[Ed note: Following is another installment from our favorite medical scribe, “Doc Gumshoe” (no, he’s not a doctor). We feature Michael’s commentary every couple weeks or so, and his thoughts and words are his own. “Doc” doesn’t pick stocks, but who knows … maybe you’ll find yourself wanting to understand a biotech company’s migraine drug someday, or perhaps you or a loved one suffers this particular plague.]
Rare is the individual who does not get a headache every once in a while. According to the American Academy of Family Practice, 93% of people surveyed reported that they had had at least one headache in the previous year. A lot of people think that a migraine is just an extra-bad headache, so why do people who have migraines make such a big deal out of it?
Migraineurs (as they are called) know better. A migraine is much, much more than “an extra-bad headache.” Most of the time (about 80%), migraines are accompanied by bad GI symptoms – nausea, vomiting – and also by marked intolerance to light and noise. And they may be preceded or accompanied by visual symptoms termed “aura,” which can be exceedingly disorienting and frightening.
In a film about migraine that I worked on a few years back, patients said this about the difference between garden-variety headaches and migraines:
“To me the difference is that, if you get migraines, even when you feel fine, even when you don’t have any symptoms, you’re always sort of watching yourself. You’re thinking, I’d better not do this, or eat that, or get too stressed or too tired, or I may get a migraine. The migraine starts to take over your life.”
“I know just what you mean. Every single person gets a headache from time to time. But those people don’t think of themselves as being sick people. They just think that every once in a while they have a headache, no big deal. The way I feel about migraines is totally different. I think that anybody that gets migraines as often as I do, which is about once every two weeks, starts to think of herself as a sick person. I’m a person with an illness. I feel like I have to be super careful all the time.”
None of this is news to migraineurs, of course – they know that a migraine is not just a really bad headache. But there are probably a good many people out there who have migraines and are not aware that the bad headaches they’re experiencing are migraines. One basic characteristic is that the pain is almost always localized to one side of the head. This has been known for at least two thousand years; the word “migraine” is derived from the Latin “hemicrania” meaning “half head;” the earlier English form was “megrim.” A megrim was what fine ladies in 18th century novels were afflicted with – and then took to their beds. Not-so-fine ladies might just have “sick headaches,” but they had to take to their beds just the same.
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 are also extremely sensitive to light and sound, frequently taking refuge in dark, quiet rooms. In some cases, odors which are not usually thought to be unpleasant are intolerable to the migraineur. And 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, experienced by a minority of migraineurs, were depicted by the 12th century mystic Hildegard von Bingen, who experienced them as visions while sick in bed in a darkened room. She drew pictures of her visions that are recognized by migraineurs as nearly identical to the auras they experience – arcs of scintillating 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!), a bite of food. And sometimes taking a prescription anti-migraine medication before the migraine hits can stave off the worst of it. We’ll say something about the available migraine drugs later on – however, in this piece we can’t go into detail about current treatment – that will have to wait for another blog.
How common is migraine?
More common than most non-migraineurs think. In the US, up to about 6% of men and about 18% of women report experiencing migraines. These figures are based on surveys by the International Headache Society, which has drawn up criteria for the diagnosis of migraine. One possible reason for this disparity is hormonal differences between the sexes. Women have higher circulating levels of estrogen, which can be involved in the migraine process through a mechanism called the “vascular hypothesis,” which we’ll describe later.
Another possibility is that male migraineurs may be more disposed to conceal their condition, perhaps even from themselves. In both males and females there may be a disinclination to accept a label as a person with a persistent chronic illness. Better to tough it out and call it a “sick headache” or “coming down with something.”
However, an attitude characterized by denial is directly contrary to the best strategies for managing this disorder, which are based on knowing as much as possible about migraine and the most effective ways of dealing with it.
Migraineurs experience considerable disability, due not only to the severity and frequency of migraine episodes, but to the migraineur’s awareness that an attack could come at any time, bringing to a halt their ability to work or even to care for themselves. More than half of female migraineurs and nearly 40% of male migraineurs report 6 or more lost work days per year due to migraines.
