00:00:00
Maybe you’re familiar with the
debilitating pain migraines can cause.
00:00:03
I am.
00:00:04
Or the constant cycle of uncertainty.
00:00:06
Or the weird sensory issues.
00:00:08
Or the half dozen other things they do.
00:00:10
If not, you definitely know someone who is.
00:00:13
After all, a billion people around
the world experience migraines.
00:00:17
And unfortunately, migraine medications
don’t work for lots of them.
00:00:21
Here’s where I’d love to say
we’re about to tell you about
00:00:23
a new breakthrough in treatments for
migraines that will change everything.
00:00:27
But we’re not.
00:00:28
Research into migraine treatments,
which gained steam in the early 1900s,
00:00:32
has progressed frustratingly
slowly for several reasons.
00:00:36
So instead, we’re going to talk about
the many treatments patients have tried,
00:00:40
the reasons we haven’t made more progress, and
what we have to do to develop a better drug.
00:00:45
[♪ INTRO]
00:00:48
What is a migraine?
00:00:49
It’s an interesting question,
because our answer to it has changed.
00:00:54
And that actually explains part of why
treatment has progressed so slowly.
00:00:58
Migraines are a neurological
condition which culminates in
00:01:01
episodes of severe headache,
nausea, and hypersensitivity.
00:01:04
While current migraine treatments
leave much to be desired,
00:01:07
they’re still an improvement
over what we used to have.
00:01:10
Especially when you consider that 19th century
00:01:12
treatments included such poisons
as arsenic, cyanide, and hemlock.
00:01:17
Between the 60s and early 90s, and
before we had a bunch of drugs that
00:01:21
were approved specifically to treat
migraines, doctors and researchers
00:01:24
often turned to medications that were
already approved for other diseases.
00:01:28
They might not sound like migraine
treatments, so we’ll explain how they relate.
00:01:32
The first two were tricyclic
antidepressants for depression
00:01:35
and beta blockers for high blood pressure.
00:01:37
These are very different medications, but they
do something similar to our brains and nerves.
00:01:43
They target messages our brains are sending
to our bodies, either by making those messages
00:01:48
last longer or turning the volume down
on messages that aren’t helping anymore.
00:01:52
Other drugs that doctors tried target
the messengers themselves, our neurons.
00:01:56
They calm our neurons down, making them
less likely to overreact to something.
00:01:59
All of these can decrease the
intensity of migraines in some people,
00:02:03
and the biggest advantage was that they
are safe to take by mouth every day.
00:02:06
So they could be used for preventing attacks,
which most migraine meds don’t actually do.
00:02:12
However, they also don’t work for everyone and
can have nasty side effects including depression,
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irregular heartbeats, and feeling very tired.
00:02:21
The last miscellaneous treatment was
discovered a bit later, but we’ll talk
00:02:25
about it now because it’s different from
all the others we’re about to get to.
00:02:29
And that’s botox injections.
00:02:30
Botox uses a toxin derived from bacteria to
prevent nerves from communicating with muscles.
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Patients are given botox injections in the face,
00:02:39
head, and neck near nerves
associated with migraines.
00:02:42
While botox does not work for most people with
migraines, it can offer a sustained decrease
00:02:48
in symptoms for the unlucky fraction who have
migraine headaches 15 or more days a month.
00:02:53
In that same era between the 70s and 90s,
00:02:56
scientists were also thinking about treating
the physiological causes for migraine head on.
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And a lot of them suspected
the blood vessels in the head.
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There are no pain receptors in the brain itself,
so pain has to be caused by something else.
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And many types of headaches are
caused or worsened by problems
00:03:14
with blood flow going in and out of our heads.
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For migraines, researchers thought the culprit
might be too much blood flowing into the skull,
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creating pressure, and activating the nerves that
sense pain in the membranes surrounding the brain.
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Researchers investigated drugs that could
partially close off those blood vessels,
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in order to reduce the amount
of blood flowing into the brain.
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Triptans, the first major drug family that
could do this, hit the market in the 1990s.
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They’re still in use, and they
do work for lots of people.
00:03:42
The drawback is triptans are a “rescue
medication,” not one you take every day.
00:03:47
Patients start taking them at the
first sign of a migraine coming on.
00:03:50
Which takes the edge off, but
can’t prevent migraines altogether.
00:03:54
Though, some people can predict
exactly when the migraines are coming.
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For example, some people reliably experience
migraines along with their period.
00:04:02
In this case, they may be able to start taking
triptans a couple days before their period starts,
00:04:07
and that may enable them to
prevent migraines entirely.
00:04:10
But since triptans’ discovery, research
has suggested that migraines may be more
00:04:14
of a neurological disorder than a vascular one.
