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.
The kids are back at school (…..finally…… ) and families everywhere are getting back into their ‘routines’.
As a young child we crave routine because so much of what is happening around is new, and ‘unknown’ and we find safety and comfort in things that are familiar. As we go through life we become exposed to the same situations over and over. Our brains quickly get used to our daily habits and are constantly seeking for patterns to the extent that our brain will begin to anticipate certain events – for example, starting every morning with a coffee, or taking a pain relieving medication at the same time every day. Your brain will anticipate the arrival of the caffeine or medication and start to make changes so that the arrival of the substance (i.e. caffeine) doesn’t come as a ‘shock’ and the system is already preparing for it. Some might refer to the feeling this gernates as a craving, and indeed the response if we don’t provide the subtsance that is expected can cause some ill feeling – a withdrawal response. The result of a disordered and ‘unepxected’ day is a stress response or ‘reacting’ and using our ‘fight, flight or flop’ response.
Migraine is a routine illness, in that, there are routines we have that create or upset the status quo. The migraine brain craves routine.
Here are two key daily routines that can impact on migraines:
Driven by our circadian rhythm our brain goes through daily sleep/wakes cycles. Someone setting their alarm for the same time everyday will often find that after a while their brain starts to rouse and wake in the minutes before the alarm goes off. The internal clock is anticipating the alarm, and rather than be ’startled’ out of sleep it begins a gentler process of progressing from deep sleep to a state of wakefulness.
Right through the migraine cycle the interaction with the sleep/wake centres is obvious to see.
Not only do we see yawning, fatigue and unusual dreams/sleep behavior as a prodrome, but in the midst of an episode many sufferers will find comfort in getting to sleep, often waking improved and reporting that the reason for taking some medication is the drowsiness and sleep they induce.
We also frequently hear that changes in sleep patterns (too much or not enough) can be a trigger, with ‘brain fog’, lethargy and inability to process information being some of the most universally shared symptoms after pain, nausea/vomiting and sensitivity to light or sound.
A small investment in good sleep health may have a positive impact on the frequency, duration and/or severity of your migraines.
For the next month try going to sleep at the same time every night, waking the same time each morning (I’m sorry, yes, even on weekends) and provide your brain with some predictability. It’s just one piece of the puzzle, but in some it may be an essential piece.
The second area we can adopt a healthy routine is good neck health.
The science is patently clear now, that the area housing the trigeminal and upper cervical nerves is the ‘powder keg’ in all primary headache types including migraine. Sitting there on a daily basis, bubbling away waiting for a ‘spark’ (aka trigger) to blow it up.
It is not hard to believe that the neck is a driving source of this problem. Not only does the research show that treating the neck decreases trigeminal nucleus activity, but the stresses we put on our neck are almost universal.
Take a look around you at work, school, or the next time you are on a bus and count how many people are looking down or sitting slouched with their head forward of their body.
Now bend your index finger right back on itself and hold it their for 20 seconds.
The postures you are seeing are doing exactly the same thing to the top of your neck as what you have just done to your index finger, but because it builds up slowly and is relatively constant most of us we don’t notice it as much.
Imagine now how often we sit with our head forward or look down. In fact even when we go to sleep on our side we tend to curl forwards, and on our back tend to use a pillow pushing the head forward.
Our poor neck doesn’t get much respite other than when we are standing and looking straight ahead. Not a big percentage of anyone’s day.
The fact is we look down a lot because that’s where our ands are and that’s where we interact mostly commonly with our world.
Take another look around in your home or office and you will see that all the things we use most often we place between hip and shoulder height – hand height. So we have to look down.
What then can we do?
There are times when we look down and don’t need to. From the position of your car seat, to the location of the television in relation to your couch, working on a laptop instead of a desktop – there a numerous areas we can easily change with little or no expense in many cases.
A phone can be held at eye level by folding one arm across your stomach to support the elbow of the hand holding the phone.
Heavier tablets can’t be held for as long. If your routine is to read/watch tv from a tablet for long periods of time consider buying a tablet holder on a stand (often sold for musicians as a music stand). This can be adjusted to any height, easily packed away, and saves your neck an hour or so of being squeezed forwards.
Lastly, have an expert examine your neck.
The long-term changes that occur in the neck due to looking down or the head sitting forward cause reactive spams in the top of the neck. Whilst stretching and massaging these can provide short term relief, correction of the fault that is triggering the spasm is paramount to a more sustained result.
Part of the genius of the Watson Headache Approach ® was not only to prove how much this problem irritates the brainstem, but to find a method of treating it that is long lasting and sustainable.
A combination of treating the problem combined with often small changes in posture can have a profound impact on the neck, and as a result a significant decrease in the irritation of the brainstem, directly impacting on the area known to be the problem in migraines.
Start your journey to better sleep and neck health today and make your migraine a ‘routine’ condition.
Migraine and Opioid based medication
In February 2018 medications containing codeine will no longer be available over the counter (OTC) but will require a doctors prescription. The looming move of codeine based products to prescription only in Australia may have many headache sufferers concerned about their ability to cope, however many may be unaware that the drug that they are taking to relieve pain may be making their condition worse.
