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.
Though migraine is complex – we’ll keep [...]
Let's get better
Tag Archive: Migraine
Theory concerning the cause and treatment of migraine
Migraine progression risks – frequency and medication overuse
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.
Migraine attacks can be prevented by inhibiting NF-kB
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.
In migraine, CGRP has no effect in the absence of nitric oxide
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.
Triptan analog inhibits NF-kB
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.
NF-kB inhibition blocks trigeminal pain
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.
Nitric Oxide, NF-kB & migraine
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.
NO synthase inhibitors antagonize CGRP effect
Nitric oxide synthase inhibitors prevent CGRP mediated dilation of blood vessels in a model of migraine.
Vascular smooth muscle dysfunction in migraine
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.
Triptans inhibit nitric oxide production
Triptans act, at least in part, by inhibiting nitric oxide production.
Natural NF-kB inhibitors in migraine
Migraine is a disease of inflammation – and NF-kB is the Master Switch for inflammation.
Emerging consensus recognizes the importance, in migraine, of the over-production of:
* TNF – NF-kB controls it.
* iNOS (NO) – NF-kB controls it.
* CGRP – NF-kB at least affects it, perhaps critically, perhaps entirely.
Therefore, by inhibiting NF-kB, a reduction in each of the above mediators of migraine inflammation might be achieved.
Inhibition of NF-kB might be achieved most effectively, and certainly most safely, with the use of natural NF-kB inhibitors.
Feverfew inhibits NO via inhibition of NF-kB in migraine
In the study below, using the nitroglycerin induced model of migraine, it was shown that parthenolide, the purported active ingredient in feverfew, inhibited nitric oxide (NO) production in the trigeminal nucleus by inhibiting NF-kB.
Excess NO production is implicated in the pathogenesis of all headache. It is also an important mediator in other disease conditions.
Migraine mix: CGRP, TNF, NF-kB, TMJ
In both TMJ and migraine, high levels of CGRP are found in the trigeminal ganglion. CGRP is a neuropeptide and its release is associated with neuroinflammation. That inflammation is associated with an increase in other pro-inflammatory cytokines.
In the study briefly summarized below, administration of TNF led to an increase in CGRP. While the authors postulate that the MAPK pathway is of greatest importance, NF-kB was also shown to be activated. NF-kB activation both results from, and results in, higher levels of TNF. That is, TNF activates NF-kB and activated NF-kB turns on the production of more TNF.
As with most inflammation events, the interaction of the various components is complex and not completely understood. What is clear is that inflammation happens, that it’s important, and that CGRP, NF-kB, TNF and the trigeminal ganglion are each involved – both in migraine and in TMJ.
Nf-kB inhibition blocks CGRP release
CGRP may be a key mediator of inflammation in migraine. Several CGRP inhibitors are now being developed. Trials conducted to date show these to be of about equal effectiveness with triptans, but without the side effects that result from vasoconstriction by triptans.
Activation of NF-kB may lead to transcription and then release of CGRP.
Inhibiting NF-kB reduced CGRP levels.
An effective inhibitor of NF-kB might therefore perform as well, or better than, an inhibitor of CGRP.
Inflammation and excitotoxicity in migraine pathogenesis
Migraine involves inflammation and neurons that are over-excited. The two are probably linked.
Nitric oxide: Key player in headache
Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), which when given generates NO, causes headache in normal volunteers and a so called delayed headache that fulfils criteria for migraine without aura in migraine sufferers.
Blockade of nitric oxide synthases (NOS) effectively treats attacks of migraine as well as chronic tension-type headache and cluster headache.
Inhibition of NO production represents a target for new drugs for treating migraine and other headaches.
Feverfew + ginger found effective in acute treatment of migraine
Feverfew and ginger, delivered sublingually, were effective in preventing migraine progression when administered at the mild pain phase of the acute attack.
Two hours after treatment, 48% of patients were pain free and another 34% had only mild headache pain.
No significant side effects were reported.
A combination of ginger and feverfew, when administered sublingualy at the mild pain phase, was found to be both safe and effective at relieving the pain and associated symptoms of migraine.
Parthenolide for migraine and MS
Parthenolide, though previously shown to inhibit NF-kB, was shown in the study summarized below to inhibit NO production through an alternate pathway. It is likely that parthenolide (the presumptive active component of feverfew) acts by various mechanisms in the body.
The investigators conclude that parthenolide might be useful in the treatment of those conditions where excess NO is believed to play a significant role, such as multiple sclerosis and migraine.
Neuronal inflammation of trigeminal ganglion in migraine
Brainstem dysfunction is favored in consideration of the diverse symptoms associated with the pain of migraine. Specifically, symptoms such as extreme sensitivity to lights and sounds most are most likely to originate in the brainstem.
The publication briefly summarized below suggests spreading inflammation of the trigeminal ganglion and associated structures as one possible means by which to account for both the pain and associated symptoms of migraine.
Ginger extract for migraine
Ginger components found to inhibit platelet aggregation, suggesting they might be useful in the treatment of migraine.
Many drugs effective in the treatment of migraine have effects on platelet aggregation.
One theory holds that a migraine begins when platelets clump, releasing serotonin and setting off an inflammatory cascade that eventually leads to full-blown migraine. Indeed, platelet ‘over-responsiveness’ is commonly observed in patients with migraine, and may account for the observed higher risk of stroke documented especially among those who have migraine with aura.
In the study briefly summarized below a traditional Japanese migraine medication is investigated. One of the four herbal extracts used in that medication is an aqueous extract of ginger. Two of the components of ginger extract, 6-shogaol and 6-gingerol, were each found to inhibit platelet aggregation.
Aging Alzheimer's Arthritis Asthma Atherosclerosis Back Pain Banjo Cancer Chronic Pain Cluster Headache Crohn's Diabetes Fatigue Fibromyalgia Gout Headache Heart Disease IBD Inflammation Joint Pain Lupus Migraine Multiple Sclerosis Muscular Dystrophy Neck Pain Neuropathic Pain NF-kB Osteoarthritis Pain Parkinson's Psoriasis Rheumatoid Arthritis Sjogren's Stroke TMJ Ulcerative Colitis
WP Cumulus Flash tag cloud by Roy Tanck and Luke Morton requires Flash Player 9 or better.