In the past few decades, it has become increasingly clear that CGRP plays a role in migraine.

One 2013 study found that levels of CGRP in the blood of women with chronic migraine were over twice as high as in women without migraine.

But what is CGRP?

“CGRP is found throughout the body and is understood to cause blood vessels to become larger (vasodilate),” explained Dr. Ailani. “Whether this is all the time or [only] during certain events, like when the body is stressed, is unclear.”

Although experts have long since thought of vasodilation as a major cause of migraine, accumulating evidence suggests that there may be more to the picture.

Indeed, research suggests that CGRP may be involved in a number of different neurological processes that play a role in pain sensitivity and inflammation, both of which contribute to migraine.

Based on these observations, scientists developed some injectable medications that function to block the activity of CGRP and either prevent or reduce the onset of migraine.

“Our current injectable treatments block CGRP activity by either sticking onto the CGRP protein or by sitting where CGRP needs to go,” said Dr. Ailani. “Both of these things will stop CGRP from being active. Studies show that by reducing CGRP activity, we can reduce migraine frequency.”

There are four options currently available for injectable migraine treatment:

• eptinezumab (Vyepti)
• erenumab (Aimovig)
• fremanezumab (Ajovy)
• galcanezumab (Emgality)

Erenumab is unique among these in that it is the only injectable that binds to the CGRP receptor, or “sits where CGRP is supposed to go,” as Dr. Ailani put it. The rest bind onto the CGRP directly.

“I would say that the four available injectable CGRP preventive medications are more similar than different when it comes to being effective in preventing migraine,” she clarified. “They all have data to show greater reduction in migraine days compared with placebo in both migraine and chronic migraine in [adults].”

The approval of these four medications has significantly expanded the arsenal of injectable treatment options for the prevention of migraine, which previously only included onabotulinumtoxinA, or Botox.

Although it is not migraine-specific like the other injectables, some studies suggest that Botox is similarly effective at preventing chronic migraine. It is likely that Botox reduces migraine pain in a number of different ways, including by preventing the release of CGRP from nerve cells.

As well as injectable treatments that help prevent migraine, there are also two injectable treatment options approved for the acute treatment of migraine.

These treatments, sumatriptan (Imitrex) and dihydroergotamine (DHE), can treat migraine episodes as they occur.

Unlike the other injectable migraine treatments, which people receive regularly to prevent migraine, Imitrex and DHE are not intended for long-term, daily use.

Both Imitrex and DHE may reduce the pain associated with migraine episodes by causing blood vessels to tighten. This is a process known as vasoconstriction.

The major difference between the available anti-CGRP injectables is their mode and frequency of delivery.

People can administer erenumab, fremanezumab, and galcanezumab at home by themselves, if they wish to. Depending on which medication they are taking, they can do this monthly or every 90 days, as in the case of fremanezumab.

“The flexibility is great,” Dr. Ailani emphasized. “Especially for [those] who travel or who want to have injections done by a nurse in the doctor’s office, being able to go to the [doctor’s] office every 90 days is much easier than [going in] monthly.”

The at-home injectables may come as an autoinjector, which is the case with erenumab, or as a prefilled syringe. Galcanezumab and fremanezumab are available as both.

“Why a prefilled syringe vs. an autoinjector? Autoinjectors are really easy to use — often a push-down or push-button — and are designed to be able to be done by the [individual],” explained Dr. Ailani. “Prefilled syringes, however, are less painful. You will see the needle, though, so this is something to consider.”

People receive eptinezumab, on the other hand, as an intravenous (IV) injection, which means that they must receive it at an infusion center.

Although this may be more inconvenient, there are some advantages. “The benefit of an IV infusion,” said Dr. Ailani, “is that the medication gets into the system and starts working faster. The trials show that eptinezumab can reduce migraine frequency the day after the infusion.”

People must also receive Botox from a healthcare provider, typically once every 3 months. They will use a small needle to inject the medication into seven areas on the head and neck.

People can self-administer Imitrex and DHE injectables at home once a migraine headache occurs. Imitrex is available as an autoinjector, whereas DHE comes as a prefilled syringe.

The main benefit of CGRP-specific injectable treatments, explained Dr. Ailani, is the specificity of the medications for migraine.

“They are designed specifically to prevent migraine, compared with other treatments we use in migraine prevention, which have been studied in migraine but were made initially for another disease state.”

She added that the specificity of injectables for CGRP means that treatments are very targeted, which reduces the number of side effects that occur with many traditional migraine treatments.

These treatments are not without their limitations, though. For example, people cannot receive injectable CGRP-specific migraine treatments while pregnant or breastfeeding.

“Since they stay in the system a long time, we ask [people] to come off these treatments about 5–6 months prior to starting to try for pregnancy. For oral treatments, we can usually stop these weeks prior to starting for pregnancy, so it is a big difference and can be problematic for some people.”

Botox and DHE are also not suitable for use during pregnancy. Doctors also do not recommend Imitrex during pregnancy, but they may consider it in some circumstances.

Cost can be another significant limitation for some people. Since these medications are relatively new, insurance may not cover them.

According to the American Migraine Foundation, these CGRP-specific drugs cost around $7,000 per year without insurance coverage. If a person’s insurance does not cover a CGRP-specific injectable, Botox may be a slightly more cost effective option, running at around $300–$600 for each treatment.

Injectable migraine treatments are not approved for use in children at this time.

“Overall, [CGRP-specific injectables] seem to be a safe medication for the majority of [people] with migraine,” said Dr. Ailani.

However, some side effects to be aware of include:

• injection site reactions
• hypersensitivity
• constipation, which may occur with erenumab
• hypertension, which may occur with erenumab
• nasopharyngitis, also known as an upper respiratory infection or rhinitis, which may occur with eptinezumab

Dr. Ailani also emphasized that there may be some unanswered safety questions among those with other underlying vascular conditions, given CGRP’s role as a vasodilator.

“For [people] with a history of recent vascular disease or poorly controlled cardiovascular disease, there are questions that remain.”

In addition to injection site reactions and flu-like symptoms, people may experience temporary drooping in the eyelid after Botox injections. However, this should resolve on its own.

The acute injectable treatments are also associated with some side effects, which may include:

• injection site reactions
• flushing, which includes redness, warmth, or tingling under the skin
• drowsiness
• nausea or vomiting
• muscle cramps, which may occur with Imitrex
• diarrhea, which may occur with DHE

A healthcare provider may ask a person to take their first injection under their supervision to monitor for side effects.

Injectable treatments represent a new frontier of migraine-specific therapy options.

However, Dr. Ailani emphasized that there is still a lot to learn about migraine injectables. These include long-term side effects and the utility of these treatments for the prevention of other types of headaches, such as post-traumatic headaches.

“Our hope in the field is that this is only the start of migraine-specific options.”