications that block calcitonin gene-related peptide (CGRP) do not constrict blood vessels and have fewer adverse events but cost a lot more if not covered by insurance.

Another newer, nontriptan nasal spray is dihydroergotamine (DHE) mesylate for acute care. It is one of the best medications to use if the patient’s migraine has been going on for 24 hours, as it tends to work well for a long-lasting headache. It also works for a long period, giving the patient a rest before their next attack. A nasal spray works faster than a tablet form, as the medication is absorbed from the nasal mucosa and does not have to make its way through the GI tract, then to the liver for metabolism, and finally, up to the brain before it begins to work. There can be some side effects in the nose such as discomfort or stuffiness, but if it works well, patients usually tolerate it. 

There's also a newer class of medicine called ditans. In a recent study, lasmiditan, which comes in a 50-mg and a 100-mg tablet for acute care of migraine, showed no vasoconstrictive effects, suggesting that ditans could be a safe option for patients living with chronic cardio- and cerebrovascular disease. Lasmiditan could be an alternative to triptans when they are contraindicated in patients with blood vessel disease, obesity, high blood pressure or cholesterol levels, or in nonresponsive patients. Lasmiditan does cause some dizziness and drowsiness, so patients cannot drive for 8 hours after taking it. However, it does have good efficacy.

When do you prescribe gepants?

Gepants are small-molecule CGRP receptor blockers. They are tablets that sit on the receptor, preventing the CGRP from docking on the receptor and increasing the headache during a migraine attack. There are 2 gepants that can be used to stop a headache that is just starting or in progress: ubrogepant and rimegepant. 

Ubrogepant is a regular tablet that is available in 50-mg or 100-mg strengths. If the first dose does not make a patient pain free, a second dose is recommended about 2 hours later. Rimegepant is a meltaway tablet and only comes in a 75-mg strength. It should be taken early in the attack, and usually the patient does not need further treatment that day. If they do, they need to switch to another treatment, as rimegepant should not be repeated that day. Rimegepant may be used for both acute care and prevention. It is the only tablet that can be used for both. 

Both drugs have been shown to provide pain freedom for about 20% of patients at 2 hours, which is statistically better than the patients that received the placebo. These drugs generally don’t cause many adverse events but can cause a little nausea or drowsiness in some patients. Ubrogepant has a few contraindications; patients on certain medications such as antibiotics or antifungals cannot take it. If a patient is not doing well on a triptan or should not be given a drug that constricts blood vessels, I often switch them to one of these gepants (if covered by insurance). Both drugs have a plan to let the patient try them at a low cost. 

How are the gepants used acutely?

Gepants are used just like a triptan. As soon as the patient has a migraine headache starting, they take either ubrogepant or rimegepant as quickly as possible. Some patients say they feel the gepant begin to work within an hour or less, and some patients say it doesn't work at all, so I have them try the other gepant. 

Gepants are probably a better option than triptans if the patient is >40 years because triptans can constrict blood vessels. Older patients, and certainly those who have any kind of cardiac or cerebral blood vessel issues or even peripheral blood vessel disease, should not be given triptans.

When do you consider using preventive treatment in migraine?

If a patient has ≥4 moderate-to-severe headache days a month, or fewer with severe disability, or does not respond to acute care medications or those drugs are contraindicated, I consider giving them preventive therapy for migraine. The goal is to decrease the number of migraine days per month and to decrease the intensity, duration, and disability of the attacks.

Which gepants can you use for prevention of migraine?

I discussed rimegepant as an acute care medication, but the same 75-mg meltaway tablet given every other day works preventively to decrease the number of headaches. I like it, as it has few adverse events—<3% of patients experience nausea and abdominal pain—and it can also be used to stop a headache on days the patient did not take a tablet.

Atogepant is a newer, US Food and Drug Administration (FDA)-approved gepant taken once daily by mouth for prevention of migraine, and it works to decrease headache days per month. It has more side effects than the other gepants, including constipation, drowsiness, and nausea. If a patient does not have many adverse events while taking it, it is a good migraine preventive. 

How do you feel about monoclonal antibodies that bind to CGRP or its receptor for migraine preventive treatment?

Before the gepants became available, 4 different pharmaceutical companies were making monoclonal antibodies (mAbs) that bind to either CGRP or its receptor. This class of medication can be quite effective for most patients needing migraine prevention, as these medications last for a long time if the patient keeps taking it. 

Antibodies, when injected, continue to work for 1 to 3 months, making them perfect for migraine prevention, but they must be given either by the patient using an autoinjector with a tiny needle or by intravenous (IV) infusion in a hospital or office. They tend to be quite effective and have few adverse events.  

The first one to come out was erenumab, then frenanezumab, and galcanezumab. The newest one is eptinezumab, given by IV infusion over 30 minutes. Erenumab is the only mAb that sits on the receptor to prevent the CGRP from docking on the receptor, and it's the only one that seems to cause adverse events such as constipation and increased blood pressure in some patients. Eptinezumab is the only drug in this category given by IV infusion; patients must come to the office to receive the injection every 3 months. Even though eptinezumab is a powerful drug, I find that patients generally don't like coming in for IV treatment. I reserve it for when a patient has failed several other preventive treatments. The other 3 drugs (erenumab, fremanezumab, galcanezumab) are subcutaneous injections that the patient can self-administer at home. Fremanezumab can be taken once a month or once every 3 months, depending on the dose prescribed. 

What migraine devices do you like to prescribe?

The device that I tend to have my patients use is called Nerivio®; it has been cleared by the FDA for acute treatment of migraine in patients ≥12 years. An article was just published in the journal Headache on its use in prevention of migraine. The company expects the FDA to clear it very soon for prevention when used for 45 minutes every other day.

Nerivio® is an electrical stimulator that is placed on the upper arm like a blood pressure cuff. It is battery-powered and links to an app on a smartphone. I have my patients turn it up slowly to a higher gain, and when they feel a slight discomfort, they lower down until they do not feel it. That's where I recommend that they keep it for 45 minutes of treatment, starting at the beginning of a migraine attack. 

Nerivio® also has a behavioral medicine program incorporated into the smartphone app that lasts for 25 minutes. While the patient is receiving the 45 minutes of electrical stimulation, they are also being guided through relaxation techniques to help ease the headache. The company has done a controlled study comparing the efficacy of Nerivio® with and without the behavioral treatment and found that the 2 together are more effective than Nerivio® alone. 

The early double-blind studies of this device, as sent to the FDA for clearance, have excellent efficacy data with very few adverse events. Thus, it is used by many patients. The company has arranged a lower cost for the first month of treatment so a patient can see whether the device is effective.

There's also a device called Relivion®, which is worn like a tiara on the head to stimulate 4 nerves above the eyebrows that are part of the trigeminal system and 2 in the back of the head that affect the occipital nerves.

One of the earliest devices to launch is the gammaCore vagal nerve stimulator. It is handheld and controlled by the patient. It is placed on the front and side of the neck in the region of the vagal nerve. For acute care of migraine, the patient stimulates for 2 minutes and then waits several minutes before repeating 2 minutes of treatment. If you want to prescribe it for the prevention of migraine, a patient could do this sequence twice per day. It has been approved for acute care and prevention of migraine and, along with other medication for cluster headaches, it is easy to use and approved for almost any kind of headache. Unfortunately, it is extremely expensive for patients and is not covered well by insurance unless the patient is a veteran or goes to a Veterans Health Administration hospital for care. 

There are a few other devices that also work for migraine. Most electrical stimulation devices are costly, but we do hope that insurance companies will begin to cover them soon. Most devices cause few adverse events, have few contraindications, and will be used more as they become more affordable.

Can you summarize migraine treatment for us in one paragraph?

No, but I will try. We have many acute care treatments for migraine that are effective. Some, such as the triptans, do constrict blood vessels, and certain patients should not be taking medications that affect blood vessels. Some medications cause certain side effects or take too long to work, and we have other options for those patients. If a patient has ≥4 headache days per month or fewer associated with a lot of disability, we need to consider prevention. We have older preventives such as beta blockers and epilepsy medications, which are less expensive and can work but usually have many side effects. Now we have 4 mAbs that bind to CGRP or its receptor, which work well for a month or more with few adverse events. We also have 2 oral gepants for prevention. When you add in several devices, I have so many options for my patients today that I am a lucky neurologist, and my patients are even luckier!

Do you use nonpharmacologic approaches to treat your patients living with migraines? Which ones do you prefer?
I always like to start with nonpharmacologic approaches (also termed bio-behavioral approaches) with my patients. I talk to patients about sleep hygiene because if they don't sleep well, they're going to have more headaches. Most of my patients have issues with sleep and rarely feel refreshed in the morning. Most of them have middle insomnia; they wake up between 2 am and 4 am and cannot get back to sleep.

I also talk to my patients about eating properly. If patients don't eat on time or miss a meal, they often get headaches.  While timing is probably more critical, what they eat is important also. Poor diet can lead to decreased energy, and patients can become obese. Obesity impacts headache—especially migraine. I am not sure if there are any particularly good or bad foods for migraine patients, but in general, they should eat fewer fatty foods, fewer carbohydrates, more chicken, and fish than red meat, and a lot of fruits, vegetables, salads, nuts, and whole grains. A good trick is to limit the volume of each meal; do not go back for seconds and limit desserts and alcohol. 

Exercise is beneficial to decrease headaches, and the converse is even more true. Patients should start with low-impact, brief exercise like short walks and slowly build up to 20 minutes of cardio as tolerated, 3 to 5 times per week. Like poor diet choices, a sedentary lifestyle can lead to obesity and then not doing well with headaches and so on. 

What are your goals for treating your patients at the start of a migraine attack?

The goals for treating a migraine attack are to reduce the intensity of the pain quickly and, if possible, make the patient pain-free in ≤2 hours. We also try to reduce their most bothersome symptom, which is usually sensitivity to light or nausea, without causing any adverse effects from the treatment. Possibly as important, we want to get the patient back to functioning at work or at home, so they need no further treatment for that attack.

Unfortunately, many of the medicines we have available do cause adverse events, which are sometimes worse than the headache itself.  A patient can't continue to take a medication that causes significant side effects.

It is also critical to stop the headache quickly, as we don't want patients to take the prescribed acute care medicine and then, if they don’t feel like it’s working, proceed to take aspirin and then acetaminophen and then an anti-inflammatory tablet. The more medicine they take, the more likely they'll get medication overuse headache (MOH).  

MOH is not a great name, but it does imply that patients are taking one or many medications per week to stop their headaches, not realizing that this can worsen and prolong their headaches rather than helping them. They can also experience adverse events from taking so much medication. 

Finally, we want the patients to get rid of a headache so that they do not need to go to an emergency room, and we want to use medication that is cost effective and gets the patient functioning. Some medicines and devices are extremely expensive and not well covered by insurance companies but imagine the patient who takes a new medicine or uses a new device and gets better rapidly. If they hadn't done that, they may have lost a day or 2 of pay from missing work, or they might have gone to work and not done a very effective job because they were feeling miserable and couldn’t think or speak well. 

Do you prescribe triptans?

Definitely. The triptans first became available 30 years ago. There are 7 different triptans, and some work better for some patients than others. They come in tablets, injections, and nasal sprays. Sometimes patients need to try 2 or 3 different triptans to see which one is the most effective for them. If a patient has no success with tablets, there's a possibility that an injection or even a nasal spray would be more effective.
There are 2 triptans available as a nasal spray. I happen to like a triptan nasal spray called zolmitriptan, which usually works faster with fewer adverse events than the tablets.

There's also an injection of sumatriptan available, which is the fastest way to get relief from a triptan. Patients usually don't prefer it because it is an injection that they give themselves via an auto injector, and it may hurt and can be a bit complex to administer. There are definitely more adverse events when sumatriptan is given by injection, but because an injection can deliver very fast results that stop the headache reliably, some patients prefer it.

Triptans have been the mainstay treatment to stop an ongoing migraine attack for 30 years. We have always known there is some constriction of blood vessels and triptan-related side effects such as dizziness, drowsiness, and tingling sensations, so not every patient can take them. The newer medications that block calcitonin gene-related peptide (CGRP) do not constrict blood vessels and have fewer adverse events but cost a lot more if not covered by insurance.

Another newer, nontriptan nasal spray is dihydroergotamine (DHE) mesylate for acute care. It is one of the best medications to use if the patient’s migraine has been going on for 24 hours, as it tends to work well for a long-lasting headache. It also works for a long period, giving the patient a rest before their next attack. A nasal spray works faster than a tablet form, as the medication is absorbed from the nasal mucosa and does not have to make its way through the GI tract, then to the liver for metabolism, and finally, up to the brain before it begins to work. There can be some side effects in the nose such as discomfort or stuffiness, but if it works well, patients usually tolerate it. 

There's also a newer class of medicine called ditans. In a recent study, lasmiditan, which comes in a 50-mg and a 100-mg tablet for acute care of migraine, showed no vasoconstrictive effects, suggesting that ditans could be a safe option for patients living with chronic cardio- and cerebrovascular disease. Lasmiditan could be an alternative to triptans when they are contraindicated in patients with blood vessel disease, obesity, high blood pressure or cholesterol levels, or in nonresponsive patients. Lasmiditan does cause some dizziness and drowsiness, so patients cannot drive for 8 hours after taking it. However, it does have good efficacy.

When do you prescribe gepants?

Gepants are small-molecule CGRP receptor blockers. They are tablets that sit on the receptor, preventing the CGRP from docking on the receptor and increasing the headache during a migraine attack. There are 2 gepants that can be used to stop a headache that is just starting or in progress: ubrogepant and rimegepant. 

Ubrogepant is a regular tablet that is available in 50-mg or 100-mg strengths. If the first dose does not make a patient pain free, a second dose is recommended about 2 hours later. Rimegepant is a meltaway tablet and only comes in a 75-mg strength. It should be taken early in the attack, and usually the patient does not need further treatment that day. If they do, they need to switch to another treatment, as rimegepant should not be repeated that day. Rimegepant may be used for both acute care and prevention. It is the only tablet that can be used for both. 

Both drugs have been shown to provide pain freedom for about 20% of patients at 2 hours, which is statistically better than the patients that received the placebo. These drugs generally don’t cause many adverse events but can cause a little nausea or drowsiness in some patients. Ubrogepant has a few contraindications; patients on certain medications such as antibiotics or antifungals cannot take it. If a patient is not doing well on a triptan or should not be given a drug that constricts blood vessels, I often switch them to one of these gepants (if covered by insurance). Both drugs have a plan to let the patient try them at a low cost. 

How are the gepants used acutely?

Gepants are used just like a triptan. As soon as the patient has a migraine headache starting, they take either ubrogepant or rimegepant as quickly as possible. Some patients say they feel the gepant begin to work within an hour or less, and some patients say it doesn't work at all, so I have them try the other gepant. 

Gepants are probably a better option than triptans if the patient is >40 years because triptans can constrict blood vessels. Older patients, and certainly those who have any kind of cardiac or cerebral blood vessel issues or even peripheral blood vessel disease, should not be given triptans.

When do you consider using preventive treatment in migraine?

If a patient has ≥4 moderate-to-severe headache days a month, or fewer with severe disability, or does not respond to acute care medications or those drugs are contraindicated, I consider giving them preventive therapy for migraine. The goal is to decrease the number of migraine days per month and to decrease the intensity, duration, and disability of the attacks.

Which gepants can you use for prevention of migraine?

I discussed rimegepant as an acute care medication, but the same 75-mg meltaway tablet given every other day works preventively to decrease the number of headaches. I like it, as it has few adverse events—<3% of patients experience nausea and abdominal pain—and it can also be used to stop a headache on days the patient did not take a tablet.

Atogepant is a newer, US Food and Drug Administration (FDA)-approved gepant taken once daily by mouth for prevention of migraine, and it works to decrease headache days per month. It has more side effects than the other gepants, including constipation, drowsiness, and nausea. If a patient does not have many adverse events while taking it, it is a good migraine preventive. 