The Australian Therapeutic Goods Administration said misuse of over-the-counter codeine products contributes to severe health outcomes, including "liver damage, stomach ulceration, respiratory depression and death". An Australian study using coronial data showed there had been over 1,400 deaths in a little over a decade related to codeine use.
Many headache sufferers will still be able to access codeine based products with a doctors prescription, but the question is should they?
Repeated use of opioids such as codeine don’t prevent symptoms, and in their attempt to temporarily mask pain, cause disease progression and bad clinical outcomes, in particular the transformation to daily headache. The physiologic changes occur rapidly and can be permanent, and include decreased grey matter, release of CGRP (implicated in migraine pathogenesis), dynorphin and pro-inflammatory peptides, and activation of excitatory glutamate receptors. Opioids are pro-nociceptive, prevent reversal of migraine central sensitisation and interfere with triptan effectiveness. 
One study  showed that people who suffered episodic or occasional migraine and took narcotics or barbiturates more frequently were more likely to develop transformed migraine. That means they have increased their migraine days per month to more than 15, ‘transforming’ from episodic to chronic.
Its not just headache and migraine sufferers that need to be concerned.
Opioids have been shown to be problematic in inducing headache in many chronic pain conditions such as back pain and oncologic pain. Use of opioids in non-headache chronic pain was associated with a 20% likelihood of developing headache (including migraine) in the next 11 years, compared to only 3.1% in those not using opioid-based analgesics. [3,4]
We are sympathetic to those who have tried many different forms of pain relief and find codeine-based products to be the only thing to help. However we strongly support the move to prescription based access and hope that the broader chronic pain community is successful finding alternative avenues, both pharmaceutical and non-pharmaceutical to help reduce pain and improve outcomes for sufferers.
We are also conscious that this is only one part of a much bigger picture, both within migraine health and outside.
Inside the 'migraine bubble' factors relating to diet, sleep, and daily activities are always part of the picture, and recent research is indicating the issues run a lot deeper than many people will understand. Through this year we will be looking more deeply into the research outside of our own neck based treatment to try and broaden the understanding of factors influencing migraine in the hope of getting the best possible result for those in our care.
 Tepper, SJ 2012 Opioids Should not be used in Migraine Headache, 54 (S1) pp 30-34
 Bigal, M.E. and Lipton, R. A. (2008) Excessive acute migraine medication use and migraine progression. Neurology, 71 (22); 1821-8.
 Johnson, J. L., et al. “Medication-overuse headache and opioid-induced hyperalgesia: a review of mechanisms, a neuroimmune hypothesis and a novel approach to treat- ment.” Cephalalgia 33 (2012): 52–64
 Zwart, J.-A., et al. “Analgesic use: a predictor of chronic pain and medication overuse headache: The Head–HUNT Study.” Neurology 61(2) (2003): 160–164.
We recently had National Headache and Migraine Awareness week in Australia.
Unlike other years there seemed to be more happening around it, and congratulations must go to Headache Australia for putting on a number of events, which were accessible online.
Two talks in particular gave me pause, the first from Dr David Williams of Monash Medical Centre, and the second from Dr Gerald Edmunds from Headache Australia.
The first talk from Dr David Williams I wrote about during the week, and expressed my frustration at people being labelled as ‘wired for life’ for migraines and that the best we can do is to try and increase the time between events, and try our best to minimise the severity when it does happen - primarily by using medications, botox or electrical stimulation.
All sound advice, however botox is only used once the condition has already become chronic, and medications and electrical stimulation are not preventive measures.
A broader view must be taken to recognise the extent to which we can minimise the number of events and decrease the frequency. There was certainly a sense of resignation to ‘learn to live with and minimise’ them.
At the end of the 'Awareness week' Gerald Edmunds, Secretary General for Headache Australia was interviewed on 3AW’s health show “House of Wellness”.
Gerald referred to one of the differences between a ‘headache’ and a ‘migraine’ is that migraine has a genetic basis.
"other than genes what causes migraines and whether environmental factors could be significant?
Gerald responded that that was more likely to be ‘headache’ as once you’ve got the migraine gene, you will be subject to them regardless. You just have to accept that they are going to happen and deal with them when they do.
Gerald Quigley, a pharmacist who co-hosts the show then commented that he is puzzled as to why amongst patients, particularly female, there seemed to be a ‘resignation’ that migraines are ‘just part of my lot in life’
I think it is hardly surprising that people (not only women) that they are ‘resigned to this being their lot in life’ when the key message being purveyed by ‘experts’ in awareness week is - "Learn to live with it, its genetic".
The disappointing aspect for me was not that the message of managing your triggers, relaxation and good healthy habits was being pushed. I couldn’t agree more with these sentiments.
My concern is that an opportunity has been missed to educate, and to de-mystify headache in all its forms, and that many sufferers will hear the 'its genetic so learn to live with it' line as a reason to not pursue treatments, and misrepresents what 'genetics' means and what we can do about it.
