On cytokines, inflammation, pain and fibromyalgia

Cytokines are inter-cellular chemical messengers produced mostly by white blood cells. Some are generally pro-inflammatory (inflammatory cytokines turn inflammation ‘on’) while others are generally anti-inflammatory (they turn inflammation ‘off’). High levels of inflammatory cytokines indicate an ongoing inflammatory process. There might not be the appearance of ‘inflammation’ as we generally think of it – but there is a ‘type’ of inflammation at work – the ‘inflammatory response system’ is active – the process of inflammation has begun.

The primary study referenced below is important because it provides good evidence that inflammation (inflammatory cytokines, or the inflammatory response system) plays a significant role in fibromyalgia.

Specifically, circulating levels of IL-8 (a pro-inflammatory cytokine) were found to be elevated in those with fibromyalgia. That’s important, but what’s more significant is that the severity of pain was observed to correlate with the level of IL-8. That is, when there was more IL-8 there was more pain. When there was less IL-8 there was less pain. Does IL-8 cause the diffuse pain of fibromyalgia? Let’s see.

Inflammatory cytokine IL-8 seems to play an important role in fibromyalgia.

In the study summarized below, 20 fibromyalgia patients and 80 healthy controls were monitored over the course of six months. Circulating levels of various ‘markers’ of inflammation (inflammatory cytokines IL-6, IL-8 and TNF, as well as anti-inflammatory cytokines IL-4 and IL-10) were evaluated over time. Any changes in response to therapy were noted.

At the beginning of the study, before any treatment was administered, fibromyalgia patients were found to have substantially higher than normal levels of IL-8 and TNF (tumor necrosis factor – another inflammatory cytokine.) No other cytokine differences were observed.

Once treatment was initiated (multi-modal therapy including oral pain medications) the level of TNF quickly decreased to normal – within 10 days. But the decrease in TNF had no impact on pain. TNF dropped but pain remained high. So the inflammatory cytokine TNF may not be all that important in fibromyalgia – at least not as a direct cause of pain. (IL-8 levels were unchanged at this point.)

What happened next?

Over the remaining 6 months of therapy, IL-8 decreased in most patients, but only by a little, and only very slowly. At the end of six months most patients still had relatively high levels of both IL-8 and pain.

But a few patients had a much more substantial decrease in their IL-8 level. What happened to them?

Those patients with significantly lower IL-8 at the end of the study also had significantly less pain!

Not only that, but it turns out those with the highest levels of IL-8 at the end of the study also had the most pain.

How closely did pain severity track with IL-8? Well, a perfect correlation (as these things are defined) would be 1.0. The actual correlation in this study was 0.78 – which is very high. That suggests a strong link between IL-8 and pain.

Growth hormone is one of the numerous chemical mediators of the hypothalamic-pituitary-adrenal axis (HPAA,) a very complex system that governs many functions, including the immune response to stress.

Various abnormalities of the HPAA have been implicated in fibromyalgia, including abnormalities in the production and release of growth hormone. Some research has suggested that the level of growth hormone is consistently low in about one-third of those with fibromyalgia.

Other research (including the publication summarized below) suggests that average growth hormone levels might often be normal, but that most of those with fibromyalgia have diminished release of growth hormone in response to exercise. In fact 153 out of 165 fibromyalgia patients (93%) were found to have deficient growth hormone release in response to strenuous exercise.

So it seems fibromyalgia is often associated with a significant defect in the regulation of growth hormone. Growth hormone may be chronically low in some and low in response to exercise in nearly all.

What symptoms could result from growth hormone defect?

It’s reasonable to suspect that such a growth hormone defect might be responsible for many symptoms of fibromyalgia. Growth hormone deficiency has been linked to weight gain, diminished energy, depressed mood, sleep disturbance, impaired thinking, poor memory, reduced exercise capacity, stiffness, muscle weakness, and cold intolerance – all of which are common in fibromyalgia.

How might a growth hormone defect result in symptoms?

If a growth hormone defect is at least partly to blame for the symptoms of fibromyalgia, the question is – why? How might diminished growth hormone release in response to exercise worsen the symptoms of fibromyalgia? More generally, why is growth hormone deficiency associated with all of the above listed symptoms?

The answer – it appears – is that growth hormone release in response to stress (e.g. exercise) limits the production of inflammatory cytokines. So a defective growth hormone response results in the excess production of pro-inflammatory cytokines.

