Category Archives: Migraine

Notes on migraine and chronic headache.

The global impact of migraine – research facts

Migraine Incidence and Demographics

* Migraine is a disease affecting approximately 30 million Americans, equivalent to roughly 13% of the adult U.S. population, or one migraine sufferer in every four U.S. households.

* Migraine is much more common among women than men. Migraine affects approximately 18% of women and 6% of men.

* The prevalence of migraine is widespread during the most productive adult years, between the ages of 25 and 55. The incidence of migraine increases from childhood through adolescence and early adult life. The highest frequency of migraine attacks is observed in 35-45 year-old patients, with the prevalence declining somewhat among older patients.

* The incidence of migraine has been on the rise in the United States. From 1980 to 1989, the prevalence of migraine increased nearly 60%. From 1989 to 1999, the number of migraine sufferers in the United States increased from 24 million to 28 million.

Pediatric migraine

5-10% of school-aged children get migraines.

An estimated 10% of US school-aged children miss an avg. of 2 days/month of school due to migraine.

20% of migraine patients experience their first migraine before age 5.

Uncommon Migraine

A number of complicated and variant forms of migraine are known. While there is some debate over whether certain entities are actually “migraine” – they are generally classified as such because they often have the same triggers as migraine and, in addition to their unusual features, share many features in common with more typical migraine. Unusual forms of migraine may be especially frightening because they mimic life-threatening emergency situations. While generally ‘benign’ (self-limiting and not caused by another disease or condition,) each requires a thorough medical examination. Emergency medical care should be immediately obtained if there is any doubt concerning the origin of symptoms.

Primary vs. secondary headache

The vast majority of headache is of ‘benign’ origin. Benign meaning that they are self-limiting (they will eventually go away on their own) and do not indicate that anything ‘worse’ is going on.
Primary Headache:

‘Primary’ headaches are those that do not result from another cause (e.g. intra-cranial bleeding, tumor.) Differentiating between migraine, tension-type, and cluster headaches (all of which are primary headaches) is important, as optimal treatment may differ. However, more important is knowing when to suspect the possibility of secondary headache.

Perspective on menstrual migraine

About 60% of women who have migraine experience attacks before or during their menstrual period, although only about 10% to 15% will have migraine only when they have their menstrual period. The majority of women will have migraine at other times of their cycle but will experience attacks of greater severity one to two days before or during their menstrual period.

Episodic migraine. How common is migraine? How many attacks on average?

About 5% of the US population has 18 or more days/year of migraine.

Median attack frequency is 1.5/month.

Roughly 6% of men and about 15% of women have migraine disease.

About 35% of those with migraine have…

Perspective on chronic migraine

Migraine can be characterized as a chronic disorder with episodic attacks and the potential for progression to chronic migraine.

Unlike other neurological disease, migraine does not worsen over time as a matter of course. Migraine may be stable. It may diminish in frequency or severity. Or migraine can worsen, most often gradually, until the chronic pattern emerges.

Migraine progression to chronic migraine is not the norm. Migraine is more likely to be stable, or to remit (especially over age 50.) Nonetheless, migraine progression is not uncommon. Because it is associated with severe impairment, it deserves special attention.

Five stages of migraine

Migraine is a common and often debilitating neurovascular disease affecting up to 35 million people in the US. Despite its relative frequency and oft times severity, migraine remains under-diagnosed, under-treated and poorly understood. One source of misunderstanding might be that “migraine” is so often equated with “headache.” In fact there are many who continue to believe that migraine is “just a bad headache.”

So rather than risk perpetuating that myth by jumping straight to the headache part of migraine disease, let’s look at the five stages of migraine as they occur.

Chronic migraine

Chronic migraine is migraine headache more than 15 days/month.

Also called “migraine transformation” because in most it begins with episodic migraine – the migraine pattern then gradually transforms to one of near daily headache.

Near constant headaches are often a mix of migraine and ‘tension-type’ headaches.

Approximately 1% of adults meet the criteria for chronic migraine.

90% of chronic migraine patients are women who first had episodic migraine without aura.

Up to 30% of those with migraine may eventually develop chronic migraine.

Prevalence of headache in the United States and its impact

Headache is extremely common:

Studies show 76 percent of women and 57 percent of men report at least one significant headache per month.

In the United States, an estimated 60 million to 80 million people experience recurring headaches (but only 30 percent of these people seek help, in many cases due to fear of being accused of “faking” the headache or being thought mentally ill.)

Significant chemical mediators in migraine

migraine is complex

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.

Migraine progression risks – Who is most at risk of progressing to chronic migraine?

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.

Drugs used to prevent migraine may do so by affecting NF-kappaB

menstrual associated migraine

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-kappaB

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-kappaB 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-kappaB & 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-kappaB 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 use in migraine reduces NO production via inhibition of NF-kappaB

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-kappaB, TMD

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-kappaB 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 plus 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.

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 may have beneficial effects in 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.

Review: Feverfew in migraine prevention

Feverfew may be no better than placebo in the treatment of migraine, but it’s safe.