How do you feel about monoclonal antibodies that bind to CGRP or its receptor for migraine preventive treatment?

Before the gepants became available, 4 different pharmaceutical companies were making monoclonal antibodies (mAbs) that bind to either CGRP or its receptor. This class of medication can be quite effective for most patients needing migraine prevention, as these medications last for a long time if the patient keeps taking it. 

Antibodies, when injected, continue to work for 1 to 3 months, making them perfect for migraine prevention, but they must be given either by the patient using an autoinjector with a tiny needle or by intravenous (IV) infusion in a hospital or office. They tend to be quite effective and have few adverse events.  

The first one to come out was erenumab, then frenanezumab, and galcanezumab. The newest one is eptinezumab, given by IV infusion over 30 minutes. Erenumab is the only mAb that sits on the receptor to prevent the CGRP from docking on the receptor, and it's the only one that seems to cause adverse events such as constipation and increased blood pressure in some patients. Eptinezumab is the only drug in this category given by IV infusion; patients must come to the office to receive the injection every 3 months. Even though eptinezumab is a powerful drug, I find that patients generally don't like coming in for IV treatment. I reserve it for when a patient has failed several other preventive treatments. The other 3 drugs (erenumab, fremanezumab, galcanezumab) are subcutaneous injections that the patient can self-administer at home. Fremanezumab can be taken once a month or once every 3 months, depending on the dose prescribed. 

What migraine devices do you like to prescribe?

The device that I tend to have my patients use is called Nerivio®; it has been cleared by the FDA for acute treatment of migraine in patients ≥12 years. An article was just published in the journal Headache on its use in prevention of migraine. The company expects the FDA to clear it very soon for prevention when used for 45 minutes every other day.

Nerivio® is an electrical stimulator that is placed on the upper arm like a blood pressure cuff. It is battery-powered and links to an app on a smartphone. I have my patients turn it up slowly to a higher gain, and when they feel a slight discomfort, they lower down until they do not feel it. That's where I recommend that they keep it for 45 minutes of treatment, starting at the beginning of a migraine attack. 

Nerivio® also has a behavioral medicine program incorporated into the smartphone app that lasts for 25 minutes. While the patient is receiving the 45 minutes of electrical stimulation, they are also being guided through relaxation techniques to help ease the headache. The company has done a controlled study comparing the efficacy of Nerivio® with and without the behavioral treatment and found that the 2 together are more effective than Nerivio® alone. 

The early double-blind studies of this device, as sent to the FDA for clearance, have excellent efficacy data with very few adverse events. Thus, it is used by many patients. The company has arranged a lower cost for the first month of treatment so a patient can see whether the device is effective.

There's also a device called Relivion®, which is worn like a tiara on the head to stimulate 4 nerves above the eyebrows that are part of the trigeminal system and 2 in the back of the head that affect the occipital nerves.

One of the earliest devices to launch is the gammaCore vagal nerve stimulator. It is handheld and controlled by the patient. It is placed on the front and side of the neck in the region of the vagal nerve. For acute care of migraine, the patient stimulates for 2 minutes and then waits several minutes before repeating 2 minutes of treatment. If you want to prescribe it for the prevention of migraine, a patient could do this sequence twice per day. It has been approved for acute care and prevention of migraine and, along with other medication for cluster headaches, it is easy to use and approved for almost any kind of headache. Unfortunately, it is extremely expensive for patients and is not covered well by insurance unless the patient is a veteran or goes to a Veterans Health Administration hospital for care. 

There are a few other devices that also work for migraine. Most electrical stimulation devices are costly, but we do hope that insurance companies will begin to cover them soon. Most devices cause few adverse events, have few contraindications, and will be used more as they become more affordable.

Can you summarize migraine treatment for us in one paragraph?

No, but I will try. We have many acute care treatments for migraine that are effective. Some, such as the triptans, do constrict blood vessels, and certain patients should not be taking medications that affect blood vessels. Some medications cause certain side effects or take too long to work, and we have other options for those patients. If a patient has ≥4 headache days per month or fewer associated with a lot of disability, we need to consider prevention. We have older preventives such as beta blockers and epilepsy medications, which are less expensive and can work but usually have many side effects. Now we have 4 mAbs that bind to CGRP or its receptor, which work well for a month or more with few adverse events. We also have 2 oral gepants for prevention. When you add in several devices, I have so many options for my patients today that I am a lucky neurologist, and my patients are even luckier!

Medication overuse headache, previously known as rebound headache or medication-induced headache, may be caused by the frequent or excessive use of various acute care medications. When these medications are used too frequently, they can cause headaches rather than relieving them. (Some headache specialists feel that MOH is the result of recurring severe headaches, and the patients’ overuse of medications to relieve them.) These medications, some of which are painkillers or analgesics, include over-the-counter products such as acetaminophen, aspirin, and anti-inflammatories, as well as prescription medications such as triptans, ergots opioids, opioids, and barbiturates. The one category of acute care medication that does not seem to cause MOH is the gepants, such as rimegepant and ubrogepant.

MOH is the fourth most common headache disorder. It is defined by the International Classification of Headache Disorders (ICHD-3) as a headache present 15 days per month, evolving from regular use of strong acute medication (10 or more days of triptans, ergotamines, butalbital medications, opioids, or combination medications or 15 or more days per month of simple analgesics such as aspirin, acetaminophen, or nonsteroidal anti-inflammatories) for 3 months. 

Patients are usually not aware they have MOH, and this is the most problematic aspect of the condition. Patients do not realize that the medicine they are taking is making their headaches worse. It can be difficult to explain to the patient exactly what is going on with MOH, and why they are doing the wrong thing by taking the very medication that was prescribed by their doctor to stop a migraine attack. Many doctors do not fully understand MOH either, which can make it difficult to treat patients with this type of headache; therefore, it is imperative to educate both doctors and patients on the causes and treatments of MOH.

One of the most important facets of treating MOH traditionally has been the process of detoxifying patients from their overused medication by gradually or precipitously withdrawing the offending medication. There is variability in how detoxification can be accomplished. Some of my patients stopped medications abruptly and experienced very bad headaches. Others tried reducing dosages on their own and reported experiencing the worst headaches of their lives—some of which lasted for a few weeks. I have found that if patients can endure 2 to 3 weeks of detox, they start to feel better. But because the headaches can worsen before they get better, patients understandably try to avoid the detoxification process. 

I start patients on preventive medicine, then slowly increase it to an effective dose, and have them come back in a month for an evaluation. I then have them gradually reduce, but not completely stop, the pain medication before they return. Once I feel their preventive medication is at a therapeutic level, I have them begin a slow detox. After a month of preventive medication, there is a reasonable chance that headaches will start to decrease and be less severe. I tell them that if their headache is less severe try to avoid taking the medicine that they were overusing to prevent perpetuating the MOH.

One plausible physiologic mechanism behind MOH is that chronic exposure to acute care migraine treatment leads to suppression of the serotonergic/norepinephrinergic  endogenous antinociceptive system in the upper brain stem, with facilitation of the trigeminal nociceptive process via up-regulation of calcitonin gene-related peptide (CGRP).This increase in CGRP at the end of peripheral nerve terminals in the trigeminovascular system may facilitate pain transmission. An increase in cortical CGRP may cause cortical spreading depression: a wave of excitement traveling through the cortex, followed by a wave of electrical depression seems to cause headache.  

Good, effective prevention often helps avoid MOH; medications such as topiramate, nortriptyline, gabapentin, onabotulinumtoxinA, and CGRP monoclonal antibodies or some type of local nerve block have improved MOH in patients, but detoxification is usually necessary is some patients. 

Monoclonal antibodies targeting CGRP or its receptor (CGRP-R), given by subcutaneous or intravenous injection or small molecule CGRP receptor antagonists given orally (gepants), seem to be able to treat MOH in some patients without a detoxification. This has been best demonstrated in the monoclonal antibody group, but there is some evidence showing that it may also occur with gepants. These treatments seem to work even when patients are overusing acute care medications; this helps some patients to self-detoxify at their own pace, which is easier for both the patient and the doctor.

Currently, there are 4 monoclonal antibodies against CGRP or the CGRP-R. Erenumab is the only completely human one and the only antibody that blocks the CGRP receptor to prevent the CGRP ligand from docking and exerting its effect. The other 3 (fremanezumab, galcanezumab, and eptinezumab) are humanized monoclonal antibodies that selectively bind to the CGRP ligand, preventing it from docking on its receptor.  Patients started on the monoclonal antibodies against CGRP or its receptor usually have fewer headaches in the first week or two of therapy, and this helps make the self-detox easier for the patient. 

Further, substantial data have shown that onabotulinumtoxinA reduces the number/frequency of headaches and reduces the need for patients to take acute medication. OnabotulinumtoxinA is currently the only medication approved for preventive treatment of chronic migraine; it has long-term safety data available and has reported efficacy lasting for up to 3 years when given in multiple injection sites every 3 months. Interestingly, although topiramate is used as a preventive medication, a recent study comparing erenumab vs topiramate for reducing monthly migraine days (MMD) showed that erenumab outperformed topiramate with a 50% reduction in MMD, and with fewer reported adverse events.

We are just starting to learn about some other potential cellular mechanisms that could be causing MOH in patients; these data could help create new and improved therapies for treating and possibly preventing MOH in the future. Patient outcomes could also be improved by encouraging the inclusion of MOH as part of a continuing education program for physicians who could potentially be treating new patients presenting with MOH. 

Medication overuse headache, previously known as rebound headache or medication-induced headache, may be caused by the frequent or excessive use of various acute care medications. When these medications are used too frequently, they can cause headaches rather than relieving them. (Some headache specialists feel that MOH is the result of recurring severe headaches, and the patients’ overuse of medications to relieve them.) These medications, some of which are painkillers or analgesics, include over-the-counter products such as acetaminophen, aspirin, and anti-inflammatories, as well as prescription medications such as triptans, ergots opioids, opioids, and barbiturates. The one category of acute care medication that does not seem to cause MOH is the gepants, such as rimegepant and ubrogepant.

MOH is the fourth most common headache disorder. It is defined by the International Classification of Headache Disorders (ICHD-3) as a headache present 15 days per month, evolving from regular use of strong acute medication (10 or more days of triptans, ergotamines, butalbital medications, opioids, or combination medications or 15 or more days per month of simple analgesics such as aspirin, acetaminophen, or nonsteroidal anti-inflammatories) for 3 months. 

Patients are usually not aware they have MOH, and this is the most problematic aspect of the condition. Patients do not realize that the medicine they are taking is making their headaches worse. It can be difficult to explain to the patient exactly what is going on with MOH, and why they are doing the wrong thing by taking the very medication that was prescribed by their doctor to stop a migraine attack. Many doctors do not fully understand MOH either, which can make it difficult to treat patients with this type of headache; therefore, it is imperative to educate both doctors and patients on the causes and treatments of MOH.

One of the most important facets of treating MOH traditionally has been the process of detoxifying patients from their overused medication by gradually or precipitously withdrawing the offending medication. There is variability in how detoxification can be accomplished. Some of my patients stopped medications abruptly and experienced very bad headaches. Others tried reducing dosages on their own and reported experiencing the worst headaches of their lives—some of which lasted for a few weeks. I have found that if patients can endure 2 to 3 weeks of detox, they start to feel better. But because the headaches can worsen before they get better, patients understandably try to avoid the detoxification process. 

I start patients on preventive medicine, then slowly increase it to an effective dose, and have them come back in a month for an evaluation. I then have them gradually reduce, but not completely stop, the pain medication before they return. Once I feel their preventive medication is at a therapeutic level, I have them begin a slow detox. After a month of preventive medication, there is a reasonable chance that headaches will start to decrease and be less severe. I tell them that if their headache is less severe try to avoid taking the medicine that they were overusing to prevent perpetuating the MOH.

One plausible physiologic mechanism behind MOH is that chronic exposure to acute care migraine treatment leads to suppression of the serotonergic/norepinephrinergic  endogenous antinociceptive system in the upper brain stem, with facilitation of the trigeminal nociceptive process via up-regulation of calcitonin gene-related peptide (CGRP).This increase in CGRP at the end of peripheral nerve terminals in the trigeminovascular system may facilitate pain transmission. An increase in cortical CGRP may cause cortical spreading depression: a wave of excitement traveling through the cortex, followed by a wave of electrical depression seems to cause headache.  

Good, effective prevention often helps avoid MOH; medications such as topiramate, nortriptyline, gabapentin, onabotulinumtoxinA, and CGRP monoclonal antibodies or some type of local nerve block have improved MOH in patients, but detoxification is usually necessary is some patients. 

Monoclonal antibodies targeting CGRP or its receptor (CGRP-R), given by subcutaneous or intravenous injection or small molecule CGRP receptor antagonists given orally (gepants), seem to be able to treat MOH in some patients without a detoxification. This has been best demonstrated in the monoclonal antibody group, but there is some evidence showing that it may also occur with gepants. These treatments seem to work even when patients are overusing acute care medications; this helps some patients to self-detoxify at their own pace, which is easier for both the patient and the doctor.

Currently, there are 4 monoclonal antibodies against CGRP or the CGRP-R. Erenumab is the only completely human one and the only antibody that blocks the CGRP receptor to prevent the CGRP ligand from docking and exerting its effect. The other 3 (fremanezumab, galcanezumab, and eptinezumab) are humanized monoclonal antibodies that selectively bind to the CGRP ligand, preventing it from docking on its receptor.  Patients started on the monoclonal antibodies against CGRP or its receptor usually have fewer headaches in the first week or two of therapy, and this helps make the self-detox easier for the patient. 

Further, substantial data have shown that onabotulinumtoxinA reduces the number/frequency of headaches and reduces the need for patients to take acute medication. OnabotulinumtoxinA is currently the only medication approved for preventive treatment of chronic migraine; it has long-term safety data available and has reported efficacy lasting for up to 3 years when given in multiple injection sites every 3 months. Interestingly, although topiramate is used as a preventive medication, a recent study comparing erenumab vs topiramate for reducing monthly migraine days (MMD) showed that erenumab outperformed topiramate with a 50% reduction in MMD, and with fewer reported adverse events.

We are just starting to learn about some other potential cellular mechanisms that could be causing MOH in patients; these data could help create new and improved therapies for treating and possibly preventing MOH in the future. Patient outcomes could also be improved by encouraging the inclusion of MOH as part of a continuing education program for physicians who could potentially be treating new patients presenting with MOH. 

Medication overuse headache, previously known as rebound headache or medication-induced headache, may be caused by the frequent or excessive use of various acute care medications. When these medications are used too frequently, they can cause headaches rather than relieving them. (Some headache specialists feel that MOH is the result of recurring severe headaches, and the patients’ overuse of medications to relieve them.) These medications, some of which are painkillers or analgesics, include over-the-counter products such as acetaminophen, aspirin, and anti-inflammatories, as well as prescription medications such as triptans, ergots opioids, opioids, and barbiturates. The one category of acute care medication that does not seem to cause MOH is the gepants, such as rimegepant and ubrogepant.

MOH is the fourth most common headache disorder. It is defined by the International Classification of Headache Disorders (ICHD-3) as a headache present 15 days per month, evolving from regular use of strong acute medication (10 or more days of triptans, ergotamines, butalbital medications, opioids, or combination medications or 15 or more days per month of simple analgesics such as aspirin, acetaminophen, or nonsteroidal anti-inflammatories) for 3 months. 

Patients are usually not aware they have MOH, and this is the most problematic aspect of the condition. Patients do not realize that the medicine they are taking is making their headaches worse. It can be difficult to explain to the patient exactly what is going on with MOH, and why they are doing the wrong thing by taking the very medication that was prescribed by their doctor to stop a migraine attack. Many doctors do not fully understand MOH either, which can make it difficult to treat patients with this type of headache; therefore, it is imperative to educate both doctors and patients on the causes and treatments of MOH.

