​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……….

References:
 
(1). Goadsby PJ, et al (2012). Pathophysiology of migraine. Annals of Indian Academy of Neurology. Aug: 15 (1) S15-S22. 
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(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.

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).’

​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.

​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.

​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.

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.
 
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