Finding a Migraine Treatment
It’s not unusual to see migraines dismissed as just “bad headaches.” But the problem of migraines is greater than that. Migraines are the 6th most disabling illness in the world, and in the U.S., one person in every four households suffers from migraines. An effective treatment for migraines could help a lot of people. As someone who experiences migraines, I was curious about this topic and researched the status of migraines treatments. In this article, I want to share the interesting process that eventually led to one of the newest FDA-approved drugs for migraines. But first, it is necessary to understand what migraines are and how they affect migraineurs.
The Basics
A migraine is a neurological condition that generally presents itself as intense headaches that may cause throbbing or pulsing.
Before a migraine begins, people can sometimes experience a preliminary symptom called an aura. In general, an aura is a series of symptoms that precede a neurological event. Some common manifestations of an aura are blurry vision or the appearance of dancing or zig-zag lines. It can also be something stranger, like numbness, pins and needles, weakness in one side of the body, or dizziness. One of the most absurd migraine auras is called Alice in Wonderland Syndrome because people who experience this kind of aura may see things as bigger, smaller, closer, or farther than they are in reality. An aura is a good indication that what someone is experiencing is a migraine and not just a regular headache.
Additionally, unlike regular headaches, migraines are generally accompanied by various symptoms such as nausea, light or sound sensitivity, disorientation, and trouble speaking.
Migraines can be caused by various triggers: fatigue, heat, hormonal changes, dehydration, etc. Each person has their own triggers, which makes migraines difficult to predict and control. Sometimes, the best scenario is to take a few painkillers and wait until the migraine passes. But for those who suffer from migraines many times a month, migraines are a constant roadblock for getting through their lives.
So, how well do we understand how migraine occur and what are we doing about them?
It turns out that there is currently no clearly identified source of migraines in the brain. As a result, researchers have been studying molecules that seem to be correlated with migraines in hopes that this will lead to a treatment. One such molecule is calcitonin gene-related peptide (CGRP), which has been shown to increase in number during migraines.
CGRP is a protein and a neurotransmitter, meaning it is a molecule which sends messages among neurons. It is also a very strong vasodilator, meaning it causes inflammation. CGRP is believed to be the cause of migraine pain for many patients. As a result, a number of migraine treatments have aimed to decrease levels of CGRP in migraineurs. I want to share two different methods in which researchers have used this idea to develop migraine treatments, one of which is now successfully used today.
Take 1: Block the CGRP
One study tried to create a drug that would block CGRP neurotransmitter receivers. In order to better understand how this works, here is a quick overview of the structure of the neuron.
The neuron has 4 main parts:
- The dendrites, which receive signals from other neurons
- The cell body, or the center of the neuron
- The axon, which sends signals from the neuron
- The axon terminals, which release neurotransmitters to other neurons
The most important component for understanding the creation of this medicine is the release of neurotransmitters from the axon terminals. This occurs at a synapse, which is the site where neurotransmitters are sent from one neuron to the next.
Let’s zoom in on one such release:
The presynaptic cell is the first neuron that releases neurotransmitters when triggered. The neurotransmitters travel across a minute gap between the neurons, called the synaptic cleft. They then reach the postsynaptic cell, the second neuron that receives the neurotransmitters. The dark blue “teeth” of the lower neuron in the photo above are called neurotransmitter receptors, and they are where the neurotransmitters bind. CGRP goes through this process and normally binds to receptors, sending the message to neurons to increase inflammation.
In one study run by Henri Doods and others, researchers released a different molecule into the area that was also able to bind to the CGRP receptors. However, the researcher-introduced molecule was designed to inhibit the overall effect of CGRP. In this way, CGRP would no longer cause inflammation and pain for migraineurs… right?
It wasn’t so simple. Although this type of medication saw a decrease in the number of patient migraines, clinical trials also saw unexplained liver side effects in patients and had to be discontinued. But research pressed on!
Take 2: Attack the CGRP Itself
In a different study, run by Vladimir Skljarevski and others, researchers focused on making monoclonal antibodies, which are engineered proteins. These antibodies attach to and destroy the CGRP molecules themselves. This treatment was delivered through an injection. In this way, researchers did not have to worry about messing with the CGRP receptors at all, and they also did not have to introduce a second molecule.
The clinical trial of a drug called galcanezumab, which functions as described above, showed promising results. Patients were placed in three groups: those who received 120 mg of the drug, those who received 240 mg, and one placebo group. I have summarized the results below.
Of the patients who received 120 mg and 240 mg of treatment:
- 59% and 57% of patients reported ≥ 50% reduction in migraine frequency
- 34% of both groups reported ≥ 75% reduction
- 12% and 14% reported 100% reduction
In comparison, in the placebo group, only 36%, 18%, and 6% of the three groups reported the same, showing that galcanezumab did have an effect in decreasing migraine frequency.
There were also much less drastic side effects from this type of treatment, the most common being injection site pain and swelling. After passing numerous trials, galcanezumab has been recently approved by the FDA as a treatment for migraines.
The Caveat
There is still one small problem: galcanezumab shouldn’t actually work. The reason? Our brain has a kind of filter called the blood-brain barrier. This barrier only allows certain types of molecules to enter the brain in order to keep the brain safe and functioning. And it turns out, the antibodies used in this treatment are not on the list of molecules that can enter the brain.
This may suggest that the treatment is working in the periphery of the brain, not in the central nervous system.
Perhaps the source of migraines is in the peripheral nervous system rather than inside the brain, or perhaps, the blood-brain barrier does not function as previously thought. Either way, the success of this treatment leads to more questions about migraines and the structure of our brain.
Citations
Photo Citation:
Brockschmidt, Marc, and Miltos Allamanis. Minimizing Trial and Error in the Drug Discovery Process. 17 June 2019, www.microsoft.com/en-us/research/blog/minimizing-trial-and-error-in-the-drug-discovery-process/.
CNX OpenStax. “Biology.” Wikimedia Commons, commons.wikimedia.org/wiki/File:Figure_09_01_02.jpg.
https://commons.wikimedia.org/wiki/File:Neuron1.jpg
Website Citations:
Doods, H., Hallermayer, G., Wu, D., Entzeroth, M., Rudolf, K., Engel, W., & Eberlein, W. (2009, January 30). BPS Publications. Retrieved July 11, 2019, from https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1038/sj.bjp.0703110
“Migraine Facts.” Migraine Research Foundation, 10 Dec. 2019, migraineresearchfoundation.org/about-migraine/migraine-facts/.
“Migraine with Aura.” The Migraine Trust, 17 Mar. 2020, www.migrainetrust.org/about-migraine/types-of-migraine/migraine-with-aura/.
Nazario, Brunilda. “Alice in Wonderland Syndrome (AIWS): Symptoms, Causes, and Treatment.” WebMD, WebMD, 24 Aug. 2020, www.webmd.com/migraines-headaches/alice-wonderland-syndrome.
Skljarevski, V., Matharu, M., Millen, B. A., Ossipov, M. H., Kim, B., & Yang, J. Y. (2018, May 31). Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial — Vladimir Skljarevski, Manjit Matharu, Brian A Millen, Michael H Ossipov, Byung-Kun Kim, Jyun Yan Yang, 2018. Retrieved July 11, 2019, from https://journals.sagepub.com/doi/full/10.1177/0333102418779543
