Another Look at the Current Migraine Scene

By Michael Jorrin, "Doc Gumshoe", October 8, 2020

Thinking about COVID-19 almost gives me a migraine, or at least a heavy and achy sensation in my noggin – perhaps not an actual migraine, thankfully, but threatening and unpleasant all the same.   Happily, thinking about migraines will not give me COVID-19.   But migraines are by no means a topic of no consequence, even when COVID-19 is on our collective minds.   Migraine has been characterized as the most painful non-fatal ailment.   And, make no mistake, migraine really is an ailment – an illness or disease – and certainly much more than a casual headache. 

The bit of news that steers me to thinking about migraines once again came from the results of the OVERCOME study, which looked at a nationally representative sample of 21,143 persons who had a diagnosis of either chronic or episodic migraine.   (Buse D. Neurology 4/14/20:15 Suppl)

This was a study in what is described as “acute treatment optimization,” which supposedly contributes to reduced disability and improved health-related quality of life.   What was surprising and disturbing about the OVERCOME study is the finding that a large percentage of persons with migraine, whether chronic or episodic, simply did not receive treatment – either acute treatment, meant to help to resolve a migraine headache in progress, or prophylactic treatment, meant to help prevent recurring migraine episodes.   These individuals were not just plain folks who had occasional bad headaches that they figured were probably migraines.   Most of them had received a migraine diagnosis from a health professional, and nearly all had fulfilled the diagnostic criteria of the American Migraine Study.   More than half had at least a mild migraine disability, meaning that migraine episodes had the effect of preventing them from living their normal daily lives – missing work, or keeping to their beds in a darkened room.   About a quarter had such migraine headaches at least four times per month.       

Rejection of medical treatment of any kind can be based on many different factors, some more rational than others.   For example, a person who experiences an occasional migraine might rationally decide that he/she prefers to tough it out than to take a drug that is supposed to prevent the migraine, but is linked to side effects of consequence.   And that person might also be reluctant to take a drug for the acute treatment of migraine if that drug is known to be associated with rebound – that is, after the initial palliative effect of the drug, the migraine returns.   However, the OVERCOME study found that only about 20% of the individuals who experienced 15 or more migraine headaches per month took preventive drugs.   The percentage of those severely affected individuals who took acute treatment drugs was higher – 35%.   But that still meant that about two-thirds of persons who experience migraine headaches very frequently – about every other day – do not take drugs to manage their symptoms.   

Why might this be?   What it comes down to, in the opinion of Doc Gumshoe, is that migraine drugs, whether for acute or prophylactic treatment, do not have a reputation for a high level of efficacy.   

Coming up with drugs for the treatment of migraines is a complex task, made more complex by several factors.   One is that a migraine is much, much more than a bad headache.   Migraines are almost always accompanied by a range of non-headache symptoms that complicate the treatment options.   About 80% of the time migraines come with bad GI symptoms, including nausea and vomiting, which makes treatment with usual analgesics much less effective.

Another factor is that the precise etiology of migraines is not yet clearly understood.   As you know, in most cases drug treatment takes careful aim at the causes of an illness or condition.   If the condition is an infection, one directs the bullet at the pathogen.   If it is hypertension, the treatment aims at the mechanisms that raise blood pressure, such as constriction of the arteries.   But in the case of migraines, the target is not sharply outlined.

Let’s step back and take a look at migraine and what is known (or speculated) about its causes.   A headache is not considered to be a migraine unless it is accompanied by other clinical symptoms, the most usual of which is nausea, sometimes with vomiting.   Migraineurs (which is what people afflicted with migraines are called) are also extremely sensitive to light and sound, frequently taking refuge in dark, quiet rooms when they feel a migraine coming on.   In some cases, odors which are not usually thought to be unpleasant are intolerable to the migraineur.   And, in addition to the acute head pain, they may experience blurry vision, stuffy nostrils, diarrhea, stomach cramps, pallor, flushing, or localized swelling of the face, hot or cold sensations, sweating, stiff neck, tenderness of the scalp, and a range of mental symptoms including anxiety, depression, irritability, and impairment of concentration.

Visual auras are also experienced by some migraineurs.   These can be arcs of flashing lights in a zigzag or herringbone pattern passing across the visual field and growing in size.

