Maybe you’re familiar with the  debilitating pain migraines can cause.

I am. Or the constant cycle of uncertainty.

Or the weird sensory issues. Or the half dozen other things they do. If not, you definitely know someone who is.

After all, a billion people around  the world experience migraines. And unfortunately, migraine medications  don’t work for lots of them. Here’s where I’d love to say  we’re about to tell you about   a new breakthrough in treatments for  migraines that will change everything.

But we’re not. Research into migraine treatments,  which gained steam in the early 1900s,   has progressed frustratingly  slowly for several reasons. So instead, we’re going to talk about  the many treatments patients have tried,   the reasons we haven’t made more progress, and  what we have to do to develop a better drug. [♪ INTRO] What is a migraine?

It’s an interesting question,  because our answer to it has changed. And that actually explains part of why  treatment has progressed so slowly. Migraines are a neurological  condition which culminates in   episodes of severe headache,  nausea, and hypersensitivity.

While current migraine treatments  leave much to be desired,   they’re still an improvement  over what we used to have. Especially when you consider that 19th century   treatments included such poisons  as arsenic, cyanide, and hemlock. Between the 60s and early 90s, and  before we had a bunch of drugs that   were approved specifically to treat  migraines, doctors and researchers   often turned to medications that were  already approved for other diseases.

They might not sound like migraine  treatments, so we’ll explain how they relate. The first two were tricyclic  antidepressants for depression   and beta blockers for high blood pressure. These are very different medications, but they  do something similar to our brains and nerves.

They target messages our brains are sending  to our bodies, either by making those messages   last longer or turning the volume down  on messages that aren’t helping anymore. Other drugs that doctors tried target  the messengers themselves, our neurons. They calm our neurons down, making them  less likely to overreact to something.

All of these can decrease the  intensity of migraines in some people,   and the biggest advantage was that they  are safe to take by mouth every day. So they could be used for preventing attacks,  which most migraine meds don’t actually do. However, they also don’t work for everyone and  can have nasty side effects including depression,   irregular heartbeats, and feeling very tired.

The last miscellaneous treatment was  discovered a bit later, but we’ll talk   about it now because it’s different from  all the others we’re about to get to. And that’s botox injections. Botox uses a toxin derived from bacteria to  prevent nerves from communicating with muscles.

Patients are given botox injections in the face,   head, and neck near nerves  associated with migraines. While botox does not work for most people with  migraines, it can offer a sustained decrease   in symptoms for the unlucky fraction who have  migraine headaches 15 or more days a month. In that same era between the 70s and 90s,   scientists were also thinking about treating  the physiological causes for migraine head on.

And a lot of them suspected  the blood vessels in the head. There are no pain receptors in the brain itself,  so pain has to be caused by something else. And many types of headaches are  caused or worsened by problems   with blood flow going in and out of our heads.

For migraines, researchers thought the culprit  might be too much blood flowing into the skull,   creating pressure, and activating the nerves that  sense pain in the membranes surrounding the brain. Researchers investigated drugs that could  partially close off those blood vessels,   in order to reduce the amount  of blood flowing into the brain. Triptans, the first major drug family that  could do this, hit the market in the 1990s.

They’re still in use, and they  do work for lots of people. The drawback is triptans are a “rescue  medication,” not one you take every day. Patients start taking them at the  first sign of a migraine coming on.

Which takes the edge off, but  can’t prevent migraines altogether. Though, some people can predict  exactly when the migraines are coming. For example, some people reliably experience  migraines along with their period.

In this case, they may be able to start taking  triptans a couple days before their period starts,   and that may enable them to  prevent migraines entirely. But since triptans’ discovery, research  has suggested that migraines may be more   of a neurological disorder than a vascular one. Which begs the question, why  do the triptans work at all?

Well, it turns out triptans bind receptors that  influence both blood flow and pain sensation. When researchers made a drug  that only targeted just those   pain sensation nerves, it also treated migraines. Except it was less effective  than the original triptans,   so we’re still not a hundred  percent on what’s going on there.

Researchers continued working on this though. In the late 1990s and 2000s, researchers  honed in on a small protein called CGRP   they thought may be the root cause of migraines. CGRP does a lot of things,   but it’s linked to dilating blood vessels  and altering pain reception in the brain.

In clinical trials, if you inject humans  who are susceptible to migraines with CGRP,   most develop migraine-like  symptoms, like a severe headache. So, two types of drugs were made to target CGRP. And the fact that both were effective  further underlined that CGRP was important.

The first is gepants. Gepants bind up CGRP,   reducing the number available to do  whatever harm they do during migraines. Gepants come in pill form.

Some of them are rescue medications, and  some can be taken daily to prevent headaches. Lastly we have antibody treatments. As background, antibodies are created by  our immune system to fight off infections.

They bind to things like viruses and tell the immune system, “Hey! Get ‘em!” We can also engineer antibodies  to bind other things – like CGRP. For every CGRP that binds an antibody,   that’s one fewer binding the  nerves associated with migraines.

Antibody treatments cut the  number of headache days in half   or better for about 60% of people with  migraines after 3 months of treatment. That rises to a little over 90% after 11 months. Antibodies are also nice because  it’s just one injection a month,   and they often work for people whose  other migraine treatments have failed.

But antibody treatments are super expensive  – they can cost hundreds of dollars per dose. And insurance will often refuse to cover  them unless you try many other options first. That is a steep price to pay, especially if you   have to wait 11 months just  to know if they work for you!

