Migraine headaches are one of the most common neurological disorders seen in medical practice, affecting 16% of the population in the United States. These headaches are characterized by a pulsing or throbbing pain which is located behind the eyes on either side of the face. Usually there are symptoms across many systems during a migraine attack like nausea, sensitivity to light, sounds, smells and motion. and These headaches are often misunderstood by the general populace who have not suffered one. The court of public opinion is that they cannot be all that bad, but this is far from the truth. Migraines can be debilitating, 43% of persons with migraines suffer from Moderate to severe disability. In a 2019 survey Migraine was found to be the second highest cause of years lived with a disability, among women under 50 it is the highest. The numbers go to highlight how damaging and universal this disorder truly is.
fig. 1 The anatomical name for the fifth cranial nerve is the Trigeminal Nerve. This nerve is responsible for sensory information in the areas shown.
Calcitonin Gene-Related Peptide (CGRP) is an amino acid neuropeptide discovered in 1982. A Neuropeptide is a peptide secreted by a neuron that acts as a signaling molecule. Neuropeptides are often colloquially referred to as “messagers” to the cells. When CGRP is released, inflammation occurs. This inflammation is shown to activate the fifth cranial nerve which results in the pain and autonomic nervous system symptoms associated with migraine headaches. The fifth cranial nerve is responsible for sensory information from the face and most of the front of the head. Despite this knowledge, the broad availability of CGRP is a very recent development. These medications have all received FDA approval within the past 10 years.
These new types of treatment work in two different ways. There are Monoclonal antibodies (mAbs) treatments which work with the immune system to desensitize the receptors to the peptides responsible, and there are gepants, which are small molecule antagonists. In medicine, antagonists are a category of drug that binds to the corresponding receptor of the class they inhibit. In the case of CGRP, the gepant class will inhibit the binding make the receptor unavailable. An occupied receptor means there is nowhere for these signals to be received. In the instance of mAbs, the antibodies target and bind to either the CGRP receptor or the anti-CGRP receptor antibodies. Both of these medications use the same mechanism of action to inactivate CGRP, but the effectiveness of either class is slightly varied along with cost.
artistic representation of a synapse.
Monoclonal Antibody CGRP targeting treatments for migraine headaches are injectables, with the exception of Vyepti, which is given as an intrveinous infusion. These treatments are given monthly, or quarterly. In the gepant class the formulation is a pill taken by mouth, with the dosing schedule depending on the medication. Some are to be taken as needed to stop an active migraine, and others are taken every other day or every day as a preventative treatment. The potency of the gepant class is somewhat less than triptans but for people who have trialed triptans to no effect, this is still helpful. From my expieriance, triptans can have some strange side effects as well that not everyone can deal with.
To qualify for trial of mAbs for migraine treatment resistant chronic migraine headache or for treatment resistant episodic migraine, the patient must have tried at least two other classes of medications to no or limited benefit. These may include beta blockers, tricyclical antidepressants, and SNRI’s.
For Gepants to be considered as a line of treatment the patent must have failed trial with at least two or more triptans. Both gepants and mAbs are one of the last lines of treatment for migraine headache, the last option being botox injections.
For those who suffer chronic migraines, or status migrainosus (a migraine headache that lasts 72 hours +) these medications are invaluable. In clinical studies with the available CGRP targeting medications there has been a marked improvement in the number of monthly migraine days reported, and greater levels of functional improvement than the placebo.
Cohen, Fred, et al. “Calcitonin Gene-Related Peptide (Cgrp)-Targeted Monoclonal Antibodies and Antagonists in Migraine: Current Evidence and Rationale.” BioDrugs, vol. 36, no. 3, 2022, pp. 341–358., https://doi.org/10.1007/s40259-022-00530-0.
Image credits:
figure 1: https://www.physio-pedia.com/Trigeminal_Nerve
header: https://www.pexels.com
synapse: https://www.europeanpharmaceuticalreview.com/news/78898/artificial-synaptic-device/
Special thanks to Dr. Seth Davis, Ph.D