Two households, both alike in dignity. In fair Verona…

1. Prodrome - generally as a result of the environment and triggers, rather than a genetic cause.
   1. The prodrome is a pre-headache and can signal that a migraine is about to start. Treatment during this phase may stop or lessen the severity of the migraine attack.
   2. Some triggers of migraines include certain foods (alcohol, nicotine, citrus, dairy, and aged foods like wine or cheese), poor sleep, emotional stress, hormonal changes especially around the menses or oral contraceptive use, and even weather changes.
2. Aura - about 25% of patients have a characteristic neurological set of symptoms that precede just before the headache.
   1. If a person has an aura, this can be the biggest indication that finding a quiet place to rest is best. In general, an aura presents as positive symptoms or negative symptoms
      1. Positive symptoms (addition of something bad) - flashing lights, spots or lines in the vision, pins and needles feeling around the eye
      2. Negative symptoms (subtraction of something good) - blurry vision, numbness, sensory deficits, inability to understand language, dizziness, muscle dysfunction
   2. The first time a person develops an aura, it can be incredibly frightening. It can develop slowly as the vision distorted but luckily it is completely reversible and usually lasts less than 60 minutes.

1. Headache - the migraine headache is the worst part of the attack itself. Although many patients would argue waiting for it to happen may be worse than having the attack itself.
   1. A migraine headache is a localized attack that usually affects an entire side of the head but can sometimes be bilateral. Likewise, a unilateral migraine may oscillate from one side to another or front to back in waves.
   2. The headache may last as little as 4 hours or up to 24 hours (although up to 72 hours has been reported). Patients report it as a pulsating and pounding pain that inhibits their ability to think about anything.
   3. Other symptoms like photophobia (light insensitivity), phonophobia (sound insensitivity) and nausea or vomiting may mean that a dark quiet place is needed, further disrupting a person’s day.
2. Postdrome - described as the migraine hangover
   1. With such an intense condition, patients can often feel exhausted and weak following a migraine attack. Likewise, patients can feel a loss of appetite for up to a day or have intense food cravings. Paradoxically, some people report a euphoria-like “high” following the migraine and actually come out of it feeling great (lucky them!)

“I was diagnosed with migraines when I was 11. That was when I experienced my first headache. I inherited them from my dad. I knew he got severe headaches, but I had never had one until then. As I got older, I experienced more and more headaches to the point that some weeks I would get the migraine aura every other day. The pain was so much I wanted to die or take a drill to my head to relieve the pressure. I didn't obviously, but the thought was there that anything was better than this constant slew of migraines. I was over diagnosed when I was a kid with hemiplegic migraines, which is a super rare disorder that causes paralysis on one side of the body. That wasn't the case with me. I think that was the encouragement of an over protective mom. I still don't know why.” — Robert

• From here the diagnostician must rule out any more serious reasons for why the person is experiencing the intense headache. Could it be a symptom of another disease like an infection? Is it tenderness and swelling of the temporal artery leading to intense pain? Does the patient have a history of cancer suggesting metastases? Perhaps an HIV opportunistic disease or Lyme infection that has spread to the brain? Did the headache happen during sex, which is an indication of intracranial hermorrhage? Lots of different potential pathologies.
  • If those can be ruled out, then the doctor focuses on differentiating just what kind of headache it could be:

“Before my diagnosis, I was much harder on myself. I was (and still am, really) an overachiever, and I consumed an unhealthy amount of caffeine. My peers did the same, so I saw nothing wrong with it. However, after my migraines became much more severe in May, I could not consume any caffeine. Even the tiniest little bit triggered the most painful migraines. Some other things I’ve had to give up that turned out to be triggers are chocolate, caffeinated tea, gluten, and alcohol. Living in New York and going into law with that set of triggers is not exactly a cakewalk. Since I was a teenager, I’ve had less severe migraines, many of them being “silent” migraines. That made it extremely hard to diagnose, so I was bouncing between doctors, with many of them shrugging or throwing out diagnoses that landed nowhere. I got a lot of “it’s all in your head”s, which, in hindsight, wasn’t completely off. It’s still frustrating that such things are dismissed so easily as hypochondria though.” — Kate

The Cause of Migraines… we think.

