Migraine i
s complex.
At least migraine seems complex – because we don’t know what causes it.
But we’re making progress. There is an emerging consensus about what’s important in migraine – and what’s not important. So in this brief summary we’ll stick to what most experts think are the important parts.
Though migraine is complex – we’ll keep it simple – adding only those details required for a basic understanding – keeping in mind that the goal is getting better, not just getting smarter.
Migraine is simple.
At the most basic level, having migraine means having a sensitive neurovascular system. I don’t have migraine (my wife does) but if my brain was sufficiently ’stressed’ (challenged by things it does not like), a migraine attack would eventually ensue – it’s just that quite a bit of stress would be required to make that happen. The level of stress required to trigger an attack is what defines migraine disease – and the severity of migraine disease.
Migraine is triggered by nerve signals that cause the release of inflammation causing substances. Odd as it might seem, nerve impulses release these inflammation causing substances all the time – in everyone – in moderation. Migraine means that something’s not quite right. It might be that too many nerve signals are being generated – or too much of the ’substance’ is being released – or that there is an excessive reaction to that substance – or some other thing/combination that results in excess sensitivity.
The inflammation that’s caused by nerve activity is called neurogenic inflammation. In the case of migraine, it’s the blood vessels of the brain that become inflamed – and probably the nerve itself . We’ll look at that nerve in a moment. It’s a big one – the trigeminal – with a central portion located in the brainstem and numerous branches – some of which go to the face – others of which go to the blood vessels of the brain.
Once nerve signals trigger the initial inflammation of the brain’s blood vessels, that inflammation irritates and inflames other, nearby nerves. That causes those nerves (which are very close by) to send return signals that ’something is wrong’ (e.g. pain signals.) Unfortunately, those signals only make things worse, because they cause more inflammation back at the site where the first signal originated.
That original site (sometimes called the “migraine generator”) ends up being more ‘excited’ (and inflamed) than it was to begin with – so it starts sending even more inflammation-causing signals back up to the blood vessels of the brain. It’s a vicious cycle – one that ultimately leads to a full-blown migraine attack.
The most likely structure responsible for initiating and perpetuating that vicious cycle of neurogenic inflammation is the trigeminal nerve and its associated structures.
Without going into detail, the trigeminal nerve is a very large nerve – actually more like a big bundle of nerves. The trigeminal nerve ‘bundle’ has branches that go to the face. It also has branches that go to the blood vessels of the brain.
The various ‘bundles’ of the trigeminal nerve come together in the brainstem in a big clump. Different parts of the big clump can be referred to as a “ganglion” or a “nucleus”. It’s all part of one big interconnected nerve bundle, so we’ll just refer to all of it as the trigeminal or, sometimes, the “trigemino-vascular” system (to emphasize the fact that it connects with, affects, and is affected by the blood vessels in the brain.)
When the trigeminal becomes inflamed, that inflammation can affect other parts of the brainstem, which could explain the nausea, vomiting and certain other symptoms common to migraine. Plus, there’s some ‘inter-mingling’ of trigeminal nerve fibers with those of the seventh cranial nerve, which might explain why migraine can cause symptoms like tearing, bloodshot eyes and stuffy nose – because stimulation of the seventh cranial nerve can have those effects.
So there’s a number of reasons to believe that the “migraine generator” is in the brainstem – and that it might be the trigeminal itself.
In fact that’s one point on which there is emerging consensus – that the trigeminal is critical in migraine. To keep things simple, we’ll assume that migraine starts in the trigeminal and is perpetuated by the trigemino-vascular system.
Likewise, it’s pretty well accepted that inflammation plays a critical role in migraine – specifically neurogenic inflammation. What’s less certain are which chemical mediators of inflammation are most important in the neurogenic inflammation process. Molecules considered possibly important include calcitonin gene-related peptide (CGRP), nitric oxide (NO), substance P, glutamate, tumor necrosis factor (TNF), neurokinin A, serotonin – and quite a few others. Of those listed above, there is emerging consensus on the importance of at least two: CGRP and NO.
CGRP is known to be released, in excess, by the trigeminal during migraine. CGRP is associated with pain and inflammation. Migraine is relieved when CGRP receptors are blocked, and a new class of anti-migraine drugs is being developed which do just that – block CGRP receptors. In clinical trials, the CGRP receptor blockers have shown about the same effectiveness in treating migraine as triptans, but they may have fewer side effects. Speaking of triptans, at least part of their effectiveness may result from their ability to inhibit the release of CGRP. So there are many reasons to believe that CGRP is important in migraine.