00:04:17
Which begs the question, why
do the triptans work at all?
00:04:20
Well, it turns out triptans bind receptors that
influence both blood flow and pain sensation.
00:04:26
When researchers made a drug
that only targeted just those
00:04:30
pain sensation nerves, it also treated migraines.
00:04:33
Except it was less effective
than the original triptans,
00:04:37
so we’re still not a hundred
percent on what’s going on there.
00:04:40
Researchers continued working on this though.
00:04:42
In the late 1990s and 2000s, researchers
honed in on a small protein called CGRP
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they thought may be the root cause of migraines.
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CGRP does a lot of things,
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but it’s linked to dilating blood vessels
and altering pain reception in the brain.
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In clinical trials, if you inject humans
who are susceptible to migraines with CGRP,
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most develop migraine-like
symptoms, like a severe headache.
00:05:06
So, two types of drugs were made to target CGRP.
00:05:09
And the fact that both were effective
further underlined that CGRP was important.
00:05:14
The first is gepants.
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Gepants bind up CGRP,
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reducing the number available to do
whatever harm they do during migraines.
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Gepants come in pill form.
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Some of them are rescue medications, and
some can be taken daily to prevent headaches.
00:05:29
Lastly we have antibody treatments.
00:05:31
As background, antibodies are created by
our immune system to fight off infections.
00:05:36
They bind to things like viruses and
tell the immune system, “Hey! Get ‘em!”
00:05:41
We can also engineer antibodies
to bind other things – like CGRP.
00:05:46
For every CGRP that binds an antibody,
00:05:49
that’s one fewer binding the
nerves associated with migraines.
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Antibody treatments cut the
number of headache days in half
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or better for about 60% of people with
migraines after 3 months of treatment.
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That rises to a little over 90% after 11 months.
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Antibodies are also nice because
it’s just one injection a month,
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and they often work for people whose
other migraine treatments have failed.
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But antibody treatments are super expensive
– they can cost hundreds of dollars per dose.
00:06:18
And insurance will often refuse to cover
them unless you try many other options first.
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That is a steep price to pay, especially if you
00:06:26
have to wait 11 months just
to know if they work for you!
00:06:29
Moreover, both gepants and antibodies can
have side effects, ranging from common but
00:06:35
unpleasant – like constipation – to rare
but dangerous – like severe liver disease.
00:06:41
We’re gonna get to why these don’t
work for everyone, but first,
00:06:44
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00:08:02
Okay, so we’ve named a handful of families of
drugs that each treat migraines for some people.
00:08:07
It’s possible that a single drug that
works for everyone just doesn’t exist.
00:08:12
If our research strategy had been
comprehensive and flawless up to
00:08:16
this point, then I might even say that’s probable.
00:08:18
But our research into migraine treatments
has not been comprehensive or flawless.
00:08:23
In fact, most treatments are only tested
on a small subset of migraine symptoms.
00:08:28
Namely, the “headache so
bad I’m throwing up” phase.
00:08:32
And to what extent the drugs could
reduce the number of days with headache.
00:08:36
Which means we’re finally ready
to come back to the question at
00:08:38
the start of this video: “What is a migraine?”
00:08:41
If you don’t get migraines, you might be under the
impression that they’re just really bad headaches.
00:08:46
An event that happens and then goes away.
00:08:49
But not everyone with migraines gets headaches,
and you never really stop getting migraines.
00:08:55
Migraine is a cycling neurological
condition that has two major phases.
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The headache happens in the ictal phase.
00:09:03
This phase can be further broken down into the
wind-up, the attack itself, and the aftermath.
00:09:09
In the multi-hour to multi-day wind-up, patients
can experience brain fog, nausea, and tiredness.
00:09:15
In the final stretch, some feel aura,
which is a sort of brain misfire where
00:09:20
someone might see flashes that
aren’t there or feel tingling.
00:09:24
Then comes the full-blown, hours-to-days-long,
mind-splitting headache that’s often
00:09:29
accompanied by vomiting and extreme
sensitivity to light, sound, and smell.
00:09:34
In the wind-down, patients feel
tired, mentally and physically.
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They can have difficulty concentrating
and often feel dehydrated.
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Almost like a neurological hangover.
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After that, they enter the interictal phase.
00:09:47
But this isn’t just a waiting
period between attacks.
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This phase often has milder
versions of the same symptoms.
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That waiting period is stressful too.
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Having no idea when the next attack will turn your
00:09:59
life upside down can have a huge impact
on your mental health and social life.
00:10:04
Up to this point, treatments have been
focused on headache severity and frequency,
00:10:08
but that misses a big chunk of the picture.