One of the most important facets of treating MOH traditionally has been the process of detoxifying patients from their overused medication by gradually or precipitously withdrawing the offending medication. There is variability in how detoxification can be accomplished. Some of my patients stopped medications abruptly and experienced very bad headaches. Others tried reducing dosages on their own and reported experiencing the worst headaches of their lives—some of which lasted for a few weeks. I have found that if patients can endure 2 to 3 weeks of detox, they start to feel better. But because the headaches can worsen before they get better, patients understandably try to avoid the detoxification process. 

I start patients on preventive medicine, then slowly increase it to an effective dose, and have them come back in a month for an evaluation. I then have them gradually reduce, but not completely stop, the pain medication before they return. Once I feel their preventive medication is at a therapeutic level, I have them begin a slow detox. After a month of preventive medication, there is a reasonable chance that headaches will start to decrease and be less severe. I tell them that if their headache is less severe try to avoid taking the medicine that they were overusing to prevent perpetuating the MOH.

One plausible physiologic mechanism behind MOH is that chronic exposure to acute care migraine treatment leads to suppression of the serotonergic/norepinephrinergic  endogenous antinociceptive system in the upper brain stem, with facilitation of the trigeminal nociceptive process via up-regulation of calcitonin gene-related peptide (CGRP).This increase in CGRP at the end of peripheral nerve terminals in the trigeminovascular system may facilitate pain transmission. An increase in cortical CGRP may cause cortical spreading depression: a wave of excitement traveling through the cortex, followed by a wave of electrical depression seems to cause headache.  

Good, effective prevention often helps avoid MOH; medications such as topiramate, nortriptyline, gabapentin, onabotulinumtoxinA, and CGRP monoclonal antibodies or some type of local nerve block have improved MOH in patients, but detoxification is usually necessary is some patients. 

Monoclonal antibodies targeting CGRP or its receptor (CGRP-R), given by subcutaneous or intravenous injection or small molecule CGRP receptor antagonists given orally (gepants), seem to be able to treat MOH in some patients without a detoxification. This has been best demonstrated in the monoclonal antibody group, but there is some evidence showing that it may also occur with gepants. These treatments seem to work even when patients are overusing acute care medications; this helps some patients to self-detoxify at their own pace, which is easier for both the patient and the doctor.

Currently, there are 4 monoclonal antibodies against CGRP or the CGRP-R. Erenumab is the only completely human one and the only antibody that blocks the CGRP receptor to prevent the CGRP ligand from docking and exerting its effect. The other 3 (fremanezumab, galcanezumab, and eptinezumab) are humanized monoclonal antibodies that selectively bind to the CGRP ligand, preventing it from docking on its receptor.  Patients started on the monoclonal antibodies against CGRP or its receptor usually have fewer headaches in the first week or two of therapy, and this helps make the self-detox easier for the patient. 

Further, substantial data have shown that onabotulinumtoxinA reduces the number/frequency of headaches and reduces the need for patients to take acute medication. OnabotulinumtoxinA is currently the only medication approved for preventive treatment of chronic migraine; it has long-term safety data available and has reported efficacy lasting for up to 3 years when given in multiple injection sites every 3 months. Interestingly, although topiramate is used as a preventive medication, a recent study comparing erenumab vs topiramate for reducing monthly migraine days (MMD) showed that erenumab outperformed topiramate with a 50% reduction in MMD, and with fewer reported adverse events.

We are just starting to learn about some other potential cellular mechanisms that could be causing MOH in patients; these data could help create new and improved therapies for treating and possibly preventing MOH in the future. Patient outcomes could also be improved by encouraging the inclusion of MOH as part of a continuing education program for physicians who could potentially be treating new patients presenting with MOH. 

Since the mid-2010s, the US Food and Drug Administration (FDA) has approved or cleared no fewer than 10 migraine treatments in the form of orals, injectables, nasal sprays, and devices. The medical achievements of the last decade in the field of migraine have been nothing less than stunning for physicians and their patients, whether they relied on off-label medications or those sanctioned by the FDA to treat patients living with migraine.

That said, the newer orals and injectables cannot help everyone living with migraine. The small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and the monoclonal antibodies that target the CGRP ligand or receptor, while well received by patients and physicians alike, have drawbacks for some patients, including lack of efficacy, slow response rate, and adverse events that prevent some patients from taking them. The gepants, which are oral medications—as opposed to the CGRP monoclonal antibody injectables—can occasionally cause enough nausea, drowsiness, and constipation for patients to choose to discontinue their use.

Certain patients have other reasons to shun orals and injectables. Some cannot swallow pills while others fear or do not tolerate injections. Insurance companies limit the quantity of acute care medications, so some patients cannot treat every migraine attack. Then there are those who have failed so many therapies in the past that they will not try the latest one. Consequently, some lie in bed, vomiting until the pain is gone, and some take too many over-the-counter or migraine-specific products, which make migraine symptoms worse if they develop medication overuse headache. And lastly, there are patients who have never walked through a physician’s door to secure a migraine diagnosis and get appropriate treatment.

Non interventional medical devices cleared by the FDA now allow physicians to offer relief to patients with migraine. They work either through various types of electrical neuromodulation to nerves outside the brain or they apply magnetic stimulation to the back of the brain itself to reach pain-associated pathways. A 2019 report on pain management from the US Department of Health and Human Services noted that some randomized control trials (RCTs) and other studies “have demonstrated that noninvasive vagal nerve stimulation can be effective in ameliorating pain in various types of cluster headaches and migraines.”

At least 3 devices, 1 designed to stimulate both the occipital and trigeminal nerves (eCOT-NS, Relivion, Neurolief Ltd), 1 that stimulates the vagus nerve noninvasively (nVNS, gammaCORE, electroCore), and 1 that stimulates peripheral nerves in the upper arm (remote electrical neuromodulation [REN], Nerivio, Theranica Bio-Electronics Ltd), are FDA cleared to treat episodic and chronic migraine. nVNS is also cleared to treat migraine, episodic cluster headache acutely, and chronic cluster acutely in connection with medication.

Real-world studies on all migraine treatments, especially the devices, are flooding PubMed. As for a physician’s observation, we will get to that shortly.

The Devices

Nerivio

Theranica Bio-Electronics Ltd makes a REN called Nerivio, which was FDA cleared in January 2021 to treat episodic migraine acutely in adults and adolescents. Studies have shown its effectiveness for chronic migraine patients who are treated acutely, and it has also helped patients with menstrual migraine. The patient wears the device on the upper arm. Sensory fibers, once stimulated in the arm, send an impulse to the brainstem to affect the serotonin- and norepinephrine-modulated descending inhibitory pathway to disrupt incoming pain messaging. Theranica has applied to the FDA for clearance to treat patients with chronic migraine, as well as for prevention.

Relivion

Neurolief Ltd created the external combined occipital and trigeminal nerve stimulation device (eCOT-NS), which stimulates both the occipital and trigeminal nerves. It has multiple output electrodes, which are placed on the forehead to stimulate the trigeminal supraorbital and supratrochlear nerve branches bilaterally, and over the occipital nerves in the back of the head. It is worn like a tiara as it must be in good contact with the forehead and the back of the head simultaneously. It is FDA cleared to treat acute migraine.

gammaCORE

gammaCORE is a nVNS device that is FDA cleared for acute and preventive treatment of migraine in adolescents and adults, and acute and preventive treatment of episodic cluster headache in adults. It is also cleared to treat chronic cluster headache acutely along with medication. The patient applies gel to the device’s 2 electrical contacts and then locates the vagus nerve on the side of the neck and applies the electrodes to the area that will be treated. Patients can adjust the stimulation’s intensity so that they can barely feel the stimulation; it has not been reported to be painful. nVNS is also an FDA cleared treatment for paroxysmal hemicrania and hemicrania continua. 

SAVI Dual

The s-TMS (SAVI Dual, formerly called the Spring TMS and the sTMS mini), made by eNeura, is a single-pulse, transcranial magnetic stimulation applied to the back of the head to stimulate the occipital lobes in the brain. It was FDA cleared for acute and preventive care of migraine in adolescents over 12 years and for adults in February 2019. The patient holds a handheld magnetic device against their occiput, and when the tool is discharged, a brief magnetic pulse interrupts the pattern of neuronal firing (probably cortical spreading depression) that can trigger migraine and the visual aura associated with migraine in one-third of patients.

Cefaly

The e-TNS (Cefaly) works by external trigeminal nerve stimulation of the supraorbital and trochlear nerves bilaterally in the forehead. It gradually and automatically increases in intensity and can be controlled by the patient. It is FDA cleared for acute and preventive treatment of migraine, and, unlike the other devices, it is sold over the counter without a prescription. According to the company website, there are 3 devices: 1 is for acute treatment, 1 is for preventive treatment, and 1 device has 2 settings for both acute and preventive treatment.

The Studies

While most of the published studies on devices are company-sponsored, these device makers have underwritten numerous, sometimes very well-designed, studies on their products. A review by VanderPluym et al described those studies and their various risks of bias. 

There are at least 10 studies on REN published so far. These include 2 randomized, sham-controlled trials looking at pain freedom and pain relief at 2 hours after stimulation begins. Another study detailed treatment reports from many patients in which 66.5% experienced pain relief at 2 hours post treatment initiation in half of their treatments. A subgroup of 16% of those patients were prescribed REN by their primary care physicians. Of that group, 77.8% experienced pain relief in half their treatments. That figure was very close to another study that found that 23 of 31 (74.2%) of the study patients treated virtually by non headache providers found relief in 50% of their headaches. REN comes with an education and behavioral medicine app that is used during treatment. A study done by the company shows that when a patient uses the relaxation app along with the standard stimulation, they do considerably better than with stimulation alone.

The eCOT-NS has also been tested in an RCT. At 2 hours, the responder rate was twice as high as in the sham group (66.7% vs 32%). Overall headache relief at 2 hours was higher in the responder group (76% vs 31.6%). In a study collecting real-world data on the efficacy of eCOT-NS in the preventive treatment of migraine (abstract data were presented at the American Headache Society meeting in June 2022), there was a 65.3% reduction in monthly migraine days (MMD) from baseline through 6 months. Treatment reduced MMD by 10.0 (from 15.3 to 5.3—a 76.8% reduction), and reduced acute medication use days (12.5 at baseline to 2.9) at 6 months.

Users of nVNS discussed their experiences with the device, which is the size of a large bar of soap, in a patient registry. They reported 192 attacks, with a mean pain score starting at 2.7 and dropping to 1.3 after 30 minutes. The pain levels of 70% of the attacks dropped to either mild or nonexistent. In a multicenter study on nNVS, 48 patients and 44 sham patients with episodic and chronic cluster headache showed no significant difference in the primary endpoint of pain freedom at 15 minutes between the nVNS and sham. There was also no difference in the chronic cluster headache group. But the episodic cluster subgroup showed a difference; nVNS was superior to sham, 48% to 6% (P ≤ 0.01). Those in the chronic cluster headache group reported a lower percentage of pain-free status than the sham group (5% vs 13%). In another study of 477 patients, those patients who adhered to treatment more than 67% of the time per month showed a reduction in migraine days (2.27 vs 1.53). Patients with aura also fared better than those without aura.

The e-TNS device is cleared for treating adults with migraine, acutely and preventively. It received initial clearance in 2017; in 2020, Cefaly Technology received clearance from the FDA to sell its products over the counter. The device, which resembles a large diamond that affixes to the forehead, has received differing reviews between various patient reports (found online at major retailer sites) and study results. In a blinded, intent-to-treat study involving 538 patients, 25.5% of the verum group reported they were pain-free at 2 hours; 18.3% in the sham group reported the same. Additionally, 56.4% of the subjects in the verum group reported they were free of the most bothersome migraine symptoms, as opposed to 42.3% of the sham group.

Adverse Events

The adverse events observed with these devices were, overall, relatively mild, and disappeared once the device was shut off. A few nVNS users said they experienced discomfort at the application site. With REN, 59 of 12,368 patients reported device-related issues; the vast majority were considered mild and consisted mostly of a sensation of warmth under the device. Of the 259 e-TNS  users, 8.5% reported minor and reversible occurrences, such as treatment-related discomfort, paresthesia, and burning.

Patients in the Clinic

A few observations from the clinic regarding these devices:

Some devices are easier to use than others. I know this, because at a recent demonstration session in a course for physicians on headache treatment, I agreed to be the person on whom the device was demonstrated. The physician applying the device had difficulty aligning the device’s sensors with the appropriate nerves. Making sure your patients use these devices correctly is essential, and you or your staff should demonstrate their use to the patient. No doubt, this could be time-consuming in some cases, and patients who are reading the device’s instructions while in pain will likely get frustrated if they cannot get the device to work. 

Some patients who have failed every medication class can occasionally find partial relief with these devices. One longtime patient of mine came to me severely disabled from chronic migraine and medication overuse headache but was somewhat better with 2 preventive medications. Triptans worked acutely, but she developed nearly every side effect imaginable. I was able to reverse her medication overuse headache, but the gepants, although they worked somewhat, took too long to take effect. We agreed the next step would be to use REN for each migraine attack, combined with acute care medication if necessary. (She uses REN alone for a milder headache and adds a gepant with naproxen if necessary.) She has found using the relaxation module on the REN app increases her chances of eliminating the migraine. She is not pain free all the time, but she appreciates the pain-free intervals.

One chronic cluster patient has relied on subcutaneous sumatriptan and breathing 100% oxygen at 12 liters per minute through a mask over his nose and mouth for acute relief from his headaches. His headache pain can climb from a 3 to a 10 in a matter of minutes. It starts behind and a bit above the right eye where he feels a tremendous pressure building up. He says that at times it feels like a screwdriver has been thrust into his eye and is being turned. Along with the pain, the eye becomes red, the pupil constricts, and the eyelid droops. He also has dripping from the right nostril, which stuffs up when the pain abates. The pain lasts for 1 to 2 hours, then returns 3 to 5 times a day for 5 days a week, on average. The pain never goes away for more than 3 weeks in a year’s time, hence the reason for his chronic cluster headache diagnosis.  He is now using nVNS as soon as he feels the pain coming on. If the device does not provide sufficient relief, he uses oxygen or takes the sumatriptan injection.

Some patients who get cluster headaches think of suicide if the pain cannot be stopped; but in my experience, most can become pain free, or at least realize some partial relief from a variety of treatments (sometimes given at the same time).

Doctors often do not think of devices as options, and some doctors think devices do not work even though they have no experience with using them. Devices can give good relief on their own, and when a severe headache needs stronger treatment, medications added to a device usually work better than either treatment alone.

Since the mid-2010s, the US Food and Drug Administration (FDA) has approved or cleared no fewer than 10 migraine treatments in the form of orals, injectables, nasal sprays, and devices. The medical achievements of the last decade in the field of migraine have been nothing less than stunning for physicians and their patients, whether they relied on off-label medications or those sanctioned by the FDA to treat patients living with migraine.

That said, the newer orals and injectables cannot help everyone living with migraine. The small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and the monoclonal antibodies that target the CGRP ligand or receptor, while well received by patients and physicians alike, have drawbacks for some patients, including lack of efficacy, slow response rate, and adverse events that prevent some patients from taking them. The gepants, which are oral medications—as opposed to the CGRP monoclonal antibody injectables—can occasionally cause enough nausea, drowsiness, and constipation for patients to choose to discontinue their use.

Certain patients have other reasons to shun orals and injectables. Some cannot swallow pills while others fear or do not tolerate injections. Insurance companies limit the quantity of acute care medications, so some patients cannot treat every migraine attack. Then there are those who have failed so many therapies in the past that they will not try the latest one. Consequently, some lie in bed, vomiting until the pain is gone, and some take too many over-the-counter or migraine-specific products, which make migraine symptoms worse if they develop medication overuse headache. And lastly, there are patients who have never walked through a physician’s door to secure a migraine diagnosis and get appropriate treatment.