1. It all starts with some sort of stimulus. Like we discussed, this could be a known trigger like a food or stress or it could be unknown (perhaps too much light or sound). This stimulus activates the trigeminal nerves (base of the skull) which causes the release of CGRP and substance P.
2. Both CGRP and substance P (which stands for substance Pain by the way) are pro-inflammatory proteins that cause intracranial blood vessels to dilate. This dilation is further increased by other proinflammatory molecules like histamine, bradykinin, and prostaglandins. The result is a much wider brain blood vessel than what was there before.
3. This super wide blood vessel then pushes on the inside of the brain causing pressure. Our brain detects pressure through our nociceptors and relays it as a pain, yay!
4. Likewise, excitation and inhibition in the cortex and thalamus causes further dysregulation of the trigeminal nerves leading to even more inflammation and hypersensitivity. This culminates in the intense nausea, vomiting, and visual effects.
5. To top it all off, the autonomic nervous system now tries to regulate this sudden increase of pressure in the brain by randomly constricting and dilating other blood vessels through the brain. This leads to an uneven pressure distribution activating the parasympathetic tone of the brain which may account for the tears and nasal congestion some get during their migraine.

“When I was younger, I saw several doctors who could not pinpoint an exact issue. I had the other symptoms, including aura, but I am also severely nearsighted, so they assumed it was something to do with my vision instead. Unfortunately, the first time I received a proper diagnosis of migraine was when they turned chronic in May 2020. It immediately became evident that headaches took up at least half of the month, and a solid 2/3 days per week were legitimate, full-on migraines.” — Kate

Making a Hole for the Mind Demons

• Later, ancient Egyptians would introduce the concepts of diagnosis, prognosis, and medical examination. The Ebers Papyrus (c. 1550 BC) is thought of as the oldest textbook in the world. According to the scroll, Egyptians would “bind a clay crocodile holding grain in its mouth to the head of the patient using linen” which was engraved with the names of Egyptians gods and spirits. Thus appeasing the gods would cure the headache! While the mission may have been misplaced the result was actually beneficial—compressing the skull in this way could have relieved the pain as well as collapsing the blood vessels that were causing pain. The Egyptians were also known to do trepanation.
  • The use of trepanation as a headache relief is actually much more common than we may even initially believe. For those savvy in Greek mythology you may remember the story of Athena’s birth: mighty Zeus, god of all heaven and all that exists was struck ill by a terrible headache. He called upon his son Hephaestus to relieve this pain, to which Hephaestus split Zeus’ skull in two, thus allowing Athena to burst forth. Despite the pretty metal origin story, remember that myths are stories that guide everyday people and it could be thought that this myth was actually a parallel to Greek trepanation too.
  • The story of Athena’s birth was first established 700 BC, much before the birth of the Father of Medicine Hippocrates (460-370 BC). Hippocrates revolutionized medicine for one great reason: he thought of disease as a malfunction of the body rather than a spell from demons or the gods. In his work, On Injuries of the Head, Hippocrates details instructions for proper trepanation and its dangers. Likewise, he described the first account of the visual symptoms of migraines—a shining light in the right eye followed by terrible pain in the temples that spread to the entire head and neck.
    • About 500 years after Hippocrates, the great Roman physician Galen (129-216 AD) described the connection between food and migraines.

“Lately my day to day is normal. Ever since I found out what my main trigger is for migraines, I've had a relatively normal life. Still need to watch certain foods that I eat, no red 40 for example. And get regular sleep, which can be hard with kids and work. Before, when my migraines were more frequent, it had a huge influence. Couldn't party late with friends. Or sleep in on the weekends. At the time I didn't know what my main trigger was. I didn't know red 40 could have such a huge impact. I love m&ms and didn't understand that those were a cause of my migraines. How could something so small have such a huge impact? (I'm using that as an example and don't want any misunderstanding that I was eating copious amounts of m&ms.)” — Robert

So what if I don't want a hole in my head?