So, it’s clear that a migraine is considerably more than an extra-bad headache. But what exactly is a migraine?
How much do we know about the pathophysiology of migraines?
The short answer is, “not as much as we’d like,” although certainly a good deal more than we used to know. We could start by stating definitely what migraines are not. Migraines are not due to traumas or infections. They are not progressive – that is, migraineurs do not typically experience worse or more frequent episodes as time goes on. They are not allergic reactions – even though migraineurs usually have specific migraine triggers (we’ll say more about those later), the reaction to the migraine trigger is not a typical allergic reaction. Migraines don’t appear to be linked to the usual “life-style” culprits – smoking, obesity, junk food, substance abuse, texting while driving, etc. They are not cancers, nor, in the usual sense, autoimmune disorders. They are not neurodegenerative diseases, like Alzheimer’s or Parkinson’s.
Something we do know about migraines is that they tend to run in families; many migraineurs have first-degree relatives who are also migraineurs, and identical (monozygotic) twins are more likely to share the disorder than fraternal (dizygotic) twins. So there’s obviously a genetic component, and researchers are trying to identify it precisely.
A factor that likely merits further investigation is a mutation that leads to enhanced glutamate release. A related mutation, also leading to a buildup of glutamate, involves the triggering of epileptic seizures, suggesting that the purely neurological manifestations that are grouped under the term “aura” are in some form related to epilepsy. This association is supported by two further observations: one, many migraineurs are highly sensitive to MSG – monosodium glutamate. And, two, the antiseizure drug topiramate (Topamax, Janssen, a Johnson & Johnson affiliate [JNJ]) is effective in preventing (although not treating) migraines.
A theory that was strongly favored until about 20 years ago was the vascular hypothesis, which proposes that the migraine headache is caused by a period of vasodilation around the periphery of the brain. The dilated blood vessels were thought to press on the sensory nerve endings, causing the headache. It was presumed that the vasodilation was in response to a period of intracranial vasoconstriction, which accounted for the premonitory symptoms that most migraineurs feel. This theory 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 vasoconstriction – vasodilation phenomenon be unilateral? Also, brain imaging studies have shown that during the headache phase of the migraine, blood flow is not increased, which, if the cause of the headache were vasodilation, would be the case.
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 labelled substance P, which conveys pain information. So far, however, research into forms of treatment that block these neurotransmitters has not proved effective in preventing migraine pain.
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, that 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 sets off a migraine?
The number of possible migraine triggers, as they are commonly called, would go on and on. Here’s a partial list, courtesy of the National Headache Foundation, which is part of the National Institutes of Health
- Foods & beverages
- Ripened cheeses (such as cheddar, Emmenthaler, Stilton, Brie, and Camembert)
- Marinated, pickled, or fermented food
- Foods that contain nitrites or nitrates (bacon, hot dogs) or MSG (soy sauce, meat tenderizers, seasoned salt)
- Sour cream
- Nuts, peanut butter
- Sourdough bread
- Broad beans, lima beans, fava beans, snow peas
- Figs, raisins, papayas, avocados, red plums
- Citrus fruits
- Excessive amounts (more than 2 cups total) of caffeinated beverages such as tea, coffee, or cola
- Alcohol (including red wine and beer)
- MenstruationFor many women, the menstrual cycle is a major trigger. Attacks usually occur a few days before or during their period or, for some women, at ovulation. A drop in estrogen is believed to be the culprit. As women near menopause, fluctuating estrogen levels may also trigger an increase in migraines.
- EnvironmentStrong perfume is an immediate trigger for some, making common spaces (offices, churches) a challenge, and the beauty counters in big department stores a particular hell. For others, it can be flickering lights—even a movie screen in a darkened theater or sunshine flashing through trees on a road as they’re driving.
- StressThe most common migraine trigger is stress. Migraine sufferers are thought to be highly responsive emotionally. Anxiety, worry, shock, and sadness can all release certain brain chemicals that lead to a migraine headache. (Ironically, the sense of release after a stressful period can also lead to migraines, which could be the cause of weekend headaches.)