Growth hormone deficiency may be only one of several means (albeit an important one) by which excess pro-inflammatory cytokine production leads to the onset or worsening of fibromyalgia symptoms.

Evidence connecting low growth hormone to elevated cytokines.

The publication summarized below investigated the connections between exercise, growth hormone, cytokines and fibromyalgia symptoms. The researchers, having noted the connection between the HPAA system and the immune system, and that the symptoms of growth hormone deficiency seem to mimic those of “sickness syndrome” (which is known to result from excess production of pro-inflammatory cytokines,) hypothesized that serum cytokine levels and fibromyalgia symptom severity would be higher in patients who had deficient growth hormone release after exercise.

Their findings generally confirmed that hypothesis. Defective growth hormone response to exercise was found to be associated with elevated resting levels of some inflammatory cytokines and levels of pain, as follows.

Symptoms were more severe in those with defective growth hormone response.

Only one-third of those with a defective growth hormone response were able to work outside the home, vs over 85% of those with a normal growth hormone response to exercise. While work status is only an indirect measure, the inability to work outside the home suggests greater symptom severity.

Those with growth hormone defect had more pain and more tender points at baseline (before exercising.)

Higher cytokine levels.

At baseline (pre-exercise) those with a defective growth hormone response to exercise were found to have substantially higher IL-1, IL-6 and IL-8. No difference in IL-10 (an anti-inflammatory cytokine) was noted, and no difference was observed in TNF-alpha (another pro-inflammatory cytokine that has previously been linked in some studies to fibromyalgia.)

In addition, physical endurance during exercise was found to correlate with resting levels of IL-1, IL-6 and IL-8 (actually a ‘negative’ correlation, since higher cytokine levels predicted lower exercise endurance.)

Finally, IL-8 levels varied directly in response to the extent of growth hormone defect. IL-8 has previously been shown to be elevated in fibromyalgia and several studies have shown that IL-8 levels are predictive of pain in fibromyalgia. This study seems to confirm that IL-8 may be of special significance in relation to fibromyalgia.

Is a growth hormone defect the cause of fibromyalgia?

Probably not, because a growth hormone defect cannot explain many of the symptoms of fibromyalgia. Also, while growth hormone defect may be very common among those with fibromyalgia, some patients show no evidence of growth hormone defect.

Of interest, the summarized study found that those with defective growth hormone release had an average duration of illness more than 6 years longer than those with normal growth hormone function. This may explain, in part, the sometimes progressive nature of fibromyalgia. It has been observed that, even where symptom severity does not worsen over time, patients with fibromyalgia of longstanding duration may respond less favorably to medications. Perhaps one reason fibromyalgia patients become more difficult to treat over time is because the defect in growth hormone response becomes more pronounced?

It is more likely, as suggested above, that the symptoms of growth hormone deficiency occur as a result of the effect on pro-inflammatory cytokines. And since these same inflammatory cytokines also feed back on the HPAA, the relationship between growth hormone and inflammatory cytokines in fibromyalgia might define a vicious cycle – each worsening the other.

If so, then an effective treatment might be one that interrupts that vicious cycle, either by reducing the impact (or production) of pro-inflammatory cytokines, or by supplementing the growth hormone deficiency.

Could growth hormone be a good treatment for fibromyalgia?

Human growth hormone administration (it must be injected) to healthy adults has been shown to increase muscle mass, reduce fat and increase bone density. Treatment is expensive, requires a prescription, and has only been approved in the US as an adjunct therapy for those with HIV/AIDS related muscle wasting.

Nonetheless, several researchers have investigated the possibility of using growth hormone as a treatment for fibromyalgia.

While further investigation is required, initial evidence suggests that growth hormone may be an effective treatment for fibromyalgia, at least for those patients with severe symptoms who show evidence of growth hormone defect.

The term ‘sickness syndrome’ refers to a constellation of non-specific symptoms that develop in connection with many ailments, especially infections. Simply stated, when you get an infection you feel lethargic, fatigued, sleepy, and somewhat depressed. You feel sick.

Fibromyalgia results in those same symptoms, not (of course) because it’s caused by a ‘bug’, but fibromyalgia might trick your brain into thinking you’ve got one doozy of an infection – an infection that never seems to go away.

To see how fibromyalgia does that, and the results of such trickery – read on.