Many migraineurs can feel the migraine coming on.   These are known as “prodromal symptoms,” and sometimes, but not always, migraineurs can head off the migraine by taking action.   Sometimes simple activities can prevent the onset of the full-fledged migraine – vigorous exercise, a hot or cold shower, sex (yes, sex!), or a bite of food.   

How common are migraines?

In the US, somewhere around 10% of the population experience at least one migraine headache per year.   That is about the same as the global prevalence of migraines.   Migraines affect women more than men – about 18% of women have migraines, compared with about 6% of men.   Migraines account for about two-thirds of severe headaches in women and just over 40% in men.

Migraine incidence starts earlier in boys than in girls – about age 5 for boys and 12 to 13 for girls.   However, prevalence is greater in females than males – about 2.5 to 1 at puberty, increasing to 3.5 to 1 after age 30.   Migraines tend to decrease both in frequency and severity after age 40. 

In the US, the cost of migraines resulting from loss of work time is calculated at more than $13 billion per year.   Male migraineurs typically require about 4 days of bed-rest per year, and females need almost 6 bed-rest days per year.

What do we know about the cause of migraines? 

The essential root cause of migraines is still somewhat mysterious.   The last time I wrote about migraines I quoted two sentences from two recent papers about the pathophysiology of migraine.   The first is the very last line from a paper entitled “Migraine: Multiple Processes, Complex Pathophysiology.”   (Burstein R. J Neuroscience 2015;3 5;6619-6629)   

 “Given the enormous burden to society, there is an urgent imperative to focus on better understanding the neurobiology of the disease to enable the discovery of novel treatment approaches.”

What the authors of that paper are saying is that, despite a great deal of meticulous research into the possible causes of this disorder, they are quite far from having it nailed down. 

The second sentence is the first line from a paper by Peter J. Goadsby, who recently chaired the meeting of the American Headache Society.   (Goadsby PJ. Ann Indian Acad Neurol 2012;15(Supp1)S1-S22)   

“Migraine is likely to be a brain disorder involving altered regulation and control of afferents, with a particular focus on the cranium.”

I call your attention to the word “likely.”   (“Afferent” in that sentence refers to signals travelling to any of various brain centers rather than away from those centers.)   Goadsby is saying that the cause of migraine is more likely to be a brain disorder than a disorder of the vascular system, which was the explanation that had held sway for quite a number of years.   That previous explanation was that the migraine headache was caused by the dilation of blood vessels around the periphery of the brain.   The idea was that these dilated blood vessels would press on the sensory nerve endings, which would naturally result in a headache.   This theory, the “vascular hypothesis” is supported by the greater prevalence of migraines in women; estrogen makes blood vessels more flexible, which makes them more likely to dilate and press on nerve endings.

But the vascular hypothesis fails to account for the observation that migraines are almost always on one side of the head only; why would the vasodilation phenomenon be unilateral?   Also, brain imaging studies have shown that during the headache phase of the migraine, blood flow is not increased, which would be the case if the cause of the headache were vasodilation.       

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An alternative theory, which has more recently gained currency, is the sterile inflammatory response hypothesis.   (A sterile inflammatory response, as the name suggests, is an inflammatory response to a non-infectious trigger.)    This suggests that the migraine symptoms result from the release of plasma, which can press on the trigeminal nerve fibers, resulting in pain.    

Several substances have been identified as possibly or likely to be involved in the pathway that leads to the characteristic headache pain.   These include calcitonin gene-related peptide (CGRP) and another peptide labeled substance P, which conveys pain information.   Research into forms of treatment that block these neurotransmitters has demonstrated some effectiveness in preventing migraines. .

Another chain of reactions that is linked to migraines involves glutamate release.   A mutation which is common in about half of persons who are migraine sufferers involves the calcium channel gene.   The calcium channel transports calcium ions from the plasma into cells throughout the body.   This particular mutation results in increased release of glutamate.   Perhaps not coincidentally, a similar mutation, also resulting in higher circulating levels of glutamate, is linked with epilepsy and seizures.   This may have some bearing on the widely reported heightened sensitivity to monosodium glutamate (MSG) reported by some individuals who experience migraines. 

