Episodic migraine is defined as migraine that occurs less than 15 times per month. Episodic migraine is further classified on the basis of aura.

Migraine with aura, formerly called "classic migraine" is routinely experienced by about 25% of sufferers. Migraine without aura was formerly referred to as "common migraine."

Episodic Migraine

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 3 or more migraines per month.

Median attack duration is 24 hours, with 20% of attacks lasting 2-4 days.

In over 50% of those with migraine, attacks are often severely disabling and require bed rest.

Nearly 40% of those with episodic migraine ’should’ be on a migraine prevention medication.

Only 13% of those with episodic migraine use a medication to prevent attacks.

Migraine is a disease of inflammation.

Let’s get better.

Introduction to Banjo

Banjo provides fast, effective relief from pain and inflammation because it enables your body’s immune system to function properly. It works just like the fruits and vegetables you eat every day – by naturally inhibiting NF-kB, the inflammation Master Switch.

Banjo works better because it combines the most effective natural extracts and delivers them in a form that ensures maximum bio-availability. You get the full spectrum of phytonutrients your body needs to turn off excess inflammation.

Navigation

Scroll past "five stages" for a list of recent episodic migraine posts, followed by all episodic migraine posts.

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alert!I don't want to read - I just want relief from migraine.

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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.

Note that most classifications include only 4 stages, but we’ll add the “between migraine” stage – which is appropriate. While there are many with migraine whose lives are only modestly impacted by the disease, those with moderate to severe migraine are more likely to feel its impact every day of their life.

Prodrome Stage:

Sometimes also referred to as the “premonitory stage” this phase can begin hours or even days prior to the onset of the acute pain phase. It may be characterized by sleepiness, irritability, other change in mood or any number of diverse symptoms specific to the individual sufferer.

About half of all migraine patients report consistent awareness of a prodrome stage. They ‘just know’ when a migraine is coming. However, it has been found that about 80% of those with migraine can learn to recognize a prodrome stage. By keeping a migraine journal, and armed with the knowledge that most migraine attacks are preceded by tell tale signs, an individual can usually learn to recognize the sometimes subtle clues that precede the attack. Those clues might include tiredness, irritability, intense hunger, yawning, slightly slurred speech, feeling less coordinated or some other constellation of signs and symptoms that consistently emerge in the hours or days before a migraine attack. The ability to anticipate an attack can provide an advantage in that it allows one to make or change plans appropriately and especially because it might allow for early, more effective treatment. Essentially all migraine medications work best when taken as early as possible after the attack has begun. Nonetheless, despite its ‘advantages’, the prodrome represents a period of diminished function and adds to the burden of migraine.

Aura Stage:

The migraine aura is a complex of neurological symptoms that usually precede but may accompany the headache phase or even occur in isolation. A commonly held misconception (by those who don’t suffer with migraine) is that all true migraines are preceded by aura. In fact migraine with aura is relatively less common migraine without aura. Only 20-30% of those with migraine ever get an aura, and many of those with aura only sometimes have an aura. While generally brief, and not specifically painful, migraine patients who experience aura often describe it as extremely unpleasant.

The aura usually develops over 5-20 minutes and lasts less than 60 minutes. It is most often visual but can involve any of the other senses. The most common visual aura is what’s called a scintillating scotoma (about 65% of all auras.) A scintillating scotoma begins with a change in visual perception near the center of the visual field, then gradually expands outward in a ’shimmering’ pattern and eventually includes a dark spot or blind spot, usually in the same part of the visual field where the aura began.

Paresthesias (strange feelings such as tingling in part of the body) are reportedly present in about 40% of auras. The most common form is called “cheiro-oral” which is generally defined by numbness starting in the hand which then migrates to the arm before ‘jumping’ to the face, lips, and tongue. Sensory aura most often follows visual aura, but may occur alone. Just as with the visual aura where a positive symptom (lights, change in perception) is followed by a negative one (dark spot or blind spot) so paresthesias are often followed by numbness.

The rate at which an aura spreads helps distinguish it from the stroke-like transient ischemic attack (TIA). Both visual aura and paresthesias usually  take about 10-20 minutes to spread. This is a much slower progression of symptoms than is witnessed in the case of a stroke or TIA.

The aura is not harmful and results in no permanent damage. But for someone who has never had a migraine, or never had an aura, the experience can be a very frightening one.

The aura usually disappears before the start of headache pain, which usually follows the aura by a few minutes to an hour. Infrequently the aura may continue during the time of headache pain. Even more infrequently the headache pain may never arrive. When an aura is not followed by a headache, it is called a migraine equivalent, acephalic migraine or silent migraine.

Migraine Headache – Acute Pain Stage:

The characteristic feature of migraine disease is, of course, the migraine headache. But even the term, “migraine headache” is, if not entirely misleading, at least deficient. While the headache pain may be severe, the symptoms of an acute attack are not limited to pain. Migraine headache is accompanied by a host of autonomic symptoms. These may include nausea, vomiting, aversion to bright lights (photophobia), aversion to loud sounds (phonophobia), aversion to strong odors (osmophobia), and any number of other symptoms.

The headache of migraine generally exhibits at least some of the following characteristics:

  • Throbbing, pounding, or pulsating pain
  • Often on just one side of the head, or begins on one side before spreading to both sides
  • Pain may alternate sides from one attack to the next
  • Made worse with mild activity, such as walking or bending
  • Most intense pain is often concentrated around the temple(s) – on the side of the forehead
  • Commonly lasts from 4 to 72 hours in adults, 30 minutes to 48 hours in children
  • Nausea is reported by almost 90% of migraine sufferers
  • Vomiting may occur with up to 35% of migraine attacks

Other symptoms frequently accompanying migraine headache:

  • Dizziness, described as being light headed
  • Loss of appetite
  • Fatigue
  • Visual disturbances, blurred vision (different than the aura)
  • Eye pain
  • Parts of your body may feel numb, weak, or tingly
  • Irritability or altered mood
  • Impaired concentration
  • Nasal stuffiness
  • Diarrhea
  • Frequent urination (polyuria)
  • Pallor (look pale) or sweating
  • Neck pain and/or facial pain
  • Scalp tenderness
  • Bulging veins or arteries
  • Allodynia – even light touch results in a painful sensation

Post-headache Stage:

Also referred to as “postdrome,” this is a period of diminished functioning experienced by many migraine patients after the pain of migraine headache has resolved. Simply stated, the migraine headache is gone but migraine disease remains active. Commonly, patients experience migraine-associated non-headache symptoms for an additional 24 to 48 hours. Frequent symptoms include fatigue, lethargy, muscle soreness, poor concentration and lack of appetite. Impaired functioning during this phase adds substantially to the burden of migraine.

Given an average prodrome stage lasting 24 hours, an acute pain stage that averages 24-48 hours and post-headache impairment lasting an additional 24-48 hours, the total duration of migraine impairment, per attack, can be from three to six days. Of course some attacks are more or less severe, and the extent to which migraine impairs functioning is obviously greatest during the acute pain stage. Nonetheless, considering that a person with moderate migraine disease may experience two to four attacks per month, it is often the case that there are more days with migraine impairment than there are without migraine impairment.

Between Attacks:

Also referred to as “interictal” period, this is the entire period between attacks. While there may be differences in autonomic functioning, especially increased pain perception between attacks, the primary burden of migraine during this time period relates to the expectation (dread) of the next attack. Patients are unable to plan with confidence. Work, family and social interactions can be severely affected. Anxiety and depression are common. These may result,  at least in part, from the perceived (and actual) loss of control that comes with recurring migraine attacks.

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ALL EPISODIC MIGRAINE POSTS

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December 18, 2009

Migraine attacks can be prevented by inhibiting NF-kB

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A medication designed to inhibit NF-kB might be very 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 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.

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

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

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

Based on that proposed series of events in migraine, an inhibitor of NF-kB should be effective in the prevention of 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-kB.

The fact that each of the discussed pharmaceuticals has been shown to inhibit NF-kB 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) is in fact the key to their 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-kB.
  • The general safety of NF-kB inhibition.

But if NF-kB inhibition is the key to effective migraine prevention, then the use of agents not designed for that purpose is inefficient and unnecessary. Such agents are likely to be only weak inhibitors of NF-kB (an accidental effect) while yet causing significant side effects. Of course even the intended effects of these drugs are, for most migraine patients, just more side effects.

Banjo combines a number of natural plant extracts – each a known inhibitor of NF-kB and each with 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-kB, 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 than medications presently in use for that purpose.

Many existing migraine preventatives inhibit NF-kB.

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:

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Neuropharmacology. 2008 Oct;55(5):826-34. Epub 2008 Jun 29.

Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants.

Hwang J, Zheng LT, Ock J, Lee MG, Kim SH, Lee HW, Lee WH, Park HC, Suk K.

Department of Pharmacology, School of Medicine, Brain Science and Engineering Institute, Kyungpook National University, Joong-gu, Daegu 700-422, Republic of Korea.

Summary of the abstract

Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and HIV dementia. Activated glial cells can secrete various proinflammatory cytokines.

In the present study, the antiinflammatory and neuroprotective effects of tricyclic antidepressants were investigated.

  • Clomipramine and imipramine significantly decreased the production of nitric oxide or tumor necrosis factor-alpha (TNF-alpha) in microglia and astrocyte cultures.
  • Clomipramine and imipramine also attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1beta and TNF-alpha at mRNA levels.
  • Clomipramine and imipramine inhibited NF-kB.

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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:

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Bipolar Disord. 2007 Aug;9(5):513-20.

Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-kappaB DNA binding activity and COX-2 mRNA.

Rao JS, Bazinet RP, Rapoport SI, Lee HJ.

Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

Summary of the abstract

OBJECTIVES: Valproic acid (VPA) is used to treat bipolar disorder, but its mechanism of action is not clear.

METHODS: We examined the effect of chronic VPA administration on transcription factors, that are known to regulate the COX-2 gene, including NF-kappaB.

RESULTS: Chronic VPA significantly decreased NF-kB activation.

CONCLUSIONS: VPA downregulates NF-kB DNA binding activity, likely by decreasing the p50 protein levels. This effect may explain its downregulation of COX-2 mRNA. The decrease in NF-kappaB activity by chronic VPA may affect other NF-kappaB-regulated genes and may be related to VPA’s action in bipolar disorder. Chronic VPA may decrease the reported increased brain NF-kappaB components in bipolar patients.

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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:

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Inflamm Res. 2006 Mar;55(3):108-13.

Verapamil modulates LPS-induced cytokine production via inhibition of NF-kappa B activation in the liver.

Li G, Qi XP, Wu XY, Liu FK, Xu Z, Chen C, Yang XD, Sun Z, Li JS.

School of Medicine, Nanjing University, Department of General Surgery, Jinling Hospital, 305 Zhongshangdong Road, Nanjing, 210002, Jingsu Province, China.

Summary of the abstract

OBJECTIVE: To investigate the effect of verapamil on Lipopolysaccharide (LPS)-induced cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-10 (IL-10)] and nuclear factor kappa B (NF-kappa B) in the  liver.

RESULTS: LPS alone stimulated production of TNF-alpha, IL-6 and IL-10, and activated NF-kB in the liver. Pretreatment with verapamil before LPS challenge reduced acute liver injury, down-regulated production of LPS-induced pro-inflammatory cytokines (TNF-alpha and IL-6), up-regulated production of anti-inflammatory cytokines (IL-10) and inhibited NF-kB activation in the liver in a dose-dependent manner.

CONCLUSION: Verapamil can attenuate acute liver injury by down-regulating the production of TNF-alpha and IL-6 and up-regulating IL-10 in the liver, possibly via inhibition of NF-kappaB.

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December 16, 2009

In migraine, CGRP has no effect in the absence of nitric oxide

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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.

The publication:

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Neuroreport. 2008 Aug 27;19(13):1307-11.

Nitroglycerin facilitates calcitonin gene-related peptide-induced behavior.

Yao D, Sessle BJ.

Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.

Summary of the abstract

Nitric oxide and calcitonin gene-related peptide (CGRP) have been implicated in craniofacial pain including migraine headache.

The aim of this study was to test whether systemic administration of nitroglycerin (NTG) influences the CGRP-induced behavior in awake rats and whether sumatriptan, a 5-HT1B/1D receptor agonist, can block the effects of NTG.

CGRP was not significantly different from normal saline in inducing face-grooming behavior but NTG facilitated the effect of CGRP. Furthermore, sumatriptan was found to block the effect of NTG.

These data suggest that facilitatory processes involving nitric oxide may be necessary for CGRP to play a role in some craniofacial pain conditions including possibly migraine headache.

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December 16, 2009

Triptan analog inhibits NF-kB

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A triptan analog, a non-specific 5-HT1 agonist, is shown to reduce the production of pro-inflammatory cytokines via inhibition of 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.

The publication:

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Int Immunopharmacol. 2008 Dec 10;8(12):1686-94. Epub 2008 Sep 2.

Anti-inflammatory effects of m-chlorophenylpiperazine in brain glia cells.

Hwang J, Zheng LT, Ock J, Lee MG, Suk K.

Department of Pharmacology, School of Medicine, Brain Science and Engineering Institute, CMRI, Kyungpook National University, Daegu, South Korea.

Summary of the abstract

Glia cells are regarded as a mediator of neuroinflammation releasing pro-inflammatory cytokines and nitric oxide in the central nervous system.

m-Chlorophenylpiperazine (m-CPP) is used clinically to manipulate serotonergic function, though its precise mechanisms of actions are not well understood. m-CPP alters synaptic transmission and neuronal function in vertebrates by non-selective agonistic actions on 5-HT1 and 5-HT2 receptors.

In the present study, the anti-inflammatory effect of m-CPP was investigated.

Rresults showed that m-CPP significantly decreased the production of nitric oxide, TNF, and IL-1beta in microglia and astrocyte cultures. m-CPP also attenuated the expression of inducible nitric oxide synthase and pro-inflammatory cytokines such as IL-1beta and TNF-alpha at mRNA levels. In addition, m-CPP inhibited NF-kB activation, providing molecular mechanisms of the anti-inflammatory effects.

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December 16, 2009

NF-kB inhibition blocks trigeminal pain

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Trigeminal NMDA receptors are upregulated via NF-kB in response to inflammation.

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.

The publication:

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Pain. 2009 Jan;141(1-2):97-103. Epub 2008 Dec 5.

Regulation of the trigeminal NR1 subunit expression induced by inflammation of the temporomandibular joint region in rats.

Wang S, Lim G, Mao J, Sung B, Mao J.

MGH Center for Translational Pain Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, WACC 324, Boston, MA 02114, USA.

Summary of the abstract

Expression of the N-methyl-d-aspartate (NMDA) receptor in trigeminal nuclei has been shown to play a role in the mechanisms of trigeminal pain.

Here, we examined the hypothesis that the upregulation of the NR1 subunit of the NMDA receptor (NR1) in the trigeminal subnucleus caudalis (Sp5c) following inflammation of the temporomandibular joint (TMJ) region would be regulated by interleukin-6 (IL-6) and the nuclear factor-kappa B (NF-kB).

Once daily intracisternal injection of an IL-6 antiserum or NF-kappaB inhibitor (PDTC) for 6 days, beginning on day 1 immediately after the CFA injection, prevented both the upregulation of NR1 in the ipsilateral Sp5C and pain behavior.

Moreover, once daily intracisternal IL-6 administration for 6 days in naïve rats induced the NR1 upregulation and pain behavior similar to that after TMJ inflammation. These results indicate that the upregulation of IL-6 and NF-kappaB after inflammation of the unilateral TMJ region is a critical regulatory mechanism for the expression of NR1 in the ipsilateral Sp5c, which contributed to the development of TMJ pain behavior in rats.

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December 16, 2009

Nitric Oxide, NF-kB & migraine

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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.

The publication:

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CNS Neurol Disord Drug Targets. 2007 Aug;6(4):258-64.

Nitric oxide in migraine.

Neeb L, Reuter U.

Charité Campus Mitte, Universitätsmedizin Berlin, Department of Neurology, Charitéplatz 1, 10117, Berlin, Germany.

Summary of the abstract

The potent vasodilatator and messenger molecule nitric oxide (NO) is believed to play a key role in migraine pathogenesis.

NO donors such as glyceryl trinitrate (GTN) can cause headache. Infusion of GTN leads to a migraine attack in migraineurs with a latency of 4 to 6 hours.

This review focuses on the role of nitric oxide and the transcription factor nuclear factor-kappaB (NF-kB) in migraine pathophysiology.

NO is involved in pain transmission, hyperalgesia, chronic pain, inflammation and central sensitization.

NO is implicated in the induction of a migraine attack in migraineurs.

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December 16, 2009

NO synthase inhibitors antagonize CGRP effect

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Nitric oxide synthase inhibitors prevent CGRP mediated dilation of blood vessels in a model of migraine.

The publication:

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Br J Pharmacol. 2002 Sep;137(1):62-8.

Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels.

Akerman S, Williamson DJ, Kaube H, Goadsby PJ.

Headache Group, Institute of Neurology, Queen Square, London WC1N 3BG.

Summary of the abstract

CGRP antagonists can block both neurogenic and CGRP-induced dural vessel dilation.

Nitric oxide synthase (NOS) inhibitors are effective in the treatment of acute migraine.

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December 16, 2009

Vascular smooth muscle dysfunction in 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.

The publication:

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Neurology. 2009 Jun 16;72(24):2111-4.

Vascular smooth muscle cell dysfunction in patients with migraine.

Napoli R, Guardasole V, Zarra E, Matarazzo M, D’Anna C, Saccà F, Affuso F, Cittadini A, Carrieri PB, Saccà L.

Department of Internal Medicine, University Federico II School of Medicine, Naples, Italy.

Summary of the abstract

BACKGROUND: Migraine is associated with increased risk of cardiovascular disease, but the mechanisms are unclear.

OBJECTIVE: To investigate the activity of endothelial and vascular smooth muscle cells (VSMCs) in patients with migraine.

RESULTS: In patients with migraine, the vasodilating effect of acetylcholine (ACh), an endothelium-dependent vasodilator, was markedly reduced. In response to the highest dose of ACh, forearm blood flow (FBF) rose to 8.6 in patients with migraine and to 22.7 . in controls.

The dose-response curve to nitroprusside, a vasodilator directly acting on VSMCs, was depressed in patients with migraine. The maximal response of FBF to nitroprusside was 12.1 in patients with migraine and 24.1 in controls.

CONCLUSIONS: Patients with migraine are characterized by a distinct vascular smooth muscle cell dysfunction, revealed by impaired response to nitric oxide.

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December 16, 2009

Triptans inhibit nitric oxide production

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Triptans effect in migraine may result, at least in part, from their ability to inhibit nitric oxide production.

The publication:

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Cephalalgia. 2003 Oct;23(8):825-32.

5-HT(1B/1D) serotonin receptor agonist attenuates nitroglycerin-evoked nitric oxide synthase expression in trigeminal pathway.

Suwattanasophon C, Phansuwan-Pujito P, Srikiatkhachorn A.

Department of Physiology, King Chulalongkorn Memorial Hospital and Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Summary of the abstract

This study was conducted to investigate the effect of 5-HT(1B/1D) receptor activation on nitroglycerin (NTG)-induced cerebral hyperaemia and neuronal nitric oxide synthase (nNOS) expression in trigeminovascular neurones.

The results showed that pretreatment with sumatriptan could significantly shorten the period of NTG-induced cerebral hyperaemia without compromising the magnitude of hyperaemic peak. Sumatriptan pretreatment also attenuated the NTG-evoked expression of nNOS in all studied areas. Based on these findings, we suggest that 5-HT(1B/1D) receptor has an important role in stabilizing the trigeminovascular system by attenuating the expression of nNOS enzyme, hence reducing nitric oxide production.

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December 15, 2009

Natural NF-kB inhibitors in migraine

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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.

The publication:

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Mini Rev Med Chem. 2006 Aug;6(8):945-51.

Naturally occurring NF-kappaB inhibitors.

Nam NH.

University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Vietnam.

Summary of the abstract

NF-kappaB is a ubiquitous and well-characterised protein responsible for the regulation of complex phenomena, with a pivotal role in controlling cell signalling in the body under certain physiological and pathological conditions.

Among other functions, NF-kB controls the expression of genes encoding the pro-inflammatory cytokines (e. g., IL-1, IL-2, IL-6, TNF-alpha, etc.), chemokines (e. g., IL-8, MIP-1alpha, MCP1, RANTES, eotaxin, etc.), adhesion molecules (e. g., ICAM, VCAM, E-selectin), inducible enzymes (COX-2 and iNOS), growth factors, some of the acute phase proteins, and immune receptors, all of which play critical roles in controlling most inflammatory processes.

Since NF-kappaB represents an important and very attractive therapeutic target for drugs to treat many inflammatory diseases, including arthritis, asthma, and the auto-immune diseases, most attention has been paid in the last decade to the identification of compounds that selectively interfere with this pathway.

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Recently, a great number of plant-derived substances have been evaluated as possible inhibitors of the NF-kB pathway.

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December 15, 2009

Feverfew inhibits NO via inhibition of NF-kB in migraine

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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.

The publication:

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Cephalalgia. 2005 Aug;25(8):612-21.

Parthenolide is the component of tanacetum parthenium that inhibits nitroglycerin-induced Fos activation: studies in an animal model of migraine.

Tassorelli C, Greco R, Morazzoni P, Riva A, Sandrini G, Nappi G.

Laboratory of Pathophysiology of Integrative Autonomic Systems, IRCCS Neurological Institute C. Mondino Foundation and University Centre for the Study of Adaptive Disorder and Headache, Pavia, Italy.

Summary of the abstract

Tanacetum parthenium (TP) – also known as feverfew – has long been used as an herbal remedy for migraine.

In this study, the biological effects of different TP extracts and purified parthenolide were tested in an animal model of migraine based on neuronal activation induced by nitroglycerin.

The extract enriched in parthenolide significantly reduced nitroglycerin-induced effects in the nucleus trigeminalis caudalis. Purified parthenolide inhibited nitroglycerin-induced neuronal activation in additional brain nuclei and, significantly, the activity of NF-kB.

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December 15, 2009

Migraine mix: CGRP, TNF, NF-kB, TMJ

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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.

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December 15, 2009

Nf-kB inhibition blocks CGRP release

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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.

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December 15, 2009

Inflammation and excitotoxicity in migraine pathogenesis

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Migraine involves inflammation and neurons that are over-excited. The two are probably linked.

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December 15, 2009

Nitric oxide: Key player in headache

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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.

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December 15, 2009

Feverfew + ginger found effective in acute treatment of migraine

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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.

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December 15, 2009

Parthenolide for migraine and MS

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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.

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December 15, 2009

Neuronal inflammation of trigeminal ganglion in migraine

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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.

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December 15, 2009

Ginger extract for migraine

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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.

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December 15, 2009

Review: Feverfew in migraine prevention

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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.

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December 15, 2009

Feverfew extract for migraine

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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.

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December 15, 2009

Migraine: Inflammation of the trigemino-vascular system

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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.

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December 15, 2009

Migraine & restless leg syndrome

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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.

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December 15, 2009

Traditional migraine medications inhibit NF-kB

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Traditional Chinese medications used in the treatment of migraine are shown to inhibit NF-kB.

The authors suggest that traditional Chinese medications are effective in the treatment of migraine because they inhibit NF-kB.

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December 15, 2009

NF-kB activation in trigeminal nucleus in migraine

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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.

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December 15, 2009

Role of estrogen in trigeminal nerve sensitization

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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.

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November 18, 2009

Inflammation in pediatric migraine

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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.

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November 18, 2009

NF-kB inflammation in migraine

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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.

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November 16, 2009

Ginger for migraine

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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.

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November 16, 2009

Migraine treatment via NF-kB inhibition

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

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November 10, 2009

Inflammation proven in migraine

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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.

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