Migraines cause a lot of pain and trouble to lots and lots of people, and managing this chronic condition is far from simple and straightforward. Unfortunately, even though there are some fairly effective treatment options for migraineurs (what people who are prone to migraines are called), migraines tend to be undertreated.

Migraines are one of the most common medical conditions on the planet. The estimate is that 14.7% of the global population experience migraines – that’s about a billion of us here on Planet Earth. Here in the US, approximately 40 million people are affected by this condition, according to the National Headache Foundation, which is part of NIH. However, migraine is generally underdiagnosed and undertreated. The total number of people in the US who experience migraines may be a good deal higher, perhaps 60 million.

Migraines cause not only severe and disabling headaches, but a number of other symptoms. 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.

Women are about three times more likely than men to have migraines. In the US, each year, as many as 18% of women experience migraine attacks, compared with 6% of men. In both women and men, migraines generally start occurring in the teen years, grow more prevalent up to about age 40, and taper off later in life.

These figures are based on surveys by the National 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.

What are the causes of migraines?

There are basically two approaches to finding a way of treating a medical condition. One is to keep trying different interventions in the hope that something will really work. As we know, many highly effective treatment options have been discovered by this trial-and-error process. (Who knows how many remedies may have been tried before we humans finally learned that a tincture of willow bark – the predecessor of aspirin – would help relieve pain?) The other is to arrive at an understanding of the causes of the specific medical condition and look for an intervention that will block that specific mechanism.

Both of these approaches have been employed in trying to find something that will effectively deal with migraines.

Trying to zero in on the physiologic mechanism that causes migraines has led to a number of theories. One that was strongly favored until about 25 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 does not entirely account for the observation that migraines are almost always on one side of the head only; why would the vasoconstriction – vasodilation phenomenon be unilateral? Of course, left and right brain dimensions are not the same, which might account in part for that factor. Brain imaging studies have shown that during the headache phase of the migraine blood flow is not increased, which is what would happen if the entire cause of the headache were vasodilation. So other factors are probably involved.

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 proved somewhat effective in preventing migraine pain. We’ll discuss specific CGRP antagonists below.

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 serotonin 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, serotonin levels fall by as much as 40%; third, agents that deplete serotonin and other amines can trigger a migraine attack; and, fourth, intravenous serotonin can abort migraine attacks. However, we need to note, intravenous serotonin 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. A class of widely-used 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.

We’ll take a look at the current range of medications for migraine a bit further in this piece. First, let’s consider a strategy to avoid migraines by staying away from migraine “triggers” – foods or environmental factors that migraineurs have identified as, if not specifically causing a migraine, frequently connected with or followed by migraines.

Here is a list of possible triggers, courtesy of the National Headache Foundation.

Foods & beverages

• Ripened cheeses (such as cheddar, emmenthaler, stilton, brie, and camembert)
• Chocolate
• 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 two cups total) of caffeinated beverages such as tea, coffee, or cola
• Alcohol (including red wine and beer)

Menstruation

For 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.

Environment

Strong perfume is an immediate trigger for some, making some common spaces (offices, auditoriums, churches) a challenge, and the beauty counters in big department stores a particular hell. For others, it can be flickering lights. Movie screens in a darkened theater can flicker, triggering migraines. Sunshine flashing through trees as we drive on a road can produce a flickering or flashing sensation..

Stress

The 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.)

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 apparently 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.

And to the environmental factors, we should add the prevalence of exceedingly bright piercing lights that we see everywhere these days – bicycles with pinpoint flashing headlamps that burn little holes in the retina, flashing lights on every kind of vehicle, whether responding to a real emergency or racing to the corner deli for a cup of java, the flashing lights on the deli itself, flickering LEDs and compact fluorescents. These definitely pose threats to migraineurs. And they also can trigger epileptic seizures in some susceptible individuals.

Casting doubt on migraine “triggers” as a fundamental cause of migraines

Data were presented at a meeting of the American Headache Society that cast doubt on the relationship between these triggers and migraine episodes. A study enrolled 774 migraineurs who tracked their migraine headaches and also their food consumption. Of these, just over half (53.7%) suspected that chocolate was a trigger for migraines. Most (27%) characterized chocolate as a mild trigger, 14.6% thought it was a moderate trigger, and 12% thought it was a strong trigger. But when these participants entered their actual migraine experience, using a web-enabled smartphone app, chocolate was found to be associated with an increased risk for migraine in only 10 people, which amounted to 1.7% of the 606 study subjects with enough data for analysis. For the huge majority, 95.7%, no association at all was noted. Similar results were found for nitrates and MSG.