Moreover, both gepants and antibodies can  have side effects, ranging from common but   unpleasant – like constipation – to rare  but dangerous – like severe liver disease. We’re gonna get to why these don’t  work for everyone, but first,   all science needs funding,  so here’s a quick break. Thanks to Incogni for  supporting this SciShow video!

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You get a full refund if you  aren’t happy with the service. And if you are happy, you can keep  their protection for years to come. Okay, so we’ve named a handful of families of  drugs that each treat migraines for some people.

It’s possible that a single drug that  works for everyone just doesn’t exist. If our research strategy had been  comprehensive and flawless up to   this point, then I might even say that’s probable. But our research into migraine treatments  has not been comprehensive or flawless.

In fact, most treatments are only tested  on a small subset of migraine symptoms. Namely, the “headache so  bad I’m throwing up” phase. And to what extent the drugs could  reduce the number of days with headache.

Which means we’re finally ready  to come back to the question at   the start of this video: “What is a migraine?” If you don’t get migraines, you might be under the  impression that they’re just really bad headaches. An event that happens and then goes away. But not everyone with migraines gets headaches,  and you never really stop getting migraines.

Migraine is a cycling neurological  condition that has two major phases. The headache happens in the ictal phase. This phase can be further broken down into the  wind-up, the attack itself, and the aftermath.

In the multi-hour to multi-day wind-up, patients  can experience brain fog, nausea, and tiredness. In the final stretch, some feel aura,  which is a sort of brain misfire where   someone might see flashes that  aren’t there or feel tingling. Then comes the full-blown, hours-to-days-long,  mind-splitting headache that’s often   accompanied by vomiting and extreme  sensitivity to light, sound, and smell.

In the wind-down, patients feel  tired, mentally and physically. They can have difficulty concentrating  and often feel dehydrated. Almost like a neurological hangover.

After that, they enter the interictal phase. But this isn’t just a waiting  period between attacks. This phase often has milder  versions of the same symptoms.

That waiting period is stressful too. Having no idea when the next attack will turn your   life upside down can have a huge impact  on your mental health and social life. Up to this point, treatments have been  focused on headache severity and frequency,   but that misses a big chunk of the picture.

Drug studies should be assessed based on  how well drugs offer relief throughout the   migraine cycle, for the full range  of symptoms patients experience. That strategy could be used to  reassess the drugs we already have. Some of them might be helpful  in the interictal phase.

But even if we do that research, and we should,   it wouldn’t change that these  drugs don’t work for everyone. We need new treatment options. How do we find them?

Well, the simplest but least inspiring answer  is combining the medications we already have. The thought process here is that each of these  drugs treats migraines in a different way. If we combine them, they  might have an additive effect.

Early research shows that this might work  when combining antibody treatments with   botox, perhaps because they both  target different pain pathways. But remember that botox is used for patients  who have 15 or more headache days a month. Meaning this strategy is benefiting only  the absolute most severe of sufferers.

While any relief for those patients is good,   this isn’t an option for 80 to  90% of people with migraines. And waiting for your migraines to get bad  enough to be eligible just sounds miserable. So, how do we make new treatments?

Well, in general, designing new medicines   starts with having a strong fundamental  understanding of what causes a disease. But for long stretches of history, what  we thought caused migraines was either   flawed or incomplete looking at you,  “migraines are a blood vessel thing.” We need to keep refining our molecular  definition of what a migraine is. Beyond even CGRP.

Yes, it seems to be a factor,  but if it was the only cause,   we would expect treatments targeting  it to be effective in more people. That means we need to look even harder. What does it look like when a migraine starts?

What happens just before that? These are types of questions  that nuts-and-bolts lab research,   what we call basic science, can answer. It’s not always flashy, but it helps us understand   how our bodies work so we can design  a cure, rationally and intentionally.

It turns out that glial cells, the cells in  our brain which support and defend our neurons,   play a critical role in initiating aura. Glial cells also influence how sensitive our   brains are to pain which might be  crucial for treating migraines. We can think of pain as our body’s fire alarm.

When something in our body is wrong, our  brains will pull the alarm making us feel pain. In normal one-off situations, like when you put  your hand on a hot stove, that pain is helpful. It prompts you to pull your hand back.

But that same process can cause problems  in people who have chronic or recurring   bouts of pain in the same body  part—like migraine patients. In a process called central sensitization,   our brains get better at sensing  anything wrong in that area of our body. But that also makes them more  trigger happy with the alarm.

Eventually, our brains start pulling that severe,   knee-buckling pain alarm for things that  would only give other people mild discomfort. This doesn’t just affect migraine patients,  it affects everyone with chronic pain. And since glial cells play a role  in this process and migraine aura,   scientists have started looking  at drugs that could target them.

They haven’t found any that were  effective at treating migraines yet. The current versions don’t specifically  target glial cells, which may be the problem. So scientists are exploring other ways to target   glial cells, like using viruses or  regrowing glial cells from scratch.

In the meantime, some non-pharmacological  treatments have been shown to help migraine   patients, though to a lesser  extent than proven drugs. Still, treatments on top of meds  like cognitive behavioral therapy,   conscious relaxation of muscles in the head  and neck, and working with doctors to train   your brain to process pain differently  can provide some relief to patients. At least in the interim.

We’re way behind on understanding  and treating migraines. There’s no getting around that, but  we’re making progress every year. Soon, we should be able to create drugs  which interrupt earlier steps of the process.

And when those drugs make it to clinical trials,   we can test how well they treat  all of migraine’s symptoms. With these steps, and continued funding, we  hope to eventually find a treatment strategy   that can bring relief to all patients  who suffer from this horrible condition. [♪ OUTRO]