Scientists are chasing the cure for migraines
One billion people suffer from migraines. The reason is that a healthy protein causes their sensory nerves to run amok. Researchers have developed a drug that prevents headaches from occurring - but they are still chasing the answer to why some people are sensitive to the protein.
Migraines hit the entire head
A migraine attack can be anywhere from four hours to three days and the pain differs from the usual headache by giving many different symptoms.
Most migraine patients become extremely sensitive to sounds and light, which intensifies the pain. Some are also bothered by smell and taste.
A typical migraine patient feels confused, gets dizzy and can in rare cases even faint.
The pains are throbbing or pulsating and can be very violent. They usually just sit on one side of the head.
Prior to the migraine attack, some patients experience visual disturbances in the form of flickering areas of the visual field. The phenomenon is called aura.
The pain is exacerbated by the slightest movement, so that you have to lie completely still.
Almost everyone becomes nauseous and some vomit.
Some migraine patients feel that different parts of the body "sleep" or lose their sensation before a migraine attack.
the risk of migraine itself is 70% if one's parents also suffer from migraine. So far, researchers have found a single gene, called TRESK, that can have a bearing on whether we will suffer from migraines.
4 factors trigger headaches
Substances in red wine, yogurt and cheese cause migraine attacks in some patients. Also, hormone fluctuations and chronic stress can cause the brain to secrete the protein CGRP that starts a migraine attack.
A violent pain is throbbing in one side of the woman’s head. Through the clear window, the rays of the sun are pouring in, and she feels how the light drills into the brain and amplifies the pain.
Outside, the birds sing, but the sound hits her head like small hammer beats that make her nauseous and make it turn in her stomach.
Preferably, she wants to close the window and pull for the curtain, but at the slightest movement, the pain increases in strength, so she has to lie completely motionless in bed.
The woman suffers from migraines, like about a billion people in the world.
The violent headaches cost the earth’s population a total of 30 million active years, as the pain prevents people from doing their work and their daily chores.
Most migraine attacks last for a couple of hours but, in the worst case, can last for up to three days. The frequency of attacks will vary from person to person.
Some get migraines every few days, others only get a couple of seizures a year, but two to four seizures a month are common.
In particular, middle-aged people in the western world suffer from migraines and women are affected two to three times more often than men.
Although so many people suffer from the disease, doctors and researchers have not yet fully understood why the pain occurs, and many patients have so far found it difficult to find an effective treatment.
But in May 2018, the US health authority approved a drug that could halve the number of migraine attacks in the severely affected patients.
Clinical trials showed that 26 percent of patients responded maximally to treatment and were cured entirely of migraines. Erenumab, which is called the drug, was also approved in the EU in June 2018 and maybe the first of several pioneering treatment options for migraine patients worldwide.
Erenumab is an antibody that works by neutralizing the effect of a small protein, CGRP, which in recent years, has been identified as the culprit behind migraine.
In most people, it is entirely harmless, but in migraine patients, it makes the nervous system in the head extremely hypersensitive, and researchers are now looking for the answer to what goes wrong.
Drilled holes to ease the pain
In the Middle Ages, it was believed that migraine was due to evil spirits in the head. In some patients, holes were drilled in the head to release the evil spirits and to release the plagues.
It was not until 1918 that doctors developed a remedy for the severe headache in the form of the substance ergotamine, which was recovered from the fungus dandruff.
Ergotamine is still used and, like the newer group of drugs, the so-called triptans causes the blood vessels around the brain to contract.
In 1982, researchers discovered the natural protein CGRP. They later revealed that it was present in extra large quantities during a migraine attack and had just a marked ability to widen blood vessels.
Thus, the causal link appeared to be clear, and for many years it was the general belief that migraine arose when the CGRP protein caused the blood vessels to expand so that the blood flow to the brain became higher than usual.
But in 2008, neurologist Guus Schoonman from Leiden University Medical Center in the Netherlands used a unique form of MRI brain imaging to study the blood flow in the brains of 27 migraine patients.
The researcher utilized that small amounts of nitroglycerin are known to both dilate blood vessels and induce migraine attacks.
The scan results surprisingly showed that the blood vessels only expanded in the first few minutes after injection with nitroglycerin. That blood flow was back down to an average level when the migraine attack started after 1.5-5 hours.