David Williams started to talk to the ‘migraine circuit’ but instead of going on to explain what this circuit is, and what types of things switch it on, he moved on to accepting that it’s a ‘bad circuit’ and lets try not to upset it.
At the end of the session Sally Obermeder suggests that maybe our modern lifestyle of looking down at our phones a lot is playing a role here. Unfortunately there was no support for the comment other than Gerald Quigley talking briefly to the effect of blue light. With the three nerves from the top of the neck feeding directly into the 'migraine circuit' in the brainstem our posture can be critical.
While I will talk quite heavily to the role of the neck in 'irritating' the migraine circuit, and the research that sows its fundamental to a well rounded approach, I will also touch on other topics over the coming weeks and months:
- such as the role of diet (not only as a trigger avoidance measure, but what foods may assist the body to minimise attacks)
- Importance of good sleep patterns
- Medication overuse headache: what is it and what drugs might pose the greatest risk
- Genetics and migraine: what does it mean?
Whilst I am not a specialist in any of these areas I think it is important to broaden the discussion across all areas, and bring you the opinions of those who are experts in the area for your own information, in the hope it may prompt you to discuss this first hand with someone who within their chosen profession (i.e. nutritionist) also has a good handle on the role their field plays in headache and migraine.
I was watching a talk by Dr David Williams from Melbourne as part of Headache and Migraine awareness week, and for the most part I was really pleased with what I heard.
He spoke about the sensitivity of the trigeminal nerves as being the underlying issue.
He spoke about not being too caught up in the classification system and that all the different types of headache are effectively slightly different variations of the same underlying process.
And that this process effectively starts in the headache centre, down in the lower part of the brain, known as the brainstem (which is where the nerves from the neck mix with the nerves from the head and face).
TICK! TICK! TICK!
At this point he went on to describe how a migraine evolves after that point and the role of medications at different stages of the migraine cycle. He is working on the assumption that you are 'wired for migraine' and that rather than change this, you need to accept it, and we need to lessen the likelihood of triggering migraines by:
a) Avoiding triggers
b) doing things both with drugs and lifestyle to 'calm down the nerve system
Whilst there is nothing wrong with this advice, I would like to discuss two assumptions that underpin some of his talk.
The first I will do in a separate blog because it is a big issue - the comments he made regarding the increased sensitivity in the face, scalp, head and neck as all being part of the migraine - which it 'can' be, without any recognition that input from these areas can in fact cause the sensitivity. More on this later.
The second one is that people are 'wired for migraine for life'.
At this comment I got frustrated. Why? Simply because this is where we blame the patient rather than the treatments.
"If I can't do more than temporarily block your migraine or decrease the frequency by 50% then its not my treatment that's at fault........you just can't be fixed and it's your 'faulty wiring' that is to blame."
I have people arrive at my clinic equally frustrated by the 'just learn to live with it' or 'you can't be fixed' comment.
Instead I would prefer this:
"The treatment I have to offer you has been effective, but only in part. We can see that there has been improvement, but to try and find the other pieces of the puzzle you really need to look beyond medications and a strictly neurological approach. You need to seek experts in other fields who focus heavily on migraine (or headaches) and see if they can help you unlock some other pieces of the puzzle.
So right now you are thinking "what's this got to do with firemen??" right?
Well, expecting a neurologist to have a deep understanding of psychology, upper cervical spine pathology and its impact on the brainstem or relaxation techniques is a lot like expecting a fireman to have an in-depth knowledge of town planning, building codes, fire retardant building materials, power pole maintenance etc. Whilst they may understand it at a basic level, our firemen are there to put out fires once they start and most of their resources are built around fire suppression. They don't have a huge role in developing and using many of the preventive measures we now take for granted.
In a similar way neurologists are about headache and migraine suppression - they try to help put the fire out - working on the assumption that 'you will always get them because of your wiring', and I don't blame them for having that as their focus.
What we need to understand is there really is a lot more we can do to 'calm down' the headache centre before episodes begin and the research is currently pointing directly at the top of the neck and particularly at the Watson Headache® Approach at being able to do this.
To his credit Dr David Williams did mention:
"It's important to consider the role of these other allied ‘specialists’ and some are going to have more important roles than others – consider the role of acupuncture and massage, the role of a psychologist, the role of a physiotherapist and even a personal trainer."
There is a lot in this one little sentence, and not enough is known and broadly understood about how impactful this aspect of the approach to treating headache and migraine can be.
Again, I don't blame the Neurologists and in fact I applaud Dr Williams for recognising, at least in some form that there is a broader aspect to management.
We focus entirely on the role of the neck in headache (all forms), but we also don't have the entire solution - we don't have an in-depth knowledge of medications, diet, or exercise physiology. It's time to work as a team and check all the boxes - prevention hand in hand with acute management or symptom suppression.
Roger O'Toole is the Director and Senior Clinician of the Melbourne Headache Clinic and has over 10 years experience as a physiotherapist.