Non interventional medical devices cleared by the FDA now allow physicians to offer relief to patients with migraine. They work either through various types of electrical neuromodulation to nerves outside the brain or they apply magnetic stimulation to the back of the brain itself to reach pain-associated pathways. A 2019 report on pain management from the US Department of Health and Human Services noted that some randomized control trials (RCTs) and other studies “have demonstrated that noninvasive vagal nerve stimulation can be effective in ameliorating pain in various types of cluster headaches and migraines.”

At least 3 devices, 1 designed to stimulate both the occipital and trigeminal nerves (eCOT-NS, Relivion, Neurolief Ltd), 1 that stimulates the vagus nerve noninvasively (nVNS, gammaCORE, electroCore), and 1 that stimulates peripheral nerves in the upper arm (remote electrical neuromodulation [REN], Nerivio, Theranica Bio-Electronics Ltd), are FDA cleared to treat episodic and chronic migraine. nVNS is also cleared to treat migraine, episodic cluster headache acutely, and chronic cluster acutely in connection with medication.

Real-world studies on all migraine treatments, especially the devices, are flooding PubMed. As for a physician’s observation, we will get to that shortly.

The Devices

Nerivio

Theranica Bio-Electronics Ltd makes a REN called Nerivio, which was FDA cleared in January 2021 to treat episodic migraine acutely in adults and adolescents. Studies have shown its effectiveness for chronic migraine patients who are treated acutely, and it has also helped patients with menstrual migraine. The patient wears the device on the upper arm. Sensory fibers, once stimulated in the arm, send an impulse to the brainstem to affect the serotonin- and norepinephrine-modulated descending inhibitory pathway to disrupt incoming pain messaging. Theranica has applied to the FDA for clearance to treat patients with chronic migraine, as well as for prevention.

Relivion

Neurolief Ltd created the external combined occipital and trigeminal nerve stimulation device (eCOT-NS), which stimulates both the occipital and trigeminal nerves. It has multiple output electrodes, which are placed on the forehead to stimulate the trigeminal supraorbital and supratrochlear nerve branches bilaterally, and over the occipital nerves in the back of the head. It is worn like a tiara as it must be in good contact with the forehead and the back of the head simultaneously. It is FDA cleared to treat acute migraine.

gammaCORE

gammaCORE is a nVNS device that is FDA cleared for acute and preventive treatment of migraine in adolescents and adults, and acute and preventive treatment of episodic cluster headache in adults. It is also cleared to treat chronic cluster headache acutely along with medication. The patient applies gel to the device’s 2 electrical contacts and then locates the vagus nerve on the side of the neck and applies the electrodes to the area that will be treated. Patients can adjust the stimulation’s intensity so that they can barely feel the stimulation; it has not been reported to be painful. nVNS is also an FDA cleared treatment for paroxysmal hemicrania and hemicrania continua. 

SAVI Dual

The s-TMS (SAVI Dual, formerly called the Spring TMS and the sTMS mini), made by eNeura, is a single-pulse, transcranial magnetic stimulation applied to the back of the head to stimulate the occipital lobes in the brain. It was FDA cleared for acute and preventive care of migraine in adolescents over 12 years and for adults in February 2019. The patient holds a handheld magnetic device against their occiput, and when the tool is discharged, a brief magnetic pulse interrupts the pattern of neuronal firing (probably cortical spreading depression) that can trigger migraine and the visual aura associated with migraine in one-third of patients.

Cefaly

The e-TNS (Cefaly) works by external trigeminal nerve stimulation of the supraorbital and trochlear nerves bilaterally in the forehead. It gradually and automatically increases in intensity and can be controlled by the patient. It is FDA cleared for acute and preventive treatment of migraine, and, unlike the other devices, it is sold over the counter without a prescription. According to the company website, there are 3 devices: 1 is for acute treatment, 1 is for preventive treatment, and 1 device has 2 settings for both acute and preventive treatment.

The Studies

While most of the published studies on devices are company-sponsored, these device makers have underwritten numerous, sometimes very well-designed, studies on their products. A review by VanderPluym et al described those studies and their various risks of bias. 

There are at least 10 studies on REN published so far. These include 2 randomized, sham-controlled trials looking at pain freedom and pain relief at 2 hours after stimulation begins. Another study detailed treatment reports from many patients in which 66.5% experienced pain relief at 2 hours post treatment initiation in half of their treatments. A subgroup of 16% of those patients were prescribed REN by their primary care physicians. Of that group, 77.8% experienced pain relief in half their treatments. That figure was very close to another study that found that 23 of 31 (74.2%) of the study patients treated virtually by non headache providers found relief in 50% of their headaches. REN comes with an education and behavioral medicine app that is used during treatment. A study done by the company shows that when a patient uses the relaxation app along with the standard stimulation, they do considerably better than with stimulation alone.

The eCOT-NS has also been tested in an RCT. At 2 hours, the responder rate was twice as high as in the sham group (66.7% vs 32%). Overall headache relief at 2 hours was higher in the responder group (76% vs 31.6%). In a study collecting real-world data on the efficacy of eCOT-NS in the preventive treatment of migraine (abstract data were presented at the American Headache Society meeting in June 2022), there was a 65.3% reduction in monthly migraine days (MMD) from baseline through 6 months. Treatment reduced MMD by 10.0 (from 15.3 to 5.3—a 76.8% reduction), and reduced acute medication use days (12.5 at baseline to 2.9) at 6 months.

Users of nVNS discussed their experiences with the device, which is the size of a large bar of soap, in a patient registry. They reported 192 attacks, with a mean pain score starting at 2.7 and dropping to 1.3 after 30 minutes. The pain levels of 70% of the attacks dropped to either mild or nonexistent. In a multicenter study on nNVS, 48 patients and 44 sham patients with episodic and chronic cluster headache showed no significant difference in the primary endpoint of pain freedom at 15 minutes between the nVNS and sham. There was also no difference in the chronic cluster headache group. But the episodic cluster subgroup showed a difference; nVNS was superior to sham, 48% to 6% (P ≤ 0.01). Those in the chronic cluster headache group reported a lower percentage of pain-free status than the sham group (5% vs 13%). In another study of 477 patients, those patients who adhered to treatment more than 67% of the time per month showed a reduction in migraine days (2.27 vs 1.53). Patients with aura also fared better than those without aura.

The e-TNS device is cleared for treating adults with migraine, acutely and preventively. It received initial clearance in 2017; in 2020, Cefaly Technology received clearance from the FDA to sell its products over the counter. The device, which resembles a large diamond that affixes to the forehead, has received differing reviews between various patient reports (found online at major retailer sites) and study results. In a blinded, intent-to-treat study involving 538 patients, 25.5% of the verum group reported they were pain-free at 2 hours; 18.3% in the sham group reported the same. Additionally, 56.4% of the subjects in the verum group reported they were free of the most bothersome migraine symptoms, as opposed to 42.3% of the sham group.

Adverse Events

The adverse events observed with these devices were, overall, relatively mild, and disappeared once the device was shut off. A few nVNS users said they experienced discomfort at the application site. With REN, 59 of 12,368 patients reported device-related issues; the vast majority were considered mild and consisted mostly of a sensation of warmth under the device. Of the 259 e-TNS  users, 8.5% reported minor and reversible occurrences, such as treatment-related discomfort, paresthesia, and burning.

Patients in the Clinic

A few observations from the clinic regarding these devices:

Some devices are easier to use than others. I know this, because at a recent demonstration session in a course for physicians on headache treatment, I agreed to be the person on whom the device was demonstrated. The physician applying the device had difficulty aligning the device’s sensors with the appropriate nerves. Making sure your patients use these devices correctly is essential, and you or your staff should demonstrate their use to the patient. No doubt, this could be time-consuming in some cases, and patients who are reading the device’s instructions while in pain will likely get frustrated if they cannot get the device to work. 

Some patients who have failed every medication class can occasionally find partial relief with these devices. One longtime patient of mine came to me severely disabled from chronic migraine and medication overuse headache but was somewhat better with 2 preventive medications. Triptans worked acutely, but she developed nearly every side effect imaginable. I was able to reverse her medication overuse headache, but the gepants, although they worked somewhat, took too long to take effect. We agreed the next step would be to use REN for each migraine attack, combined with acute care medication if necessary. (She uses REN alone for a milder headache and adds a gepant with naproxen if necessary.) She has found using the relaxation module on the REN app increases her chances of eliminating the migraine. She is not pain free all the time, but she appreciates the pain-free intervals.

One chronic cluster patient has relied on subcutaneous sumatriptan and breathing 100% oxygen at 12 liters per minute through a mask over his nose and mouth for acute relief from his headaches. His headache pain can climb from a 3 to a 10 in a matter of minutes. It starts behind and a bit above the right eye where he feels a tremendous pressure building up. He says that at times it feels like a screwdriver has been thrust into his eye and is being turned. Along with the pain, the eye becomes red, the pupil constricts, and the eyelid droops. He also has dripping from the right nostril, which stuffs up when the pain abates. The pain lasts for 1 to 2 hours, then returns 3 to 5 times a day for 5 days a week, on average. The pain never goes away for more than 3 weeks in a year’s time, hence the reason for his chronic cluster headache diagnosis.  He is now using nVNS as soon as he feels the pain coming on. If the device does not provide sufficient relief, he uses oxygen or takes the sumatriptan injection.

Some patients who get cluster headaches think of suicide if the pain cannot be stopped; but in my experience, most can become pain free, or at least realize some partial relief from a variety of treatments (sometimes given at the same time).

Doctors often do not think of devices as options, and some doctors think devices do not work even though they have no experience with using them. Devices can give good relief on their own, and when a severe headache needs stronger treatment, medications added to a device usually work better than either treatment alone.

Since the mid-2010s, the US Food and Drug Administration (FDA) has approved or cleared no fewer than 10 migraine treatments in the form of orals, injectables, nasal sprays, and devices. The medical achievements of the last decade in the field of migraine have been nothing less than stunning for physicians and their patients, whether they relied on off-label medications or those sanctioned by the FDA to treat patients living with migraine.

That said, the newer orals and injectables cannot help everyone living with migraine. The small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and the monoclonal antibodies that target the CGRP ligand or receptor, while well received by patients and physicians alike, have drawbacks for some patients, including lack of efficacy, slow response rate, and adverse events that prevent some patients from taking them. The gepants, which are oral medications—as opposed to the CGRP monoclonal antibody injectables—can occasionally cause enough nausea, drowsiness, and constipation for patients to choose to discontinue their use.

Certain patients have other reasons to shun orals and injectables. Some cannot swallow pills while others fear or do not tolerate injections. Insurance companies limit the quantity of acute care medications, so some patients cannot treat every migraine attack. Then there are those who have failed so many therapies in the past that they will not try the latest one. Consequently, some lie in bed, vomiting until the pain is gone, and some take too many over-the-counter or migraine-specific products, which make migraine symptoms worse if they develop medication overuse headache. And lastly, there are patients who have never walked through a physician’s door to secure a migraine diagnosis and get appropriate treatment.

Non interventional medical devices cleared by the FDA now allow physicians to offer relief to patients with migraine. They work either through various types of electrical neuromodulation to nerves outside the brain or they apply magnetic stimulation to the back of the brain itself to reach pain-associated pathways. A 2019 report on pain management from the US Department of Health and Human Services noted that some randomized control trials (RCTs) and other studies “have demonstrated that noninvasive vagal nerve stimulation can be effective in ameliorating pain in various types of cluster headaches and migraines.”

At least 3 devices, 1 designed to stimulate both the occipital and trigeminal nerves (eCOT-NS, Relivion, Neurolief Ltd), 1 that stimulates the vagus nerve noninvasively (nVNS, gammaCORE, electroCore), and 1 that stimulates peripheral nerves in the upper arm (remote electrical neuromodulation [REN], Nerivio, Theranica Bio-Electronics Ltd), are FDA cleared to treat episodic and chronic migraine. nVNS is also cleared to treat migraine, episodic cluster headache acutely, and chronic cluster acutely in connection with medication.

Real-world studies on all migraine treatments, especially the devices, are flooding PubMed. As for a physician’s observation, we will get to that shortly.

The Devices

Nerivio

Theranica Bio-Electronics Ltd makes a REN called Nerivio, which was FDA cleared in January 2021 to treat episodic migraine acutely in adults and adolescents. Studies have shown its effectiveness for chronic migraine patients who are treated acutely, and it has also helped patients with menstrual migraine. The patient wears the device on the upper arm. Sensory fibers, once stimulated in the arm, send an impulse to the brainstem to affect the serotonin- and norepinephrine-modulated descending inhibitory pathway to disrupt incoming pain messaging. Theranica has applied to the FDA for clearance to treat patients with chronic migraine, as well as for prevention.

Relivion

Neurolief Ltd created the external combined occipital and trigeminal nerve stimulation device (eCOT-NS), which stimulates both the occipital and trigeminal nerves. It has multiple output electrodes, which are placed on the forehead to stimulate the trigeminal supraorbital and supratrochlear nerve branches bilaterally, and over the occipital nerves in the back of the head. It is worn like a tiara as it must be in good contact with the forehead and the back of the head simultaneously. It is FDA cleared to treat acute migraine.

gammaCORE

gammaCORE is a nVNS device that is FDA cleared for acute and preventive treatment of migraine in adolescents and adults, and acute and preventive treatment of episodic cluster headache in adults. It is also cleared to treat chronic cluster headache acutely along with medication. The patient applies gel to the device’s 2 electrical contacts and then locates the vagus nerve on the side of the neck and applies the electrodes to the area that will be treated. Patients can adjust the stimulation’s intensity so that they can barely feel the stimulation; it has not been reported to be painful. nVNS is also an FDA cleared treatment for paroxysmal hemicrania and hemicrania continua. 

SAVI Dual

The s-TMS (SAVI Dual, formerly called the Spring TMS and the sTMS mini), made by eNeura, is a single-pulse, transcranial magnetic stimulation applied to the back of the head to stimulate the occipital lobes in the brain. It was FDA cleared for acute and preventive care of migraine in adolescents over 12 years and for adults in February 2019. The patient holds a handheld magnetic device against their occiput, and when the tool is discharged, a brief magnetic pulse interrupts the pattern of neuronal firing (probably cortical spreading depression) that can trigger migraine and the visual aura associated with migraine in one-third of patients.

Cefaly

The e-TNS (Cefaly) works by external trigeminal nerve stimulation of the supraorbital and trochlear nerves bilaterally in the forehead. It gradually and automatically increases in intensity and can be controlled by the patient. It is FDA cleared for acute and preventive treatment of migraine, and, unlike the other devices, it is sold over the counter without a prescription. According to the company website, there are 3 devices: 1 is for acute treatment, 1 is for preventive treatment, and 1 device has 2 settings for both acute and preventive treatment.

The Studies

While most of the published studies on devices are company-sponsored, these device makers have underwritten numerous, sometimes very well-designed, studies on their products. A review by VanderPluym et al described those studies and their various risks of bias. 

There are at least 10 studies on REN published so far. These include 2 randomized, sham-controlled trials looking at pain freedom and pain relief at 2 hours after stimulation begins. Another study detailed treatment reports from many patients in which 66.5% experienced pain relief at 2 hours post treatment initiation in half of their treatments. A subgroup of 16% of those patients were prescribed REN by their primary care physicians. Of that group, 77.8% experienced pain relief in half their treatments. That figure was very close to another study that found that 23 of 31 (74.2%) of the study patients treated virtually by non headache providers found relief in 50% of their headaches. REN comes with an education and behavioral medicine app that is used during treatment. A study done by the company shows that when a patient uses the relaxation app along with the standard stimulation, they do considerably better than with stimulation alone.

The eCOT-NS has also been tested in an RCT. At 2 hours, the responder rate was twice as high as in the sham group (66.7% vs 32%). Overall headache relief at 2 hours was higher in the responder group (76% vs 31.6%). In a study collecting real-world data on the efficacy of eCOT-NS in the preventive treatment of migraine (abstract data were presented at the American Headache Society meeting in June 2022), there was a 65.3% reduction in monthly migraine days (MMD) from baseline through 6 months. Treatment reduced MMD by 10.0 (from 15.3 to 5.3—a 76.8% reduction), and reduced acute medication use days (12.5 at baseline to 2.9) at 6 months.