NO is also known to be present, in excess, in association with migraine. Nitroglycerin (NTG) administration (generates NO in the body) causes a migraine headache, especially in those with migraine disease. NO stimulates the release of pro-inflammatory agents from the trigeminal, especially CGRP. In fact, the presence of excess NO might be required for CGRP release. Plus, NO is generated in the blood vessels of the brain in response to the excess serotonin released during a migraine attack. Finally, blocking NO has been shown to be effective in the treatment of migraine. So there are many reasons to believe that NO is important in migraine.
Here’s where it seems science is at – the present consensus on what’s important in migraine:
- Neurogenic inflammation is important.
- The trigeminal – or trigemino-vascular system – is important.
So going forward those things are about all we’ll talk about. Except that we’ll also talk about NF-kB, because NF-kB is the inflammation Master Switch, and because everything that’s important in migraine might relate back to NF-kB.
Migraine is a disease of inflammation.
According to the theory advanced on this site (in brief) every ‘disease of inflammation’:
- Is caused by inflammation…
- that results from over-activation of NF-kB…
- that can be treated by administering NF-kB inhibitors – especially natural (plant derived) NF-kB inhibitors.
That’s a very simple theory. It might be wrong. It’s definitely incomplete. But at least it’s actionable.
If it’s right – or to the extent it’s right – then we can treat migraine by using a combination of natural NF-kB inhibitors. That might be quite advantageous because – in addition to helping a lot of people – such a product would be:
- Relatively free from side effects – and perhaps entirely free from serious side effects.
The brief outline that follows is a little more complicated than it might be (sorry) – but I want to stay consistent with the expert consensus on what’s important.
Evidence for each of the following – if found – would support (but not prove) the theory in regard to migraine:
- Migraine is associated with inflammation, and more specifically:
- Migraine is associated with inflammation in the trigeminal, and/or;
- Migraine is associated with inflammation of the blood vessels of the brain.
- Migraine is associated with excess NF-kB activation, and more specifically:
- Migraine is associated with excess NF-kB activation in the trigeminal, and/or;
- Migraine is associated with excess NF-kB activation in the blood vessels of the brain.
- Migraine is associated with a defect (especially genetic) or vulnerability that results in excess activation of NF-kB.
- Inhibiting NF-kB is beneficial in the treatment of migraine, and more specifically:
- Inhibiting NF-kB in the trigeminal is beneficial, and/or;
- Inhibiting NF-kB in the blood vessels of the brain is beneficial.
- Natural NF-kB inhibitors are beneficial in treating or preventing migraine, especially:
- If they specifically act in the trigeminal, and/or;
- If they specifically act in the blood vessels of the brain.
Hopefully that makes sense. Now we’ll go through the outline and check for evidence in support of each statement. Note that “true” means only that there is evidence in support of that contention.
Migraine is associated with inflammation – true.
- Migraine is specifically associated with inflammation in the trigeminal – also true.
- Migraine is specifically associated with inflammation of the blood vessels of the brain – seems to be true.
Given all the above, it’s clear that migraine is a disease of inflammation. Next…
Migraine is associated with excess NF-kB activation – true.
- Elevated NF-kB is among the markers of inflammation found in the blood during an acute migraine attack.
- NF-kB is upregulated prior to the surge in iNOS (generates NO) expression associated with migraine.
- Migraine is specifically associated with NF-kB activation in the trigeminal – also true.
- Migraine is specifically associated with NF-kB activation in the blood vessels of the brain – also true.
- During an acute migraine attack, blood drawn from the internal jugular vein showed excess activation of NF-kB. The authors even suggest that NF-kB inhibitors might be used in the successful treatment of migraine.
So it appears migraine is associated with a lot of NF-kB activation, both in the trigeminal and in the blood vessels of the brain.
Migraine is associated with a defect (especially genetic) or vulnerability that results in excess activation of NF-kB – no evidence.
- Migraine is clearly linked to genetic inheritance, but the basis for that linkage remains elusive – we can’t find the genes.
- Not what we’re looking for, but perhaps of interest: migraine is associated with a lack of responsiveness by vascular smooth muscle to NO. The researchers who investigated seemed to be looking for a way to explain the higher cardiovascular risk in migraine – and found that the vessels were not very responsive to NO – they had trouble dilating (getting bigger.) This is the opposite of what I would have guessed. I would have guessed that they became enlarged (as in migraine) very easily. Hmmm…
- Could it be that migraine results (genetically) from some dysfunction in NO processing by the blood vessels?
