Melissa, a 32-year-old accountant who lives and works in Charlotte, North Carolina, writes:

Dear Doctor,

I’ve been having migraine headaches since junior high school, but almost immediately after I delivered my second child my headaches increased dramatically. Over the next 6 months they just kept coming, and eventually I was having headaches practically every day. At least once a week I have a headache that is so severe and makes me so sensitive to light that I can’t leave my totally dark bedroom.

My doctor told me that I have chronic migraine, and he referred me to a neurologist  to start getting Botox injections. That was OK with me, as my best friend and her sister both had a headaches like mine and are now almost headache-free since they started Botox.

But now, after 9 months and 4 sets of Botox injections, my headaches are if anything, worse.  And none of the medicines for acute migraine headache that seem to work for everyone else – sumatriptan, Nurtec, Ubrelvy – don’t help at all. I take handfuls of Excedrin just to do something, but that doesn’t really help either.

What is wrong with me? Is my diagnosis wrong? 

Feeling like a loser in Charlotte

PS 

I just had a MRI scan of my brain. To my surprise, it’s completely normal. A relief…
I guess.

The Doctor’s Reply:

Dear Melissa,

That your chronic migraine has failed to respond to the therapies you have tried so far hardly means you are a “loser”. Of those who have chronic migraine, a healthy percentage will experience a significant reduction in migraine burden thanks to Botox…but many will not. The same goes for all therapies currently indicated for migraine prevention or acute migraine treatment. 

Why is this? There are a myriad of reasons why patients experience a variable response to the evidence-based medications available for acute migraine treatment, but in responding to your letter we’ll stick to chronic migraine prevention medications only.

In the case of the oral medications for migraine prevention – and especially the older medications – treatment failure at times may be a consequence of inadequate dose or an inadequate duration of therapy. While certain of the newer oral medications – most notably, atogepant (Qulipta) – may begin to exert a positive therapeutic effect as early as one week after treatment is started, with the older oral medications it may take 4 to 6 weeks or longer to know whether or not the medication is going to be effective.

Aside from this, many patients may find the older oral medications difficult to tolerate because of side effects. 

There are 6 therapies that possess a strong evidence base for use in suppressing chronic migraine: topiramate (Topamax), onabotulinumtoxin A (BotoxA), Qulipta, erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), and epitenzumab (Vyepti). Topiramate can be a difficult medication to take consequent to its side effect profile, and typically healthcare providers start the drug at a low dose and then sequentially increase the dose at intervals to reach the recommended regimen of 50 milligrams taken twice-daily. As the likelihood of side effects increases in parallel to dose, that dosing regimen can be difficult to achieve. And, as with the older oral medications that possess less of an evidence base for treating chronic migraine, it also may take some time for topiramate to exert a positive therapeutic effect even at the recommended dose.

Dosing issues are not really a problem with the others. There is only one approved dose of Botox A for suppression of chronic migraine: 155 international units. Of the 4 injectable medications, 2 (Aimovig and Vyepti) are available in 2 dosages; the other 2 (Emgality and Ajovy) have only a single recommended dose. Qulipta is available in 3 doses (10, 30 or 60 milligrams taken once-daily, but no topiramate-like dose escalation regimen is required. While patient compliance is always an issue with prevention therapy for migraine, that issue is minimized when the patient is coming in for Botox injections every 12 weeks, self-injecting an anti-CGRP monoclonal antibody once monthly or receiving intravenous infusions of Vyepti every three months.

Even so, there are patients who do not respond positively to any of these therapies, and while some portion of that group may respond to a combination of these medications (prophylactic polytherapy), there still remain many who simply do not improve.

We have come a long way in our understanding of migraine’s biology…all the way from a simple vascular theory that focused almost exclusively on blood vessels of the head expanding and contracting to a complex circuit that runs from the cortex of the brain through the brain’s subcortical regions, the brainstem, the spinal cord, and, finally, a cranial nerve that terminates on blood vessels located within the lining of the brain. Like all nervous system circuits, that complex circuit runs on electrochemical transmission, and two of the big chemicals involved in the transmission of head pain signal are serotonin and calcitonin gene related peptide (CGRP). Our evolving understanding of serotonin’s role in the migraine circuitry led to the development of the triptans, and for the past decade attention has turned to blocking or disabling CGRP.

So why do these highly targeted “designer drugs” not work for every migraineur? For one very important thing, a wide variety of genetic permutations may yield the common endpoint of chronic migraine, and it seems quite likely that those genetic permutations also yield subtle and not so subtle differences in the make-up of the individual migraineur’s circuitry. While your friend and her sister obviously have circuitry that is Botox responsive, your genes and your migraine circuitry may be quite different from theirs…even though you experience the very same clinical symptoms as they do. You simply may not be a “Botox person”.

While your problem may be solved by switching to another type of migraine prevention therapy with a different mechanism of action, it is also quite possible that those who spend their careers investigating the circuitry of migraine not yet identified the biologic variation that is responsible for your chronic migraine.  For example, those investigators have identified another chemical (a protein/neuropeptide), with the tongue-twisting name of pituitary adenylate cyclase-activatin the light cyclase – activating polypeptide (PACAP) which is distinct from serotonin or CGRP and may prove to be an excellent target for patients who have failed to respond to our existing therapies.

I will close by sharing one of the of the great paradoxes of migraine. In assessing the chronic medical disorders that adversely affect quality of life - disorders, such as malaria, AIDS, sickle cell, anemia - the World Health Organization ranks migraine number one for females. And yet despite the high prevalence of this disorder, and its tremendously negative impact on the public health, there are relatively few medical providers who possess the experience, expertise and inclination to effectively manage patients with migraine…and especially chronic migraine.

That said, it appears to be time for you to seek out a healthcare provider who has particular expertise in managing “difficult to treat” chronic migraine. One way to do so: go to: Find A Doctor/American Migraine Foundation.

And, again,…failure to respond to Botox does not make you a “loser”.

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