Users of nVNS discussed their experiences with the device, which is the size of a large bar of soap, in a patient registry. They reported 192 attacks, with a mean pain score starting at 2.7 and dropping to 1.3 after 30 minutes. The pain levels of 70% of the attacks dropped to either mild or nonexistent. In a multicenter study on nNVS, 48 patients and 44 sham patients with episodic and chronic cluster headache showed no significant difference in the primary endpoint of pain freedom at 15 minutes between the nVNS and sham. There was also no difference in the chronic cluster headache group. But the episodic cluster subgroup showed a difference; nVNS was superior to sham, 48% to 6% (P ≤ 0.01). Those in the chronic cluster headache group reported a lower percentage of pain-free status than the sham group (5% vs 13%). In another study of 477 patients, those patients who adhered to treatment more than 67% of the time per month showed a reduction in migraine days (2.27 vs 1.53). Patients with aura also fared better than those without aura.

The e-TNS device is cleared for treating adults with migraine, acutely and preventively. It received initial clearance in 2017; in 2020, Cefaly Technology received clearance from the FDA to sell its products over the counter. The device, which resembles a large diamond that affixes to the forehead, has received differing reviews between various patient reports (found online at major retailer sites) and study results. In a blinded, intent-to-treat study involving 538 patients, 25.5% of the verum group reported they were pain-free at 2 hours; 18.3% in the sham group reported the same. Additionally, 56.4% of the subjects in the verum group reported they were free of the most bothersome migraine symptoms, as opposed to 42.3% of the sham group.

Adverse Events

The adverse events observed with these devices were, overall, relatively mild, and disappeared once the device was shut off. A few nVNS users said they experienced discomfort at the application site. With REN, 59 of 12,368 patients reported device-related issues; the vast majority were considered mild and consisted mostly of a sensation of warmth under the device. Of the 259 e-TNS  users, 8.5% reported minor and reversible occurrences, such as treatment-related discomfort, paresthesia, and burning.

Patients in the Clinic

A few observations from the clinic regarding these devices:

Some devices are easier to use than others. I know this, because at a recent demonstration session in a course for physicians on headache treatment, I agreed to be the person on whom the device was demonstrated. The physician applying the device had difficulty aligning the device’s sensors with the appropriate nerves. Making sure your patients use these devices correctly is essential, and you or your staff should demonstrate their use to the patient. No doubt, this could be time-consuming in some cases, and patients who are reading the device’s instructions while in pain will likely get frustrated if they cannot get the device to work. 

Some patients who have failed every medication class can occasionally find partial relief with these devices. One longtime patient of mine came to me severely disabled from chronic migraine and medication overuse headache but was somewhat better with 2 preventive medications. Triptans worked acutely, but she developed nearly every side effect imaginable. I was able to reverse her medication overuse headache, but the gepants, although they worked somewhat, took too long to take effect. We agreed the next step would be to use REN for each migraine attack, combined with acute care medication if necessary. (She uses REN alone for a milder headache and adds a gepant with naproxen if necessary.) She has found using the relaxation module on the REN app increases her chances of eliminating the migraine. She is not pain free all the time, but she appreciates the pain-free intervals.

One chronic cluster patient has relied on subcutaneous sumatriptan and breathing 100% oxygen at 12 liters per minute through a mask over his nose and mouth for acute relief from his headaches. His headache pain can climb from a 3 to a 10 in a matter of minutes. It starts behind and a bit above the right eye where he feels a tremendous pressure building up. He says that at times it feels like a screwdriver has been thrust into his eye and is being turned. Along with the pain, the eye becomes red, the pupil constricts, and the eyelid droops. He also has dripping from the right nostril, which stuffs up when the pain abates. The pain lasts for 1 to 2 hours, then returns 3 to 5 times a day for 5 days a week, on average. The pain never goes away for more than 3 weeks in a year’s time, hence the reason for his chronic cluster headache diagnosis.  He is now using nVNS as soon as he feels the pain coming on. If the device does not provide sufficient relief, he uses oxygen or takes the sumatriptan injection.

Some patients who get cluster headaches think of suicide if the pain cannot be stopped; but in my experience, most can become pain free, or at least realize some partial relief from a variety of treatments (sometimes given at the same time).

Doctors often do not think of devices as options, and some doctors think devices do not work even though they have no experience with using them. Devices can give good relief on their own, and when a severe headache needs stronger treatment, medications added to a device usually work better than either treatment alone.

Remote upper arm neuromodulation and combined occipital and trigeminal neuromodulation lead the way as the newest entries to the field, followed by 8 other devices that are now available or are expected to be soon.

The increasing array of prescription medications for the treatment of migraine are welcome additions for patients who suffer from this life-altering condition and the clinicians who treat it; but not all individuals tolerate oral and injectable therapies, and others face the risk of adverse events and medication overuse headache.¹ Fortunately, there are a number of devices available to consider, and still others are awaiting approval from the US Food and Drug Administration (FDA).

Two of the most promising devices are remote upper arm neuromodulation (REN) and combined occipital and trigeminal neuromodulation. Here we highlight data from pivotal trials evaluating these 2 treatment options and provide information about other devices worth consideration.

Remote Upper Arm Neuromodulation (REN)

Nerivio was initially authorized by the FDA for the acute treatment of episodic migraine. Available by prescription, the device is administered by the patient at home.² It stimulates upper arm peripheral nerves, which induces conditioned pain modulation (CPM) that inhibits pain in remote parts of the body. In other words, a descending, endogenous analgesic “pain inhibits pain” mechanism is used.

The initial authorization was based on the results of a randomized, double-blind, sham-controlled, multicenter study involving 252 individuals who were experiencing 2 to 8 migraine headaches per month. Participants were assigned to either a treatment group (n=126), where the device was applied for 30 to 45 minutes within an hour of a migraine attack, or to a sham treatment group (n=126). Investigators looked at migraine pain levels at baseline and at 2 and 48 hours post-treatment, as well as patient-reported most bothersome symptoms. They found that REN provided superior, clinically meaningful relief from migraine pain and the most bothersome symptoms, as follows³:

• 67% of patients in the active treatment group achieved a response at 2 hours vs 39% of individuals in the sham-treatment group
• Pain-free rates at 2 hours in each group were 37% and 18%, respectively
• Most bothersome symptom relief rates at 2 hours were 46% and 22%, respectively

Additionally, pain relief and pain-free responses were sustained at 48 hours. Nearly 40% of active treatment participants still reported pain relief at 48 hours, with pain-free rates at 48 hours in each group of 21% and 8%, respectively. The adverse event rate was low. The most commonly reported adverse event in the active-treatment group was a sensation of warmth (2.4%). Arm pain (1.6%), redness (1.6%), and numbness (0.8%) were also reported in those receiving active treatment.³

In 2020, REN received authorization for the acute treatment of chronic migraine in adults, and the following year authorization was expanded to include adolescent migraine. This development offered a nonpharmacologic treatment approach for migraine sufferers who experience 15 or more headache days per month, which is significant because it reduces the likelihood of medication overuse headache.

Approval for chronic migraine was based on results of an open-label, single-arm, dual-center study involving 38 individuals with chronic migraine. Participants used the device over 4 weeks within 1 hour of a migraine attack. Investigators assessed pain levels at 2 and 24 hours after use; they defined consistency of response as response to at least half of the treatments. The study demonstrated the following⁴:

• 74% of patients attained pain relief at 2 hours
• 26% were pain free at 2 hours
• 84% achieved sustained pain relief at 24 hours
• 45% achieved sustained pain relief at 24 hours in at least half of their treated attacks
• <2% of participants experienced device-related adverse events

The authors concluded that REN could be used for a series of migraine attacks and is a safe and effective nonpharmacologic approach for individuals who suffer from chronic migraine.⁴

The findings from these trials are supported by a subsequent trial published earlier this year. This open-label, single-arm study evaluated 91 individuals with chronic migraine who were treated with REN for 4 weeks. Investigators assessed pain levels, associated pain symptoms, and functional disability at baseline as well as at 2 and 24 hours post-treatment. Of the patients in this study⁵:

• At 2 hours, 59% achieved pain relief, and 21% reported that their pain disappeared
• 73% noted sustained pain relief at 24 hours
• REN was shown to impact nausea, photophobia, and phonophobia favorably, and patients’ functional ability also improved after use

Results from 2 additional trials were also recently released. One study involving 35 adolescents treated with either REN or standard-of-care medications showed REN to be superior with regard to pain freedom (37% vs 9%), consistency of pain freedom (40% vs 9%), pain relief (71% vs 57%), and consistency of pain relief (80% vs 57%).⁶ The other study included 91 women with a history of menstrual migraine and at least 4 REN treatments. Nearly 75% of patients reported Nerivio to be at least moderately effective, 45% said they were satisfied with the treatment, and all participants noted that it was at least moderately tolerable.⁷

Combined Occipital and Trigeminal Neuromodulation

In March 2021, the FDA authorized combined occipital and trigeminal neuromodulation (Relivion) for self-treatment of acute migraine.⁸ It is not yet commercially available, but it will require a prescription. The headset-like device stimulates the occipital and trigeminal nerves by delivering precise modulated pulses simultaneously to 6 branches of the occipital and trigeminal nerves via 3 adaptive output channels. The occipital and trigeminal nerves conduct the signals directly to the brainstem, which maximizes the synergistic effect.⁹

The results of 2 clinical trials led to FDA approval. These studies have not yet been published in a peer-reviewed journal. The first study, presented at the 61st Annual Scientific Meeting of the American Headache Society in 2019, was a prospective, randomized, double-blind, parallel-group, sham-controlled clinical study involving 55 individuals with chronic or episodic migraine. Participants administered the device for 1 hour soon after migraine onset or administered a sham treatment. Researchers looked at pain score change from baseline to 1 hour post-treatment, as well as pain intensity at baseline and at 1, 2, and 24 hours post-treatment. The study showed that 76% of participants in the active-treatment group experienced headache relief at 2 hours vs 32% in the sham-treatment contingent. No serious adverse events were reported.¹⁰ The investigators hypothesized that the positive results observed were a result of the synergistic neuromodulatory effect elicited by concurrent activation of the occipital and trigeminal neural pathways.

Following this study, there was a multi-center, prospective, randomized, double-blind, placebo-controlled clinical trial involving 131 individuals with migraine with or without aura. Participants were assigned to either active treatment or placebo. Investigators assessed reported migraine pain reduction at 2 hours, as well as improvement in most bothersome symptoms after 2 hours, reported pain reduction at 1 hour, and being pain-free at 2 hours. At 2 hours post-treatment¹¹:

• 46% of individuals who were actively treated reached complete freedom from pain vs 12% in the control group
• 75% of active-treatment participants reported being completely free of their most bothersome symptom vs 47% of control patients
• The rates of complete freedom from migraine symptoms were 47% and 11%, respectively
• The rates of pain relief after 2 hours were 60% and 37%, respectively
• No serious adverse events were noted

A systematic review and meta-analysis of 13 studies involving 221 individuals published earlier this year looked at changes in pain scores and response rates to implantable peripheral nerve stimulation for trigeminal neuropathic pain. The response rate to neuromodulation therapy was 61%, the reduction in overall pain scores (2.363) was significant, and a subgroup assessment revealed that the stimulation target (peripheral branch, trigeminal ganglion, or trigeminal nerve root) was responsible for heterogeneity across the studies analyzed. Furthermore, stimulating the trigeminal peripheral branch resulted in better clinical outcomes. The authors noted that their findings reinforce the promise of implantable therapy, particularly for individuals who do not tolerate traditional therapies.¹²

Looking forward, new data are scheduled to be presented at the International Headache Virtual Congress in September 2021 showing that neuromodulation therapy is highly effective in reducing monthly headache days in individuals who suffer from difficult-to-treat migraine. A larger-scale, double-blind, sham-controlled study is planned to further establish these findings.

Other FDA-Approved Therapies
A number of other devices are available for treatment of migraine headache, including:

• Transcranial magnetic stimulation (TMS). In a randomized trial involving 164 individuals with migraine, 39% of the individuals receiving treatment were pain-free at 2 hours vs 22% of those given sham treatment¹³
• Noninvasive vagal nerve stimulation (nVNS). This is performed using a handheld device that is controlled by the patient, which preferentially activates afferent A and large B fibers. In a randomized trial involving 243 individuals, pain-free rates at 30, 60, and 120 minutes for patients receiving active treatment were 13%, 21%, and 30%, respectively. Rates for those receiving sham treatment were 4%, 10%, and 20%, respectively.¹⁴
• Sumatriptan nasal spray (10 mg) with a permeation enhancer. A randomized phase 2 trial involving 107 individuals found that 44% of participants in the treatment group achieved pain freedom at 2 hours vs 23% who received placebo. The spray appears to work quickly and with fewer adverse events than generic sumatriptan 20 mg nasal spray.¹⁵
• Transcutaneous supraorbital nerve stimulation (tSNS). Available without a prescription, there are 3 devices that can treat acute migraine; prevent acute migraine; or both.

Therapies Awaiting FDA Approval

There are several therapeutic options in the pipeline that have not yet been authorized by the FDA.

• Zavegepant (formerly known as vazegepant) nasal spray.¹⁶ This third-generation small molecule calcitonin gene-related peptide (CGRP) receptor antagonist has been demonstrated to work as a nasal spray in individuals with migraine. In a phase 1 study, the spray was shown to reach maximal concentration earlier than with other CGRP receptor antagonists.¹⁷ A phase 2/3 placebo-controlled trial demonstrated sustained pain freedom from 2 to 48 hours with 5-mg, 10-mg, and 20-mg dosages. The 10-mg and 20-mg doses were statistically superior to placebo on the co-primary endpoints of pain freedom and freedom from most bothersome symptom at 2 hours using a single dose. Sustained pain relief from 2 to 48 hours was seen with the 5-mg and 10-mg dosages¹⁸
• Sphenopalatine ganglion (SPG) stimulation. This is a microstimulator that is inserted orally, designed to fit the face, and directly targets SPG. Stimulation is active and controlled by the patient. A randomized, sham-controlled trial evaluated acute pain relief as well as pain freedom and found that those receiving treatment were more than twice as likely to experience pain relief and pain freedom¹⁹
• Adhesive dermally applied microneedle system (ADAM). This is a transdermal patch containing microprojections, which can be coated with both large and small molecules. In a randomized trial, 42% of treated participants reported being pain free at 2 hours vs 14% of placebo-treated patients. Rates of freedom from most bothersome symptom were 68% and 43%, respectively²⁰
• Dihydroergotamine (DHE) nasal powder spray and intranasal liquid. Both therapies are awaiting FDA approval. The mucoadhesive powder formulation facilitates rapid drug absorption and is offered in a single-use nasal delivery device. In clinical trials, the spray demonstrated the device’s simplicity, reliability, and ease of use.²¹ The intranasal liquid is designed to deliver the drug into the vascular-rich upper nasal space. In the phase 3 trial that included 354 patients, 66.3% of patients reported pain relief, 38% of patients reported pain freedom, and 52% had freedom from their most bothersome migraine symptom at 2 hours following their first dose.²²

Remote upper arm neuromodulation and combined occipital and trigeminal neuromodulation lead the way as the newest entries to the field, followed by 8 other devices that are now available or are expected to be soon.

The increasing array of prescription medications for the treatment of migraine are welcome additions for patients who suffer from this life-altering condition and the clinicians who treat it; but not all individuals tolerate oral and injectable therapies, and others face the risk of adverse events and medication overuse headache.¹ Fortunately, there are a number of devices available to consider, and still others are awaiting approval from the US Food and Drug Administration (FDA).