Participants at the AHS meeting were divided on the issue of avoiding triggers, with some experts saying that migraineurs should shun all triggers like the plague, and others opining that, on the contrary, they should go ahead and consume those triggers and “learn to cope.” Dr Peter J. Goadsby had his own take on the matter. I will quote what he said:

“What we’re learning by studying the premonitory phase that occurs in the days or hours before the attack, when the patient will feel tired or get a bit moody or crave sweet or savory things, is that the brain has actually started to have the attack. Chocolate is an excellent example. When the brain drives you to take some chocolate and a day and a half later you get migraine, the association is absolutely correct, but the causality is different — the mechanism has already started.

What we’re learning from the diary work is that while you can recommend general regularity, an individual needs to ask themselves whether what they’re calling a trigger is actually the beginning of their attack. That releases them from the punishment of worrying about the trigger and gives them information about what is about to happen. Obviously, if you feel you’re in the premonitory phase that is not a night to go out, to stay up late, to find your favorite alcohol. It’s a night to be careful, to look after yourself, to prepare for the next day. This understanding is going to empower patients to get better control.”

I’m not sure that Dr Goadsby is asserting that those changes in the brain in the premonitory (or as it is sometimes termed “prodromal”) phase are specifically what drive people to eat chocolate or drink red wine. Migraineurs as well as non-migraineurs can be smitten by chocolate or red wine or Camembert cravings at any time for any reason or no reason, and these do indeed originate in brain activity. The difference is that the migraineurs, looking for some kind of source for their misery, may blame whatever it was that they consumed before the headache descended on them. It’s a natural assumption, and it might or might not be correct.

Despite the positions cited above, I am not at all prepared to dismiss the idea that triggers do have something to do with migraine symptoms. I definitely agree with Goadsby that migraine is “likely” to originate in a brain disorder, but that certainly does not eliminate the possibility that there are external stimuli at work. I would definitely not concur with the view that migraineurs should go ahead and consume the triggers and “learn to cope.” For some migraineurs, coping consists of taking to their beds in a darkened room and waiting for the excruciating pain and other symptoms to pass. Avoiding the trigger in the first place is a better tactic, if at all possible.

What about those premonitory / prodromal symptoms?

Many migraineurs can feel the migraine coming on. Sometimes, but not always, migraineurs can head off the migraine by taking action. Sometimes simple activities may for some migraineurs 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.

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. These symptoms can occur before the onset of the migraine headache, in which case they are known as prodromal symptoms.

Visual auras, experienced by a minority of migraineurs, were depicted by the 12th century mystic and musician 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. To some migraineurs, these visual auras serve as a warning that the headache is about to attack, and a strong hint to take whatever medication they have found useful.

Migraine treatment options

Now we come to what this epistle is really supposed to be about: how can this painful and highly troubling condition be managed? Obviously, if one can simply avoid having a migraine episode, such as by carefully staying away from possible triggers, that would be the simplest course. However, as we observed earlier, the cause-and-effect link between triggers and migraines is blurry, to say the least. Yes, if every time you eat chocolate, you get hit with a migraine, best to avoid the chocolate cake and go for angel food instead. But the experience of migraineurs is that they can meticulously avoid all their known triggers and have a migraine anyway. So let’s look at the available medical options for treatment.

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 may simply 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.

The first drugs specifically developed to treat migraines 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), 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.

A study in the journal Neurology, based on self-reported data from about 278,000 migraineurs, mostly women, in which study subjects rated migraine treatments as “helpful,” “somewhat helpful,” or “unhelpful.” The study attempted to rate 25 different medications from seven drug classes. The triptans were rated as the most helpful. After triptans, the next most helpful drug classes were ergots such as dihydroergotamine and anti-emetics such as promethazine, which can help ease nausea, another common migraine symptom. These will be discussed later.

The most frequently used drug in the study was ibuprofen (sold over the counter as Advil or Motrin. Participants rated it as “helpful” only 42% of the time. Acetaminophen (Tylenol) was even less helpful, just 37% of the time.

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.
• Relpax may be the most effective triptan, perhaps followed by Imitrex.
• 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, supposedly the most effective triptan, 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 would call those results pretty good.

Drugs to prevent migraines

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 vascular theory, which as we discussed, has been questioned , some physicians continue to prescribe these antihypertensive drugs for migraine sufferers, and some migraineurs report that they get some relief from these drugs.