Your brain does what it’s told.

Basically, when your body senses that you have a bacterial or viral infection, it sends a message to your brain: “Hey, there’s an infection out here, please make the person act sick so that we can get better faster.”

“Will do!” says the brain And it sets to work making you feel lethargic, fatigued, sleepy and depressed.

It’s good for you.

It’s pretty easy to see how being sleepy might help you heal faster (you go to bed!) And of course being fatigued means you’re less likely to start any new projects (so that energy can instead be used to fight infection.) The same goes for depression. When depressed, you’re more likely to stay home alone (and heal) than go to a party (where you’ll both waste energy and be likely to spread the infection.)

So ‘sickness syndrome’ makes sense. It’s good for you (assuming you actually have an infection.)

But what if the message is wrong?

What if your brain is doing what it’s supposed to – based on the message its receiving – but that message is wrong?

Ouch! Sickness syndrome is no longer ‘good for you’. In fact it’s bad for you – really bad. Especially if that same misleading message never stops – “we’re infected, we’re infected, we’re infected….”

That’s what seems to happen in fibromyalgia.

To understand how and why fibromyalgia sends that message to your brain, we need to take a quick look at the role played by cytokines.

Cytokines

Cytokines are the messengers of the immune system.

As described in the first publication below, infections cause the release of pro-inflammatory cytokines. Those travel to your brain where, in response, the brain then makes even more pro-inflammatory cytokines. The result is sickness syndrome.

The problem is, your brain can’t tell whether the message it’s receiving is accurate or not. It ‘assumes’ that, yes, there really is an infection, that’s why I’m getting bombarded with all these cytokines, so I really should make this person act sick. Oddly enough, your brain can’t think for itself. It just does what it’s told.

Fibromyalgia

Both publications referenced below discuss sickness syndrome in relation to infection and inflammation. Fibromyalgia isn’t an infection, and it may not be (strictly speaking) an inflammatory condition. But it seems having fibromyalgia means, among other things, that your body starts producing too many pro-inflammatory cytokines. That might happen as a result of whatever causes fibromyalgia, or it might be the actual cause of fibromyalgia.

Either way, the result is the same. Fibromyalgia means your body sends the same (wrong) message over and over. Pro-inflammatory cytokines keep telling the brain, “There’s an infection, make this person act sick.” And the brain does what it’s told.

Depression

If you’re sick for a long time (fibromyalgia) then it seems your brain starts trying even harder (to make you sick.) “Argh, (says the brain) we’re not getting better. I’m still being getting hit with all these cytokines – so the infection must still be there. I should make this person really, really fatigued and even more depressed. Maybe then we’ll get better.”

That’s basically what the second publication is saying. Depression results when your body constantly sends pro-inflammatory signals to the brain. Regardless of whether those signals are ‘right’ (you have a chronic infection) or wrong (you have fibromyalgia) – the result is the same. You are very likely to become depressed. It’s not a weakness, or a flaw, or something that you can just ‘snap out of’. Your brain is doing what your body is telling it to do – it’s making you depressed.

Pro-inflammatory cytokines released in the brain result in less sleep,  more pain.

The immune system, and the body in general, is more complex and interconnected than we imagine.

In the article briefly summarized below, communication between the immune system and the brain and the way that affects sleep is discussed.

The immune system is activated

Basically, the immune system becomes activated during times of stress. ‘Stress’ can be an infection, an injury, or emotional/psychological stress. The activated immune system releases cytokines (pro-inflammatory cytokines) that communicate with your brain by stimulating nerves. Then your brain also begins releasing cytokines, with a resulting effect on sleep, mood and certain behaviors.

That makes sense, because if you have an injury, an infection, or you’re under a great deal of psychological stress, it’s probably good for you to sleep more. A general sense of fatigue is also beneficial. Your body wants you to stay home, not go out, not work – just lay low until you feel better.

Ultimately the infection clears, the injury heals, or the stressful time passes. Your body sounds the ‘all-clear’ and you’re good to go again.

The immune system (the inflammatory response system) gets ‘stuck’ in the ‘on’ position

But what happens if your immune system gets ‘stuck’ in the ‘we’re sick’ mode? What if the processes for reducing cytokine levels back to normal never kick in. What if they inadvertently turned on when there was never any real problem to begin with?

