Migraine is many things, but one thing it’s not is “just a headache”.

“Migraine” comes from the Greek word “hemicrania”, referring to the common experience of migraine being predominantly one-sided.

Some people experience an “aura” preceding the headache phase – usually a visual or sensory experience that evolves over five to 60 minutes. Auras can also involve other domains such as language, smell and limb function.

Migraine is a disease with a huge personal and societal impact. Most people cannot function at their usual level during a migraine, and anticipation of the next attack can affect productivity, relationships and a person’s mental health.

What’s happening in my brain?

The biological basis of migraine is complex, and varies according to the phase of the migraine. Put simply:

The earliest phase is called the prodrome. This is associated with activation of a part of the brain called the hypothalamus which is thought to contribute to many symptoms such as nausea, changes in appetite and blurred vision.

Next is the aura phase, when a wave of neurochemical changes occur across the surface of the brain (the cortex) at a rate of 3–4 millimetres per minute. This explains how usually a person’s aura progresses over time. People often experience sensory disturbances such as flashes of light or tingling in their face or hands.

In the headache phase, the trigeminal nerve system is activated. This gives sensation to one side of the face, head and upper neck, leading to release of proteins such as CGRP (calcitonin gene-related peptide). This causes inflammation and dilation of blood vessels, which is the basis for the severe throbbing pain associated with the headache.

Finally, the postdromal phase occurs after the headache resolves and commonly involves changes in mood and energy.

What can you do about the acute attack?

A useful way to conceive of migraine treatment is to compare putting out campfires with bushfires. Medications are much more successful when applied at the earliest opportunity (the campfire). When the attack is fully evolved (into a bushfire), medications have a much more modest effect.

Aspirin

For people with mild migraine, non-specific anti-inflammatory medications such as high-dose aspirin, or standard dose non-steroidal medications (NSAIDS) can be very helpful. Their effectiveness is often enhanced with the use of an anti-nausea medication.

Triptans

For moderate to severe attacks, the mainstay of treatment is a class of medications called “triptans”. These act by reducing blood vessel dilation and reducing the release of inflammatory chemicals.

Triptans vary by their route of administration (tablets, wafers, injections, nasal sprays) and by their time to onset and duration of action.

The choice of a triptan depends on many factors including whether nausea and vomiting is prominent (consider a dissolving wafer or an injection) or patient tolerability (consider choosing one with a slower onset and offset of action).

As triptans constrict blood vessels, they should be used with caution (or not used) in patients with known heart disease or previous stroke.

Gepants

Some medications that block or modulate the release of CGRP, which are used for migraine prevention (which we’ll discuss in more detail below), also have evidence of benefit in treating the acute attack. This class of medication is known as the “gepants”.

Gepants come in the form of injectable proteins (monoclonal antibodies, used for migraine prevention) or as oral medication (for example, rimegepant) for the acute attack when a person has not responded adequately to previous trials of several triptans or is intolerant of them.

They do not cause blood vessel constriction and can be used in patients with heart disease or previous stroke.

Ditans

Another class of medication, the “ditans” (for example, lasmiditan) have been approved overseas for the acute treatment of migraine. Ditans work through changing a form of serotonin receptor involved in the brain chemical changes associated with the acute attack.

However, neither the gepants nor the ditans are available through the Pharmaceutical Benefits Scheme (PBS) for the acute attack, so users must pay out-of-pocket, at a cost of approximately A$300 for eight wafers.

What about preventing migraines?

The first step is to see if lifestyle changes can reduce migraine frequency. This can include improving sleep habits, routine meal schedules, regular exercise, limiting caffeine intake and avoiding triggers such as stress or alcohol.

Despite these efforts, many people continue to have frequent migraines that can’t be managed by acute therapies alone. The choice of when to start preventive treatment varies for each person and how inclined they are to taking regular medication. Those who suffer disabling symptoms or experience more than a few migraines a month benefit the most from starting preventives.

Almost all migraine preventives have existing roles in treating other medical conditions, and the physician would commonly recommend drugs that can also help manage any pre-existing conditions. First-line preventives include:

• tablets that lower blood pressure (candesartan, metoprolol, propranolol)
• antidepressants (amitriptyline, venlafaxine)
• anticonvulsants (sodium valproate, topiramate).

Some people have none of these other conditions and can safely start medications for migraine prophylaxis alone.

For all migraine preventives, a key principle is starting at a low dose and increasing gradually. This approach makes them more tolerable and it’s often several weeks or months until an effective dose (usually 2- to 3-times the starting dose) is reached.

It is rare for noticeable benefits to be seen immediately, but with time these drugs typically reduce migraine frequency by 50% or more.

‘Nothing works for me!’

In people who didn’t see any effect of (or couldn’t tolerate) first-line preventives, new medications have been available on the PBS since 2020. These medications block the action of CGRP.