The most successful theory, from a purely pragmatic perspective, is that migraine is a syndrome characterized by low levels of serotonin in the plasma.   Serotonin (5-hydroxytryptamine, or 5-HT) has a number of physiologic effects, including the ability to suppress pain and to contribute to normal sleep.   The evidence is as follows: first, during the headache phase of a migraine episode, the main metabolite of 5-HT is found in increased amounts in the urine (meaning that it is being broken down more quickly); second, during the onset of the migraine attack, 5-HT levels fall by as much as 40%; third, agents that deplete amines including 5-HT can trigger a migraine attack; and, fourth, intravenous 5-HT can abort migraine attacks.   However, we need to note, intravenous 5-HT has a number of adverse effects, such as rapid vasoconstriction and increases in blood pressure, which make it unacceptable for clinical use.

Serotonin acts through a number of receptors, classified as 5-HT1 through 5-HT7.   The 5-HT1 subclass includes those most likely to be involved in pathophysiology of migraine, especially 5-HT1B and 5-HT1D.   Most of the current generation of migraine medications    i.e., the triptans, which we’ll say a bit more about later – are activators of those serotonin receptors.   They are both potent constrictors of blood vessels in the brain, and, perhaps more important, inhibitors of the sterile inflammatory response.

What all this comes down to, however, is that the root cause or causes of migraines have not been precisely identified.   It’s clear that something is impacting the nociceptors (the nerves that detect any possible damage and transmit a warning signal in the form of pain) in the brains of migraineurs, whether it’s the dilation of the blood vessels in their immediate proximity, or an inflammatory reaction in the brain tissue triggered by an ionic reaction, or a deficiency in circulating serotonin, or an excess of glutamate, or a number of other reactions.   These possible pathologies continue to be investigated, and more effective treatment modalities for migraine will – we hope! – emerge.   

So, what medications have some migraineurs (at least) found to be helpful?

For a start, many of the over-the-counter analgesics that are specifically marketed as anti-migraine drugs are only marginally effective.   In a recent survey of migraineurs, only 17% reported that they got “a lot” of relief from these drugs.   The efficacy of prescription analgesics sometimes prescribed for migraines was no better.   A problem with the use of analgesics for migraine relief is that one of the effects of the migraine is gastric stasis.   That means that the pain killer doesn’t get absorbed, and indeed may aggravate the nausea that migraineurs usually experience.   So, while the usual remedy for non-migraine headaches is an analgesic, this mostly does not work for migraines.   The use of drugs usually used to treat depression or anxiety has been suggested as a potential way to provide relief of the migraine headache.   However, these seem to work even less well than analgesics – only about 4% of migraineurs got “a lot” of relief from these psychoactive drugs.

Some older antidepressants, such as the tricyclic amitryptaline, as well as the anti-seizure drug topiramate are used chronically by some migraineurs.   A new formulation of topiramate, Qudexy XR (Upsher-Smith Laboratories) was recently approved by the FDA for prevention of migraine in adults and adolescents over the age of 12.   The newly approved drug is an extended-release formulation which, it is hoped, will also improve adherence to migraine prophylaxis.   As you may have noticed earlier in this piece, only about 20% of persons who experience frequent migraines stick with prophylaxis, so any improvement in adherence should be seen as a good thing.   I’ll say a bit more about migraine prophylaxis later in this piece.                                                                                                         

A definite drawback with these drugs is that they cannot be taken in response to a specific migraine episode.   Instead, in order for them to be at all helpful, some of these drugs need to be taken every day, although some of the newer prophylactic drugs can be taken monthly or even quarterly..   However, the risk of adverse effects increases with chronic use of any drug, and one would have to weigh these risks extremely carefully before taking a drug to prevent migraines that only occur sporadically.

The first drugs specifically developed to treat migraines drugs were the triptans, which are agonists (activators) of certain serotonin receptors, designated 5-HT1B/1D.   The first of these was sumatriptan (Imitrex, from Glaxo SmithKline), initially marketed as a subcutaneous injection and later as an oral medication.   At least six other triptans have followed sumatriptan, and sumatriptan is now available as an oral medication, a nasal spray and also in combination with naproxen.   