“I try not to let my illness stop me too much, but there are only so many things I can do. Before things became this severe, I would not sleep, eat, or take care of myself very well. However, if I do not get enough sleep (or sleep too much), if I do not eat on time or stress myself out too much, that’s almost always a migraine trigger. If it’s storming out, that’s a migraine day. If someone around me has on a pungent perfume, my head starts to pound. I have to plan around things that I cannot control and hope for the best, but the lack of predictability can be frustrating. The pain, nausea, and vision loss are just the icing on top. Migraines can be an “invisible” disability because we do not “look sick.” I can’t tell you how many times I’ve had people tell me that, thinking it’s reassuring. I feel very fortunate that I can still exercise and am able-bodied in most other ways. However, saying someone “does not look sick” is rude, dismissive, and ableist.” — Kate

• One of the first plants used for the treatment of migraines is Feverfew, a very unassuming daisy. In ancient Greece and Persia, Feverfew was known as Parthenium, named after the Pathenon which was the Doric temple of Athena on the Acropolis in Athens. One of the greatest herbalists (perhaps ever) Nicolas Culpepper described the many benefits of Feverfew, especially for headaches. He also had a penchant for describing herbs with astrology and likened Feverfew to Venus: “[Venus] commands this herb, and has commended it to succor her sisters (women), to be a general strengthener of their wombs.” In later editions he would describe how Feverfew could be used to relieve teething pain in infants as well as a useful douche and enema to reduce inflammation as well for “St. Anthonies fire, to all hot inflammations and hot swellings.”
  • The principal chemical in Feverfew is thought to be Parthenolide, a sesquiterpene lactone of the germacranolide class. Parthenolide is found in the highest concentrations of the leaves and flowers and works by decreasing pro-inflammatory molecules. In migraines, it is thought to modulate the downstream activity of CGRP and substance P, thus limiting the effect of the migraine. Interestingly, Parthenolide is being researched for its anti-cancer properties in acute myelogenous leukaemia (AML).

• Yarrow is a wide, flat flower from the Aster family which includes other favorites such as sunflowers, chicory, and artichokes. Yarrow is widely distributed across Europe, Asia, and the Americas and I would bet that you’ve seen this plant growing in meadows and sunny areas. Yarrow’s latin name, Achillea millefolium, is derived from Achilles who apparently relied heavily on the herb to heal his wounds. In fact, yarrow has a long history as a battlefield herb for its ability to slow and stop the flow of blood. For headaches, Yarrow contains the compound Apigenin which has a potent anti-inflammatory property.

Will a plant solve my migraines? Let’s talk serotonin

• Ergotism swept through communities for as long as humans cultivated rye. Ingestion of the fungi would cause one of two effects: convulsive ergotism or gangrenous ergotism. The convulsive type was characterized by nervous dysfunction where a person would be twisting and contorting in extreme pain. According to some reports the muscle spasms could be so bad it would “tear limb from body” and “wrench the head from the neck, leaving nothing but a stump.” Gangrenous ergotism resulted in major deformations of the extremities which often resulted in auto-amputation. The Ergot would constrict blood vessels so tightly that it would cut off the flow of blood allowing infection to take hold without the immune system getting to the site of infection. Once gangrene had occurred in the fingers, toes, or ears the appendage would become mummified and eventually fall off. In both conditions, patients would have intense hallucinations.
  • In 857 AD, the first documented outbreak of Ergotism in the Rhine valley and was called the Holy Fire due to the burning sensation one felt. In 1039, another outbreak in France compelled Gaston de la Valloire to construct the first hospital for Holy Fire, dedicated to St. Anthony. Eventually over 400 hospitals would be built across France to treat the disease locking in the association as St. Anthony’s Fire. In 1056, over 40,000 people would die from a single outbreak of Ergotism. It wouldn’t be until 1670 that Dr. Thuillier would discover the link between rye and Holy Fire.
  • So what is going on here? Why was Ergot so deadly?.

• Ergotamine sparked investigations in improving its structure for therapeutic use. One of the first synthetic ergot alkaloids produced was lysergic acid diethylamide or LSD in 1943. The potent hallucinogenic activity enraptured the scientific community and sparked a huge uproar for what the mechanism is. Their result: serotonin (5HT).

