Folic acid has gained a lot of attention in the past 20 years due to the impact vitamin B9 supplementation during pregnancy has on neural tube defects. However, folic acid is playing an increasingly important role for a particular group of people with migraine.
What is Folic Acid?
Folic Acid is the synthetic form of folate (vitamin B9), which plays a critical role in the growth and development of new cells, especially during rapid cell growth. Folate is required for making DNA, and it is also important in cell division. For this reason it is especially important during certain embryonic developmental stages (hence its importance in pregnancy and neural tube defects), but also has been implicated in certain types of cancer.
Does folic acid or folate play a role in the cause of migraine?
There are a number of pieces of evidence demonstrating a link between folate or folic acid and a subset of migraine with aura sufferers: genetic factors, diagnostic tests of a key biomarker, and folic acid supplementation studies.
Folate is a key element in the production of nucleotides (building blocks of DNA) and the supply of methyl groups during methionine synthesis by an enzyme called methylenetetrahydrofolate reductase (MTHFR).
Deficiencies of dietary folate, along with vitamins B6 (pyridoxine) and B12 (cobalamin) or reduced activity of the MTHFR enzyme results in reduced conversion of homocysteine to methionine, leading to a build up of homocysteine levels in the blood.
This causes a condition known as hyperhomocysteinemia, which has been linked to a range of conditions such as atherosclerosis, stroke, osteoporosis, rheumatism, Alzheimer’s and Parkinson’s diseases (1), and has been inconsistently linked to migraine with aura.
Pooled data from a number of different meta-analysis involving over nine thousand migraine patients and twenty seven thousand controls confirmed a significant association between the T-allele of the gene MTHFR C677T (which reduces the activity of the MTHFR enzyme by up to 50%) and migraine with aura, but is heavily influenced by geography and ethnicity. (2)
The question remains as to whether these increased levels of homocysteine relate to migraine, and study results are quite inconsistent. Whilst some studies have shown extreme levels of homocysteine in the cerebrospinal fluid of migraine with aura sufferers (3) others looking at blood plasma levels have been less consistent with some studies showing significant changes (4) and others no difference between controls and migraineurs (5).
Does folic acid or folate play a role in migraine treatment?
Intervention studies have also provided conflicting results, however the majority seem to indicate a positive effect on both lowering homocysteine levels and decreasing migraine with aura attacks and disability.
Australian researchers under the lead of Professor Lyn Griffiths at the University of Queensland have been examining the role of vitamin B in migraine and provided high dose supplementation (2mg folic acid, 25mg vitamin B6 and 400µg of vitamin B12) to migraine with aura patients. Migraine disability measured using the MIDAS was reduced from 60% to 30%, and there was also a reduction in headache severity and frequency. Oddly the effect was greater for the other variants of the MTHFR gene compared to the T-allele, and as noted above it is the T-allele that has a greater impact on homocysteine levels. (6)
A follow up study examined the same supplementation protocol and looked at another gene MTRR and noted significant changes in migraine disability and homocysteine levels as well. (7)
With some concerns expressed over the safety of such a high dose of folic acid, the same group examined the effect of 1mg folic acid, 25mg of vitamin B6 and 400µg of vitamin B12 and found no improvement in homocysteine levels or migraine disability. (8)
Is folic acid supplementation for migraine with aura safe?
The common misconception with vitamins is that they are all safe and what your body doesn’t need it will just get rid of. Whilst there is no conclusive evidence that 2mg daily of folic acid is dangerous, long term and large scale studies are lacking. Smaller epidemiological studies and animal studies show signs that caution should be exercised, rather than assuming it is safe.
A study looking at residual folic acid at doses of 1mg per day (through consumption of fortified flour-based products) noted significant residual folic acid in all subjects. Someone eating grain based cereal in the morning and bread at lunchtime could already be consuming between 200-400µg per day. (9)
In the USA the Food and Drug Administration set an upper limit of 1mg per day primarily citing concerns over the potential for folic acid to mask deficiencies in vitamin B12, which if gone undetected can cause irreversible neurological damage.
However there are serious concerns and ongoing epidemiological research examining the impact of folic acid supplementation promoting the progression of colorectal adenomas, potentially increasing the risk of maternal breast cancer (though an exceedingly high 5mg dose was involved), possible reduction of effectiveness of natural killer cells, increase in twin births, increased insulin resistance of offspring, concerns with interference with epilepsy treatments. (10-12) Further concerns have been raised over the potential contribution of excessive folic acid supplementation and the increase of incidence in autism spectrum disorders. (13)
It is not known whether it is the increase in intake of folic acid or the residual folic acid in the the plasma that leads to the increased risk.
Currently the recommended daily dietary intake of folate is 400µg. This increases for women in their reproductive years up to 600µg during pregnancy. The dose of 2mg shown to be effective in the studies above is 5 times higher than the recommended daily intake and double the upper limit set by the FDA in the USA. Whilst the indication for folic acid supplementation is strong for early pregnancy the potential risks posed for those seeking relief from migraine with aura may be too great at present to warrant the risk.
What should you do next?
Whether its a medication that is potentially addictive or has toxic or overwhealming side effects, or a vitamin that may promote growth of cancers, surely the best way to manage your migraines is without supplements at all?
Between 30% and 50% of the population have the MTHFR C677T polymorphism (14), yet less than 3% of the population suffer from migraine with aura, and only a fraction of these can relate it to this gene. This is because there are many other factors that lead to the development of migraines, and a key link is the sensitisation of the trigeminal nucleus - the heart of migraine headache.
Here at the Melbourne Headache Centre we use a technique that focuses on decreasing the sensitivity of the trigeminal nucleus. So the system that drives migraine becomes less reactive, whether its being ‘set off’ by homocysteine levels, hormone levels, stress levels or no obvious triggers at all - the great thing is it doesn’t matter. We treat the factor that is common to them all.
Call us before you and see if we can stop the migraines before you need to take any supplements at all.
We will know within two weeks if the treatment is going to work for you. If not, and you suffer migraine with aura then you need to discuss the potential risks and possible benefits of taking supplements, including folic acid.
Life with migraine is hard enough, without missing out on one of life’s great pleasures – chocolate.
It’s entirely understandable how you would just try and avoid everything that you suspect might possibly trigger an episode, but the research tells a story that might suggest a change in eating habits won’t bring on an attack for the majority of sufferers.
For the rest, decreasing the underlying sensitivity in the brainstem using a natural drug free treatment may mean what was once a trigger is now a pleasure!
Migraine Triggers - Why Chocolate?
Whenever I ask someone during a consultation what their triggers are, or what they avoid to try and keep migraines at bay, there are several that come up in most cases. Stress is number one without question, and this supports the research with up to 80% of migraineurs reporting stress as a trigger (1)– it’s rare that this won’t be listed, along with hormonal changes, sleep disturbance and skipping meals. When it comes to dietary triggers alcohol is in a similar boat with an overwhelming majority reporting this, however not far behind is chocolate. The odd thing about chocolate is that a relatively small percentage of those who say they avoid it will say it is definitely a trigger. They just avoid it because it could potentially be.
Anecdotal evidence of clients saying their migraine attack came on not long after eating chocolate led researchers to speculate on how chocolate could be a migraine trigger.
The first suspect was tyramine, a natural byproduct of the breakdown of proteins in certain foods when they age, leading people to avoid leftovers and cheeses. Tyramine is another migraine trigger ‘suspect’ with little proof to support its villain status.
Decades of research have not been able to establish whether tyramine does or does not trigger migraine attacks, but research from Pastore and colleagues (2) makes the presence of tyramine irrelevant to the 'chocolate migraine trigger' debate. Not only did they show that chocolate contains very little tryamine, but it in fact contains two substances more likely to have a protective impact in dopamine and serotonin.
The next suspect was caffeine. Caffeine enjoys a complicated relationship with migraine, and with 100g of dark chocolate containing up to 81mg of caffeine, (similar to a double espresso), the impact could be significant. Read more on Migraine Headache and Caffeine here.
On the one hand caffeine has been added to headache and migraine medication due to it’s ability to increase absorption from the gut, helping the action of acute pain relieving medications.
Secondly it binds to adenosine receptors which prevents drowsiness in some parts or the brain, but inhibits pain transmission and sensitisation in the brainstem where migraine and recurrent headache occurs. This is why many migraineurs report a ‘strong black coffee’ as their ‘go to’ to abort an attack.
Despite the mechanism and anecdotal evidence, research into caffeine suggest it is no more effective than placebo at stopping attacks. Consuming more than 300mg of caffeine per day has been shown to increase the risk of chronification (i.e. increase the frequency of attacks), and people taking around 200mg per day might decrease the effectiveness of their abortive migraine medication. So again the role of caffeine is not clear and it’s certainly not ‘an obvious trigger’
Migraine Triggers - Chocolate Research
According to Professor Peter Goadsby (3), for something be considered a migraine trigger it should trigger an episode 9 times out of 10 and within a couple of hours (e.g. glycerine trinitrate triggers >90% in under 10 minutes).
As far back as 1974 researchers Moffett, Swash and Scott (4), began exploring the possible links between chocolate and headaches.