And the list is far, far from complete; in fact, I would question whether a complete list is possible, since migraine triggers vary enormously among individual migraineurs. For every migraineur who is exquisitely sensitive to chocolate, there will be another one who can feast on chocolate with impunity; for every migraineur to whom a glass of red wine is forbidden, there will be another who can drink red wine with no ill effects, but is laid low by a cup of coffee.
As we look over the list of potential food triggers, it’s worth thinking about what’s in some of those foods that makes them risky for some migraineurs. To the list of ripened cheeses (which could go on and on and on, of course), we should add preserved and smoked meats, which also contain purines. Chocolate and coffee (and tea also) contain related methylxanthines; caffeine is a methylxanthine, but not all methylxanthines are the same; thus the migraineur who shuns chocolate may be able to drink coffee and vice versa.
The list mentions foods that contain MSG, which is monosodium glutamate. We noted earlier that glutamate receptors are involved both in the migraine mechanism and in the triggering of epileptic seizures.
Migraineurs and the environment
The brief mention of environmental factors only scratches the surface. Migraineurs vary with regard to sensitivity to light, for example. Some cannot tolerate bright lights of any kind. Others are highly sensitive to the quality of light. Recent innovations in lighting have made several new kinds of light sources much more common in the environment, and some of these present major challenges to migraineurs.
Some migraineurs cannot tolerate compact fluorescent lamps (CFLs), finding them much more likely to trigger a migraine than the old fashioned tube fluorescents. While neither CFLs or tube fluorescents emit a full continuous spectrum of light (as do regular incandescent lights), the CFLs are supplied with an individual ballast, which is intended to even out the flicker that would affect all fluorescent lights. However, tube fluorescents are mounted in a fixture that includes a robust, well-functioning ballast, while CFLs were designed to replace ordinary incandescent bulbs and to screw into ordinary sockets. Therefore, the robust ballast in tube fluorescent fixtures has been replaced by the tiny, cheap ballast in the CFLs themselves that don’t totally even out the flicker. You may not notice it, but your brain does. So, for migraineurs, the CFL may be a double curse – an uneven color spectrum plus constant subliminal flicker.
Some migraineurs cannot tolerate the flashing lights of emergency vehicles for even a few moments. Flashing lights of this type have been known to trigger seizures in epileptics, and migraineurs may share that sensitivity.
Light-emitting diodes (LEDs) may also be a problem for migraineurs, as the light is at a single point in the spectrum and is intensely specular, meaning that it does not radiate evenly from the source, but tends to be piercingly sharp. Halogens, being a form of incandescent lighting, are considerably easier for migraineurs to live with.
And besides sensitivity to light of different forms, many migraineurs are highly sensitive to sound – and it doesn’t even have to be especially loud. Yes, a rock concert (remember those?) or a football game can put a migraineur over the edge, but so can some low-volume sounds. During the aura phase, for those migraineurs who experience aura, little tiny noises can seem amplified to a startling degree. So, to photophobia, we have to add phonophobia.
Migraine trigger denial
No manufacturer of anything at all wants to have the goods they produce tagged with the label of “possible migraine trigger.” Therefore, along with their products, they also try to manufacture evidence that their product does not trigger migraines. This is not difficult at all, since migraineurs exhibit a huge range of sensitivities regarding triggers, and individual migraineurs might have a migraine in response to a trigger on one occasion and not on another.
I am well acquainted with a woman who normally cannot drink even a small amount of red wine without having a migraine. Her neurologist thought it would be valuable to do a brain MRI while she was having a migraine, so she was given several glasses of red wine in the hospital in the expectation that it would produce a migraine. No migraine ensued. Similarly, groups of migraineurs have been exposed to MSG, bright and flashing lights, foods with nitrites and purines, and similar triggers, and not enough of them developed migraines to attain more than a random association.
What does this tell us?
Keep track of your own triggers, and learn to avoid them!