Two of the most promising devices are remote upper arm neuromodulation (REN) and combined occipital and trigeminal neuromodulation. Here we highlight data from pivotal trials evaluating these 2 treatment options and provide information about other devices worth consideration.

Remote Upper Arm Neuromodulation (REN)

Nerivio was initially authorized by the FDA for the acute treatment of episodic migraine. Available by prescription, the device is administered by the patient at home.² It stimulates upper arm peripheral nerves, which induces conditioned pain modulation (CPM) that inhibits pain in remote parts of the body. In other words, a descending, endogenous analgesic “pain inhibits pain” mechanism is used.

The initial authorization was based on the results of a randomized, double-blind, sham-controlled, multicenter study involving 252 individuals who were experiencing 2 to 8 migraine headaches per month. Participants were assigned to either a treatment group (n=126), where the device was applied for 30 to 45 minutes within an hour of a migraine attack, or to a sham treatment group (n=126). Investigators looked at migraine pain levels at baseline and at 2 and 48 hours post-treatment, as well as patient-reported most bothersome symptoms. They found that REN provided superior, clinically meaningful relief from migraine pain and the most bothersome symptoms, as follows³:

• 67% of patients in the active treatment group achieved a response at 2 hours vs 39% of individuals in the sham-treatment group
• Pain-free rates at 2 hours in each group were 37% and 18%, respectively
• Most bothersome symptom relief rates at 2 hours were 46% and 22%, respectively

Additionally, pain relief and pain-free responses were sustained at 48 hours. Nearly 40% of active treatment participants still reported pain relief at 48 hours, with pain-free rates at 48 hours in each group of 21% and 8%, respectively. The adverse event rate was low. The most commonly reported adverse event in the active-treatment group was a sensation of warmth (2.4%). Arm pain (1.6%), redness (1.6%), and numbness (0.8%) were also reported in those receiving active treatment.³

In 2020, REN received authorization for the acute treatment of chronic migraine in adults, and the following year authorization was expanded to include adolescent migraine. This development offered a nonpharmacologic treatment approach for migraine sufferers who experience 15 or more headache days per month, which is significant because it reduces the likelihood of medication overuse headache.

Approval for chronic migraine was based on results of an open-label, single-arm, dual-center study involving 38 individuals with chronic migraine. Participants used the device over 4 weeks within 1 hour of a migraine attack. Investigators assessed pain levels at 2 and 24 hours after use; they defined consistency of response as response to at least half of the treatments. The study demonstrated the following⁴:

• 74% of patients attained pain relief at 2 hours
• 26% were pain free at 2 hours
• 84% achieved sustained pain relief at 24 hours
• 45% achieved sustained pain relief at 24 hours in at least half of their treated attacks
• <2% of participants experienced device-related adverse events

The authors concluded that REN could be used for a series of migraine attacks and is a safe and effective nonpharmacologic approach for individuals who suffer from chronic migraine.⁴

The findings from these trials are supported by a subsequent trial published earlier this year. This open-label, single-arm study evaluated 91 individuals with chronic migraine who were treated with REN for 4 weeks. Investigators assessed pain levels, associated pain symptoms, and functional disability at baseline as well as at 2 and 24 hours post-treatment. Of the patients in this study⁵:

• At 2 hours, 59% achieved pain relief, and 21% reported that their pain disappeared
• 73% noted sustained pain relief at 24 hours
• REN was shown to impact nausea, photophobia, and phonophobia favorably, and patients’ functional ability also improved after use

Results from 2 additional trials were also recently released. One study involving 35 adolescents treated with either REN or standard-of-care medications showed REN to be superior with regard to pain freedom (37% vs 9%), consistency of pain freedom (40% vs 9%), pain relief (71% vs 57%), and consistency of pain relief (80% vs 57%).⁶ The other study included 91 women with a history of menstrual migraine and at least 4 REN treatments. Nearly 75% of patients reported Nerivio to be at least moderately effective, 45% said they were satisfied with the treatment, and all participants noted that it was at least moderately tolerable.⁷

Combined Occipital and Trigeminal Neuromodulation

In March 2021, the FDA authorized combined occipital and trigeminal neuromodulation (Relivion) for self-treatment of acute migraine.⁸ It is not yet commercially available, but it will require a prescription. The headset-like device stimulates the occipital and trigeminal nerves by delivering precise modulated pulses simultaneously to 6 branches of the occipital and trigeminal nerves via 3 adaptive output channels. The occipital and trigeminal nerves conduct the signals directly to the brainstem, which maximizes the synergistic effect.⁹

The results of 2 clinical trials led to FDA approval. These studies have not yet been published in a peer-reviewed journal. The first study, presented at the 61st Annual Scientific Meeting of the American Headache Society in 2019, was a prospective, randomized, double-blind, parallel-group, sham-controlled clinical study involving 55 individuals with chronic or episodic migraine. Participants administered the device for 1 hour soon after migraine onset or administered a sham treatment. Researchers looked at pain score change from baseline to 1 hour post-treatment, as well as pain intensity at baseline and at 1, 2, and 24 hours post-treatment. The study showed that 76% of participants in the active-treatment group experienced headache relief at 2 hours vs 32% in the sham-treatment contingent. No serious adverse events were reported.¹⁰ The investigators hypothesized that the positive results observed were a result of the synergistic neuromodulatory effect elicited by concurrent activation of the occipital and trigeminal neural pathways.

Following this study, there was a multi-center, prospective, randomized, double-blind, placebo-controlled clinical trial involving 131 individuals with migraine with or without aura. Participants were assigned to either active treatment or placebo. Investigators assessed reported migraine pain reduction at 2 hours, as well as improvement in most bothersome symptoms after 2 hours, reported pain reduction at 1 hour, and being pain-free at 2 hours. At 2 hours post-treatment¹¹:

• 46% of individuals who were actively treated reached complete freedom from pain vs 12% in the control group
• 75% of active-treatment participants reported being completely free of their most bothersome symptom vs 47% of control patients
• The rates of complete freedom from migraine symptoms were 47% and 11%, respectively
• The rates of pain relief after 2 hours were 60% and 37%, respectively
• No serious adverse events were noted

A systematic review and meta-analysis of 13 studies involving 221 individuals published earlier this year looked at changes in pain scores and response rates to implantable peripheral nerve stimulation for trigeminal neuropathic pain. The response rate to neuromodulation therapy was 61%, the reduction in overall pain scores (2.363) was significant, and a subgroup assessment revealed that the stimulation target (peripheral branch, trigeminal ganglion, or trigeminal nerve root) was responsible for heterogeneity across the studies analyzed. Furthermore, stimulating the trigeminal peripheral branch resulted in better clinical outcomes. The authors noted that their findings reinforce the promise of implantable therapy, particularly for individuals who do not tolerate traditional therapies.¹²

Looking forward, new data are scheduled to be presented at the International Headache Virtual Congress in September 2021 showing that neuromodulation therapy is highly effective in reducing monthly headache days in individuals who suffer from difficult-to-treat migraine. A larger-scale, double-blind, sham-controlled study is planned to further establish these findings.

Other FDA-Approved Therapies
A number of other devices are available for treatment of migraine headache, including:

• Transcranial magnetic stimulation (TMS). In a randomized trial involving 164 individuals with migraine, 39% of the individuals receiving treatment were pain-free at 2 hours vs 22% of those given sham treatment¹³
• Noninvasive vagal nerve stimulation (nVNS). This is performed using a handheld device that is controlled by the patient, which preferentially activates afferent A and large B fibers. In a randomized trial involving 243 individuals, pain-free rates at 30, 60, and 120 minutes for patients receiving active treatment were 13%, 21%, and 30%, respectively. Rates for those receiving sham treatment were 4%, 10%, and 20%, respectively.¹⁴
• Sumatriptan nasal spray (10 mg) with a permeation enhancer. A randomized phase 2 trial involving 107 individuals found that 44% of participants in the treatment group achieved pain freedom at 2 hours vs 23% who received placebo. The spray appears to work quickly and with fewer adverse events than generic sumatriptan 20 mg nasal spray.¹⁵
• Transcutaneous supraorbital nerve stimulation (tSNS). Available without a prescription, there are 3 devices that can treat acute migraine; prevent acute migraine; or both.

Therapies Awaiting FDA Approval

There are several therapeutic options in the pipeline that have not yet been authorized by the FDA.

• Zavegepant (formerly known as vazegepant) nasal spray.¹⁶ This third-generation small molecule calcitonin gene-related peptide (CGRP) receptor antagonist has been demonstrated to work as a nasal spray in individuals with migraine. In a phase 1 study, the spray was shown to reach maximal concentration earlier than with other CGRP receptor antagonists.¹⁷ A phase 2/3 placebo-controlled trial demonstrated sustained pain freedom from 2 to 48 hours with 5-mg, 10-mg, and 20-mg dosages. The 10-mg and 20-mg doses were statistically superior to placebo on the co-primary endpoints of pain freedom and freedom from most bothersome symptom at 2 hours using a single dose. Sustained pain relief from 2 to 48 hours was seen with the 5-mg and 10-mg dosages¹⁸
• Sphenopalatine ganglion (SPG) stimulation. This is a microstimulator that is inserted orally, designed to fit the face, and directly targets SPG. Stimulation is active and controlled by the patient. A randomized, sham-controlled trial evaluated acute pain relief as well as pain freedom and found that those receiving treatment were more than twice as likely to experience pain relief and pain freedom¹⁹
• Adhesive dermally applied microneedle system (ADAM). This is a transdermal patch containing microprojections, which can be coated with both large and small molecules. In a randomized trial, 42% of treated participants reported being pain free at 2 hours vs 14% of placebo-treated patients. Rates of freedom from most bothersome symptom were 68% and 43%, respectively²⁰
• Dihydroergotamine (DHE) nasal powder spray and intranasal liquid. Both therapies are awaiting FDA approval. The mucoadhesive powder formulation facilitates rapid drug absorption and is offered in a single-use nasal delivery device. In clinical trials, the spray demonstrated the device’s simplicity, reliability, and ease of use.²¹ The intranasal liquid is designed to deliver the drug into the vascular-rich upper nasal space. In the phase 3 trial that included 354 patients, 66.3% of patients reported pain relief, 38% of patients reported pain freedom, and 52% had freedom from their most bothersome migraine symptom at 2 hours following their first dose.²²

Remote upper arm neuromodulation and combined occipital and trigeminal neuromodulation lead the way as the newest entries to the field, followed by 8 other devices that are now available or are expected to be soon.

The increasing array of prescription medications for the treatment of migraine are welcome additions for patients who suffer from this life-altering condition and the clinicians who treat it; but not all individuals tolerate oral and injectable therapies, and others face the risk of adverse events and medication overuse headache.¹ Fortunately, there are a number of devices available to consider, and still others are awaiting approval from the US Food and Drug Administration (FDA).

Two of the most promising devices are remote upper arm neuromodulation (REN) and combined occipital and trigeminal neuromodulation. Here we highlight data from pivotal trials evaluating these 2 treatment options and provide information about other devices worth consideration.

Remote Upper Arm Neuromodulation (REN)

Nerivio was initially authorized by the FDA for the acute treatment of episodic migraine. Available by prescription, the device is administered by the patient at home.² It stimulates upper arm peripheral nerves, which induces conditioned pain modulation (CPM) that inhibits pain in remote parts of the body. In other words, a descending, endogenous analgesic “pain inhibits pain” mechanism is used.

The initial authorization was based on the results of a randomized, double-blind, sham-controlled, multicenter study involving 252 individuals who were experiencing 2 to 8 migraine headaches per month. Participants were assigned to either a treatment group (n=126), where the device was applied for 30 to 45 minutes within an hour of a migraine attack, or to a sham treatment group (n=126). Investigators looked at migraine pain levels at baseline and at 2 and 48 hours post-treatment, as well as patient-reported most bothersome symptoms. They found that REN provided superior, clinically meaningful relief from migraine pain and the most bothersome symptoms, as follows³:

• 67% of patients in the active treatment group achieved a response at 2 hours vs 39% of individuals in the sham-treatment group
• Pain-free rates at 2 hours in each group were 37% and 18%, respectively
• Most bothersome symptom relief rates at 2 hours were 46% and 22%, respectively

Additionally, pain relief and pain-free responses were sustained at 48 hours. Nearly 40% of active treatment participants still reported pain relief at 48 hours, with pain-free rates at 48 hours in each group of 21% and 8%, respectively. The adverse event rate was low. The most commonly reported adverse event in the active-treatment group was a sensation of warmth (2.4%). Arm pain (1.6%), redness (1.6%), and numbness (0.8%) were also reported in those receiving active treatment.³

In 2020, REN received authorization for the acute treatment of chronic migraine in adults, and the following year authorization was expanded to include adolescent migraine. This development offered a nonpharmacologic treatment approach for migraine sufferers who experience 15 or more headache days per month, which is significant because it reduces the likelihood of medication overuse headache.

Approval for chronic migraine was based on results of an open-label, single-arm, dual-center study involving 38 individuals with chronic migraine. Participants used the device over 4 weeks within 1 hour of a migraine attack. Investigators assessed pain levels at 2 and 24 hours after use; they defined consistency of response as response to at least half of the treatments. The study demonstrated the following⁴:

• 74% of patients attained pain relief at 2 hours
• 26% were pain free at 2 hours
• 84% achieved sustained pain relief at 24 hours
• 45% achieved sustained pain relief at 24 hours in at least half of their treated attacks
• <2% of participants experienced device-related adverse events

The authors concluded that REN could be used for a series of migraine attacks and is a safe and effective nonpharmacologic approach for individuals who suffer from chronic migraine.⁴

The findings from these trials are supported by a subsequent trial published earlier this year. This open-label, single-arm study evaluated 91 individuals with chronic migraine who were treated with REN for 4 weeks. Investigators assessed pain levels, associated pain symptoms, and functional disability at baseline as well as at 2 and 24 hours post-treatment. Of the patients in this study⁵:

• At 2 hours, 59% achieved pain relief, and 21% reported that their pain disappeared
• 73% noted sustained pain relief at 24 hours
• REN was shown to impact nausea, photophobia, and phonophobia favorably, and patients’ functional ability also improved after use

Results from 2 additional trials were also recently released. One study involving 35 adolescents treated with either REN or standard-of-care medications showed REN to be superior with regard to pain freedom (37% vs 9%), consistency of pain freedom (40% vs 9%), pain relief (71% vs 57%), and consistency of pain relief (80% vs 57%).⁶ The other study included 91 women with a history of menstrual migraine and at least 4 REN treatments. Nearly 75% of patients reported Nerivio to be at least moderately effective, 45% said they were satisfied with the treatment, and all participants noted that it was at least moderately tolerable.⁷

Combined Occipital and Trigeminal Neuromodulation

In March 2021, the FDA authorized combined occipital and trigeminal neuromodulation (Relivion) for self-treatment of acute migraine.⁸ It is not yet commercially available, but it will require a prescription. The headset-like device stimulates the occipital and trigeminal nerves by delivering precise modulated pulses simultaneously to 6 branches of the occipital and trigeminal nerves via 3 adaptive output channels. The occipital and trigeminal nerves conduct the signals directly to the brainstem, which maximizes the synergistic effect.⁹

The results of 2 clinical trials led to FDA approval. These studies have not yet been published in a peer-reviewed journal. The first study, presented at the 61st Annual Scientific Meeting of the American Headache Society in 2019, was a prospective, randomized, double-blind, parallel-group, sham-controlled clinical study involving 55 individuals with chronic or episodic migraine. Participants administered the device for 1 hour soon after migraine onset or administered a sham treatment. Researchers looked at pain score change from baseline to 1 hour post-treatment, as well as pain intensity at baseline and at 1, 2, and 24 hours post-treatment. The study showed that 76% of participants in the active-treatment group experienced headache relief at 2 hours vs 32% in the sham-treatment contingent. No serious adverse events were reported.¹⁰ The investigators hypothesized that the positive results observed were a result of the synergistic neuromodulatory effect elicited by concurrent activation of the occipital and trigeminal neural pathways.