• If any neurotransmitter deserves to be personified, it's serotonin. Serotonin was discovered in the 1940s and triggered a massive investigation into its potential therapeutic benefit. By the 60s, it had grown a bit and decided that it didn’t have to listen to the ‘man’, went out partying on LSD and pretty much died of an overdose by the 1970s—the scientific community was over serotonin. While it was interesting to talk about the neurotransmitter implicated in regulating sexual behavior and hallucinogens, by the 80s everyone cared about methamphetamine. At one point, it was thought that serotonin doesn’t do anything.
  • It's true, serotonin doesn’t do any one thing, it's the case of doing too many things. Serotonin is implicated in the treatment of psychiatric disorders like anxiety and depression to more physiological symptoms like vomiting, cardiovascular function, and sedation. Most receptors have a few subtypes with tight regulation dictating exactly what the effect will be. Serotonin on the other hand has 15 known subtypes of receptors with some estimates putting the true amount at 20 to 25. Today we will be looking at the 5HT-1 receptor family and its related drugs.

“Treatments… hooo boy. I’m very, very lucky - I managed to talk my doctors into trying different treatments without any resistance, but this is very much the exception, not the norm. I was first prescribed sumatriptan as an acute medication. It did help at first, but there’s a “hangover” that leaves you feeling drained and sick the next day. Over time, the sumatriptan made the pain much worse and lost efficacy, so I tried other triptans instead. Ultimately, I settled on eletriptan, which I still use.”
— Kate

• Let’s take another look at Ergotamine now that we believe serotonin is useful. Up in the top right we can see how Ergots work in two ways: direct vasoconstriction on blood vessels in the periphery (causing abortion and cutting off blood flow to fingers and toes) but it also works works on serotonin receptors in the brain. Activation of the 5HT-1B, 1D, and 1F receptors reduces the release of CGRP, which is the pro-inflammatory molecule we talked about in section 2. Remember that CGRP causes vasodilation which increases intracranial pressure resulting in the migraine. Blocking the release of CGRP stops that from happening and would decreases the effect of the migraine and potentially prevent it (or at least make it better).
  • Ergotamine is still used to this day as an anti-migraine medication although has been largely replaced by safer agents. Ergots as a class can have nasty side effects that don't make them the best choice anymore. Firstly, activation of 5HT-1b receptor can cause constriction in the arteries that feed the heart blood and oxygen. This can cause a feeling of heaviness and may even cause a heart attack in some patients. Likewise, nonselective activity on the 5HT-2a receptor found in the uterus is responsible for the spontaneous abortion and is contraindicated in pregnant patients. Finally, activation of 5HT-2b on the cardiac valves can lead to overgrowth of the valve tissue, sealing them closed resulting in pulmonary hypertension or death.

• So the hunt for something better began. By the 1970s, the effects of Ergotamine was widely known and the pathology of migraines was developing. Scientists knew that vasodilatory drugs could induce a migraine, like alcohol, and vasoconstriction medications could abort one. When serotonin was implicated in intracranial vasoconstriction, modifications of serotonin began almost immediately. By 1991 the first drug in a new class was discovered: Sumatriptan (Imitrex). All triptans have an tryptamine structure identical to serotonin; however it was soon discovered that modifying the backbone could produce potent 5HT-1B/1D effects which would results in vasoconstriction.

• All triptans operate on the same basic pharmacophore: the aromatic group (indole), protonated amine (a hydrogen donator), a hydrogen bond acceptor like oxygen or nitrogen, and a hydrophobic region. This resulted in a structure that was hydrophobic on one side while hydrophilic on the other (amphipathic).
• What is interesting about triptans is their administration. After Sumatriptan pioneered the group, the second generation of triptans were given a different formulation to aid in a quick onset of action. The most common form is an orally disintegrating tablet (ODT) whose function is to dissolve on the tongue leading to higher blood concentrations quicker than swallowing the tablet. Likewise, bypassing GI tract absorption prevents first pass metabolism or the ability of the body to deactivate a drug once ingested. Most triptans have low bioavailability (40-60%) while sumatriptan has a bioavailability of just 14% of the dose being available following absorption. Later formulations included subcutaneous injections, nasal sprays, and suppositories.