- Might the result of diminished vascular response to NO be some compensatory overproduction of NO – which might then lead to inflammation of the trigeminal?
Inhibiting NF-kB is beneficial in the treatment of migraine – true.
- Specifically inhibiting NF-kB in the trigeminal is beneficial in the treatment of migraine – also true.
- Specifically inhibiting NF-kB in the blood vessels of the brain is beneficial in the treatment of migraine – no evidence. (But the finding of elevated NF-kB in the internal jugular, combined with the fact that NF-kB controls inflammation, and that inflammation of the vessels plays a role in migraine, strongly suggests this would be true.)
So far, so good – it looks like migraine is a disease of inflammation – that is associated with NF-kB activation – and that inhibiting NF-kB is helpful. Two publications go so far as to say that NF-kB would be a good target for a migraine drug. I agree. Let’s continue.
Natural NF-kB inhibitors are beneficial in treating or preventing migraine – true.
- Natural NF-kB inhibitors that specifically inhibit NF-kB in the trigeminal have been shown beneficial in migraine – true.
- Natural NF-kB inhibitors have specifically been shown beneficial in migraine through the inhibition of NF-kB in the blood vessels of the brain – no evidence.
There is evidence that natural NF-kB inhibitors are effective in the treatment of migraine – specifically that parthenolide, the purported active ingredient in feverfew, is effective – and that it works by inhibiting NF-kB in the trigeminal.
One problem with feverfew is that it does not seem to be all that effective. A comprehensive review of feverfew use for the prevention of migraine concluded that feverfew might work – or it might not. There just wasn’t enough evidence (but the review did conclude that feverfew was safe.) Even if we look at the trial where feverfew seemed to perform best, it just wasn’t all that effective. The active product decreased the monthly number of migraine attacks from 4.8 to 2.9, a decrease of 1.9, but the placebo reduced attacks by 1.3 each month. And it took 2-3 months before the effect of feverfew extract kicked in.
Another problem is that we only have evidence for feverfew/parthenolide. There are many other natural NF-kB inhibitors – but it seems their use in the treatment of migraine has not been investigated.
One reason for that – the lack of investigation – is that once a molecule looks interesting, and has been shown to do something, it’s going to be further investigated. So if you go to the PubMed database and search for “parthenolide” you’ll find (as of 12-18-09) 353 citations (and 18 citations for parthenolide + migraine.) Search curcumin (an NF-kB inhibitor and the active ingredient in turmeric) and you’ll find 3,112 results – but zero results for curcumin + migraine. That’s because curcumin, unlike feverfew, has no history of use in migraine.
Which means curcumin does not work for treating migraine. At least not by itself. We would know if curcumin worked for migraine because millions of people use curcumin. If it worked, someone would have figured it out by now (“Hey, ever since I started taking curcumin I don’t get migraine headaches!”)
That doesn’t mean curcumin can’t act with other NF-kB inhibitors to enhance their efficacy.
We’ll get to that in a moment. But for now let’s forget about feverfew, or any specific plant, and instead focus on the principle. Natural NF-kB inhibitors may be effective. We have evidence for one. We have ignorance regarding many. We know that we need more effect than what feverfew alone can deliver.
But let’s keep going. This is fun, right?
CGRP vs. NO – which is more important?
Both calcitonin gene-related peptide (CGRP) and nitric oxide (NO) appear to play a critical role in the initiation and progression of a migraine attack – but is one more important than the other? If so, which one? (And does it matter?)
One way to view ‘importance’ is to look at which factor is dependent on, or ‘downstream’, from the other. Generally speaking we’re much better off targeting the ‘upstream’ factor – at least so far as efficacy is concerned.
NO controls CGRP – so NO is more important, and a better target for therapeutic intervention.
That appears to be the case, because:
NO is upstream from CGRP – so it’s a better target than CGRP – but what’s upstream from NO?
NF-kB controls NO (and CGRP) – so NF-kB is more important, and a better target for therapeutic intervention.
Both NO and CGRP are important – and both are controlled by NF-kB.
Here’s the stream: NF-kB => NO => CGRP
First choice for an effective migraine medication would be to inhibit excess NF-kB, second choice would be to inhibit NO, third choice to inhibit CGRP.
Both triptans and CGRP receptor blockers work at the CGRP level, which is probably why their efficacy in migraine is ‘only’ about 60% at 2 hours.
Inhibiting excess NF-kB activation might produce far better results. And if we could inhibit NF-kB, then it wouldn’t really matter (to answer an earlier question) whether CGRP or NO is more important – since they are both downstream from, and under the control of, NF-kB.