Most triptans usually provide reasonably prompt headache relief – i.e., within less than 2 hours.   However, there are significant drawbacks to triptan use.   One is that many migraineurs experience recurrence of headaches after initial relief.   In some studies, 40% to 70% of migraineurs reported rebound headaches, and repeated dosing with triptans is usually not recommended.   Thus, rather than taking the triptan, some migraineurs prefer to seek relief without any specific drug treatment, using their own strategies – bed-rest in a darkened room, ice-packs, warm compresses, scalp massage, sleep.

Another significant drawback is that, since a principal mechanism of action of the triptans is vasoconstriction, there is some associated cardiac risk, and migraineurs who have heart disease risk factors are not recommended to take triptans.

The differences between the seven triptans are fairly minor.   Here’s a quick summary of the chief differences:

  • Imitrex (sumatriptan, GSK) in a subcutaneous formulation has the fastest onset of action, about 10 minutes.    
  • Zomig (zolmitriptan, Impax) is available in a nasal formulation, whose onset of action is just a bit slower than that of Imitrex.   
  • Amerge (naratriptan, GSK) onset of action may be as long as 3 hours – the longest of any triptan.   
  • Axert (almotriptan, Janssen), Relpax (eletriptan, Pfizer), Frova (frovatriptan, Endo), Maxalt (rizatriptan, Merck), as well as the tablet formulations of Imitrex and Zomig, have onsets of action ranging from 30 minutes to perhaps 2 hours.
  • Frova has the longest duration of action, up to 6 hours. Most of the triptans have a fairly short duration of action, in the neighborhood of 2 hours.
  • Probably the most effective triptans are Imitrex and Relpax..
  • Axert and Maxalt are approved for pediatric use – Axert in children age 12 or older, and Maxalt in children age 6 or older.   The nasal formulation of Zomig  is also approved for children age 6 or older.
  • Patients taking the short-acting triptans often take a repeat dose to get them through their migraine episode, even though this is generally not recommended.    
  • The adverse effects that clinicians will be on the alert for in their patients taking triptans are cardiovascular.   The subcutaneous Imitrex formulation is associated with the greatest cardiac risk, while Axert appears to have the lowest cardiac risk.  
  • Amerge (naratriptan) has the lowest incidence of side effects, followed by Axert (almotriptan).

Migraineurs by no means need to stick with one triptan.   If he or she (she, usually) feels the headache coming on quickly, the best option might be the subcutaneous Imitrex or perhaps the nasal Imitrex or Zomig.   Those same options might be optimal for the person who has to cope with nausea and might not be able to manage the oral triptan formulations.   On the other hand, if the migraineur is in the grip of an extended bout of prodromal symptoms and anticipates a long-lasting headache, the optimal choice might be Frova.

The differences between those seven triptans suggests that in the event that a migraineur does not get a satisfactory response to any individual triptan, the patient and clinician should keep trying the alternatives.   The overall response to subcutaneous Imitrex, one of the most effective triptans, is about 70%.   But there is evidence that in the 30% of patients who do not respond to Imitrex, up to 80% will respond to another triptan.   So, adding that number (80% of 30% is 24% by my perhaps antiquated arithmetic) and we get a total response rate approaching 94%.   I say, not bad, if those numbers are really on the up-and-up.

Are there any effective ways to prevent migraines through the use of drugs?

Prophylactic drugs have been tried in some migraineurs, especially those whose episodes are more frequent, severe, or of greater duration.   Classes of drugs include calcium channel blockers and beta blockers, which are essentially blood pressure medications, based on the idea that lowering blood pressure would relieve pressure on nerve endings in the brain.   Although use of these drugs is based on the perhaps discredited vascular theory, which we discussed earlier, some physicians continue to prescribe these antihypertensive drugs for migraine sufferers, and some migraineurs report that they get some relief from these drugs.   

The first FDA-approved prophylactic treatment option for migraines was Botox, which as we all know is botulinum toxin, used cosmetically to reduce, or perhaps totally obliterate, those little facial wrinkles that identify us as grown-ups.   Botox does this by blocking the receptors that trigger the contraction of facial muscles.   It basically works the same way in inhibiting migraines, by