“I was first treated over 20 years ago when I was 11. The medications I've taken over the years are: imitrex (Sumatriptan) (both nasal and pill), depakote (Valproic Acid) (which had altering personality effects on me when I was 16, Maxalt (Rizatriptan), Zomig (Zolmitriptan), Relpax (Eletriptan), Lamictal (Lamotrigine), and other injectables like Emgality. Studies apparently showed that anti seizure meds have helped prevent migraines in some patients. I tried quite a few and none really decreased the consistency or intensity of my migraines.” — Robert

• The triptans changed the game for migraines as abortive agents—they stop a migraine as it is happening. In the 2000s and 2010s, a series of other drugs classes came on the market to assist in resistant abortive migraine treatment.

• In 2019, Lasmiditan (Reyvow) was discovered as the first drug part of the Ditan drug class. Right now Lasmiditan is the only drug of its class but there are two other drugs under investigation that show similar results. Lasmiditan acts exclusively on the 5HT-1F receptor which decreases the release of CGRP thus stopping vasodilation. As with any new drug, physicians have been apprehensive to use the drug first line but many view it is as an effective second or third line agent.

• The real breakthrough came with the gepants or the CGRP receptor antagonists (CGRPRAs). Instead of focusing on serotonin, these drugs prevent the binding of CGRP to its receptor, thus blocking the downstream vasodilation. Both Rimegepant (Nurtec ODT) and Ubrogepant (Ubrelvy) have shown great efficacy in aborting migraines as they happen. Likewise, since they don’t activate the serotonin receptors, there is no cardiovascular risk making them safe for patients with heart complications.

• Currently the three most used monoclonal antibody treatments for migraines are Aimovig (Erenumab), Ajovy (Fremanezumab), and Emgality (Galcanezumab). All three injections work by blocking CGRP from getting to its receptor, thus preventing the migraine. Each is administered each month or sometimes every 3 months but can be extremely expensive costing up to $700 per injection.
• A final word on some of the other adjunctive medications some may have come across are worth talking about. Since anti-migraine medications can be expensive, sometimes using a less expensive, older drug for an off label use can be just as effective as the expensive ones.
  • For pain relief, Acetaminophen, Aspirin and NSAIDs like Ibuprofen or Naproxen are often used first. Ketorolac or Diclofenac can often be added in too for anti-nausea and anti-vomiting effects. NSAIDs block the production of thromboxane which reduces platelet aggregation. This results in a reduction in the release of serotonin across the body as well providing some pain relief.

• Often you will also see Caffeine added in to boost the pain relieving properties of the NSAIDs but it also has intrinsic vasoconstrictive properties, thus acting against the pathology of the migraine. However, caffeine can also be a trigger for some, so careful use is needed.
• Another prescription combo out there is Fioricet, a combination product of acetaminophen, caffeine, and butalbital. Butalbital is a barbiturate which acts as a sedative in this combination.
• Another approach is using antihypertensive medications to help relax the vasodilation happening in the brain.
  • Beta blockers like propranolol and timolol are used to block vasodilation mediated by beta-2 adrenoreceptors. Likewise, by slowing down the heart rate, it leads to a reflexive vasoconstriction thus helping with the migraine.

Some final words from our not-so love birds

“Artificial food coloring was a huge trigger of my migraines that I recently uncovered. I know it's a trigger for others. The elimination diet, and strictly sticking to the process, I think could help figure out what food related triggers there are. Some such as strobe lights or loud sounds are easier to avoid while foods are a hit or miss. There are a lot of diets out there, might as well try out a diet to avoid migraines.” — Robert

“I just want to say I am so sorry that you have to go through this too. To everyone else crying in a dark room, praying for the pain to stop, to everyone else gritting their teeth and trying their best to get through the workday without calling out yet again, you are so valid. To our families and loved ones, please be patient. I know that this condition doesn’t just affect the migraineurs themselves, but sometimes, there is nothing else we can do. I can’t speak for everyone, but I know I’ve tried almost everything under the sun, and I still get my ass handed to me. Trust me; we don’t like sitting out on vacations or rescheduling dates and hangouts last minute any more than you. But more than that, thank you for bearing with us and supporting us when we need it most.
Many people on migraine say that you feel a lot freer once you accept that there is no “cure” to migraines. I get where they’re coming from, even if I don’t agree entirely. There is only so much you can do. I’m obnoxiously tenacious, but even I’ve come to see that sometimes, you just have to forgive yourself for not “doing more” and just meet yourself where you can be in the moment.
Good luck, and hang in there. Here’s to getting through another day.” — Kate