This doesn’t necessarily mean that if you experience a migraine after having eaten a dish of mango sherbet, you must forever shun mango sherbet or risk another migraine. It could well have been something else. What migraineurs need to track are the triggers that are more than coincidental. It’s definitely worth keeping a diary, so as to be able to identify the common triggers. If you develop a migraine after a breakfast of bacon and eggs, and this happens a few times, but when you have eggs and no bacon no migraine ensues, you might point the finger at the bacon. You might then try the “no nitrite” bacon and see what happens, since nitrites are known migraine triggers. What’s important is to be vigilant in spotting your own triggers, which are likely to be quite different than the triggers of other migraineurs.
What can we say about effective treatment for migraines?
The one thing just about everybody would agree on is that we wish migraine treatment choices were better – more effective, as well as safer. In spite of the size of the problem – there are probably close to 40 million migraineurs in the US alone – no currently available treatment is anywhere close to 100% percent effective.
A question that a non-migraineur would ask is, if a migraine is usually a really bad headache, why won’t the usual headache remedies work? Some migraineurs may, in fact, be able to stave off a migraine by taking an analgesic at the very first hint that a migraine is coming on. But once the migraine episode has actually begun, the usual accompanying symptom is gastric stasis. That means that the pain killer doesn’t get absorbed, and indeed may aggravate the nausea that migraineurs usually experience.
If migraine episodes are really that painful and disabling, wouldn’t the best approach be to try to prevent them in the first place? Avoiding migraine triggers is an attempt to prevent migraines, but what about some kind of prophylactic drug treatment?
In fact, 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, on the theory that lowering blood pressure would relieve pressure on nerve endings in the brain, also some older antidepressants, and, as mentioned earlier, the anti-seizure drug topiramate. However, the risk of adverse effects increases with chronic use of any drug, and one would have to weigh extremely carefully taking a drug every day to prevent migraines that only occur sporadically.
The most effective current migraine drugs are the triptans, which are agonists (activators) of certain serotonin receptors, designated 5-HT1B/1D. The first of these was sumatriptan (Imitrex, from Glaxo SmithKline [GSK]), 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 a nasal spray and also in combination with naproxen.
The 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.
There is some recent information about the comparative efficacy of triptans, which I will review in an upcoming blog. In one study, eletriptan (Relpax, Pfizer [PFE]) was reported to be somewhat more effective than the other triptans. Almotriptan (Axert, Janssen [JNJ]) supposedly is associated with the lowest cardiac risk.
In the meantime, I will pass on the bad news about the other classes of drugs that might be used to treat migraines: for example, in a survey of migraineurs, only 17% reported that they got “a lot” of relief from drugs that were specifically marketed as anti-migraine drugs. This was about the same as for over-the-counter analgesics and prescription analgesics. When it came to psychoactive drugs, only 4% got “a lot” of relief.
This doesn’t mean that there’s no hope on the horizon for migraineurs. Currently, 544 clinical trials are on-going in migraine medications, including some that target entirely different pathways. Some of these include agents that do not cause vasoconstriction, and thus may be more appropriate in patients with cardiac risk factors. Also, agents that specifically target the pathways that lead to migraine aura are being studied. One drug, tonabersat, has shown encouraging early results. Another experimental drug is based on botulism toxin, as unlikely as that sounds.
So the research goes on, and Doc Gumshoe will try to keep track of it.
In the meantime, let me repeat the Four Golden Rules for How to Live With Migraine, according to Dr Alan Rapoport, President of the International Headache Society:
I Avoid the migraine (if possible)
II Nip the migraine in the bud when you feel it coming on
III Learn to weather the migraine
IV Live a normal life
* * * * * * *
I’ll follow up in the near future with a piece that goes into a bit more detail on treatment options for migraine and turns over some stones to see where the current research is going. You can bet that with so many migraineurs on the planet whose needs are not being met, there’s a lot going on. In the meantime, Doc Gumshoe is turning his beady eyes on the way the FDA grants approval to some drugs and some medical devices. He is definitely not a conspiracy theorist, but there may be some practices that need mending.
Thanks for all the comments, whether thumbs up or down! Michael Jorrin (aka Doc Gumshoe)