CGRP inhibitors provide new options for migraine treatment
Two types of CGRP therapies help block the signals that trigger migraine attacks.
- Reviewed by Howard E. LeWine, MD, Chief Medical Editor, Harvard Health Publishing; Editorial Advisory Board Member, Harvard Health Publishing
Pinpointing an exact cause for a migraine can be challenging; people have different triggers and experiences with this often-debilitating type of headache. But research has shown that levels of a specific chemical called calcitonin gene-related peptide (CGRP) increase during a migraine attack and fall as the migraine subsides - and that people with chronic migraine have elevated levels of CGRP even when they're not experiencing a migraine attack.
Based on that research, the U.S. Food and Drug Administration (FDA) has approved two different types of migraine therapies targeting CGRP. The first CRGP inhibitors were designed as preventive therapy to reduce both the frequency and severity of migraine attacks. Since then, the FDA has also approved drugs to help stop or greatly reduce the symptoms of an acute headache. Here's what you should know if you're considering trying CGRP inhibitors.
What is CGRP?
Calcitonin gene-related peptide is a chemical in the body that has long been known to influence the onset of a migraine headache. It's a neuropeptide, or a small protein made up of amino acid chains that acts as a chemical messenger in the body. It can modulate various bodily functions and increase or decrease the strength of signals transmitted between nerves. In the case of migraine, elevated levels of CGRP trigger various systems that lead to a pain response. As CGRP levels in the body decline, the migraine also subsides.
Where in the body is CGRP produced?
CGRP is produced mainly in the central and peripheral nervous system and is also produced at lower levels in other tissues like the heart, gut, and reproductive organs.
In the central nervous system, CGRP is produced by neurons in the brainstem and spinal cord. In the peripheral nervous system, it's produced by neurons in the dorsal root ganglia (alongside the spinal nerve) and trigeminal ganglia (a set of cranial nerves in your head). It's released from nerve endings in the central and peripheral nervous systems.
How does CGRP act in the body?
CGRP has a variety of functions in the body, but the three that are known to play a role in the events leading up to a migraine are:
- Promoting an inflammatory response
- As a potent vasodilator, causing blood vessels to widen and your blood pressure to drop
- Transmitting pain signals
Here's how that appears to play a role specific to a migraine: First, CGRP inflames nerve endings and causes blood vessels to dilate. As blood vessels widen in response to CGRP, they activate nerves that trigger a pain response. When those nerves are activated, they release even more CGRP into the bloodstream, causing a migraine. As the headache subsides, CGRP levels decline.
In addition to its role in causing migraines, CGRP also promotes bone formation and improves airflow by bronchodilation. It may also play a protective role against neuronal injury or damage during a stroke.
What are the two types of CGRP inhibitors used for migraine?
The two types of CGRP inhibitors used for migraine are CGRP monoclonal antibodies and CGRP receptor antagonists.
Both CGRP inhibitors work by interrupting the CGRP pathway and preventing GCRP signaling, but they work in different ways.
- CGRP monoclonal antibodies bind to CGRP, changing the structure of the peptide. Altered peptides are not able to attach to CGRP cell receptors. While there is not always complete blocking of the pathway, the disruption of the connection means no or incomplete signaling to initiate the cascade of inflammation, vasodilation and pain needed to trigger a migraine.
By preventing the initial signal from transmitting, the entire process is halted or delayed, effectively preventing a migraine before it can even get started. Think of it as sacking the quarterback in football; if he's tackled before he can run or throw the ball to a receiver, the play is over before it even begins.
- CGRP receptor antagonists are small molecule drugs that link to and block the CGRP receptors, preventing them from receiving messages to trigger inflammation, vasodilation, or the pain response.
Small molecule CGRP receptor antagonists act more like defensive backs; the quarterback might be able to throw the ball, but CGRP antagonists stick to and block the receiver, preventing the ball from reaching its destination. The play is essentially halted without any forward progress.
What is the difference between CGRP monoclonal antibodies and small molecule CGRP receptor antagonists?
While both types of CGRP inhibitors target a different stage in the migraine-signaling process, both help prevent the frequency and severity of migraine attacks.
- CGRP monoclonal antibodies must be injected or infused. Infusions must be performed at a doctor's office or infusion center. Injections can be self-administered at home using a pen-type injector like an EpiPen. They are only used as migraine prevention strategy.
- Small molecule CGRP receptor antagonists can be taken orally. Some of these drugs are only approved for migraine prevention, while others may also be used to help stop or lessen the symptoms of an acute migraine attack.
They also differ in how long they last in the body. Monoclonal antibodies (the type that are infused or injected) have a longer half-life and can remain active in the body for weeks or months after a single administration. Small molecule CGRP receptor antagonists typically are only effective for about 24 hours after taking them.
Who should avoid CGRP therapies?
Some groups of people should avoid both types of CGRP therapies, including:
- Pregnant or breastfeeding women
- People with severe liver or kidney disease
Some groups of people should avoid CGRP monoclonal antibodies, including:
- People with a history of cancer
- People with infections
- Those allergic to any ingredient (CGRP monoclonal antibodies contain ingredients like latex)
Other groups of people should avoid CGRP antagonists, including:
- People who are allergic or hypersensitive to CGRP antagonists or any of their ingredients
- People taking certain other medications. People taking medications like statins or HIV antiretrovirals should discuss potential interactions with their doctor.
- Those with a history of heart disease or stroke
About the Author
Lindsay Warner, Content Licensing Editor, Harvard Health Publishing
About the Reviewer
Howard E. LeWine, MD, Chief Medical Editor, Harvard Health Publishing; Editorial Advisory Board Member, Harvard Health Publishing
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