Results from controlled trials were mixed. The overall conclusion is that feverfew has not been shown to be better than placebo in the prevention of migraine.

No significant side effects or safety issues were identified with the use of feverfew.

Feverfew extract for migraine

Feverfew extract found to be safe and effective in the prevention of migraine.

After taking the feverfew extract three times a day, by the third month those migraine patients who experienced an average of 4.76 attacks per month were only experiencing 2.86 attacks per month – a decrease of 1.9 monthly migraine attacks. Whereas those on placebo only experienced a 1.3 migraine per month decrease in monthly attack frequency.

Migraine: Inflammation of the trigemino-vascular system

Inflammation is a key component of migraine, and can be observed in the trigeminal nerve and associated vasculature.

As the theory of what causes migraine has evolved, it is easy to neglect the fact that inflammation has always been seen as a key component of migraine pathology, regardless of whether the emphasis was on the blood vessels or the nerves.

The theory on the mechanism of action by which triptans work has also changed over the years. At first they were believed to work (and were in fact designed to work) primarily by constricting the vessels – as vessel dialtion was believed to be the source of pain in migraine.

More recently the triptans have been deemed to work by inhibiting the release of CGRP, and a new generation of CGRP inhibitors have been under development for some time. CGRP is a pro-inflammatory neuropeptide. To that extent, understanding of migraine pathology has again returned to inflammation.

In any case, ‘leaky’ blood vessels (plasma protein extravasation) are associated with migraine. Both the ergots and the triptans reduce extravasation.

While the publication briefly summarized below is somewhat dated, it nonetheless suggests inflammation, affecting the vessels, mediated through the trigeminal nerve – all of which is consistent with present day understanding of migraine, despite any change in ’emphasis’ – past or present.

Migraine always has been and always will be a disease closely associated with inflammation.

Migraine & restless legs syndrome

Migraine patients are found to maintain, even between acute attacks, certain neuronal hyper-excictability and may exhibit a certain level of autonomic dysfunction. The association between migraine and restless leg syndrome (RLS) may occur as a result.

Migraine: Functional impairment between attacks

Migraine is characterized by recurring, often frequent headache pain. The acute attack is usually accompanied by other symptoms, such as aversions to light (photophobia,) sound (phonophobia,) smells (osmophobia,) as well as nausea, vomiting and extreme tiredness.

Typical migraine lasts from 4 to 48 hours and for at least half those with migraine, results in near incapacitation and the need for bed rest. The associated symptoms of migraine headache explain the frequent need for the sufferer to retreat to a quiet, dark place during the acute attack.

That these attacks are disabling is immediately apparent. However, the impact of migraine is not limited to this acute pain phase. Each phase of migraine may be associated with significant impairment.

NF-kappaB activation in trigeminal nucleus in migraine

In those with migraine, nitroglycerin (NTG) induces severe delayed headache, resembling spontaneous migraine attacks. This has proven to be a good model for migraine.

The publication summarized below sought to explore a possible mechanism by which NTG results in migraine and found that NTG administration resulted in an increase in activated NF-kB in the trigeminal nerve.

Role of estrogen in trigeminal nerve sensitization

Estrogen plus inflammation acts via trigeminal nerve to increase pain in TMJ and perhaps migraine.

The highest incidence of TMJ is observed in women between 20 and 40.

The authors note that TMJ is associated with estrogen. Their investigation concerned the possible mechanism by which estrogen might act as a risk factor in the development of TMJ.

They found that inflammation plus estrogen increased pain perception via the trigeminal nerve through a MAPK pathway.

The MAPK pathway does interact with NF-kB, but the primary point of interest here is the overlap with migraine. Migraine is also predominant in women (approximately two to three times as many women suffer with migraine as men.) Migraine is also most prevalent between ages 20 and 40. The trigeminal nerve is also central in migraine pain.

It may be that migraine and TMJ share, at least to some extent, the same underlying pathology.

Estrogen is generally anti-inflammatory and is considered ‘protective’ against certain conditions associated with inflammation (e.g. atherosclerosis.) Nonetheless, many of the conditions most closely associated with inflammation (e.g. autoimmune conditions) are far more common in women.

If the reason for this apparent paradox could be determined, it might be of great assistance in developing effective treatments for conditions associated with inflammation.

Migraine associated with multiple sclerosis

Headache is not generally considered as a symptom of multiple sclerosis (MS), but several studies have showed that it is more frequent (about 50%) in MS patients than in controls or general population.

Chronic daily migraine among adolescents not uncommon

Culture strongly affects patient behavior relative to disease. This study, among adolescents in Taiwan, identified approximately 1.5% as having chronic daily headache. While many of those did not meet strict inclusion criteria for migraine, most had migraine features.

Most striking is the extent to which chronic daily headache went untreated. Of 82 students experiencing headache more than 15 days per month, only one was on a preventative medication and only 6 had seen a neurologist.