The latest drugs that aim to prevent migraines target the calcitonin gene-related peptide (CGRP), which participates in the transmission of pain signals.

• Erenumab (Aimovig, Amgen),
• Fremanezumab (Ajovy, Teva),
• Galcanezumab (Emgality, Lilly)

These are given by self-injection monthly. Another CGRP antagonist, eptinezumab (Vyepti, Lundbeck), is given by IV every 3 months.

In addition to its use as an acute medication to treat migraine attacks, the FDA has also approved the small molecule CGRP antagonists rimegepant (Nurtec, Pfizer) and atogepant (Qulipta, AbbVie) for prevention of migraine attacks.
Aimovig may be a valuable drug not only for persons with chronic migraine episodes, but for those with episodic migraines – a much larger patient population that has migraine episodes much less frequently than the chronic migraineurs. Aimovig was compared with placebo in three clinical trials in this population, and the results were that treatment with Aimovig resulted in between 1 and 2½ fewer monthly migraine days.

Results from a clinical trial with Emgality showed that prophylactic treatment resulted in almost 5 fewer migraine days per month relative to baseline in patients with episodic migraines, while treatment with placebo reduced migraine incidence by 2.8 days per month. The baseline migraine frequency in these subjects was as high as 14 days per month, so a reduction of 5 migraine days is clearly substantial

These results do not strike me as being totally persuasive. Avoiding as many as 5 monthly migraine days is clearly far preferable than enduring those days, but prophylactic treatment (like all drug treatment) raises the risks of side effects. The side effects of these prophylactic drugs are not especially dangerous, but, because the drugs are taken continuously, the risks of side effects are continuous as well. Among the side effects linked to prophylactic migraine drugs are weight gain, constipation, fatigue, muscle cramps, and injection site reactions.

Some older antidepressants, such as the tricyclic amitryptaline, as well as the anti-seizure drug topiramate are used chronically by some migraineurs. A formulation of topiramate, Qudexy XR (Upsher-Smith Laboratories) was approved by the FDA for prevention of migraine in adults and adolescents over the age of 12. Qudexy is an extended-release formulation which, it is hoped, will also improve adherence to migraine prophylaxis, which currently is reported to be as low as 41% after two months, and declines further over time.

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, they need to be taken every day. 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 every day to prevent migraines that only occur sporadically.

Newer anti-migraine drugs

The quest to develop new anti-migraine drugs continues, fueled by the need for more and better treatment options, and also (no doubt!) by the desire of pharmaceutical outfits for more and better sources of revenue.

• New CGRP blockers rimegepant (Nurtec, Pfizer) and ubrogepant (Ubrelvy, AbbVie). These drugs begin to relieve pain in 60 minutes. Side effects include nausea, sleepiness, and dry mouth.
• Zavegepant (Zavzpret, Pfizer) is a new CGRP antagonist in the form of a nasal spray.
• Celecoxib is a drug doctors have used for arthritis since 1998. Some recent studies show it may help some people with migraine as well, though the effects appear small. The FDA recently approved a liquid form of celecoxib (Elyxyb) to treat migraine. Celecoxib has side effects, like a higher risk of blood clots and effects on the digestive system.
• Lasmiditan (Reyvow, Lilly) specifically targets pain pathways. Side effects include dizziness, fatigue, and a tingling and numbness in the skin.

Can we arrive at a conclusion of some sort?

From my perspective, sitting on the sidelines, the overall picture looks like this: the investigators who are diligently searching for the root cause of migraines have made some progress, but still have a way to go. My guess is that there is no single root cause of migraines, and that as more research is carried out, a picture will emerge showing the interaction of several different factors in the brain.

The pragmatists, who are looking for treatment options that deliver benefit to the billion or so migraineurs on our planet, are considerably ahead of them. And as effective treatment modalities continue to emerge, that will also shed light on the essential cause (or causes) of migraines. That will be highly satisfactory. But even more satisfactory will be the development of new, more effective treatment modalities to stop the migraine episodes in their tracks.

Despite the new developments, the words that I put at the end of my previous piece about migraines still seem appropriate:

… 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

* * * * * * *

The last Doc Gumshoe posting about migraines was October 8, 2020, and I led off by saying that having to think about COVID 19 gave me something like a migraine. I hope never to have to think about COVID ever again at all, but who knows. In the meantime, I’ve been giving some thought to sleep and sleep disorders, and I’ll try to stay awake enough to give the subject proper attention. Stay well and healthy, and thanks for all comments. Best, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]