Thus, the painful headache could not be due to large amounts of blood being transported through the brain. The researchers had to look for another explanation.
Protein makes nerves hypersensitive
Research suggests that, after all, it is the CGRP protein that causes the pain during a migraine attack, but in a completely different way than the researchers previously thought.
The protein’s effect on the blood vessels around the brain is not included in the explanation. Instead, the migraine attack is triggered by another function of the CGRP protein.
It affects the sensory nerves on the face, the scalp and the membranes that protect the brain, making the nerves extra sensitive and sharpening the senses to the extreme.
The situation is rapidly developing into a real pain in hell, and a migraine attack is about to bloom. But the newly developed antibody erenumab can slow the escalating pain spiral early by disabling the CGRP protein before the sensory nerves can react to it.
In this way, the treatment works preventively, and because the antibodies – which are abundant proteins – have a long shelf life in the body, patients do not need to take more than a single dose per month to avoid new migraine attacks.
Antibody halves migraine attacks
Doctor Peter Goadsby from King’s College Hospital in London, England, is behind the development of the antibody, and in December 2017, he presented the promising results of a large clinical trial.
A total of 955 migrant-affected subjects participated, which were randomly divided into three groups. Each month for six months, they received an injection of 70 and 140 milligrams, respectively, of the antibody.
The patients initially had migraines between four and 14 days a month, but after six months of treatment, the number of monthly migraine days had decreased by 3.2 and 3.7 in the subjects who had received the low and high doses, respectively.
Of the patients treated with the low dose, 43.3 percent experienced at least half the number of days with migraine, while the corresponding figure for those who received the high dose was 50 percent.
The excellent effect of erenumab is because the antibody prevents CGRP from attaching to the sensory nerves and making them hypersensitive.
To perform its regular work, CGRP must bind to a so-called receptor on the surface of the sensory nerve, but the antibody is CGRP and attaches firmly to the receptor.
In other words, the antibody takes up the site of the receptor, so that CGRP does not have the opportunity to bind to it and trigger the hell of the pain.
Peter Goadsby has also developed another antibody, which instead attaches to the CGRP protein itself and thus prevents it from binding to the receptor.
This antibody is called Fremanezumab and has also been tested in a similar clinical trial of 1,130 migraine patients, some of whom received an injection every three months.
This was enough to reduce the average number of migraine days by 4.3 on average in all subjects, and the number of migraine days was halved for 38 percent of the participants.
Several other antibodies that release CGRP have been tested in clinical trials with similar results.
Fundamental to all of them is that they have different effects on subjects and that the result is significantly better in some patients.
In another clinical trial (published in 2017) on the topic of erenumab, four out of four patients had migraine attacks, while a test with another antibody, galcanezumab, showed that 16 percent of patients were completely cured.
Researchers gave people headaches
The researchers still don’t know why patients react to the antibodies in such different ways. The key to the answer is likely to be how their sensory nerves are affected by the CGRP protein.
All people form the protein that regulates blood flow by expanding blood vessels. But for some reason, migraine patients react differently to it.
Already in 2002, neurologist Jes Olesen from the University of Copenhagen demonstrated that an injection with CGRP quickly triggered a seizure in migraine patients, while people who did not suffer from migraines were only easily given the headache of getting the protein injected into the veins.
Thus, migraine patients respond much more strongly to CGRP than healthy individuals, whose sensory nerves become significantly less sensitive.
However, migraine patients’ response to CGRP is likely to vary as well, which explains why the antibodies do not work as effectively on them.
Medicines relieve acute attacks
Before researchers understand why some patients respond to treatment better than others (and thus may gain the knowledge that helps them develop even better antibodies), they should test if they can instead determine in advance which patients benefit the most from the antibodies.
The treatment is very costly, and if it has only a limited effect on about half of the patients, it is a good idea to target the treatment to the patients who have the most significant benefit.
Researchers are also working on developing many small molecules that can wedge into the receptor of the CGRP protein, thereby preventing the sensory nerves from being affected by it.
The small molecules are called pawns, and unlike the antibodies, they do not work preventively but instead relieve the pain during an ongoing migraine attack.
The doctors can thus apply it to migraine-causing CGRP protein on two fronts: The antibodies reduce the number of seizures, and when a seizure still sets in, the pain can be relieved with other substances.