You brain gets messed up. Your sleep gets messed up. Everything gets messed up. You may sleep a little, or a lot. But you never have refreshing sleep – and you’re fatigued all the time. You’re also more likely to become depressed, or anxious.

What are cytokines?

Cytokines small protein molecules that help control and regulate the immune system. They are released by cells of the immune system (primarily by white blood cells.) They act as messengers. Inflammatory cytokines (not surprisingly) stimulate inflammation, while anti-inflammatory cytokines do the opposite.

How do cytokines relate to inflammation?

Production of inflammatory cytokines happens at a very early step in the inflammatory cascade.

Note that inflammation is not a ‘single thing’ but is actually a long process – a chain of events. Once the inflammatory chain reaction starts – and inflammatory cytokines are generated – the process often (but not always) continues on to completion. The result in that case is ‘classic’ inflammation – the typical inflammation characterized by redness, swelling, warmth and pain.

Because of those symptoms, typical inflammation is relatively easy to detect. If a doctor looks at that area under a microscope, he or she can actually see the inflammation.

But there is another type of ‘inflammation’ that is much harder to detect. In this ‘other’ type of inflammation there is excess production of inflammatory cytokines, but that’s where the inflammation process seems to stop. So you don’t find redness, warmth or swelling – and it can’t be seen under a microscope. But it can still cause pain – and does.

Some call this ‘inflammation’, or a problem with the ‘inflammatory response system’, while others don’t call it anything. They just note that there is excess production of inflammatory cytokines.  That’s what we see in both irritable bowel syndrome and fibromyalgia. There is excess production of inflammatory cytokines. There is pain. There is no typical inflammation.

Fibromyalgia and irritable bowel syndrome

Fibromyalgia and irritable bowel syndrome frequently occur together (they are frequently “co-morbid”.) Up to around 40% of those with fibromyalgia have irritable bowel syndrome (reported figures vary from around 30% to around 60% or even higher.)

Also, up to around 30% of those with irritable bowel syndrome have fibromyalgia. So the ‘overlap’ goes both ways.

It seems that having fibromyalgia increases your risk of developing irritable bowel syndrome – and having irritable bowel syndrome increases your risk of developing fibromyalgia. That’s pretty good evidence that the two conditions are related, and that the overlap isn’t just a ‘coincidence’.

How are fibromyalgia and irritable bowel syndrome related?

As it turns out, both fibromyalgia and irritable bowel syndrome are characterized by excess production of inflammatory cytokines, as demonstrated in the study briefly summarized below.

Those with irritable bowel syndrome were found to have elevated levels of IL-6 and IL-8 (both of which are pro-inflammatory cytokines.) Those with irritable bowel syndrome and either fibromyalgia or chronic fatigue syndrome had an elevation in those same cytokines, plus an elevation in two additional inflammatory cytokines (IL-1 and TNF.)

The three conditions are (obviously) not identical, but if inflammatory cytokine excess plays a role in the cause of each – as seems the case – then it’s easy to see why having one increases your odds of developing the other.

Some of what I read was complicated – very complicated.

I read one article with a title like “Ion-gated channel activator and hyper-kinetic porphyrins in a rat model of post-encepaletic fatigue.” (OK, that wasn’t the real title – and some of those words I made up – but the actual title was at least that complex.)

I then read that the author of that publication had applied for, and received, something on the order of $3 million to continue his investigations.

Wow, that’s a lot of money. It made me wonder what sort of interesting data might emerge from that lab over the next several years. Plenty, I’m sure.

But my sense is that the money could be spent in better ways – at least if the goal is to find something that will cure or treat fibromyalgia (or any other chronic pain condition.) What we’re looking for – I think – is not just knowledge. We’re looking for something that’s more like an invention.

Thomas Edison

If so, then let’s look at the archetypal inventor: Edison.

The light bulb was an obvious need at the time. (In fact a number of other people, and corporations, were already working to develop a practical light bulb when Edison first began his efforts.)

What did Edison do? Well, what he didn’t do was begin by investigating electrons and how they move. That would have been interesting, and probably very important. But if Edison had taken that approach then it’s possible we’d all still be sitting in the dark – because the physics of electricity remain, at some deep level, a mystery. (Of course someone else would have invented the light bulb – but I’m sure you get the point.)

No, Edison didn’t worry so much about electricity. Instead, he experimented with several thousand different filaments in his search for one that would work. He didn’t (just) want knowledge – he wanted to overcome a problem. He wanted a solution. He wanted light.