Menstrual migraine is common

Menstrual migraine is common to approximately 60% of women with migraine. Fluctuating hormonal levels account to some extent for the higher prevalence of migraine among women than among men. Two-thirds to three-fourths of all migraine sufferers are female.

However, the incidence of migraine in the pediatric population is higher among boys than girls. With puberty, the percent of boys with migraine decreases, whereas that of females with migraine increases.

Some researchers and clinicians make a distinction between “menstrually associated migraine” (MAM – sometimes called menstrually related migraine) and ‘true’ menstrual migraine. In the former, migraine may occur at any time of the month, but is more frequent at or around the time of menstruation. In the latter, migraine exclusively occurs at or around the time of menstruation.

The distinction does not appear to be clinically relevant. In either case, migraine at time of menstruation is widely recognized as being more difficult to treat, of longer duration, and generally more painful than migraine not associated with menstruation.

Persistent aura without headache – Alice in Wonderland syndrome

Migraine aura without headache, otherwise known as an acephalgic or silent migraine, is a relatively uncommon form of migraine in which a migraine aura (usually visual disturbances) is not followed by headache.

The publication below describes a very unusual case in which a young girl experiences several episodes of migraine aura without headache each day for a month.

In addition, her neurological symptoms and aura define “Alice in Wonderland syndrome” (AIWS – also known as Todd’s syndrome) which includes visual perceptions of changing sizes and movements. AIWS is reported to be more common in children with most ‘growing out of them’ by adolescence.

Facial pain in migraine

Unilateral head pain focused on frontal, orbital or parietal regions is a leading symptom of migraine attacks. Rarely, head pain in migraine can extend involving the maxillary or mandibular region of the face, sometimes isolated facial pain is the only and atypical presentation of migraine.

Inflammation in pediatric migraine

Mediators of inflammation were found to be elevated in children with migraine when compared to children with episodic headache.

Inflammation may be more readily observed in the pediatric migraine population with less previous use of anti-inflammatory medications.

NF-kappaB inflammation in migraine

NF-kB was shown to be activated in migraine and was associated with an increase in mediators of inflammation. NF-kB activation returned to normal at the end of the migraine attack.

The authors conclude that these findings suggest the use of NF-kB inhibitors may be beneficial in the treatment of migraine.

The theory elaborated on this site suggests that by supplementing natural NF-kB inhibitors, migraine can be prevented or relieved. The study referenced below is consistent with that theory.

Migraine: 10x economic impact vs. other headache

Migraine has 10x the economic impact compared to other episodic headache.

Just one more ‘data point’ for those who confuse “headache” with migraine. Migraine is more than ‘just a bad headache.’

Migraine impact on work

Migraine accounts for nearly 65% of lost work productivity. That alone suggests the severity of migraine and the extent to which the lives of migraine sufferers are impacted by this disease.

Those with 11 or more headache days per month (29% of those with migraine in this study) accounted for just under half of the total productivity lost to migraine.

One might expect those with such frequent migraine to account for a larger percent of lost productivity. Apparently, they learn to work through the pain. They have to.

Surgery for chronic migraine

Many of the nearly 30 million Americans suffering with migraine headaches are not helped by standard therapies, a proportion of which can harbor undesirable side effects. The efficacy of independent surgical deactivation of three common migraine headache trigger sites is demonstrated through a double-blind, sham surgery, controlled clinical trial.

Headache in children severely impacts quality of life

Headache and migraine are common in childhood and can have a severe impact on the child’s quality of life and school performance. The extent to which headaches affect the child, and the entire family, is often unrecognized. As a result, headache in childhood is often under treated.

Headache in children: prevalence and comorbidities

No child should have to suffer with severe headache. Unfortunately, in this survey of American children ages 4 to 17, 17% were found to have experienced a severe headache in the last 12 months.

Ginger may be effective in the treatment of migraine

Ginger is suggested as both an abortive (acute) and prophylactic (preventative) medication for the treatment of migraine. My experience suggests that ginger, used alone, is unlikely to be effective, but that it can be valuable when used in combination with other herbal extracts.

Migraine treatment via NF-kappaB inhibition

An inhibitor of NF-kB might be a novel, effective, anti-migraine drug.

Medication overuse & “rebound” headaches

Rebound headache is closely associated with medication overuse. The headache medication itself makes the patient more prone to their next episode of pain – which requires further dosing – leading to a yet worse follow on headache, etc. A vicious cycle ensues in which the patient quickly finds themselves medicating daily, even continuously, while suffering now continuous, daily headache.

Chronic tension headaches affect 2-3% of the population

No one should have to live with chronic, daily headaches. Yet chronic daily headache of the ‘tension type’ affects up to 3% of the population. While not as debilitating as chronic daily migraine, these headaches nonetheless have a significant, even severe impact on the individual’s life, and affect family, friends and co-workers as well.

Inflammation demonstrated in migraine

Although neuroinflammation has been shown to play a major role in many neurodegenerative disorders – such as Parkinson’s disease and Alzheimer’s disease – only limited data exists about the role of neuroinflammation in and migraine.