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.
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Progression from episodic migraine to chronic migraine appears to take place in a step-wise fashion, as those with already frequent migraine were found to be at much greater risk of developing chronic migraine. The inclusion of those having 14 migraine days per month might be questioned – as for all practical purposes they already have chronic migraine.
The association with medication overuse is not unexpected – and I’m not sure it tells us much. Of course people use more medication as headache frequency increases. Medication overuse is often described as the use of an acute agent more than twice weekly. Given that those in the high frequency population are having headaches at least 10 times per month (an average of 2.5 times per week) it would be surprising if they were not ‘overusing’ medications for headache.
Most remarkable might be the finding that 14% of all subjects followed developed a chronic pattern within a year. That is substantially higher than reported by other studies.
Findings of the publication below include:
* 14% of all those followed in this study developed chronic headache (15 days or more, per month, of headache) within one year.
* The risk of developing chronic headache was 20x greater among those with already frequent headaches (10-14 days per month) vs. those with a low frequency of headache (average of 0-4 days of headache per month).
* The risk of developing chronic headache were 6x greater among those with already moderate headache frequency (6-9 days per month) vs. those with a low frequency of headache (average of 0-4 days of headache per month).
* The risk of developing chronic headache was nearly 20x greater when medication overuse was observed.
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A number of different medications and medication classes have been found to be at least somewhat effective in the prevention of acute migraine attacks.
However, because upstream events triggering migraine attacks 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 migraine results from over-activation of NF-kB (though some as yet unknown mechanism) and that effective migraine prevention can be achieved through the use of NF-kB inhibitors. Of particular value might be those natural NF-kB inhibitors which have been proven safe by extensive human use over the course of several millenia.
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CGRP has been postulated as an essential mediator in migraine.
However, in the study briefly summarized below, CGRP was found to have no effect in the absence of nitric oxide (NO).
This strongly suggests that NO is of greater importance in migraine pathogenesis than is CGRP.
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The triptans are an effective class of acute anti-migraine medications. Their mechanism of action has yet to be entirely determined, though they are known to be bind at 5-HT1b/d (serotonin) receptors.
In the study below, the effect of a similar molecule was investigated. m-CPP binds non-specifically to both 5-HT1 and 5-HT2 receptors. It may be that the anti-inflammatory effects of m-CPP are mediated through binding sites that are not effected by triptans. However, the triptans do exhibit certain anti-inflammatory effects that are similar to those observed for m-CPP. One possibility is that triptans also inhibit NF-kB and that some portion of their efficacy in the treatment of migraine is thereby accounted for.
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The pain of both TMJ and migraine is mediated through the trigeminal nerve.
NMDA receptors are believed to play a key role in the transmission of pain in the trigeminal.
IL-6 is an important pro-inflammatory cytokine that is under the control of NF-kB.
In the study briefly summarized below:
* Blocking IL-6 eliminated pain.
* Blocking NF-kB eliminated pain.
* Administering IL-6 in the absence of inflammation caused pain.
The implied mechanism of trigeminal pain is inflammation => NF-kB activation => IL-6 production => pain.
By inhibiting NF-kB, both migraine pain and TMJ pain can be effectively treated.
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Nitric oxide (NO) is likely the primary mediator of migraine.
NO is implicated in migraine:
* Initiation
* Pain transmission
* Hyperalgesia
* Chronic pain
* Inflammation
* Central sensitization
NO production is increased as a result of NF-kB activation and can be inhibited through the inhibition of NF-kB.
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Nitric oxide synthase inhibitors prevent CGRP mediated dilation of blood vessels in a model of migraine.
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Individuals with migraine have altered vascular tone, especially vasodilation in response to nitric oxide.
This may account for the increased risk of cardiovascular events in migraine, and may also relate to the basic pathology of migraine.
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Triptans act, at least in part, by inhibiting nitric oxide production.
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