NF-kB is the ultimate target in migraine because it’s not only the inflammation Master Switch – it’s also the migraine Master Switch.
So we really need to find a way to affect NF-kB – because we really want to get rid of migraine.
Returning to the principle – we have shown that a natural NF-kB inhibitor ’should’ work – or at least that it could work. We have one example of a natural NF-kB inhibitor that (probably) does work – feverfew and its active ingredient parthenolide. But we need more than what feverfew alone can deliver.
By expanding on what we know, it might be possible to achieve the desired effect.
The first step is to combine multiple NF-kB inhibitors. Specific natural NF-kB inhibitors have been selected, based on a rational process, with the intent of creating the most effective product while using the least possible amount of each individual extract. Each individual extract has a several thousand year history of safe use. None of the extracts would be effective (at all) if used alone.
The second step, equally important, is to deliver the extracts in such a way as to ensure maximum bio-availability. Specifically, by formulating the combination of natural NF-kB inhibitors as a lozenge, so that they can be absorbed through the mucous membranes of the mouth. That way the important molecules (whatever they might be) reach the bloodstream – and the brain (trigeminal) – without first being exposed to the very harsh environs of the stomach.
You may be familiar with the process by which natural plant extracts are separated from cellulose enclosures and presented to the mucosal membrane of the mouth for direct absorption into the bloodstream. It’s called “eating”. Assuming you chew your food, whenever you eat fruits and vegetables you’re absorbing natural NF-kB inhibitors through the mucous membranes in your mouth. There’s nothing odd or dangerous about it. What’s odd is that no one seems to think it’s important.
The end result – a combination of plant extracts in the form of a lozenge – is Banjo.
In theory it should work – and it does. No one to date has had a migraine while using Banjo – and the people who have used Banjo have had some pretty nasty migraine disease.
I’m sure I’ll need to change the above paragraph soon – and I’m not sure it should be included even now. I’m leaving it because it’s a way of letting people know what to expect. Banjo isn’t the sort of thing you use in hopes that your migraine attacks might decrease by 20% in three months. Banjo is supposed to make your migraine attacks stop – right away – entirely. That’s the goal.
Banjo can be used as an acute treatment for migraines. It works when used that way – but like all migraine medications, it works much better if taken early in the course of an attack.
The ideal use of Banjo is in the prevention of migraine attacks. There are about 2.5 million people in the US who experience acute migraine one or more days a week. Those are the people I would really like to see using Banjo – the people whose lives are most impacted by migraine – the ones for whom, it seems, nothing else works.If you know anyone like that, please send them here. I’ll be happy to send them whatever they need. For now at least, everything is free – nothing is for sale. (That will change at some point – sorry.)
One last note
The historical use of feverfew goes back thousands of years – but had somehow fallen out of favor until, sometime around 1950, a woman in England rediscovered feverfew for the prevention of migraine.
Of course she couldn’t go to the store and buy it. She simply found some feverfew and chewed on the leaves – which is probably how most herbal remedies were administered in the past. In any case, by chewing on the leaves she found that, over time, her migraines went away – or at least diminished in number.
Her discovery was eventually published in a local magazine. Word spread and soon hundreds, then thousands of people all across England began chewing on feverfew leaves. It must have worked – at least a little – because feverfew became quite popular. So popular in fact that ‘nutrition’ companies started making and selling a feverfew product. What did they sell? Well, dried up bits of feverfew leaf packed inside a gelatin capsule, of course.
Feverfew remai
ns popular to this day, and you can buy it (the dried up bits of leaf inside a gelatin capsule) in any health food store. But you can’t buy the leaves. My guess is that those capsules don’t work so well. They might not work at all. I don’t know.
But I would guess that the woman who first rediscovered the usefulness of feverfew could set us straight. I imagine her saying “I told you to chew the leaves – chewing the leaves is what works!”
And I would add – on what basis have you come to believe that chewing a fresh leaf is the same as swallowing whole a ground up, dessicated product wrapped in gelatin?
Yes, chewing the leaf might be somewhat unpleasant and inconvenient. Then again, migraine disease tends to be rather unpleasant and inconvenient.
If you want to use feverfew for migraine, then I suggest you either purchase fresh leaf (I have no idea where) or grow your own. Why not? It’s an attractive plant that grows almost anywhere. I have some in my perennial garden (in Minnesota.) It resembles a daisy.
In the alternative you can use Banjo. It tastes better than feverfew leaf (in my opinion) and it’s quite a bit more effective.
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