In their double-blind placebo controlled trial in 80 subjects who all reported small amounts of cocoa products as a trigger, found only two subjects responded consistently having headaches after consuming chocolate. Their findings suggest that chocolate on its own rarely is a precipitant of migraine.
Another double blinded trial (5) comparing chocolate to carob also found that chocolate does not appear to play a significant role in triggering headaches in typical migraine, Tension-Type Headache or combined headache sufferers.
So why is the anecdotal case strong against chocolate? The current accepted theory was outlined by Prof Peter Goadsby at the 2017 Migraine World summit (3):
‘Part of the presentation with migraine is the premonitory phase, which occurs 6-10 hours (can be up to 2 days) before pain (or typical migraine) symptoms present. One of the features is cravings for certain foods – sweet foods, salty foods etc and this is driven by the hypothalamus. So people will eat certain foods not knowing that they are in the premonitory phase and then associate that food with the migraine, when in all likelihood they were going to have a migraine anyway.’
Is it possible that your migraine has started anyway when you suddenly get the urge to eat some chocolate?
Migraine Treatment - Can Chocolate help?
The main health benefit of eating dark chocolate (>70% cocoa dark chocolate) comes from the antioxidants (oligomeric procyanidins or flavanoids) found in raw cocoa beans, which can help promote blood flow to the brain, keep arteries elastic, and lower inflammation. Antioxidants neutralise free radicals and prevent oxidative stress (damage that free radicals inflict on tissues in the body), helps to increase good cholesterol levels and decrease blood pressure (6).
We have seen that chocolate contains serotonin and dopamine both of which play significant roles in dampening excitability of pain nerves, and 30g of 84% dark chocolate shown to decrease inflammation in diabetic patients (7). It is also a rich source of magnesium with 100g block containing around 230mg of magnesium.
Researchers (8) looking more specifically at cocoa found that ‘diets enriched in cocoa increase proteins that prevent your nerve cells from becoming excited and releasing inflammatory molecules (cytokines) that are though to be involved in migraine pathology’
Every person who suffers migraine is different, so it is important to filter all of this through what you understand from your own story.
Migraine Diet - Chocolate
Chocolate - to eat or not to eat, that is the question.
If you know that every time you have eaten chocolate you have had a migraine, I am not suggesting you tempt fate. If on the other hand you think that sometimes it has been a trigger, but other times not, or if you have only avoided chocolate assuming that it is a migraine trigger then you may wish to reconsider your view.
What you should consider when deciding to try it is whether or not you have a number of other trigger factors building and whether or not you might already be in the premonitory phase.
The key is to avoid trying it if you are craving it, or feeling lethargic, yawning excessively and moody. It also makes sense that if you have been short on sleep and are feeling like your stress levels are high, or the timing of hormonal changes (leading into the start of your cycle or mid cycle) then that may not be the best time to try it.
An important note to avoid leading to increased frequency of migraines is that 100g contains up to 80mg of caffeine – as strong as a double shot espresso. Over 300g per day can lead to increased risk of chronic headaches, so be careful with how much chocolate, coffee, tea you have. You can read more about caffeine and migraines here.
Regardless of triggers - stress foods, sleep hormones, the all have to interact with an overstimulated trigeminal nucleus. This is what is at the heart of migraine, tension-type headache along with the other major headache types.
If you don't have an overloaded trigeminal nucleus - you don't get symptoms. Avoiding triggers is one thing, but dealing with the overstimulation of the trigeminal nucleus is far more significant, and will have a much bugger impact.
Picture the trigeminal nucleus in the brainstem as a coffee cup. In non-headache sufferers this cup starts the day almost empty. In migraineurs and recurrent headache sufferers the cup starts at ¾ full.
There is less capacity to absorb more input into the system, and different people will be sensitive to different inputs - these are the triggers.
Rather than walking on eggshells all the time trying to avoid spilling the coffee cup over, use a treatment that 'empties some coffee from the cup'.
That is exactly what the treatment at the Melbourne Headache Centre does. The three nerves from the top of the neck feed directly into this part of the brainstem. We can test your neck to see if they are causing some of this irritation and treat it.
Empty the coffee cup.........give yourself more capacity to 'absorb triggers' and who knows.......maybe you can have an easter egg or two!!
(1) Pavlovic, J.M., Buse, D.C., Sollars, M., Haut, S., and Lipton, R. B. (2014) Trigger Factors and Premonitory Features of Migraine Attacks: Summary of Studies.Headache; Nov/Dec 1670-1679.
(2) Pastore, P. Favaro, G. Badocco, D. Tapparo, A. Cavalli, and Saccani, G (2005) Determination of biologic amines in chocolate by ion chromatographic separation and pulsed integrated amperometric detection with implemented wave-form at Au disposable electrode.Journal Chromatography A, Dec 9; 1098 (1-2): 111-5.
(3) Professor Peter Goadsby (2017) The Top 10 Myths to Bust. Migraine World Summit
(4) Moffett, A. M., Swash, M. and Scott, D.F. (1974) Effect of Chocolate in Migraine: a double-blind study. J Neurol Neurosurg Psychology. Apr, 37 (4): 445-8.
(5) Marcus, D.A., Scharff, L. Turk, D. and Gourley, L.M. (1997) A double-blind provocative study of chocolate as a trigger of headache. Cephalalgia, Dec; 17 (8): 855-62.
(6) Saxelby, C (2010) Myths busted - How healthy dark chocolate.
(7) Jafarirad, S., Ayoobi, N., Karandish, M, Jalali, MT, Haghighizadeh, M. H., and Jahanshahi, A. (2018) Dark Chocolate Effect on serum adiponectin, biochemical and inflammatory parameters in diabetic patients: A randomized clinical trial. Int J Prev Med, Oct; 12,(9); 86.
(8) , Cady, R., Denson, J.E. and Durham, P.L. (2012) Inclusion of Cocoa as a dietary supplement represses cytokine expression in spinal trigeminal nucleus in response to chronic trigeminal nerve stimulation. Presented at 54th Annual Scientific Meeting, American Headache Society, June 21-24, 2012. Program Abstracts, Headache: May, 862-914.
What type of headache do you have?
The answer should be simple. The diagnostic criteria set out for each disorder are clear and distinct, however there are many sufferers who’s symptoms blur the boundary between headache types, and will shift from one definition to another as the headache progresses, and they just don’t fit the arbitrary boundaries that have been set by the International Classification of Headache Disorders.
What does this mean for the treatment of these people, and what does it mean for the medical approach to headaches?
In National Headache Awareness week 2018 I was fortunate enough to attend a talk given by Dr Michael Eller on ‘Migraine management and treatment options’. He began the talk with a little of the history of headache management through time and went on to talk about how migraines are classified – in other words how you can tell it’s a migraine compared to other forms of headache. I was a little shocked, but overwhelmingly in agreement with Dr Eller’s comment that the classification system is ‘a little bit silly really’.
In other words lots of people don’t fit the neat description we have for each headache type, and at different times of the day their classification would change depending on how the episode is behaving.
Anyone who has been to see more than 2 or 3 doctors for their condition will know exactly why a leading specialist in Melbourne would make such a comment. You will rarely end up with the same diagnosis from the same doctors, and despite the attestation of experts that ‘an accurate diagnosis is essential to good care’ the facts remain that this diagnosis is difficult to obtain.
The classification system is based on the differences in how each headache type looks, but many experts over the years have argued there are more similarities between headache types than there are differences, and that instead of ‘headaches being separated diagnostically by subtle clinical nuances of dubious reliability’ we should view headaches as slightly different manifestations of the same underlying process (Cady et al 2002).
So what does a migraine look like? Some people would say if they have aura then it’s a migraine, but aura only occurs in 20% of cases. Others would say if they feel nausea or the headache throbs then its migraine, but as we will see sometimes that’s not the case.
We have the following definitions according to the International Classification of Headache Disorders (ICHD) 3:
A.At least 5 attacks fulfilling criteria B-D
B.Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)
C.Headache has at least two of the following four characteristics
3.Moderate or severe pain intensity
4.Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
D.During the headache at least one of the following:
1.Nausea and/or vomiting
2.Photophobia and phonophobia
E.Not better accounted for by another ICHD-3 diagnosis
So to satisfy the criteria for a migraine we could have moderate pain on one side of the head with nausea. Easy right?
So let’s compare to a frequent tension-type headache (TTH):
A patient reporting moderate throbbing/pulsing pain on one side of the head with sensitivity to light, but no nausea or sensitivity to sound will not meet the criteria for migraine. Those having a unilateral and pulsing headache will not meet the criteria for tension-type headache either. So what do they have? That depends on the doctor you see. Is it important to know? Probably not.
What about a client with bilateral headache of moderate intensity and no nausea or sensitivity to light and sound? That’s a TTH according to the rules. If we add nausea then it’s a migraine – simple. Unless it’s occurring more than 15 days per month. Chronic TTH can have nausea as part of the diagnosis – so which do you have?
If you think you’re confused, you’re not the only one. Dr Lawrence Newman at the recent Migraine World Summit gave a talk on the differences between tension-type headache and migraine. His first comment was tension-type headache ‘is not a headache that is disabling, or one that tends to drive people to see a doctor. There is no nausea, light or sound sensitivity. It’s just a mild to moderate headache that comes and goes’.