00:10:11
Drug studies should be assessed based on
how well drugs offer relief throughout the
00:10:16
migraine cycle, for the full range
of symptoms patients experience.
00:10:21
That strategy could be used to
reassess the drugs we already have.
00:10:25
Some of them might be helpful
in the interictal phase.
00:10:28
But even if we do that research, and we should,
00:10:31
it wouldn’t change that these
drugs don’t work for everyone.
00:10:34
We need new treatment options.
00:10:36
How do we find them?
00:10:37
Well, the simplest but least inspiring answer
is combining the medications we already have.
00:10:43
The thought process here is that each of these
drugs treats migraines in a different way.
00:10:48
If we combine them, they
might have an additive effect.
00:10:51
Early research shows that this might work
when combining antibody treatments with
00:10:56
botox, perhaps because they both
target different pain pathways.
00:11:00
But remember that botox is used for patients
who have 15 or more headache days a month.
00:11:05
Meaning this strategy is benefiting only
the absolute most severe of sufferers.
00:11:10
While any relief for those patients is good,
00:11:12
this isn’t an option for 80 to
90% of people with migraines.
00:11:16
And waiting for your migraines to get bad
enough to be eligible just sounds miserable.
00:11:21
So, how do we make new treatments?
00:11:24
Well, in general, designing new medicines
00:11:26
starts with having a strong fundamental
understanding of what causes a disease.
00:11:31
But for long stretches of history, what
we thought caused migraines was either
00:11:35
flawed or incomplete looking at you,
“migraines are a blood vessel thing.”
00:11:39
We need to keep refining our molecular
definition of what a migraine is.
00:11:43
Beyond even CGRP.
00:11:45
Yes, it seems to be a factor,
but if it was the only cause,
00:11:48
we would expect treatments targeting
it to be effective in more people.
00:11:52
That means we need to look even harder.
00:11:54
What does it look like when a migraine starts?
00:11:56
What happens just before that?
00:11:58
These are types of questions
that nuts-and-bolts lab research,
00:12:02
what we call basic science, can answer.
00:12:04
It’s not always flashy, but it helps us understand
00:12:07
how our bodies work so we can design
a cure, rationally and intentionally.
00:12:12
It turns out that glial cells, the cells in
our brain which support and defend our neurons,
00:12:17
play a critical role in initiating aura.
00:12:20
Glial cells also influence how sensitive our
00:12:22
brains are to pain which might be
crucial for treating migraines.
00:12:26
We can think of pain as our body’s fire alarm.
00:12:30
When something in our body is wrong, our
brains will pull the alarm making us feel pain.
00:12:35
In normal one-off situations, like when you put
your hand on a hot stove, that pain is helpful.
00:12:40
It prompts you to pull your hand back.
00:12:42
But that same process can cause problems
in people who have chronic or recurring
00:12:46
bouts of pain in the same body
part—like migraine patients.
00:12:50
In a process called central sensitization,
00:12:53
our brains get better at sensing
anything wrong in that area of our body.
00:12:59
But that also makes them more
trigger happy with the alarm.
00:13:02
Eventually, our brains start pulling that severe,
00:13:05
knee-buckling pain alarm for things that
would only give other people mild discomfort.
00:13:10
This doesn’t just affect migraine patients,
it affects everyone with chronic pain.
00:13:15
And since glial cells play a role
in this process and migraine aura,
00:13:20
scientists have started looking
at drugs that could target them.
00:13:23
They haven’t found any that were
effective at treating migraines yet.
00:13:27
The current versions don’t specifically
target glial cells, which may be the problem.
00:13:31
So scientists are exploring other ways to target
00:13:34
glial cells, like using viruses or
regrowing glial cells from scratch.
00:13:39
In the meantime, some non-pharmacological
treatments have been shown to help migraine
00:13:43
patients, though to a lesser
extent than proven drugs.
00:13:47
Still, treatments on top of meds
like cognitive behavioral therapy,
00:13:51
conscious relaxation of muscles in the head
and neck, and working with doctors to train
00:13:56
your brain to process pain differently
can provide some relief to patients.
00:14:01
At least in the interim.
00:14:02
We’re way behind on understanding
and treating migraines.
00:14:06
There’s no getting around that, but
we’re making progress every year.
00:14:09
Soon, we should be able to create drugs
which interrupt earlier steps of the process.
00:14:14
And when those drugs make it to clinical trials,
00:14:17
we can test how well they treat
all of migraine’s symptoms.
00:14:21
With these steps, and continued funding, we
hope to eventually find a treatment strategy
00:14:26
that can bring relief to all patients
who suffer from this horrible condition.
00:14:32
[♪ OUTRO]