Following this study, there was a multi-center, prospective, randomized, double-blind, placebo-controlled clinical trial involving 131 individuals with migraine with or without aura. Participants were assigned to either active treatment or placebo. Investigators assessed reported migraine pain reduction at 2 hours, as well as improvement in most bothersome symptoms after 2 hours, reported pain reduction at 1 hour, and being pain-free at 2 hours. At 2 hours post-treatment¹¹:

• 46% of individuals who were actively treated reached complete freedom from pain vs 12% in the control group
• 75% of active-treatment participants reported being completely free of their most bothersome symptom vs 47% of control patients
• The rates of complete freedom from migraine symptoms were 47% and 11%, respectively
• The rates of pain relief after 2 hours were 60% and 37%, respectively
• No serious adverse events were noted

A systematic review and meta-analysis of 13 studies involving 221 individuals published earlier this year looked at changes in pain scores and response rates to implantable peripheral nerve stimulation for trigeminal neuropathic pain. The response rate to neuromodulation therapy was 61%, the reduction in overall pain scores (2.363) was significant, and a subgroup assessment revealed that the stimulation target (peripheral branch, trigeminal ganglion, or trigeminal nerve root) was responsible for heterogeneity across the studies analyzed. Furthermore, stimulating the trigeminal peripheral branch resulted in better clinical outcomes. The authors noted that their findings reinforce the promise of implantable therapy, particularly for individuals who do not tolerate traditional therapies.¹²

Looking forward, new data are scheduled to be presented at the International Headache Virtual Congress in September 2021 showing that neuromodulation therapy is highly effective in reducing monthly headache days in individuals who suffer from difficult-to-treat migraine. A larger-scale, double-blind, sham-controlled study is planned to further establish these findings.

Other FDA-Approved Therapies
A number of other devices are available for treatment of migraine headache, including:

• Transcranial magnetic stimulation (TMS). In a randomized trial involving 164 individuals with migraine, 39% of the individuals receiving treatment were pain-free at 2 hours vs 22% of those given sham treatment¹³
• Noninvasive vagal nerve stimulation (nVNS). This is performed using a handheld device that is controlled by the patient, which preferentially activates afferent A and large B fibers. In a randomized trial involving 243 individuals, pain-free rates at 30, 60, and 120 minutes for patients receiving active treatment were 13%, 21%, and 30%, respectively. Rates for those receiving sham treatment were 4%, 10%, and 20%, respectively.¹⁴
• Sumatriptan nasal spray (10 mg) with a permeation enhancer. A randomized phase 2 trial involving 107 individuals found that 44% of participants in the treatment group achieved pain freedom at 2 hours vs 23% who received placebo. The spray appears to work quickly and with fewer adverse events than generic sumatriptan 20 mg nasal spray.¹⁵
• Transcutaneous supraorbital nerve stimulation (tSNS). Available without a prescription, there are 3 devices that can treat acute migraine; prevent acute migraine; or both.

Therapies Awaiting FDA Approval

There are several therapeutic options in the pipeline that have not yet been authorized by the FDA.

• Zavegepant (formerly known as vazegepant) nasal spray.¹⁶ This third-generation small molecule calcitonin gene-related peptide (CGRP) receptor antagonist has been demonstrated to work as a nasal spray in individuals with migraine. In a phase 1 study, the spray was shown to reach maximal concentration earlier than with other CGRP receptor antagonists.¹⁷ A phase 2/3 placebo-controlled trial demonstrated sustained pain freedom from 2 to 48 hours with 5-mg, 10-mg, and 20-mg dosages. The 10-mg and 20-mg doses were statistically superior to placebo on the co-primary endpoints of pain freedom and freedom from most bothersome symptom at 2 hours using a single dose. Sustained pain relief from 2 to 48 hours was seen with the 5-mg and 10-mg dosages¹⁸
• Sphenopalatine ganglion (SPG) stimulation. This is a microstimulator that is inserted orally, designed to fit the face, and directly targets SPG. Stimulation is active and controlled by the patient. A randomized, sham-controlled trial evaluated acute pain relief as well as pain freedom and found that those receiving treatment were more than twice as likely to experience pain relief and pain freedom¹⁹
• Adhesive dermally applied microneedle system (ADAM). This is a transdermal patch containing microprojections, which can be coated with both large and small molecules. In a randomized trial, 42% of treated participants reported being pain free at 2 hours vs 14% of placebo-treated patients. Rates of freedom from most bothersome symptom were 68% and 43%, respectively²⁰
• Dihydroergotamine (DHE) nasal powder spray and intranasal liquid. Both therapies are awaiting FDA approval. The mucoadhesive powder formulation facilitates rapid drug absorption and is offered in a single-use nasal delivery device. In clinical trials, the spray demonstrated the device’s simplicity, reliability, and ease of use.²¹ The intranasal liquid is designed to deliver the drug into the vascular-rich upper nasal space. In the phase 3 trial that included 354 patients, 66.3% of patients reported pain relief, 38% of patients reported pain freedom, and 52% had freedom from their most bothersome migraine symptom at 2 hours following their first dose.²²

Last month’s column focused on medication overuse headache and pointed out an excellent review article by Sun-Edelstein and colleagues. Another fascinating topic also covered within that paper that warrants closer examination is pathogenesis. Developing a thorough knowledge of the pathophysiology of medication overuse headache and its underlying mechanisms positions clinicians to help patients better understand and manage this disorder.

Mechanisms impacting primary headaches

Let us start by detailing the various causes of primary headaches. Activation of the trigeminal nociceptive pathway is the last common step in headache generation. Peripheral sensitization exacerbates intracranial headache pain and leads to the pulsating nature of migraine pain. This severe discomfort is triggered by physical activity and movement. Calcitonin gene-related peptide (CGRP) is primarily responsible for this phenomenon. Increased sensitivity of central trigeminal neurons leads to central sensitization and causes scalp and forehead allodynia typically seen during a migraine attack. Sensitization of trigeminothalamic neurons is thought to be responsible for extensive cutaneous allodynia involving extracephalic regions, like face, arm, and leg.  

Clinical clues

The pathogenesis of medication overuse headache includes chronic medication intake impacting an individual’s hypersensitive trigeminovascular nociceptive system. Physicians should be aware of the 4 factors required for this disorder to develop:

1. Baseline activation of the trigeminovascular nociceptive pathways can cause migraine or tension-type headaches to transform into medication-induced headaches. This transformation typically develops in headaches with an accompanying inflammatory component, which might be related to mast cells in the dura.

2. The discontinuation of acute care headache medication leads first to a worsening and then to an improvement in headaches. Interestingly, the regular use of analgesics for non-headache conditions is not linked to chronic headache development. Non-headache patients who take chronic opiates for cancer do not develop medication overuse headache. This suggests a cause-and-effect relationship, indicating that medication use causes transformation to medication overuse headache in patients with preexisting headache disorders—and is not the result of it. Culprits include migraine-specific drugs, such as triptans or ergots, or medications that are not migraine-specific, such as opioids, non-opioid analgesics, and nonsteroidal anti-inflammatory drugs. Lengthy exposure to these medications impacts a central pathway that controls nociceptive perception, thus causing medication overuse headache. It is important for patients to understand this paradoxical effect to break the cycle of medication overuse.

3. The efficacy of anti-CGRP monoclonal antibodies in the treatment of medication overuse headache is better than that of the older preventive medication. As noted in the last installment, this class of drug is effective in patients with medication overuse headache who have not yet been weaned from the offending medication. The effect is thought to be a result of the decrease of nociception at peripheral perivascular areas, because anti-CGRP monoclonal antibodies do not cross the blood-brain barrier. It is known that CGRP increases transmission of pain signals and is also a vasodilator.

4. The higher prevalence of psychiatric comorbidities, including depression, anxiety disorders, sleep disturbance, and non-cephalic body pain, suggest that they may either be causative or just comorbid. Additionally, individuals with medication overuse headache tend to experience poor general health and quality of life. This suggests that there is also an underlying alteration in neural pathways. Since brainstem aminergic systems are known to modulate mood, it is plausible that these systems impact medication overuse headache. The decrease in serotonin in these patients probably interferes with the brainstem’s descending antinociceptive system or diffuse noxious inhibitory control (DNIC). Increased risk of suicidal ideation is also seen in these individuals. Recently-published research shows that among 603 individuals with chronic migraine headache, the presence of medication overuse headache increased the risk of suicidal ideation by 75% and odds of previous suicide attempt by 88%, even after controlling for demographics, headache profile, disabilities, depression and anxiety symptoms, and sleep quality.

The bottom line: For medication overuse headache to develop, clinicians should see an underlying primary headache worsen with frequent acute care medication use as well as peripheral trigeminal nociceptor activation.

The role of low serotonin levels

Serotonin plays a key role in the pathogenesis of migraine headache. Research shows that in individuals who experience medication overuse headache, platelet serotonin is decreased and the density of serotonin receptors on platelets is increased, implying suppressed serotonin function, as mentioned above.

A recent study showed that individuals with medication overuse headache had higher intensity dependence of auditory evoked potentials (IDAP) levels than controls who did not suffer from headache. Investigators assessed 17 women who suffered from chronic migraine headache (12 of whom experienced medication overuse headache) and 19 healthy individuals as part of a study evaluating efficacy of bilateral betamethasone-lidocaine greater occipital nerve block (GON-B). At baseline, participants were assessed for habituation of visual evoked potentials (VEP) and IDAP. While baseline VEP habituation was similar in both groups, this was not the case for IDAP. Those values were significantly higher in headache sufferers, which implies lower serotonin levels.

Additionally, researchers found that IDAP was normalized in headache sufferers via the use of GON-B, and clinical improvement was seen. They concluded that altered serotonin levels and incoming trigeminal nociceptive input are important components of the pathogenesis of medication overuse headache.

The ‘2-hit model’

Though preliminary, an animal study lends credence to the so-called 2-hit model of medication overuse headache pathogenesis. Researchers hypothesized that abortive treatment, in the form of either migraine-specific medications or analgesics, can serve as a priming mechanism—a so-called first hit that facilitates central sensitization and increases responses to subsequent stimuli. Thus, the second hit occurs via enhancement of net descending facilitation in central pain modulatory pathways.

To test their hypothesis, investigators primed rats through continuous infusion of morphine or sumatriptan and assessed DNIC 7 days later and again 2 weeks after that, when sensory thresholds returned to baseline levels. Morphine-primed rats showed opioid-induced hyperalgesia and a loss of diffuse noxious inhibitory control on day 7, whereas sumatriptan-primed rats did not. Researchers concluded that acute nociceptive stimulation causes alterations in descending pain modulation that can last for long periods. Morphine’s detrimental effect reflects the clinical experience of higher medication overuse headache risk in individuals who use opioids for headache treatment. Thus, the authors noted, migraine medications along with repeated bouts of pain can amplify the consequences of nociceptor activation and increase the odds of future migraine attacks and risk of medication overuse headache. Clinically we see overuse of opioids causing more MOH than overuse of triptans, which can still cause MOH.

In a related animal study, rats underwent a similar priming process and were exposed to migraine triggers in the presence or absence of a humanized CGRP monoclonal antibody. The antibody significantly inhibited cutaneous allodynia in rats that had previously been primed with morphine or sumatriptan. A control protein that does not bind CGRP was ineffective. The authors concluded that acute migraine medications may promote medication overuse headache in susceptible headache sufferers via CGRP-driven mechanisms. Further, anti-CGRP monoclonal antibodies appear to be useful in the treatment of medication overuse headache.

Pain processing and addiction

A recent narrative review of imaging research studies revealed that medication overuse headache is linked with unusual structure and function of brain regions that process pain and other regions normally linked with addiction. Investigators looked at studies that evaluated abnormal structure and pain processing functionality in individuals with medication overuse headache. In addition to their primary findings regarding brain regions, researchers noted that several of the studies showed a return to normal structure and pain processing functionality after discontinuing overused medication; medication overuse headache resolved. Clinically we see this in patients that are detoxified from the offending overused medication. Interestingly, abnormalities in regions typically linked with addiction persisted, even after medication discontinuation. This suggests that individuals with medication overuse headache might have a brain trait that predisposes them to overuse medication.

Another study found that certain brain metabolites in key regions of the thalamocortical pathways differed between chronic migraine sufferers with and without medication overuse headache. Investigators conducted magnetic resonance spectroscopic imaging to map metabolites in specific regions of the brains of 48 participants: 16 migraine sufferers with medication overuse headache; 16 without overuse; and 16 healthy controls.

In patients with medication overuse headache, glutamate and glutamine levels were significantly higher in the right midcingulate cortex, and myo-inositol levels were significantly higher in the left anterior cingulate cortex, relative to those without medication overuse headache. These levels were similar to those seen in healthy controls. Additionally, in both groups of migraine sufferers, researchers observed a negative association between myo-inositol laterality index in the anterior cingulate cortices and the number of days per month with acute medication use. They concluded that individuals with medication overuse headache had a distinct concentration of myo-inositol in the anterior cingulate cortices that may be a result of medication overuse and might lead to the development of medication overuse headache.

Clinical implications

An understanding of these very complex pathophysiological findings in medication overuse headache serves as a foundation for neurologists and headache specialists. From there, evaluating the frequency, duration, and quantity of analgesic use in individuals with headache is an important and necessary next step. The time-tested treatment for medication overuse headache has always been patient education, detoxification, and starting preventive medications, which in the past have caused lots of side effects and not always been effective. Today, minimal education and starting a patient on a monoclonal antibody against CGRP is often quite effective, even without detoxification.

It should be noted that there is a new class of drug called the gepants, which block the CGRP receptor peripherally; 2 such gepants are approved by the FDA and are used as acute care medication (rimegepant and ubrogepant). They do not appear to cause medication overuse headache; one of them, rimegepant, was just approved by the FDA as the first headache medication to be used both as an acute treatment and a preventive treatment for migraine. Medication overuse headache understanding and treatment is changing right before our eyes.

Last month’s column focused on medication overuse headache and pointed out an excellent review article by Sun-Edelstein and colleagues. Another fascinating topic also covered within that paper that warrants closer examination is pathogenesis. Developing a thorough knowledge of the pathophysiology of medication overuse headache and its underlying mechanisms positions clinicians to help patients better understand and manage this disorder.

Mechanisms impacting primary headaches

Let us start by detailing the various causes of primary headaches. Activation of the trigeminal nociceptive pathway is the last common step in headache generation. Peripheral sensitization exacerbates intracranial headache pain and leads to the pulsating nature of migraine pain. This severe discomfort is triggered by physical activity and movement. Calcitonin gene-related peptide (CGRP) is primarily responsible for this phenomenon. Increased sensitivity of central trigeminal neurons leads to central sensitization and causes scalp and forehead allodynia typically seen during a migraine attack. Sensitization of trigeminothalamic neurons is thought to be responsible for extensive cutaneous allodynia involving extracephalic regions, like face, arm, and leg.  

Clinical clues

The pathogenesis of medication overuse headache includes chronic medication intake impacting an individual’s hypersensitive trigeminovascular nociceptive system. Physicians should be aware of the 4 factors required for this disorder to develop:

1. Baseline activation of the trigeminovascular nociceptive pathways can cause migraine or tension-type headaches to transform into medication-induced headaches. This transformation typically develops in headaches with an accompanying inflammatory component, which might be related to mast cells in the dura.

2. The discontinuation of acute care headache medication leads first to a worsening and then to an improvement in headaches. Interestingly, the regular use of analgesics for non-headache conditions is not linked to chronic headache development. Non-headache patients who take chronic opiates for cancer do not develop medication overuse headache. This suggests a cause-and-effect relationship, indicating that medication use causes transformation to medication overuse headache in patients with preexisting headache disorders—and is not the result of it. Culprits include migraine-specific drugs, such as triptans or ergots, or medications that are not migraine-specific, such as opioids, non-opioid analgesics, and nonsteroidal anti-inflammatory drugs. Lengthy exposure to these medications impacts a central pathway that controls nociceptive perception, thus causing medication overuse headache. It is important for patients to understand this paradoxical effect to break the cycle of medication overuse.

