CGRP inhibitors for migraine: how they work and what the risks are

More and more people with chronic migraine use CGRP inhibitors. The names sound familiar: fremanezumab (Ajovy), galcanezumab (Emgality), eptinezumab (Vyepti), erenumab (Aimovig). They seem to have been developed for one clear purpose: block CGRP so that migraine attacks decrease.

But reality is more complex. CGRP is not simply a culprit that “switches on” migraine. It is a messenger that responds to processes that run much deeper. To understand why CGRP inhibitors work, why they sometimes lose their effect, and why in some people they set off new problems, we need to look at what CGRP actually does in the body.

What is CGRP and why does it play a role in migraine?

CGRP (calcitonin gene-related peptide) is a neuropeptide, a substance that nerve cells use to communicate with each other. It plays a crucial role in migraine, because it:

• Causes inflammation in the meninges [1, 2, 3]
• Dilates blood vessels, which contributes to migraine pain, although we now know that migraine is more than vasodilation alone [4, 5]
• Amplifies pain signals, making the migraine more intense [6, 7]

This is why CGRP inhibitors were developed: they block the action of CGRP and can reduce migraine attacks.

But CGRP is not only active in the brain. It also has important functions in the rest of the body.

The broader role of CGRP in the body

CGRP is not limited to migraine. It also influences:

• Blood vessels: CGRP helps dilate blood vessels and regulates blood pressure. This ensures that organs, including the brain, get enough oxygen and nutrients [8, 9].
• The immune system: CGRP works both ways. Depending on the context, it can promote inflammation, but also inhibit it. In this way it influences how the immune system responds to different stimuli and helps limit tissue damage [10, 11].
• The gut: CGRP influences how food moves through the gut and may play a role in digestive problems such as irritable bowel syndrome (IBS) [12, 13].
• Teeth and nerves: CGRP is active in the dental nerves and can increase sensitivity to pain [14, 15]. Because the trigeminal system governs both toothache and migraine, it is plausible that people with migraine are more sensitive to toothache, although this specific link has not yet been confirmed in clinical studies.

CGRP and the gut

When the gut is stimulated by, for example, herbs and spices, spicy food, acids, stress or mechanical movement, nerve endings in the gut release CGRP. That CGRP signal stimulates your goblet cells to produce more mucus [16].

That mucus is crucial:

• it forms the mucus layer
• it keeps bacteria at a distance
• it protects the gut wall
• it prevents irritation and inflammation
• it supports healthy bowel movements

When you block CGRP, this protective message is disrupted. The result: a more vulnerable gut ecosystem and a weaker gut barrier.

CGRP inhibitors can lead to:

• a thinner mucus layer [16]
• less smooth bowel movements
• constipation [17, 18]
• more contact between bacteria and the gut wall
• more immune activation and low-grade inflammation

This matters for migraine: a disrupted gut barrier means more production of inflammatory substances (cytokines). Those cytokines also reach the brain, where they can stimulate neuroinflammation, an important factor in migraine [19, 20].

So what you are trying to solve with the inhibitor can be reactivated somewhere else.

When is CGRP activated?

CGRP is released in response to specific stimuli, such as:

• Activation of the trigeminal nerve: a key player in migraine that sends pain signals to the brain [4, 21, 22].
• Inflammation: CGRP is released during inflammatory reactions and influences how the immune system responds [3, 10].
• A shortage of oxygen or energy in the brain: CGRP helps dilate blood vessels to improve blood flow [23, 24].

So it is trying to repair something. Inhibiting CGRP can dampen symptoms, but it does not remove the reason for that compensation.

How do CGRP inhibitors work?

CGRP inhibitors such as fremanezumab (Ajovy), galcanezumab (Emgality) and erenumab (Aimovig) are monoclonal antibodies (mAbs). This means they are specifically designed to block CGRP or the CGRP receptor [25].

There are two kinds of this type of CGRP inhibitor:

• CGRP receptor blockers (such as erenumab, Aimovig): these attach to the CGRP receptor, so CGRP can no longer exert its effect on blood vessels and nerves. The receptors are the little gateways through which CGRP gets into the cell so it can do its work.
• CGRP-neutralising antibodies (such as fremanezumab, galcanezumab and eptinezumab): these bind directly to CGRP itself and neutralise it before it can bind to the receptor.

Among the preventive medications there are also the gepants. They do not work with antibodies, but occupy the CGRP receptor so that CGRP itself can no longer attach to it [26].

For acute pain relief, many people also use triptans. Triptans suppress CGRP release as part of how they work. But with frequent use (more than 10 days a month), the body can start to compensate by making more CGRP and forming more CGRP receptors. Paradoxically, this leads to medication overuse headache (MOH) [27, 28]. Anti-CGRP antibodies are even used as a treatment for this form of MOH [29].

So CGRP inhibitors block the action of CGRP, but the question is: is CGRP really the cause, or just a reaction to an underlying problem?

The risks of CGRP inhibitors

When you use a CGRP inhibitor, all the CGRP in your body is blocked, not just at the place where migraine starts. This can mean you experience side effects such as higher blood pressure [30], changed pain sensitivity or an unbalanced immune system.

Why it often suddenly stops working

When less of a substance such as CGRP is circulating (in this case because the medication is clearing it), your body tries to compensate. It often does this by making more receptors, so that the little CGRP that is left has a stronger effect.

In principle, this applies to all signalling molecules in our body. If there is too much, receptor sensitivity goes down; if there is too little, receptor sensitivity goes up. When there is less of a signal, your body starts listening harder.

With CGRP inhibitors, this means some people notice less effect after a while, because their body is trying to restore the balance. This mechanism has not been specifically studied for CGRP inhibitors, but it is a well-known physiological principle that applies to many signalling molecules in our body.

Erenumab (Aimovig), on the other hand, not only blocks the receptor, but also causes the receptor to be taken up by the cell and broken down [31]. That is a much more drastic action than simply lowering the substance. This may explain why erenumab is more likely than fremanezumab, galcanezumab or eptinezumab to cause side effects such as raised blood pressure [30].

In addition, over time your immune system can develop antibodies against the medication itself, which makes it work less well. This happens in some users.*

Looking deeper at the cause

If CGRP is merely responding to other stimuli, we should be asking:

• Why is the trigeminal nerve being activated?
• Why is an inflammatory reaction occurring?
• Why is there a shortage of oxygen or energy in the brain?

CGRP inhibitors can reduce the final phase of migraine because they slow the dilation of the blood vessels, but they do not tackle the real cause. The underlying excitability of the nervous system is not taken away: the overstimulation, the fatigue and the underlying triggers remain.

Should we inhibit CGRP or tackle the underlying cause?

So CGRP inhibitors are not a magic solution. They have side effects and do not tackle the deeper causes of migraine. If CGRP is just a messenger, we need to look more broadly at the underlying causes of migraine, such as nerve activity, inflammation and energy shortage in the brain.

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If this explanation has helped you see the role of CGRP more clearly, my book HEADSTRONG will take you much further. It brings together all the building blocks that contribute to migraine, from energy balance and the gut to hormones, stress, sleep and the interaction between your brain and your immune system.

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* With comparable biological medications in rheumatology (infliximab, adalimumab), it took years before it was discovered that the formation of antibodies against the medication was an important cause of loss of effectiveness [32]. For CGRP inhibitors, this specific question has not yet been sufficiently studied. It is striking, however, that some patients who stop because of a declining effect do respond when they switch to a different CGRP antibody [33, 34].

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