Very little of what he said reflects the diagnostic criteria. There is nothing mentioned of the level of disability of the headache in ICHD-3, most likely because that is a very subjective quality. In contrast, the presence of one of sensitivity to light or sound is permitted in the tension type headache classification, yet not by Dr Lawrence.
Migraines are defined as lasting 4-72 hours whereas a TTH may last 30 minutes to 7 days. If either of those two is ‘coming and going’ it is the migraine rather than a 7 day long TTH.
Later in the same talk he mentions nausea and says ‘by definition you can have mild nausea associated with tension-type headache’. For episodic TTH that is in fact the exact opposite of the diagnostic criteria – which specifically state no nausea or vomiting and no more than one of light and sound sensitivity.
Confusing, and to quote an expert ‘a bit silly’.
A majority of the clients we see at Melbourne Headache centre would be diagnosed with Chronic migraine. That is, more than 15 headache days per month with at least 8 being migraine. Typically many of the other days include headache that fits the TTH criteria.
Despite the fuss made over an accurate diagnosis, as Dr Lawrence points out, may of the same drugs are used to try and treat both cases, such as amitriptyline (Endep) or topiramate (topomax). In fact we regularly see people who have bilateral moderate headache with mild nausea but no sensitivity to light or sound (Chronic TTH) that have been treated with Botox - a drug only available under PBS to Chronic Migraine patients. Clearly in these cases the diagnosis is not reflecting the symptoms necessarily, but might be more reflective of what treatments your doctor wants to try with you. As Dr Newman puts it:
'it doesn't matter what you call it, it's the frequency of headache that's often going to guide the treatment'.
We treat a condition that is common to all headache types, which is a sensitized brainstem, so the diagnosis isn’t particularly important. What is critical is what the source of sensitization is.
Imagine each headache type is a different train, all sitting at the platform at a major centralized railway station (i.e. Southern Cross Station). Each train begins its journey in the same place, in the same way, and looks basically the same. Then as they move out of the station some trains will head north, some south, east and west, and others elevate or go underground. From that point the journey of each train looks quite different to each other.
When your job is to try and disrupt the journey of each train at different points along its journey, (i.e. drugs targeting specific pathways of different headaches) you need to try and understand which headache type you are dealing with.
When your treatment involves stopping the train from leaving the platform at the first station (i.e. decreasing brainstem sensitivity – Melbourne Headache Centre) then it really doesn’t make a huge difference which train you are referring to. We can potentially deal with all of them.
Cady R, Schreiber C, Farmer K, and Sheftell (2002) Primary Headaches: A Convergence Hypothesis. Headache 42 ; 204-216.
The American Headache Society: International https://www.ichd-3.org
Overview of Topics
Day 1 - Essentials
Sleep, Insomnia and Energy
Dodging False Promises and Treatment Claims
How to get the Most from your Doctor
Treating Each Phase of a Migraine Attack
Day 2 - Understanding
How to Interpret Migraine Research
Scans and Tests: Do you really need one?
Tension-Type Headache vs Migraine
Clinical Errors that Undermine Migraine Care
Day 3 - Types
Alternative Treatments for Cluster Headache
Diagnosing Pressur Heqdache vs CSF Leaks
Understanding Balance, Vertigo and Dizziness
When Migraine Disables but doesn't hurt
Day 4 - Triggers and symptoms
Drug Interactions with Common Migraine Meds
Neck Pain and Migraine: Trigger or Symptom?
Hormonal Contraception and HRT for Migraine
Medication for Prevention: Know Your Options
Day 5 - Alternative Treatments
Can a Ketogenic Diet Prevent Migraine?
How Posture and Massage Affect Migraine
Migraine and Exercise: Trigger or Preventive?
CGRP and Butterbur: Comparing the evidence
Day 6 - Treatments
Treatment Spotlight: Drug-Free Devices
Botox: Separating Fact from Fiction
Treatment Spotlight: Ditans and Gepants
The Latest on Medical Marijuana for Migraine
Day 7 - Difficult Cases
The Keys to better Emergency Care
Controlling Unresponsive Chronic Migraine
Hope for Refractory Chronic Migraine
Treating Attacks: Real Patient Case Studies
Day 8 - Living
Thriving with Multiple Chronic Illnesses
Beware: CGRP Access Challenges Ahead
Understanding Your Workplace Rights
Beyond Guit and Shame: One Woman's Journey
Is Caffeine a Friend or Foe?
Why is that that the same thing can be a trigger and a treatment? Headache sufferers have had a love-hate relationship with caffeine, going from complete avoidance due to its triggering potential, to relying on a cup a day to keep pain at bay!
Hidden amongst our morning tea and coffee, soft drinks and chocolate is a potent drug that has very complex interactions that go right to the heart of headache and migraine.
What is Caffeine?
Caffeine is a chemical compound in the alkaloid family, (chemical name 1,3,7-Trimethylpurine-2,6-dione) that occurs naturally in over 60 plant species including tea, kola nuts, coffee beans, mate leaves, guarana plants, and cocoa nuts. As such caffeine is one of the most widely consumed psychoactive agents (able to change brain function/mental state) in the world. 
How Does Caffeine affect our brain?
When entering the body caffeine looks exactly the same to nerve cells as a substance called adenosine. Adenosine is active in a number of regions in the brain and is a key building block in our energy pathways, but doesn’t instantly boost energy. In fact adenosine binding to nerves in the brain causes drowsiness by slowing down nerve activity and promotes sleep. During this time our blood vessels dilate allowing more blood into the brain to nourish it during sleep.
Caffeine blocks the ‘drowsiness effect’ by binding to adenosine receptors, leading to increased nerve activity and an increase in our ‘alertness’.
In response to this increased activity the pituitary gland releases adrenaline – our fight or flight hormone. The result is what most people will feel when they drink coffee in increased activity of the central nervous system: increased heart and breathing rate, increased blood pressure, increased diuresis, cardiac muscle contraction and gastric, lacrimal (tear), nasal mucous secretions vasoconstriction of blood vessels in the brain. Blood will be moved from your periphery to your core and the liver will release more glycogen into the blood stream for extra energy.
Headache and Migraine prevention - why Does Caffeine help?
Caffeine causes vasoconstriction in the brain, and was added to numerous migraine medications on the mistaken assumption that migraine was a vascular headache.
‘Now that migraine is thought to be a neurological and not a vascular disorder, caffeine’s common inclusion in migraine treatments suggests an alternative, non-vascular mechanism of action behind its efficacy in migraine patients.’(Nathan Fried 2017)
While there may be some mild benefits with the vasoactive effects of caffeine, it is caffeine’s action in blocking adenosine receptors in the brainstem that is having the positive impact. In the brainstem (the home of the migraine circuit) adenosine is involved in pain transmission and sensitization. By blocking adenosine receptors here caffeine may help stop the spread of ‘excitability’ and abort a migraine or ease a headache. 
Despite the anecdotal evidence or a ‘strong black coffee’ aborting migraines, research into caffeine as a monotherapy (not combined with another drug) shows it is no more effective than placebo in time taken to 50% reduction in symptoms. 
The most commonly understood mechanism for helping headache and migraine sufferers comes from caffeine’s effect on your stomach. Ingesting Caffeine causes rapid lowering of gastric pH (more acidic), improving the absorption of analgesic medication. When the ergot family of drugs was in use a combination therapy known as cafergot was widely used. This has since been removed in most forms (still available as a suppository under prescription), due to deleterious cardiovascular effects of ergotamines. Today we see panadol extra on the market with caffeine combined with paracetamol. Despite some research to support its use as a combined therapy there isn’t currently a caffeine plus NSAID (like ibuprofen) on the market. This will be because both agents cause lowering of gastric pH, which indeed is the most common and concerning side effect of NSAID’s leading to stomach upset and ulcers.
Once again we see the double-edged nature of caffeine. On the one hand, here there seems to be good reason to use it as either an adjuvant to other rescue medication, or for its own effects in dampening brainstem excitability, however there is evidence to the contrary. Not unlike the opioids (with similar dependence and withdrawal profiles) caffeine may seem to ne helping with one hand, but worsening things in the long run.
Does Caffeine cause Headaches or Migraines?
A study of 36 children and adolescents (aged 6-18) who were heavy cola drinkers (minimum 1.5L per day or 192gms caffeine) and suffered daily headache examined the effect of ceasing caffeine consumption. Two weeks after stopping their caffeine intake researchers saw a complete cessation of daily headache in 33 of the 36 children in the study. 
Another study examining the factors that lead to chronification of headaches found daily consumption of caffeine to be a significant factor in the development of analgesic overuse headache and chronic migraine. 
This study was followed up 2 years later looking more closely at the amount of caffeine used, and found a history of heavy caffeine use (> 300mg daily) was associated with chronic daily headache compared to episodic headache control groups. 
In 2016 Lee and associates looked at the effect of caffeine cessation on the effectiveness of acute migraine medication. The two groups (abstinence and coffee groups) had a mean caffeine intake of 192mg per day. Given it’s adjuvant effect with analgesics one might assume that cessation of caffeine use would decrease the effectiveness of acute migraine treatment. In fact they found the exact opposite. Discontinuing caffeine use actually significantly improved the efficacy of acute migraine medication. 
Should Migraineurs have Caffeine?