Don’t get me wrong. I’m a big believer in basic research. It’s important that we gain a better understanding of the minute details of physiology. It’s possible that by doing so we’ll eventually arrive at a treatment or cure for fibromyalgia. So it’s critical that basic research on fibromyalgia continue.

But what if it takes 20 years (or a hundred, or a thousand) before we really know what’s going on with conditions like fibromyalgia? That won’t be good – no one wants to wait that long.

So let’s do the basic research – but let’s also try new things (provided they make at least some sense, of course.) Let’s not assume we need to know everything before we do anything. And let’s not assume that only a big pharmaceutical company can invent something that works. Because we have a big problem that needs a solution. We need something that works and we need it now.

Turmeric (curcumin) shown to improve multiple autoimmune conditions: multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease

Let’s take a look at a recent publication that briefly reviews curcumin for autoimmune disease.

We’ll see that curcumin (an active ingredient in turmeric,) is recognized as safe, and that it has recently been shown to be effective against several serious conditions in human and/or animal studies.

That sounds promising. But your doctor will never have a chance to prescribe it for you – and will probably never tell you about it. Why might that be?

Let’s start by taking a look at the abstract.

The history and likely future of curcumin (turmeric)

The list of disease conditions associated with “a breakdown” of the immune system is sobering. That these very serious, often debilitating and sometimes life threatening conditions collectively effect 5% of the world population should emphasize the urgency with which this problem must be addressed.

The author next observes that dietary supplement use is on the rise. Hardly surprising given the assessment that they are “effective, inexpensive, and relatively safe.”

Next comes a list the conditions for which curcumin (a component of turmeric) seems to be effective, followed by a brief explanation of how curcumin generally affects the immune system – by regulating inflammation.

Given all this, we must be well on our way to a new, effective treatment for these devastating conditions. Very exciting.

But no. Using higher doses for therapeutic treatment requires “extreme caution.” (Not just caution, mind you – “extreme” caution.) We can’t do anything, it seems, until we first have a precise understanding of the effective dose, safe regiment, and mechanism of action. (Not just an understanding – a “precise” understanding.)

I don’t want to seem as if I’m picking on this author. I’m not. I very much appreciate the review.

And I don’t disagree regarding the need for caution, especially when one component of a plant (in this case curcumin) is given in concentrated form. I think the full-spectrum extract of turmeric (e.g. as used in Banjo) is a better, more effective, safer alternative. And I happen to believe “higher doses” of curcumin are not required. But if you want concentrated curcumin you can purchase it in any health food store. Thousands do every day, and no significant side effects have been reported – ever. In fact a recent trial showed that up to 8 grams (8,000 mg) of pure curcumin taken daily for 4 months was safe.

What I object to is that natural products are viewed with such suspicion. Rather than expressing excitement over what might be an effective treatment for conditions that currently devastate the lives of millions – and for which there are few if any good treatments – only “extreme caution” is recommended. Yes, let’s be cautious – always. But let’s also recognize that curcumin has been in a real world ‘clinical trial’ for thousands of years and that it has performed well. Let’s not throw up artificial, unrealistic barriers to its use, such as the need to “precisely understand” its mechanism of action.

Here are the number of prescription pharmaceuticals for which we “precisely understand” the mechanism of action: 0.

OK, there might be a few where our understanding could be called “precise” – but there are far more where the mechanism of action is entirely unknown. The FDA does not need to know the precise (or any) mechanism of action before approving a new drug. A new drug need only be shown “safe and effective.”

Curcumin (turmeric) has a long history of safe use and is reported by thousands (millions?) to be effective. Additionally, as the author notes, a number of recent studies in animals and humans have shown it to be effective.

Given all this, it seems not much additional work should be required to determine the best dose at which curcumin can be safely and effectively used – either for autoimmune disease or the other numerous conditions it helps with.

Not much work, relatively speaking – but there is a problem. No one is doing that work.

So it’s not just that you’ll have to wait a long time for your prescription for curcumin. It will never arrive.

That might be (should be) very distressing to you. But it should not lead you to believe what is not true. No, the drug companies do not want to keep you sick. No, there is not a conspiracy among doctors to hide the cure for cancer, or warts, or any other condition. Your doctor genuinely wants you to get well and the pharmaceutical companies genuinely want to offer new, effective drugs. Yes, the pharmaceutical company wants and needs profit – just like your doctor – just like me – just like you.