3. The efficacy of anti-CGRP monoclonal antibodies in the treatment of medication overuse headache is better than that of the older preventive medication. As noted in the last installment, this class of drug is effective in patients with medication overuse headache who have not yet been weaned from the offending medication. The effect is thought to be a result of the decrease of nociception at peripheral perivascular areas, because anti-CGRP monoclonal antibodies do not cross the blood-brain barrier. It is known that CGRP increases transmission of pain signals and is also a vasodilator.

4. The higher prevalence of psychiatric comorbidities, including depression, anxiety disorders, sleep disturbance, and non-cephalic body pain, suggest that they may either be causative or just comorbid. Additionally, individuals with medication overuse headache tend to experience poor general health and quality of life. This suggests that there is also an underlying alteration in neural pathways. Since brainstem aminergic systems are known to modulate mood, it is plausible that these systems impact medication overuse headache. The decrease in serotonin in these patients probably interferes with the brainstem’s descending antinociceptive system or diffuse noxious inhibitory control (DNIC). Increased risk of suicidal ideation is also seen in these individuals. Recently-published research shows that among 603 individuals with chronic migraine headache, the presence of medication overuse headache increased the risk of suicidal ideation by 75% and odds of previous suicide attempt by 88%, even after controlling for demographics, headache profile, disabilities, depression and anxiety symptoms, and sleep quality.

The bottom line: For medication overuse headache to develop, clinicians should see an underlying primary headache worsen with frequent acute care medication use as well as peripheral trigeminal nociceptor activation.

The role of low serotonin levels

Serotonin plays a key role in the pathogenesis of migraine headache. Research shows that in individuals who experience medication overuse headache, platelet serotonin is decreased and the density of serotonin receptors on platelets is increased, implying suppressed serotonin function, as mentioned above.

A recent study showed that individuals with medication overuse headache had higher intensity dependence of auditory evoked potentials (IDAP) levels than controls who did not suffer from headache. Investigators assessed 17 women who suffered from chronic migraine headache (12 of whom experienced medication overuse headache) and 19 healthy individuals as part of a study evaluating efficacy of bilateral betamethasone-lidocaine greater occipital nerve block (GON-B). At baseline, participants were assessed for habituation of visual evoked potentials (VEP) and IDAP. While baseline VEP habituation was similar in both groups, this was not the case for IDAP. Those values were significantly higher in headache sufferers, which implies lower serotonin levels.

Additionally, researchers found that IDAP was normalized in headache sufferers via the use of GON-B, and clinical improvement was seen. They concluded that altered serotonin levels and incoming trigeminal nociceptive input are important components of the pathogenesis of medication overuse headache.

The ‘2-hit model’

Though preliminary, an animal study lends credence to the so-called 2-hit model of medication overuse headache pathogenesis. Researchers hypothesized that abortive treatment, in the form of either migraine-specific medications or analgesics, can serve as a priming mechanism—a so-called first hit that facilitates central sensitization and increases responses to subsequent stimuli. Thus, the second hit occurs via enhancement of net descending facilitation in central pain modulatory pathways.

To test their hypothesis, investigators primed rats through continuous infusion of morphine or sumatriptan and assessed DNIC 7 days later and again 2 weeks after that, when sensory thresholds returned to baseline levels. Morphine-primed rats showed opioid-induced hyperalgesia and a loss of diffuse noxious inhibitory control on day 7, whereas sumatriptan-primed rats did not. Researchers concluded that acute nociceptive stimulation causes alterations in descending pain modulation that can last for long periods. Morphine’s detrimental effect reflects the clinical experience of higher medication overuse headache risk in individuals who use opioids for headache treatment. Thus, the authors noted, migraine medications along with repeated bouts of pain can amplify the consequences of nociceptor activation and increase the odds of future migraine attacks and risk of medication overuse headache. Clinically we see overuse of opioids causing more MOH than overuse of triptans, which can still cause MOH.

In a related animal study, rats underwent a similar priming process and were exposed to migraine triggers in the presence or absence of a humanized CGRP monoclonal antibody. The antibody significantly inhibited cutaneous allodynia in rats that had previously been primed with morphine or sumatriptan. A control protein that does not bind CGRP was ineffective. The authors concluded that acute migraine medications may promote medication overuse headache in susceptible headache sufferers via CGRP-driven mechanisms. Further, anti-CGRP monoclonal antibodies appear to be useful in the treatment of medication overuse headache.

Pain processing and addiction

A recent narrative review of imaging research studies revealed that medication overuse headache is linked with unusual structure and function of brain regions that process pain and other regions normally linked with addiction. Investigators looked at studies that evaluated abnormal structure and pain processing functionality in individuals with medication overuse headache. In addition to their primary findings regarding brain regions, researchers noted that several of the studies showed a return to normal structure and pain processing functionality after discontinuing overused medication; medication overuse headache resolved. Clinically we see this in patients that are detoxified from the offending overused medication. Interestingly, abnormalities in regions typically linked with addiction persisted, even after medication discontinuation. This suggests that individuals with medication overuse headache might have a brain trait that predisposes them to overuse medication.

Another study found that certain brain metabolites in key regions of the thalamocortical pathways differed between chronic migraine sufferers with and without medication overuse headache. Investigators conducted magnetic resonance spectroscopic imaging to map metabolites in specific regions of the brains of 48 participants: 16 migraine sufferers with medication overuse headache; 16 without overuse; and 16 healthy controls.

In patients with medication overuse headache, glutamate and glutamine levels were significantly higher in the right midcingulate cortex, and myo-inositol levels were significantly higher in the left anterior cingulate cortex, relative to those without medication overuse headache. These levels were similar to those seen in healthy controls. Additionally, in both groups of migraine sufferers, researchers observed a negative association between myo-inositol laterality index in the anterior cingulate cortices and the number of days per month with acute medication use. They concluded that individuals with medication overuse headache had a distinct concentration of myo-inositol in the anterior cingulate cortices that may be a result of medication overuse and might lead to the development of medication overuse headache.

Clinical implications

An understanding of these very complex pathophysiological findings in medication overuse headache serves as a foundation for neurologists and headache specialists. From there, evaluating the frequency, duration, and quantity of analgesic use in individuals with headache is an important and necessary next step. The time-tested treatment for medication overuse headache has always been patient education, detoxification, and starting preventive medications, which in the past have caused lots of side effects and not always been effective. Today, minimal education and starting a patient on a monoclonal antibody against CGRP is often quite effective, even without detoxification.

It should be noted that there is a new class of drug called the gepants, which block the CGRP receptor peripherally; 2 such gepants are approved by the FDA and are used as acute care medication (rimegepant and ubrogepant). They do not appear to cause medication overuse headache; one of them, rimegepant, was just approved by the FDA as the first headache medication to be used both as an acute treatment and a preventive treatment for migraine. Medication overuse headache understanding and treatment is changing right before our eyes.

Last month’s column focused on medication overuse headache and pointed out an excellent review article by Sun-Edelstein and colleagues. Another fascinating topic also covered within that paper that warrants closer examination is pathogenesis. Developing a thorough knowledge of the pathophysiology of medication overuse headache and its underlying mechanisms positions clinicians to help patients better understand and manage this disorder.

Mechanisms impacting primary headaches

Let us start by detailing the various causes of primary headaches. Activation of the trigeminal nociceptive pathway is the last common step in headache generation. Peripheral sensitization exacerbates intracranial headache pain and leads to the pulsating nature of migraine pain. This severe discomfort is triggered by physical activity and movement. Calcitonin gene-related peptide (CGRP) is primarily responsible for this phenomenon. Increased sensitivity of central trigeminal neurons leads to central sensitization and causes scalp and forehead allodynia typically seen during a migraine attack. Sensitization of trigeminothalamic neurons is thought to be responsible for extensive cutaneous allodynia involving extracephalic regions, like face, arm, and leg.  

Clinical clues

The pathogenesis of medication overuse headache includes chronic medication intake impacting an individual’s hypersensitive trigeminovascular nociceptive system. Physicians should be aware of the 4 factors required for this disorder to develop:

1. Baseline activation of the trigeminovascular nociceptive pathways can cause migraine or tension-type headaches to transform into medication-induced headaches. This transformation typically develops in headaches with an accompanying inflammatory component, which might be related to mast cells in the dura.

2. The discontinuation of acute care headache medication leads first to a worsening and then to an improvement in headaches. Interestingly, the regular use of analgesics for non-headache conditions is not linked to chronic headache development. Non-headache patients who take chronic opiates for cancer do not develop medication overuse headache. This suggests a cause-and-effect relationship, indicating that medication use causes transformation to medication overuse headache in patients with preexisting headache disorders—and is not the result of it. Culprits include migraine-specific drugs, such as triptans or ergots, or medications that are not migraine-specific, such as opioids, non-opioid analgesics, and nonsteroidal anti-inflammatory drugs. Lengthy exposure to these medications impacts a central pathway that controls nociceptive perception, thus causing medication overuse headache. It is important for patients to understand this paradoxical effect to break the cycle of medication overuse.

3. The efficacy of anti-CGRP monoclonal antibodies in the treatment of medication overuse headache is better than that of the older preventive medication. As noted in the last installment, this class of drug is effective in patients with medication overuse headache who have not yet been weaned from the offending medication. The effect is thought to be a result of the decrease of nociception at peripheral perivascular areas, because anti-CGRP monoclonal antibodies do not cross the blood-brain barrier. It is known that CGRP increases transmission of pain signals and is also a vasodilator.

4. The higher prevalence of psychiatric comorbidities, including depression, anxiety disorders, sleep disturbance, and non-cephalic body pain, suggest that they may either be causative or just comorbid. Additionally, individuals with medication overuse headache tend to experience poor general health and quality of life. This suggests that there is also an underlying alteration in neural pathways. Since brainstem aminergic systems are known to modulate mood, it is plausible that these systems impact medication overuse headache. The decrease in serotonin in these patients probably interferes with the brainstem’s descending antinociceptive system or diffuse noxious inhibitory control (DNIC). Increased risk of suicidal ideation is also seen in these individuals. Recently-published research shows that among 603 individuals with chronic migraine headache, the presence of medication overuse headache increased the risk of suicidal ideation by 75% and odds of previous suicide attempt by 88%, even after controlling for demographics, headache profile, disabilities, depression and anxiety symptoms, and sleep quality.

The bottom line: For medication overuse headache to develop, clinicians should see an underlying primary headache worsen with frequent acute care medication use as well as peripheral trigeminal nociceptor activation.

The role of low serotonin levels

Serotonin plays a key role in the pathogenesis of migraine headache. Research shows that in individuals who experience medication overuse headache, platelet serotonin is decreased and the density of serotonin receptors on platelets is increased, implying suppressed serotonin function, as mentioned above.

A recent study showed that individuals with medication overuse headache had higher intensity dependence of auditory evoked potentials (IDAP) levels than controls who did not suffer from headache. Investigators assessed 17 women who suffered from chronic migraine headache (12 of whom experienced medication overuse headache) and 19 healthy individuals as part of a study evaluating efficacy of bilateral betamethasone-lidocaine greater occipital nerve block (GON-B). At baseline, participants were assessed for habituation of visual evoked potentials (VEP) and IDAP. While baseline VEP habituation was similar in both groups, this was not the case for IDAP. Those values were significantly higher in headache sufferers, which implies lower serotonin levels.

Additionally, researchers found that IDAP was normalized in headache sufferers via the use of GON-B, and clinical improvement was seen. They concluded that altered serotonin levels and incoming trigeminal nociceptive input are important components of the pathogenesis of medication overuse headache.

The ‘2-hit model’

Though preliminary, an animal study lends credence to the so-called 2-hit model of medication overuse headache pathogenesis. Researchers hypothesized that abortive treatment, in the form of either migraine-specific medications or analgesics, can serve as a priming mechanism—a so-called first hit that facilitates central sensitization and increases responses to subsequent stimuli. Thus, the second hit occurs via enhancement of net descending facilitation in central pain modulatory pathways.

To test their hypothesis, investigators primed rats through continuous infusion of morphine or sumatriptan and assessed DNIC 7 days later and again 2 weeks after that, when sensory thresholds returned to baseline levels. Morphine-primed rats showed opioid-induced hyperalgesia and a loss of diffuse noxious inhibitory control on day 7, whereas sumatriptan-primed rats did not. Researchers concluded that acute nociceptive stimulation causes alterations in descending pain modulation that can last for long periods. Morphine’s detrimental effect reflects the clinical experience of higher medication overuse headache risk in individuals who use opioids for headache treatment. Thus, the authors noted, migraine medications along with repeated bouts of pain can amplify the consequences of nociceptor activation and increase the odds of future migraine attacks and risk of medication overuse headache. Clinically we see overuse of opioids causing more MOH than overuse of triptans, which can still cause MOH.

In a related animal study, rats underwent a similar priming process and were exposed to migraine triggers in the presence or absence of a humanized CGRP monoclonal antibody. The antibody significantly inhibited cutaneous allodynia in rats that had previously been primed with morphine or sumatriptan. A control protein that does not bind CGRP was ineffective. The authors concluded that acute migraine medications may promote medication overuse headache in susceptible headache sufferers via CGRP-driven mechanisms. Further, anti-CGRP monoclonal antibodies appear to be useful in the treatment of medication overuse headache.

Pain processing and addiction

A recent narrative review of imaging research studies revealed that medication overuse headache is linked with unusual structure and function of brain regions that process pain and other regions normally linked with addiction. Investigators looked at studies that evaluated abnormal structure and pain processing functionality in individuals with medication overuse headache. In addition to their primary findings regarding brain regions, researchers noted that several of the studies showed a return to normal structure and pain processing functionality after discontinuing overused medication; medication overuse headache resolved. Clinically we see this in patients that are detoxified from the offending overused medication. Interestingly, abnormalities in regions typically linked with addiction persisted, even after medication discontinuation. This suggests that individuals with medication overuse headache might have a brain trait that predisposes them to overuse medication.

Another study found that certain brain metabolites in key regions of the thalamocortical pathways differed between chronic migraine sufferers with and without medication overuse headache. Investigators conducted magnetic resonance spectroscopic imaging to map metabolites in specific regions of the brains of 48 participants: 16 migraine sufferers with medication overuse headache; 16 without overuse; and 16 healthy controls.

In patients with medication overuse headache, glutamate and glutamine levels were significantly higher in the right midcingulate cortex, and myo-inositol levels were significantly higher in the left anterior cingulate cortex, relative to those without medication overuse headache. These levels were similar to those seen in healthy controls. Additionally, in both groups of migraine sufferers, researchers observed a negative association between myo-inositol laterality index in the anterior cingulate cortices and the number of days per month with acute medication use. They concluded that individuals with medication overuse headache had a distinct concentration of myo-inositol in the anterior cingulate cortices that may be a result of medication overuse and might lead to the development of medication overuse headache.

Clinical implications

An understanding of these very complex pathophysiological findings in medication overuse headache serves as a foundation for neurologists and headache specialists. From there, evaluating the frequency, duration, and quantity of analgesic use in individuals with headache is an important and necessary next step. The time-tested treatment for medication overuse headache has always been patient education, detoxification, and starting preventive medications, which in the past have caused lots of side effects and not always been effective. Today, minimal education and starting a patient on a monoclonal antibody against CGRP is often quite effective, even without detoxification.

It should be noted that there is a new class of drug called the gepants, which block the CGRP receptor peripherally; 2 such gepants are approved by the FDA and are used as acute care medication (rimegepant and ubrogepant). They do not appear to cause medication overuse headache; one of them, rimegepant, was just approved by the FDA as the first headache medication to be used both as an acute treatment and a preventive treatment for migraine. Medication overuse headache understanding and treatment is changing right before our eyes.