The most common PBS-listed anti-CGRP medications are injectable proteins called monoclonal antibodies (for example, galcanezumab and fremanezumab), and are self-administered by monthly injections.

These drugs have quickly become a game-changer for those with intractable migraines. The convenience of these injectables contrast with botulinum toxin injections (also effective and PBS-listed for chronic migraine) which must be administered by a trained specialist.

Up to half of adolescents and one-third of young adults are needle-phobic. If this includes you, tablet-form CGRP antagonists for migraine prevention are hopefully not far away.

Data over the past five years suggest anti-CGRP medications are safe, effective and at least as well tolerated as traditional preventives.

Nonetheless, these are used only after a number of cheaper and more readily available first-line treatments (all which have decades of safety data) have failed, and this also a criterion for their use under the PBS.

Mark Slee, Associate Professor, Clinical Academic Neurologist, Flinders University and Anthony Khoo, Lecturer, Flinders University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Our brain is an extremely complex and delicate organ. Our body fiercely protects it by holding onto things that help it and keeping harmful things out, such as bugs that can cause infection and toxins.

It does that though a protective layer called the blood-brain barrier. Here’s how it works, and what it means for drug design.

First, let’s look at the circulatory system

Adults have roughly 30 trillion cells in their body. Every cell needs a variety of nutrients and oxygen, and they produce waste, which needs to be taken away.

Our circulatory system provides this service, delivering nutrients and removing waste.

Where the circulatory system meets your cells, it branches down to tiny tubes called capillaries. These tiny tubes, about one-tenth the width of a human hair, are also made of cells.

But in most capillaries, there are some special features (known as fenestrations) that allow relatively free exchange of nutrients and waste between the blood and the cells of your tissues.

It’s kind of like pizza delivery

One way to think about the way the circulation works is like a pizza delivery person in a big city. On the really big roads (vessels) there are walls and you can’t walk up to the door of the house and pass someone the pizza.

But once you get down to the little suburban streets (capillaries), the design of the streets means you can stop, get off your scooter and walk up to the door to deliver the pizza (nutrients).

We often think of the brain as a spongy mass without much blood in it. In reality, the average brain has about 600 kilometres of blood vessels.

The difference between the capillaries in most of the brain and those elsewhere is that these capillaries are made of specialised cells that are very tightly joined together and limit the free exchange of anything dissolved in your blood. These are sometimes called continuous capillaries.

This is the blood brain barrier. It’s not so much a bag around your brain stopping things from getting in and out but more like walls on all the streets, even the very small ones.

The only way pizza can get in is through special slots and these are just the right shape for the pizza box.

The blood brain barrier is set up so there are specialised transporters (like pizza box slots) for all the required nutrients. So mostly, the only things that can get in are things that there are transporters for or things that look very similar (on a molecular scale).

The analogy does fall down a little bit because the pizza box slot applies to nutrients that dissolve in water. Things that are highly soluble in fat can often bypass the slots in the wall.

Why do we have a blood-brain barrier?

The blood brain barrier is thought to exist for a few reasons.

First, it protects the brain from toxins you might eat (think chemicals that plants make) and viruses that often can infect the rest of your body but usually don’t make it to your brain.

It also provides protection by tightly regulating the movement of nutrients and waste in and out, providing a more stable environment than in the rest of the body.

Lastly, it serves to regulate passage of immune cells, preventing unnecessary inflammation which could damage cells in the brain.

What it means for medicines

One consequence of this tight regulation across the blood brain barrier is that if you want a medicine that gets to the brain, you need to consider how it will get in.

There are a few approaches. Highly fat-soluble molecules can often pass into the brain, so you might design your drug so it is a bit greasy.

Another option is to link your medicine to another molecule that is normally taken up into the brain so it can hitch a ride, or a “pro-drug”, which looks like a molecule that is normally transported.

Using it to our advantage

You can also take advantage of the blood brain barrier.

Opioids used for pain relief often cause constipation. They do this because their target (opioid receptors) are also present in the nervous system of the intestines, where they act to slow movement of the intestinal contents.

Imodium (Loperamide), which is used to treat diarrhoea, is actually an opioid, but it has been specifically designed so it can’t cross the blood brain barrier.

This design means it can act on opioid receptors in the gastrointestinal tract, slowing down the movement of contents, but does not act on brain opioid receptors.

In contrast to Imodium, Ozempic and Victoza (originally designed for type 2 diabetes, but now popular for weight-loss) both have a long fat attached, to improve the length of time they stay in the body.

A consequence of having this long fat attached is that they can cross the blood-brain barrier, where they act to suppress appetite. This is part of the reason they are so effective as weight-loss drugs.

So while the blood brain barrier is important for protecting the brain it presents both a challenge and an opportunity for development of new medicines.

Sebastian Furness, ARC Future Fellow, School of Biomedical Sciences, The University of Queensland

This article is republished from The Conversation under a Creative Commons license. Read the original article.