And that is the problem – or a large part of the problem. There is no economic model that supports development of prescription curcumin. The clinical trials required to satisfy the FDA would cost at least (I’m guessing) $30 million? $50 million? Far more, actually, because in addition to out of pocket expenses the FDA process would require substantial time and effort on the part of many pharmaceutical employees. Other projects would have to be deferred. And since curcumin cannot be patented, their investment would amount to a donation. Anyone could sell it. Walgreen’s would have it on the end cap in all their stores. Sales at GNC would be going gangbusters.

Given that curcumin might be the greatest new drug in the last 50 years, maybe you think some generous pharmaceutical company ‘should’ make this donation – just for the good of the world. But you cannot believe they are malicious for not doing so.  That just wouldn’t be fair.

So while it’s probably true that no pharmaceutical company is working on curcumin, it’s also true that many are probably working with curcumin – trying to alter it so it becomes patentable. Maybe they can do that without diminishing its efficacy – and without creating a product that has serious side effects. Or maybe they can’t.

I guess we’ll just have to wait and see.

While we’re waiting, there’s turmeric (or curcumin.)  Use it as you see fit – but realize you’re on your own.

Very few doctors are well-informed on turmeric (or any natural product) and fewer still will advocate using anything not approved by the FDA. You will not see television commercials for turmeric. Your insurance company will not pay for it.

You’re on your own. Is this a good thing? No, but it is what it is. You and I can rail against the system, or we can spend our efforts looking for what works – trying to get better.

Should you be cautious, educate yourself and act prudently? Of course. As much or more with this issue as with any other. And yes, there is some dangerous stuff out there. And yes, people do foolish things.

But don’t let anyone tell you that it’s wrong, or dangerous, or foolish to look for what works. Don’t let anyone tell you that you should suffer silently or that you should wait patiently for a drug that might never arrive – or might not arrive in time. That just wouldn’t be fair.

Towards the end of that trip my hands became very inflamed – mostly the back of my hands. The inflammation was fairly extreme. So much so that it was limiting my ability to paddle – and my hands hurt.

I had earlier gouged my side on a tree branch during a portage. Don’t ask me why, but for some reason I connected the two, thinking that the wound plus continuous sun exposure was causing the hand inflammation.

I assumed that once the trip was over my hands would get better. But they didn’t. In fact they got worse. Even though I was staying out of the sun, and the wound on my side was healing, my hands seemed more inflamed with each passing day.

So I finally went to the doctor. He listened, found it curious, and prescribed a potent anti-inflammatory agent in the form of a medrol dose pack (methylprednisolone, a commonly used oral glucocorticoid.) By the end of day one it was like magic – “Poof!” – inflammation gone. Within three days my hands were just fine.

Recently I’ve been thinking more about that very odd experience. I have to wonder – if glucocorticoids did not exist, would my hands still be inflamed?

I think they would be. They weren’t getting any better on their own. And it seems most inflammatory disease is like that – it just doesn’t get better on its own. If anything it gets worse.

I was lucky there was something that worked for me. So I got better.

But for most of those with inflammatory disease there is nothing that works.

Migraine is 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 – 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 an overly sensitive neuro-vascular 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 been shown that nearly everyone will suffer a migraine attack under certain circumstances.

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. In those with migraine it may 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 are 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. Likely candidates 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. It has been shown that 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, those 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 also many reasons to believe that NO is important in migraine.

Here’s what seems to be the present consensus on what’s important in migraine:

• Neurogenic inflammation is important.

• The trigeminal – or trigemino-vascular system – is important.

• CGRP is important.

• NO is important.

A more effective inhibitor of NF-kB might also be more effective in the prevention of migraine.

A number of different medications and medication classes have been found to be at least somewhat effective in the prevention of acute migraine.

However, because upstream events triggering acute migraine are poorly understood, identification of these agents has largely been the result of serendipitous observations combined with presumed class effects (e.g. anticonvulsants).

A better understanding of migraine would allow for a more rational approach to the discovery and development of medications to prevent migraine attacks.

On investigation, a number of existing migraine preventatives are found to inhibit NF-kB.