There appears to be a complex association of caffeine with headaches. On the one hand many properties seem to make it a useful medication for helping relieve pain, but daily use appears to have some negative effects in increasing the likelihood on transforming from episodic to chronic headaches.
It’s the same story we have been hearing for opioid analgesics like codeine, recently taken off the shelves as an OTC (over the counter) medication. Adenosine homeostasis also plays a crucial role in narcotic drug responses and plays a role in neurobehavioural features associated with opiate addiction and withdrawal. 
Caffeine also affects dopamine by increasing its production in the brain. Dopamine is our ‘pleasure drug’ so it makes you feel euphoric. This action is very similar to two banned drugs in heroin and cocaine which both slow down dopamine reabsorption. It’s the action on dopamine that may be even stronger cause of addiction and withdrawal with caffeine.
In other words the effect of caffeine and its interaction with adenosine and dopamine receptors results in the same withdrawal/addiction responses in our central nervous system as narcotic drugs.
How much caffeine is o.k. for migraineurs and headache sufferers?
The Food Standards Code (Australian government) restricts the caffeine content of energy drinks. Whilst they have not set an upper limit in Australia, they have commented on the limit that appears to be linked to anxiety as being 3mg of caffeine per kg of body weight. This equates to around 200mg per day for an adult, and that seems to be a similar figure in the headache studies above. 
At the end of all this you firstly need to figure out whether caffeine has any interaction with your headaches at all, as triggers are a hugely individual aspect of headaches.
If you believe caffeine is a sensitive trigger with either not enough or too much (i.e. you have a ‘sweet spot’ in terms of it being helpful), you may want to monitor how much you have on a longer-term basis. 200mg per day, whilst in the short term may seem like its helping, in the longer term may actually be making you worse.
An espresso shot may contain anywhere from 30mg to 90mg per shot. This variation is in the bean and roast type with lighter roasts having more caffeine. Caffeine in other foods drinks as per Food Standards Code :
Black tea – 20-80mg/250ml (longer brewed = higher caffeine)
Coca Cola – 48.75 mg per 375ml
Milk Chocolate – 20mg /100g
Dark Chocolate – 81mg/100g
Energy drinks – 80mg/250ml
So one double shot of light roasted barista espresso coffee could have you close to the 200mg level. In the USA the recommended daily intake for caffeine is 400mg. The discussion around triggers always comes back to dealing with the common underlying theme which is an overactive brainstem. Lots of people consume caffeine but don’t get headaches, even when they stop or withdraw.
So what makes headache and migraine sufferers prone to the positive and negative impacts of caffeine. Indeed why do all these different triggers result in headache? The underlying problem is overactivity in the brainstem – in the area housing the nerves for the head/face and neck.
Regardless of the impact of triggers, the neck is the most common source of overactivity in this part of the brainstem and is the easiest to assess and treat.
Treat the underlying causes today and get your neck assessed.
 Neurology advisor Caffeine-migraine-headache-trigger-treatment
 Fried, N.T, Elliot, M. B. and Oshinsky (2017) The Role of Adenosine The Role of Adenosine Signaling in Headache: A Review. Brain Sciences, 7 (3), 30.
Diener HC, et al. The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study. Cephalalgia. 2005;
 Hering-Hanit R, Gadoth N (2003) Caffeine-induced Caffeine-induced headache in children and adolescents.Cephalalgia, 23, 332-335.
 Bigal, M.E. Sheftell, F.D, Rapoport, A.M., Tepper, S.J. and Lipton, R.B. (2002) ChronicChronic daily headache: identification of factors associated with induction and transformation.Headache, 42 (7), 575-581.
 Scher, A.I., Stewart, W.F, and Lipton, R. B. (2004) Caffeine as a risk factor for chronic daily headache: a population based studyNeurology, 14; 63 (11) 20022-7.
 Lee, M.J., Choi, H.A., Choi, H, and Chung, C.S. (2016) Caffeine discontinuation improves acute migraine treatment: a prospective clinic-based study.Journal of Headache and Pain; 17 (1); 71
 Mohong, Wu et al (2013) Opiate-induced Changes in Brain Adenosine Levels and Narcotic Drug Responses. Neuroscience, 3, 228; 235-242.
 Food Standards Code (2018) Caffeine
 Heckman et al (2010) Caffeine (1, 3, 7-trimethylxanthine) in Foods: A comprehensive Review on Consumption, Functionality, Safety and Regulatory MattersJournal of Food Science, 75, (3).
Weather Related Migraines
Up to 53% of migraineurs report weather changes as a consistent trigger making it one of the most commonly reported triggers for migraine behind stress, hormones and skipped meals. 
A subject of interest as far back as 1974, researchers have spent decades trying to examine the question: Does weather actually trigger migraine attacks, and if so, what are the factors related to weather change that is causing attacks in people?
Theories over the years have included temperature and barometric pressure changes, high and low humidity, high winds, stormy weather, and changes in light conditions (very bright or dull light as well as changes in daylight hours).
The science however has provided contrasting and often confusing results making it difficult to understand what is happening.
In 1979  researchers in London asked 310 migraineurs about the day and time of their attacks (subject to recall bias) and found no correlation with changes in wind, barometric pressure, humidity and temperature.
Jump ahead to 2011 and Karin Zebenholzer and colleagues  undertook a 90-day prospective diary study in Vienna. Whilst they found trends when analyzing change in temperature, wind speed, sunshine duration in isolation, analysis of multiple variables to account for attacks yielded no positive findings.
Their conclusion was ‘the influence of weather factors on migraine and headache is small and questionable.
Migraine Triggered by Thunder Storm or Lightening
In 2013  researchers studied the effect of lightening strikes on 90 migraineurs who kept diaries for 3-6 months. When they analysed the data they also accounted for rainfall, and barometric pressure.
When there was a lightening strike within 25 miles (40kms) there was a 25-30% increased risk of both new-onset headache or new-onset migraine. They are following up with further research to try and determine what it is that lightening strikes do that can cause a slight increase in migraine incidence.
The odds of having a new headache or migraine start increased on days with lightening that had a more negative charge leading researchers to suggest that something to do with the electromagnetic interaction is causing some irritation of the nervous system and triggering an episode.
Lead researcher Dr Vince Martin , explained that other environmental factors change in thunderstorms, in particular related to fungi and mold. Rain increases mold counts, and if lightening strikes the ground it aerosolizes the fungi. In other words we breathe in a lot of fungi and molds in the air during thunderstorms, contributing to our now famous ‘Thunderstorm Asthma’ events.
When this is coupled with the fact that migraineurs tend to have a higher incidence of non-allergic rhinitis (nasal and sinus irritation) it provides another possible mechanism for triggering an attack, but it is still interacting with a sensitized system as Dr Martin explains:
“I think that what we don’t realize is all these different things in our lives can influence that (migraine) threshold. So how much sleep you got the night before, how much stress you are under, whether you fasted for a prolonged period of time. All these things have a neurologic effect on migraine patients and can seek to lower that threshold and make people more vulnerable to migraine.”
The threshold to which he refers of course is the ‘explosiveness’ or the trigeminal nucleus. Read on for ideas on how to fix this sensitivity.
Migraine Triggered by Barometric Pressure Changes
Barometric pressure is what we see weather forecasters referring to with weather patters. Low pressure allows clouds to form and typically rain and storms. High pressure is typically associated with clear blue skies and warmer weather.
The challenge is that pressure changes ahead of the weather that comes with it, so you won’t often ‘see’ the weather that might trigger you. This might result in many migraineurs claiming to be able to ‘predict the weather’ as they might be sensitive to falling barometric pressure.
Dr Martin  explains that ‘some (migraineurs are) triggered by falling or rising barometric pressure. Interestingly if falling pressure does it then rising pressure is usually ‘protective’ and vice versa.’
Researchers in Japan  studies the effects of changing Barometric pressure in 34 migraineurs compared to a control group of tension-type headache sufferers. On face value there appears to be a link between small decreases in barometric pressure (6-10hPa) and increased incidence of migraine compared to tension-type headache controls. Unfortunately the diary-recording period only went for 18 days. The problem is that we don’t know if the migraine group had a higher incidence of attacks and whether either incidence was different to the previous 18-days prior to recording.
Cioffi and colleagues  investigated the effects of changing weather in patients with temporomandibular disorders (TMD) and migraine. Their results indicate that decrease in atmospheric pressure increased the intensity of TMD pain, however increase in pressure and temperature increased the intensity of migraine symptoms. Again the study is very limited, in part by a ‘lost' or 'not captured' data rate of 25% and no indication of the baseline activity in both groups – in other words we don’t know whether the pain fluctuations can be attributed to the weather or if these are normal fluctuations.
More disturbingly, the authors claim as a starting point in their introduction that:
‘The pain course of subjects suffering from migraine is influenced by weather conditions’
citing two publications to support the statement. On reviewing these two publications the conclusions the authors draw themselves are quite the opposite:
‘The influence of weather factors on migraine and headache is small and questionable” 
“In a sub-group of migraineurs, a significant weather sensitivity could not be observed”. 
Migraine and Weather: Conclusions
So this all seems a bit confusing, and we want a simple answer – do changes in weather cause migraines or not?
The answer is a simple as does chocolate, or wine, or perfume cause a migraine. The answer is obviously yes………..and no.
That is to say migraineurs as a group are heterogeneous. Some things that may trigger one migraineurs may not trigger another, so pooling together large groups to study effects of anything, be it a trigger (or a treatment for that matter) can dilute the effect that it might have on sub-groups. The difficulty is in discerning the sub-group in a way that allows better predictions of the effects of
The results of Hoffmann’s 12-month study , though inconclusive, did show trends leading to the conclusion that “only a sub-group of migraineurs is sensitive to specific weather conditions, explaining why previous studies, which commonly rely on pooled analysis, show inconclusive results”.
One might expect a better result in migraineurs who report weather changes as a trigger, however Zebenholzer and colleagues looked at perceived weather changes compared to weather data and found a poor correlation. 
Not unsurprisingly, the ability of a migraine brain to accurately detect weather may be impaired (similar to its response to noise, light, smells in some cases), leading to inaccurate forecasting, and the feeling that ‘the weather is changing and here comes my migraine’ whereas in fact the sense that the weather is changing may be a part of the migraine itself.
Another problem is that changes in weather do not influence migraineurs in isolation. What were the other factors occurring at the time of the study with regards to amount of sleep – over-sleeping, under-sleeping, dietary influences, hydration levels, stress levels etc
As with many other triggers, often in isolation or at low doses they may be ok, but when a strong dose or in conjunction with others triggers may cause problems.
At the end of the day the research has failed to show what we know and see in the clinic, and that is, without question, migraine can be triggered by changes in the weather – but as with many other things migraine, the exact mechanism’s have eluded researchers and remains an area of ongoing focus for some.
What to Do about Weather related Migraine: Treatment
What does chocolate, perfume, bright light, red wine, stress, hormones changes and weather changes have in common? Nothing apart from the fact that they can all (amongst a host of other things) be considered triggers for some peoples migraine.
Focusing on triggers can be helpful if you only have a small number. If on the other hand you have multiple triggers, then this line of migraine management often proves futile and frustrating as the next doctor pulls out yet another migraine diary for you (scream!).
The thing that ties these and every other migraine trigger together is that they all interact with a sensitized trigeminal nucleus to cause the symptoms we associate with primary headache conditions.
So aside from moving to somewhere with stable weather patterns that has just the right mix of heat, humidity, wind and small changes in pressure to prevent your weather related migraines, what else can you do.
I would urge you to ignore the triggers and focus on the sensitized brainstem.
The nerves from the top of the neck feed directly into this area making it the number one suspect in the frontline of fighting the underlying problems in migraine.
In recent years the migraine community has shifted away from the vascular theories to focus on a sensitized brainstem model. This brings the neck back into focus, and even Dr Andrew Charles has moved from:
‘this (neck pain) is just a symptom of their migraine’ in 2012  to a 'greater appreciation of the potential role of the cervical nerves' acknowledging the 'frequent occurrence of neck pain could indicate a role for the upper cervical nerves in the transmission of migraine pain' in 2018 .
Come and get the underlying problem assessed and treated with the only technique developed specifically to lower trigeminal nucleus sensitivity.
For those wanting more tips on how to minimise weather related migraine:
 Pavlovic J. M. et al (2014) Trigger Factors and Premonitory Features of Migraine Attacks: Summary of Studies.Headache, Nov/Dec, 1670-1679.
 Wilkinson M and Woodrow J. (1979)Migraine and Weather. Headache. 19: 375–378.
 Zebenholzer K, Rudel E, Frantal S, Brannath W, Schmidt K,
Wober-Bingol C et al. (2011) Migraine and weather: a prospective diary-based analysis.Cephalalgia. 31:391-400
 Martin, G.V. et al (2013) Lightening Lightening and its association with the frequency of headache in migraineurs: an observational cohort study.Cephalalgia, 33 (6), 375-383
 Martin, G.V. (2018) Surviving weather-related Migraine. Migraine World Summit. (2018)
 Okuma, H et al (2015) Examination of fluctuations in atmospheric pressure related to migraine. SpringerPlus Open Journal.
 Cioffi, I et al (2017) Effect of weather on temporal pain patterns in patients with temporomandibular disorders and migraine.Journal of Oral Rehabilitation. 44; 333-339.
 Hoffmann, J et al (2015) The influence of weather on migraine – are migraine attacks predictable?Annals of Clinical and Translational Neurology, 2 (1); 22-28
 Charles, A (2012) Migraine ResearchMigraine Research.ABC Health Report.
 Charles, A (2018) The pathophysiology of migraine; implications for clinical management.
Lancet Neurology. 17; 174-182.
Dr Michael Eller - Migraine Management and Treatment Options
Dr Eller is a Neurologist at Neurology Network Melbourne, and gave a presentation at The Alfred Hospital on Tuesday 11th September.
His talk focussed on a number of emerging treatment options for migraine. There were some interesting results first two based on electrical stimulation and the other was the new CGRP monoclonal antibody (mAb).
The first part of Dr Eller's talk was to discuss an often overlooked visual symptoms experienced my many migraineurs - visual snow. Visual snow is an effect where normally consistent colours look pixellated, or blotchy, or grainy in stead of clear and smooth. Sometimes the snow is coloured sometimes black or white, affecting parts of or the whole visual field.
Other interesting visual phenomena are palinopsia (trailing or ghosting as objects move through the visual field), black floaters (white blood cells passing through capillaries across the retina) and nyctalopia (impared night vision). A number of these phenomena are 'normal' such as floaters (I can see them right now!) however they are enhanced in migraineurs.
Dr Eller then went onto the part of the talk that he thought would be the most dry, but I found the most interesting. He went on to describe what a migraine is. I found this interesting because of his thoughts on the official classification rather than hearing something that I know by heart. Take from the ICHD-3 (International Classification of Headache Disorders version 3), Dr Eller described the familiar traits of a migraine attack according to the classification: Moderate to severe pain lasting 4-72 hours, containing two of - pulsatile pain, one sided, aggravated by routine activity and moderate to severe intensity. It must also have one of the following: nausea and/or vomiting, photpphobia or phonophobia.
Having laid this out he then described it as 'a bit silly' which might strike many as odd, but a sentiment I could not agree with more. The reason of course is that peoples symptoms change from one episode to the next, and despite clearly having migraine, the pain might be moderate, bilateral and aching instead of throbbing, yet if you get nausea with it its not a tension-type headache but not a migraine either - so what is it? The fact is they are all slightly different expressions of the same problem, a sensitised brainstem.
The classification system is not reflective of hundreds of different pathological problems, but slightly different variations of the same problem. Imagine if we said two ankle sprains were totally different depending on were the bruising comes out?
Dr Eller pointed out that migraine is a 'primary headache disorder'. The way he defined primary was 'you scan the brain, its fine, do blood tests, they're fine.........its just a part of you'. It's another description which defies science now, assuming there is no 'faulty bit' we can test. In fact there are a number of faulty bits. Common to all so called 'primary headache disorders' is a sensitised trigeminal nucleus - the part of the brainstem receiving input from the head and face nerve (trigeminal nerve). We know this is overactive all the time (with or without symptoms) in migraine, tension-type headache and cluster headache. The nerves from the top of the neck feed directly into this area - making them candidate number 1 for a cause of this overactivity.
Dr Eller went on to describe migraine as a 'pathological brain state in which headache is only one possible feature along with visual, sensory, language, motor, cognitive symptoms, nausea, yawning, fatigue, dizziness, cutaneous allodynia, photophobia, phonophobia, osmophobia.
Dr Eller didn't mention the trigeminal nucleus, which is constantly irritated, but did talk about the hypothalamus, which is otherwise normal, but starts to become overactive at the start of the premonitory phase, incorrectly concluding that maybe its the generator. The hypothalamus is important in our bodies homeostasis - sleep wake cycle, body temperature regulation,
If it was the generator it would precede the premonitory phase - not coincicde with it. Only the trigeminal nucleus along with the upper cervical nerves is constantly overexcited.
Migraine - New Treatment Options
Dr Eller referred to two new forms of electrical stimulation that have been approved for use in migraine.
The first is called the eNeura, pictured here on the left. It differs from the cephaly which many people may be aware of in that instead of sending electrical impulses across the surface of the head, this generates electrical impulses inside the brain, in an attempt to disrupt the evolving electrical storm that leads to a migraine attack. The device is like a plastic pillow that you hold to the back of your head (pictured) and has shown similar success rates to CGRP mAbs (see below). That is 46% of the treatment group achieved a 50% or greater reduction in symptom frequency. Cost is in the vicinity of $1000 over 3 months.
The 'gammaCore' is a vagal nerve stimulator, which is the nerve that goes down to the stomach and internal organs. Children with seizures sometimes have a vagal nerve stimulator implanted and in some of those that also had headaches they found in some cases their headaches got better as well. That led to the development of a hand held device that is pressed against the neck (pictured) that delivers an impulse to the vagal nerve as it descends in the neck. The results were similar to the above, but interestingly this also had a significant effect in cluster headache, which is often recalcitrant to treatment.
I spoke to the supplier of these products at he recent AHS scientific meeting in San Fransisco. I managed to hide my shock at the pricetag and the way they have montetised the product. There are two vairites - one can give you 30 charges a day for 3 months, the other gives you 30 days worth of charges.
Either way you then have to order another. $1000 every 3 months approximately. What annoyed me was that if I ordered one (which I can't anyway) they would send a demo to me that I can simply recharge. In other words, it expires each month and you order a new one not for any limitation in the device, but just so you have to buy another one - instead of offering a rechargabale option as well. This speaks greatly to the midset of those developing medical products (devices and drugs) in this space. Why offer you a cure if we can offer you something that makes you a customer for life?
Speaking of customer for life, Erenumab the new CGRP mAb was the last topic of the talk. This was approved in the USA in May and approved in Australia in July. The cost is going to be $750-850 per month. I have written extensively on this in previous Blogs, but pleasingly, Dr Eller presented it warts and all. Initially saying 'There's some impressive and not so impressive figures related to this Erenumab. The impressive relates to the side effects profile. Almost identical to placebo. One question on the night Dr Eller wasn't able to answer - what were the SAE's for the medications (SAE = serious adverse event). There were 8 in the treatment group and 7 in the placebo group. This can seem alarming until you understand that any adverse event you have during the trial duration is counted. In other words if you had a car accident, or brooke your ankle playing football during the trial, you are counted as an SAE. The researchers then have to investigate each SAE afterwards and see if there is any probability that the SAE is attributable to the treatment. In the case of Erenumab the SAE's attributed to the medication was 0.
The 'not so good' figures relating to Erenumab is the cost and effectiveness. It is marginally more effective than topiramate and botox. The cost at $750-$850 per month for something you will need for life it significant.
Just last week the Pharmaceutical Benefits Advisory Committee (PBAC) provided a statement in their review of Erenumab:
The evidence used for the basis of the clinical claim that erenumab was more effective than botulinum toxin had significant limitations, resulting in a clinical effectiveness and cost-effectiveness estimates that were highly unreliable for decision making. In addition, the PBAC considered that the cost to Government was underestimated by the submission, both because the number of patients with chronic migraine was underestimated by the submission and because of the significant risk of leakage outside the proposed limited PBS listing (for example, patients with episodic migraine)
It is highly likely that it will be approved but the PBAC will await preliminary data to see if a narrower target treatment group emerges.
Interestingly Norvatis, who manufacture Erenumab will provide 3 doses at no charge to see if it works for you. Dr Eller was of the belief that you would know in that time if it would be effective. After that initial period you would then revert to full price should you wish to continue.
Erenumab will only be available by Neurologist prescription (not GP), but the amazing thing here is that every Neurologist, not just the headache specialists but all of them, as a part of a familiarisation protocol, can sign up 10 clients to use the drug for free........forever!
Dr Eller didn't elaborate and seemed a little bashful when asked about it, but you may be able to access it free for life!
Follow me on a little story that describes the standard approach to headache and migraine and why it often doesn’t work in the long run.
You are sitting in the living room watching the news and the weather forecast comes on. Rain.
That little feeling in the pit of your stomach kicks in. Just relax you say. Maybe it won’t happen this time. Later in the evening the sound of rain against the roof takes the feelings up another level – you’re anxious now, trying to convince yourself things will be o.k. but deep down, knowing they won’t be.
At first tings seem o.k. and you start to think, ‘phew, not this time’……..then ‘tap, tap, tap’ the drip starts through the ceiling.
You know you only have minutes to act before this starts pouring in and floods your floor, knowing this could wipe out your house for days while carpet and furnishings dry out. Having gone through this enough times, you’re prepared now………you grab for you bucket and catch the leak. Saved!!
Until next time.
What if you’re not awake when it starts next time? Over time one bucket isn’t enough, and the storms seem to be coming with greater frequency and intensity. Where will this end? Are you going to be fighting off these leaks daily? There must be a better way.
Time to try another approach. You call a local builder, who is known to specialise in leaking ceilings. He investigates the leak inside the house and says there’s nothing wrong with the ceiling – how can that be? What about the roof or gutters you say? He takes a brief look and says ‘they look fine’.
He says while he doesn’t know what’s causing the leak he does have a solution to stop it. He needs to put a giant tarpaulin up over a large section of roof and anchor it into your walls. He says in some cases the anchors can cause a little bit of damage, but nothing compared to flood damage or a collapsing ceiling. Now you’re scared, and you’re fed up with the leaks so you go with it.
The tarpaulin is put up. The first thing you notice is it covers everything including skylights, turning a nice sundrenched lounge into a dark cave, but that’s a small price to pay.
That night he rain starts again. You still get a tiny leak but it’s really not much compared to normal. The tarpaulin seems to be working, but you can feel a draft coming in that seems new. Checking the wall, the anchor for the tarpaulin has created a major crack in the brickwork that has caused some plaster to fall off the wall and is letting the air in. You call the builder back to look at the wall. He asks you how the leak was. When you say ‘great but the wall now lets the cold air through’, he gives you a look like ‘well we can’t have everything’.
Do you remove the tarpaulin and fix the wall? Which is worse the leak on the draft? At least you had ways of dealing with the leak……….
Headache and migraine is constantly dealt with by giving you a bucket (abortive or acute/rescue medications such as the triptans) or a tarpaulin (preventive medications) which often have side effects worse than the problem they are trying to resolve.
Even the new CGRP inhibitors (CGRP-mAbs) are akin to putting a giant sponge in your roof cavity – hoping to mop up the water before it leaks through.
In the whole 4 days of the recent American Headache Society Annual Scientific meeting there wasn’t any emphasis on underlying causes. The biggest frustration I have is that the ‘cause of migraine is unknown’ myth is still perpetuated.
Whilst we can’t walk you through a complete A-Z of every aspect of attacks we have a vast amount of knowledge pointing to key structures that are implicated in the cause, but also (not surprisingly) treatment.
We know that across the board in primary headache, regardless of type, an overactive trigeminal nucleus (outside of symptoms – i.e. constant) is at its core.
We know that the major inputs into this area are the trigeminal nerve and the upper three cervical spine nerves.
We know that when we apply our technique to the upper cervical spine, the overactivty of the trigeminal nucleus normalizes.(13)
You wouldn’t dream of putting up with a leaky ceiling without getting a specialised roofing plumber to at least check the roof and gutters right?
So why would you do that with your migraines?
Hopefully you are ‘catching the drips’ effectively and maybe even ‘put on a tarp’ to cover everything, but the fact is you still have a problem – it’s just being masked. The neck remains the most logical place to investigate, as it has direct anatomical access to the trigeminal nucleus – the area known to be ‘headache central’.
One assessment can rule your neck in or out as a source of irritation for your headaches, and have you on your way to living without the leaking ceiling.
Call us today and speak to a consultant.
(1). Goadsby PJ, et al (2012). Pathophysiology of migraine. Annals of Indian Academy of Neurology. Aug: 15 (1) S15-S22.
(2). Goadsby PJ, et al (1990). Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–187
(3) Hansen et al (2010) Calcitonin gene-related peptide trigger migraine-like attacks in patients with migraine with aura. Cephalalgia, Oct: 30 (10): 1179-86
(4) Lassen et al (2002) CGRP may play a causative role in migraine. Cephalalgia, Feb: 22 (1): 54-61
(5) Nardone et al (2008) Trigemino-cervical reflex abnormalities in patients with migraine and cluster headacheHeadache, 48; pp 578-585.
(6) Nardone, R. and Tezzon, F. (2003) The trigemino-cervical reflex in tension-type headache. European Journal of Neurology, 10 (3), pp 307-312.
(7) Gantenbein, A.R. and Sandor, P.S. (2006) Physiological parameters as biomarkers of migraine. Headache, 48 (7); pp 1069-74.
(8) Varlibas, A. and Erdemoglu, A.K. (2009) Altered trigeminal system excitability in menstrual migraine patients. Journal of Headache and Pain, 10; pp 277-282.
(9) De Marinis, M. (2007) Blink reflex in cervicogenic headache. Blink reflex in cervicogenic headache. Cephalalgia, 27 (7); p 860.
(10) Sand, T. Moll-Nilsen, B. Zwart, J.A. (2006) Blink reflex R2 amplitudes in cervicogenic headache, chronic tension-type headache and migraine.Cephalalgia.26 (10); p.1186.
(11) Weiller C, May A Limmroth V, et al. (1995) Brainstem activation in spontaneous human migraine attacks. Nature Medicine. Jul;1(7):658–660.
(12) Afridi SK, Giffin NJ, et al. (2005) A positron emission tomographic study in spontaneous migraine. Archives of Neurology; 62(8): 1270–5.
(13) Watson, D.H, and Drummond, P.D. (2014) Cervical Referral of Head Pain in Migraineurs: Effect on the Nociceptive Blink Reflex. Headache: Journal of Head and Face Pain, June, 1035-1045
In part 1 of this blog we learned about the new class of drugs for migraine prophylaxis or prevention – the CGRP monoclonal antibodies (CGRP-mAbs or CGRP inhibitors).
In summary CGRP is produced by irritated nerves as part of our inflammatory/healing pathway. With the trigeminal system being irritated in migraineurs, they have more CGRP, but this is a result of, not a cause of their underlying problem. This was proven when non-migraineurs are injected with CGRP – they don’t get migraines.
We looked at the results of clinical trials that have led to the first of these drugs being approved in the USA. Of the people on CGRP-mAbs, 30% achieve 50% or greater reduction in migraine days. The effect above placebo indicates that we need to treat about 6 people with the drug to find one that responds. At $575 (USD) per month that may pose a problem for people seeking it privately, or for public health systems already struggling for funding.
In light of these results and cost, the hype and excitement around these drugs hardly seems justified, but in part II I will talk about why the neurological community are excited, what to expect when CGRP-mAbs arrive in Australia, and what CGRP tells us about the underlying causes of migraine.
CGRP inhibitors (mAbs) compared to topiramate and amitriptyline
In the midst of growing hype, it was the absence of astounding results, which prompted my attending the recent American Headache Society (AHS) scientific meeting in San Francisco. My goal was to find out what the buzz was about. The clue to the excitement over these drugs came to me from two sources.
The first was a biochemist working for Amgen (co-producer of Erenumab, the first approved CGRP-mAb sold in US as Aimovig). I asked her why there was so much excitement about Aimovig given the modest clinical trial results.
Her response, with a grin was “it’s their baby”.
Neurologists and doctors have had to rely on anti-depressants, beta-blockers, anti-seizure medications and anti-histamines, all originally made for purposes other than migraine, and all stumbled upon when people with other illnesses reported their migraines improved on said medications. The preliminary research on CGRP, through to the development of the drugs, subsequent clinical trials and FDA approval, has been primarily driven by the neurological community in aid of migraine. Justifiably, there’s a degree of pride about this class of drugs.
The second, and most significant reason for excitement is the favorable side-effect profile. At the recent AHS scientific meeting a comment from the floor following a presentation on topiramate (brand name topamax) spoke to the frustration felt at the current group of medications: ‘we know that a majority of our patients either can’t tolerate it enough to get a therapeutic dose, or if they do get there it either doesn’t help, or they can’t stay there long’.
The list of adverse reactions for the current list of preventive medications (including topiramate, amitriptyline, propranolol) includes paraesthesia (pins and needles), weight gain, weight loss, hair loss, nausea, dizziness, slowed thinking, sedation, renal calculi, acute angle closure glaucoma, headache, dry mouth, diarrhoea, constipation, loss of appetite, insomnia, weakness, lethargy. (1-3)
This can present patients with a predicament. Will the side effects of treatment be worse than the condition? A problem so eloquently recalled by Emma Larson in the movie ‘Out of my head’ (4)
Quoting her Neurologist:
‘I can give you one drug which will make you fat and your hair will fall out, or another that will make you thin and stupid’
Emma quipped sarcastically ‘I’ll take thin and stupid (I’ll be the perfect woman).’
CGRP inhibitors (mAbs) side effects
The excitement about the CGRP-mAbs is that based on the phase 3 clinical trial data, patients are far more likely to tolerate them to get a therapeutic dose, and likely to be able to stay there if they are effective. In a review of 5 clinical trials for CGRP-mAbs the only adverse event that showed a slightly higher incidence than placebo was dizziness.(5)
A word of caution needs to be read into this with regards to the stage of the drugs testing cycle. Clinical trials are conducted on very carefully targeted groups who don’t have any other co-morbidities (health conditions). This is common practice to minimise the variability amongst the treatment groups by not having other conditions or medications that can affect or interact with the test drug to get ‘cleaner’ results.
The problem is that the interactions with other conditions are unknown.
Aimovig now goes into phase 4 studies, which is closely monitored and reported ‘population’ based studies. In other words it starts getting prescribed and doctors monitor for any adverse events or interactions with other health conditions or medications, and to see the long-term effects of use.
There are some concerns about the effect of inhibiting CGRP. As a part of our inflammatory response it plays an important role in helping us avoid damage in cardiovascular events such as stroke and myocardial infarction (heart attack). As David Dodick (Leading CGRP researcher, Director of the Headache Program, Mayo Clinic) observes on the actions of CGRP:
“One of the things it does is dilate blood vessels, and that may be particularly important when a blood vessel is blocked, as occurs in patients who are having a stroke, you could be potentially blocking the body’s ability to dilate a blood vessel when it’s needed.” (6)
The consequences in that case could be fatal, or lead to more severe impairment following stroke or heart attack.
A number of medications have failed the population-based test, and it can take decades for the problems to be apparent. A recent example is Vioxx, a medication that promised superior anti-inflammatory results without gastric upset. The results were equivocal to the old medications (NSAID’s) and serious cardiac problems occurred in 15 of every 1000 people on the drug. Both the drug company ‘Merck’ and American regulatory body FDA drew criticism for not acting more promptly. (7)
David Rind (MD, MSc, ICER's chief medical officer) offers a nice summary:
"CGRP inhibitors appear to offer modest improvements in outcomes for patients with chronic migraine and frequent episodic migraine. However, there are concerns remaining regarding unanticipated harms of the medication. So far, the medication has only been tested in short trials assessing outcomes by 12 or 24 weeks. There are some concerns about the long-term effects of continuous blocking of the CGRP or its receptor, but as these are the first inventions in the class, long-term effects remain unknown. In addition, since migraine is fairly common, there may be concerns about affordability and access.”(8)
Should you be excited about CGRP-mAbs?
The short answer is yes, but temper your excitement. There will be a small ‘super-responder’ group in whom these are the ‘miracle’ they have been hoping for. Another group in whom these help decrease the frequency of migraines, and, sadly, a bigger group in whom they are ineffective. They are also likely to be more widely tolerated than the drugs they will be replacing, so the people in whom they are helping the most likely problem will be affordability rather than side-effects.
CGRP inhibitors (mAbs) in Australia
What can you expect when the drugs are approved by the Australian Therapeutic Goods Administration? Botox is probably the most recent and best comparison given the similarity in cost profile. It is most likely that initially CGRP-mAbs will be available privately through a neurologists prescription. Erenumab (the first CGRP-mAb approved in the USA) is a self-injected medication that is required to be injected monthly. In the USA the cost is approximately $575 (USD) per monthly injection. This is more than botox was before it was placed on the Pharmaceutical Benefits Scheme (PBS) at which time medicare covered the majority of the cost. This took several years after release as the drug goes through ‘phase IV’ testing. If CGRP-mAbs go onto the PBS, given the cost to taxpayers, it will most likely have the same restrictions as Botox, in that people will need to have trialed cheaper medications first, like topiramate and amitriptyline, for at least 3 months and failed before being approved to use the new medication.
The cause of migraine – what CGRP research tells us.
I think the thing that excites me the most about the research in this area, is also, sadly, the one area that received absolutely no coverage at the AHS scientific meeting. It speaks to the underlying cause of migraine.
Constantly elevated CGRP is yet another indication of chronic irritation of the trigeminal system. Previously we have seen studies on hyper-excited nociceptive blink and trigemino-cervical reflexes(9-14)and elevated PET scan signals in all forms of primary headache. SO we have another biomarker, but this one is different – we know what creates CGRP.
The next question should be ‘why is the trigeminal system in a state of constant irritation?’
CGRP is a product of the problem, not the cause, as we have seen in the studies injecting CGRP into non-migraine sufferers.
The simple fact remains that the nerves from the top three levels of the neck are the biggest input into the trigeminal nucleus, and remain the single most common source of irritation, and therefore, a likely source of increase CGRP levels.
We have already seen that techniques directed at the neck developed specifically to treat headache and migraine, ‘normalise’ elevated reflex responses. (17)
The logic is simple. Small faults at the top of the neck cause irritation of the trigeminal nerves in the brainstem. This irritation shows itself in constantly elevated reflex and CGRP responses. In susceptible people (i.e. headache sufferers) this irritation isn’t dampened but instead is allowed to build to the point of ‘exploding’ periodically, or constantly in some cases.
Drug therapy is focused on symptom suppression. A fire truck to put the fire out.
Treating the neck is targeting an underlying source of trigeminal irritation. This is fire prevention.
So yes, be excited about a medication that won’t cause toxicity, tingling in your hands or make you feel like a zombie, but please continue to pursue the underlying problems contributing to the sensitivity so you don’t become a customer of big Pharma for life.
(1) Marmura, MJ (2014) Safety of topiramate for treating migraines.Expert Opinion Drug Safety, Sept 13 (9) 1241-7.
(2) Jasmer (2018) Endep side effects. Drugs.com
(3) Robbins, L and Phenicie, B (2018) Migraine Treatment A-Z. Practical Pain Management.com
(4) Ochs, J and Styron, S (2017) Out of my head. Eleventh Hour Film Production.
(5) Min Hou et al (2017) The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis.Journal of Headache and Pain
(6)Novak Jones, Diana New drugs in development may offer serious relief from migraines. Chicago Suntimes, August 22, 2017
(7) Berenson et at (2004) Despite warnings drug giant took long path to vioxx recallNew York Times, November 14, 2014.
(8) Joszt, L (2018) Erenumab for migraine is cost-effective but long-term harms remain unclear. American Journalof Managed Care. June, 2018
(9) Nardone et al (2008) Trigemino-cervical reflex abnormalities in patients with migraine and cluster headacheHeadache, 48; pp 578-585.
(10) Nardone, R. and Tezzon, F. (2003) The trigemino-cervical reflex in tension-type headache. European Journal of Neurology, 10 (3), pp 307-312.
(11) Gantenbein, A.R. and Sandor, P.S. (2006) Physiological parameters as biomarkers of migraine. Headache, 48 (7); pp 1069-74.
(12) Varlibas, A. and Erdemoglu, A.K. (2009) Altered trigeminal system excitability in menstrual migraine patients. Journal of Headache and Pain, 10; pp 277-282.
(13) De Marinis, M.(2007) Blink reflex in cervicogenic headache. Blink reflex in cervicogenic headache. Cephalalgia, 27 (7); p 860.
(14) Sand, T. Moll-Nilsen, B. Zwart, J.A. (2006) Blink reflex R2 amplitudes in cervicogenic headache, chronic tension-type headache and migraine.Cephalalgia.26 (10); p.1186.
(15) Weiller C, May A Limmroth V, et al. (1995) Brainstem activation in spontaneous human migraine attacks. Nature Medicine. Jul;1(7):658–660.
(16) Afridi SK, Giffin NJ, et al. (2005) A positron emission tomographic study in spontaneous migraine. Archives of Neurology; 62(8): 1270–5.
(17) Watson, D.H, and Drummond, P.D. (2014) Cervical Referral of Head Pain in Migraineurs: Effect on the Nociceptive Blink Reflex. Headache: Journal of Head and Face Pain, June, 1035-1045
A new class of migraine preventive medication is on the way, and whilst you should be excited about its possibilities, it is accompanied by a lot of hype, some positive results, some misleading claims, and a hefty price-tag. Now more than ever you need to understand the facts about these drugs so you can inform yourself about their appropriateness for you.
Anyone keeping an eye on ‘migraine news’ over the last 12 months will have found it hard to miss reports of a new class of ‘wonder drugs’ for migraine prevention. The CGRP monoclonal antibodies.
A client of mine last year sent me a news video quipping ‘this will put you out of business’. Honestly, I would love nothing more that to wake up one day and find that someone has ‘cured’ headaches and migraines forever.
Some experts in the field such as lead researcher in CGRP inhibitors, David Dodick, are describing this new class of drugs as ‘the most exciting thing we've seen' in over 20 years of his practice (1).
On the other hand specialists such as Robert Cowan at a meeting of the Headache Cooperative of New England in 2017 in Boston asked:
“Why is it that a new class of drugs that appears to be marginally (if that) more efficacious than currently available medications has caused such a stir?” (2)
With seemingly conflicting opinions from experts in the neurological community, my primary goal in attending the American Headache Societies Annual scientific meeting in San Francisco in June was to find out, directly from those involved, the facts about these drugs and why they are so excited about seemingly ‘okay’ results. I’m glad to say I now understand.
I will explain what CGRP is, what the research says, why there is excitement around the antibodies and what can we realistically expect when they arrive in Australia.
What is CGRP?
CGRP or Calcitonin Gene-Related Peptide is a protein produced by certain nerve cells in the body. Performing different functions in different areas it forms part of the inflammation/healing pathway. In the spinal cord it plays a role in regeneration of nervous tissue after injury, and it is also vasoactive, dilating blood vessels that maintain blood flow to the heart and brain and plays a role in fracture healing. In the stomach it appears to play a role in regulation of gastric secretion and gastrointestinal hormone release.
After stroke it can help to limit swelling (oedema) in the brain, to such an extent that it is an area of interest (administering it, not destroying it) as an acute treatment for stroke victims (3).
Specifically for migraine the cell bodies on the trigeminal ganglion are the main source of CGRP. It acts as a pro-inflammatory mediator (along with dopamine and 5-HT), released when the trigeminal nerve is over stimulated or irritated, to excite nociceptive (pain) pathways.
It has been widely understood for decades now (4) that overactivity of the trigemino-cervical nucleus is common to all major headache types, and in 1990 researchers taking blood from migraineurs found elevated levels of CGRP (5). In line with the reflex and imaging studies, interictal (in between episodes) CGRP levels are found to be elevated.
This started researchers investigating into where CGRP was released and whether changing it would help. What they found was they were already targeting it, they just didn’t know it. The Triptans help the body absorb serotonin, which binds to excitatory trigeminal ganglion neurons and blocks their action – decreasing excitability, by blocking release of CGRP.
The hypothesis was then:
“If CGRP is present all the time, maybe elevated levels are the cause of, rather than product of, migraine”. You can imagine the excitement!
Unfortunately trials injecting CGRP into the bloodstream of non-migraine sufferers compared to sufferers did not yield the results that indicate it as a causative agent. CGRP induced migraine attacks in migraine sufferers, but does not cause migraines in non sufferers (6). Despite this result the rather misleading conclusion was drawn that CGRP may be causative in migraine (7). If it was, it would also cause migraine in non-sufferers.
Again……..CGRP does not cause migraines infused into the bloodstream of non-sufferers. You need to be a migraine sufferer already for elevated CGRP to trigger an attack.
What are CGRP monoclonal antibodies?
What has been developed is a monoclonal antibody – that is an antibody that is very specific to CGRP, and doesn’t have an immune response – but circulates in the blood stream waiting for CGRP to be released and binds to it for removal from the body.
So the trigeminal system is still overexcited, releasing CGRP, but these antibodies wait for it and bind to, and eliminate it.
It is truly amazing, and if elevated CGRP was the only issue then it would be as good as a cure.
So what are the results?
Erenumab (brand name – Aimovig), was the first of the new class of medications approved by the American FDA in May 2018.
Across a number of trials (8)-(10), with the primary outcome measure being a 50% reduction in number of migraine days per month, erenumab achieves between 30 and 40%. That is that 30-40% of people on the active medication achieved a 50% or greater reduction in migraine days per month. When you compare it to placebo we see between 15% and 30% achieving the same reduction.
What this means is that the risk reduction or ‘real’ effect over placebo is somewhere between 15-20%.
This is a good rather than great result, and has implications when we factor in cost to the healthcare system as Forbes magazine columnist Joshua Cohen points out (11).
“every 6th patient taking erenumab will benefit from this medication. A number needed to treat of 6 is not a great result. In fact, it is worse than the current standard of care – triptans. For high-dose triptans the numbers needed to treat are between 2.6 and 5.1. Adopting a conventional trial-and-error method to prescribing means that doctors would need to prescribe to 6 patients before one would get benefit from erenumab. Unfortunately, there is currently no way of knowing which patient will be the lucky one.”
The current list price in the US for Aimovig is $575 per month or $6900 per year (USD). For the one person in 6 who gets the result this may be seen to be a cost effective solution, however for the other 5 sufferers it clearly is not.
By comparison trials have shown similar 50% responder rates with far cheaper and widely available supplements:
Trimagnesium dicitrate 600mg - 52% vs placebo 34% (12)
Riboflavin - 56% (13).
There is variability amongst these trials with the trial quality and profile of subjects, so there does need to be a degree of caution with comparing a single number across trials.
Having said that all these trials were presented recently in San Francisco and the results are not insignificant, and given the significant cost involved with the new class of drugs, it’s a reasonable question to ask – are the mildly better results and potential serious side effects are worth it?
In part 2 – Side effects, after-release concerns and what to expect when these drugs arrive in Australia.
(1) Dodick, David quoted in Sciencemag.
(2) Cowan, Robert (2018) What might the migraine Landscape Look Like Post-CGRP? Practical Neurology.
(3) Liu, Z et al (2011) Calcitonin gene-related peptide prevents blood-brain barrier injury and brain edema induced by focal cerebral ischemia reperfusion. Regul Pept, Nov: 10; 171 (1-3)
(4) Goadsby PJ, et al (2012). Pathophysiology of migraine. Annals of Indian Academy of Neurology. Aug: 15 (1) S15-S22.
(5) Goadsby PJ, et al (1990). Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–187
(6) Hansen et al (2010) Calcitonin gene-related peptide trigger migraine-like attacks in patients with migraine with aura. Cephalalgia, Oct: 30 (10): 1179-86
(7) Lassen et al (2002) CGRP may play a causative role in migraine. Cephalalgia, Feb: 22 (1): 54-61
(8) Goadsby et al (2017) A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med 2017; 377:2123-2132
(9)Dodick et al (2018) ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia May; 38 (6): 1026-1037
(10) Reuter et al (2018) Efficacy and Safety of Erenumab in Episodic Migraine Patients with 2-4 Prior Preventive Treatment Failures: Results From the Phase 3b LIBERTY Study. Presented at American Headache Society 60thAnnual Scientific Meeting, San Franciso, June, 2018.
(11) Cohen, Joshua (2018) Migraine Breakthrough: Not So Fast. Forbes Magazine June 2018, https://www.forbes.com/sites/joshuacohen/2018/06/06/migraine-breakthrough-not-so-fast/#6487b94a8971
(12) Peikert et al (1996) Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia, June; 16(4): 257-63.
(13) Thompson and Saluja (2017) Prophylaxis of migraine headaches with riboflavin: A Systematic review. Jou Clinical Pharmacy and Therapeutics. 42: 394-403.
Roger O'Toole is the Director and Senior Clinician of the Melbourne Headache Clinic and has over 10 years experience as a physiotherapist.