It is proposed that chronic over-activation of NF-kappaB (though some as yet unknown mechanism) predisposes to acute migraine attacks (headaches, et al) and that effective migraine prevention can (best) be achieved through the use of NF-kappaB inhibitors. Of particular value might be those natural NF-kappaB inhibitors which have been proven safe by extensive human use over the course of several millenia.

Banjo is designed to be an effective inhibitor of NF-kappaB.

The proposed ‘stream’ of events in migraine is as follows:

NF-kappaB activation => Nitric Oxide (NO) production => CGRP production & release => Migraine

Based on that proposed series of events in migraine, an inhibitor of NF-kappaB should be effective in preventing or lessening acute attacks.

Indeed, as will be seen below, several pharmaceuticals known to be effective in the prevention of migraine appear to act, at least in part, by inhibiting NF-kappaB activation.

The fact that each of the discussed pharmaceuticals has been shown to inhibit NF-kappaB is remarkable – especially given that these drugs are of entirely different types (e.g. antidepressant, anti-convulsant, calcium channel blocker.) The ‘unexpected’ overlap in mechanism strongly suggests that said ‘overlap’ (NF-kB inhibition) may in fact define their means of efficacy in the prevention of migraine. If nothing else, the observed mechanism provides evidence in support of:

• The proposed mechanism of migraine.

• The proposed method of prevention – by inhibition of NF-kappaB.

• The general safety of NF-kappaB inhibition.

However, if NF-kB inhibition is in fact the key to effective migraine prevention, then the use of agents not designed for that purpose is likely to be inefficient (each drug is designed for other purposes, and as such migraine prevention is essentially a side effect, albeit a beneficial one.) Such agents are likely to be only weak inhibitors of NF-kB, but may have significant (other) side effects that are harmful. In fact even those effects not generally considered ‘side effects’ would be so for the migraine patient (unless they have need of an anti-depressant, and anti-convulsant or a calcium channel blocker.)

Banjo combines a number of natural plant extracts – each a known inhibitor of NF-kappaB and each with at least a thousand year history of safe use – and delivers those extracts in a form designed to ensure maximum bio-availability.

Because Banjo is specifically designed to inhibit NF-kappaB, it may be substantially more effective than those agents inadvertently discovered to reduce migraine, and may have substantially fewer and far less serious side effects.

Many existing migraine preventatives inhibit NF-kappaB.

Anti-depressants, especially the tricyclic anti-depressants, have been shown to inhibit NF-kB.

The anti-convulsant valproic acid (valproate) has been shown to inhibit NF-kB.

The calcium channel blocker verapamil has been shown to inhibit NF-kB.

Tricyclic anti-depressants inhibit NF-kB.

In the study briefly summarized below, several tricyclic antidepressants were shown to exert general anti-inflammatory effects in glial cells. Nitric oxide (NO) levels were reduced, tumor necrosis factor (TNF) levels were reduced, and inducible nitric oxide synthase (iNOS) expression was reduced, as was that of interleukin-1 (IL-1).

NO, iNOS, TNF, and IL-1 have all been proposed as important elements in migraine.

NO, iNOS, TNF, and IL-1 are all under the control of NF-kB.

Not surprising in light of the above, expression of NF-kB was found to be diminished by the tricyclic antidepressants clomipramine and imipramine.

The publication:

Valproate, an anti-convulsant, inhibits NF-kB.

Valpoic acid is used in the treatment of seizure disorders and bipolar disorders, as well as in the prevention of migraine. Its mechanism of action is not known.

In the study briefly summarized below, the effects of long-term valproate administration were investigated.

Valproate was found to decrease the expression of COX-2, presumably through the observed inhibition of NF-kB. As commented by the authors, this inhibition of NF-kB is likely to inhibit other NF-kB regulated genes. That is, NF-kB inhibition by valproate could be expected to decrease TNF, IL-1, IL-6, NO and iNOS, any or all of which might be important in the initiation and progression of migraine attacks.

One obvious implication of this study is that valproate may be effective in the prevention of migraine, at least in part, because it inhibits NF-kB.

The publication:

Verapamil, a calcium channel blocker, inhibits NF-kB.

While the study briefly summarized below looked at the effect of verapamil in the liver, it is reasonable to suspect that verapamil may exert the same effect at other locations, especially as it is known to cross the blood-brain barrier and to act on the central nervous system.

Verapamil was found to inhibit NF-kB activation, most likely leading to the observed decrease in TNF and IL-6.

The publication: