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"The roaring in my head is deafening!" – Migraines in the 21st century. - (2/19/2020)

By Dr. Ron Gasbarro

Maybe it is the food. The grilled-cheese doughnut from Tom & Chee’s, Glier's Goetta – that German meat and grain mush – or perhaps LaRosa’s pizza, Izzy’s 110 Reuben challenge, or Skyline chili. Whatever it is, the citizens of Cincinnati suffer more from migraines than any other US city. But watch out for Tennessee because out of the 10 most painful American cities, Tennessee has four of them. The most migraine-free cities are Boston, Massachusetts, and New Haven, Connecticut, according to MigraineAgain.com - a wellness community for people with migraine and frequent headaches.
  
Food can be a trigger.
Eating or even smelling certain foods can set off a migraine. Cheese, chocolate, and alcohol are the trigger most reported for a migraine [Finocchi, 2012]. Researchers have kicked around several hypotheses as to why some foods can set off a migraine. For example, does sensitivity to food activate specific antibodies? Small studies involving food restriction and the absence of antibodies to that food have shown some promises but have provided no conclusive evidence [Pascual, 2010; Arroyave, 2010]. Fasting can allegedly result in migraines because of resultant low blood glucose (hypoglycemia) [Dexter, 1978]. New evidence has revealed that while both migraineurs and regular headache patients have elevated blood sugar levels, higher insulin levels are only observed in migraineurs [Cavestro, 2007]. 

For decades, researchers have noted that chocolate is an instigator of migraines. An analysis of surveys reveals a highly varied picture, with the frequency of migraine episodes attributable to chocolate ranging from zero to 22.5% [Lippi, 2014]. Even in those studies reporting a more convincing association, the risk of migraines after chocolate ingestion was found to be 2- to 3-fold lower than that reported for exposure to other conventional triggers such as stress, fasting, lack of sleep, and alcoholic beverages. Conclusion: Since studies have varied results, researchers conclude that, in persons prone to migraines, the risk of developing an attack after consuming chocolate is as likely as administering a placebo. Thus, the common belief that migraine patients should avoid chocolate lacks a reliable scientific basis.   

Can someone please turn off the lights?
Light is a factor in migraines. 
Light can trigger a migraine. Research shows that 38% of migraineurs report light as a trigger for their attacks [Kelman, 2007]. Sunlight, fluorescent lights, and liquid crystal displays (LCD) and light-emitting diodes from computers, televisions, and smartphone screens are all causes of migraines. 
Suddenly becoming sensitive to light during an attack. A survey of more than 4,000 individuals with a migraine history revealed that almost 90% became light-sensitive during an attack [Giffin, 2016]. Furthermore, studies have shown that photophobia intolerance to light) and light sensitivity can linger during the recovery phase (postdrome) following an attack. 
A quiet room for recovery. Typically, a person with a migraine will find a dark, quiet environment in which to rest. And a dark room appears to work for 92% of the people who have tried it [Malone, 2015]. Surveys have shown that an unlit, noiseless room can repress migraine pain within 20 minutes after the onset of a migraine attack. 

The world is a hostile place for migraineurs.
Fluorescent bulbs are a significant instigator for migraine attacks. Such lighting displays a pulsing that is unnoticeable to the human eye but is still detected by the brain. Fluorescent bulbs flicker at a rate of 100 to 20,000 times per second. Sensitivity to this pulsing is so frequent it has been termed, “fluorescent sickness.” Those that experience migraine appear to be predominantly at risk. Such lighting is commonplace in most retail stores, warehouses, and workplaces. Thus, workers in these environments can experience double the frequency of their headaches [Wilkins, 2010].  

Visible light has wavelengths of about 380 nanometers (nm) to 750 nm. Studies show that blue-green light, which occurs at 480 nm, is particularly disturbing to those with eye problems. Not only can these wavelengths contribute to eyestrain and affect sleep patterns, but they also produce more significant discomfort for people with migraines and can induce attacks more easily [Tatsumoto, 2013]. The omnipresence of technology has made these wavelengths commonplace in the world around us: computers, phones, TVs, energy-saving light bulbs, compact fluorescent bulbs, and even sunlight.  

Isn’t a migraine just a bad headache? [Migraine Research Foundation, 2020]
Migraine is a neurological disease with extremely incapacitating symptoms 
It is characteristically a relentless throbbing pain, usually on one side of the head. However, in about one-third of attacks, both sides are affected
In some cases, other disabling symptoms are present without head pain, such as nausea and vomiting
Other disabling symptoms can accompany an attack: visual disturbances, dizziness, hypersensitivity to light, sound, touch, and smell, and numbness or tingling in arms, legs, or face
One in 4 migraine sufferers have a visual disturbance called an aura, which can precede the actual head pain
Attacks usually last between 4 and 72 hours

Migraines by the numbers 
Analyses of patient records demonstrate that many Americans carry the burden of migraine: [Burch, 2018]
Approximately 12% of all Americans – including children – suffer from migraine [Migraine Research Foundation, 2020]
Females have more migraine days than males: 20.7% vs. 9.7%
The prevalence of migraine or severe headache was highest in Native Americans and Alaska Natives (18.4%) compared with whites, blacks, or Hispanics, with the lowest incidence in Asians (11.3%). 
A more significant migraine burden is observed in those ages 18-44 (17.9%), unemployed people (21.4%), those with family income less than $35,000 per year (19.9%), and the elderly and disabled (16.4%).  
Headache is the fourth most common reason for emergency room visits. In women of reproductive age, headache is the third leading reason for ER visits.

The eyes have it – Ocular migraine
Some people experience a relatively rare event called an ocular migraine – also called retinal migraine [Wallis, 2015]. Migraines, in general, are usually accompanied by a precedent aura, that is, a sensation such as a bright light or a cold breeze. The difference between people with cranial migraines compared to those with ocular migraines is that the latter only affects one eye and lasts only 10 to 20 minutes before vision gradually returns. Pain on one side of the head has also been reported. The symptoms involve seeing scintillations (an extreme onset of brightness), scotoma (dizziness), or blindness. The event typically resolves itself without medication. However, this type of migraine can be dangerous if one is driving or operating machinery of any kind.   

Researchers believe that ocular migraines are the result of a brief reduction in blood flow, which may be caused by a spasm in the blood vessels. One study of 80 migraineurs with unilateral head pain found that blood flow to the pupil on the side of the head with pain was less than the blood flow in the pupil of the other eye [Drummond, 1990]. The pupil on the side with head pain was also less dilated and took longer to dilate than the pupil on the other side. Subsequent research indicates that neurotransmitters are released during an attack, which inflames brain tissue and blood vessels [Yuan, 2018].  

Ancient treatments – What’s in your toolbox?
The first descriptions of migraine reach back almost four millennia from the ancient civilizations of Mesopotamia as well as through Egyptian, Roman, and Greek times. Through Byzantine, Arabic, and Medieval epochs, only erratic references exist until the 17th century, when European physicians began to give full case reports [Rose, 1995]. Writings recovered from ancient Egypt described the visual aura that can herald the headache and a partial relief that occurred via vomiting [Borsook, 2012]. However, the surgical procedures used could be far more severe than the migraine. 

Craniotomy is the surgical procedure in which a hole is drilled through the skull to access the brain. The remains of many ancient people have been found throughout the world who have had craniotomies. Trepanation is an ancient form of a primitive craniotomy [Hobert, 2017]. Extensive evidence shows that ancient civilizations performed this practice in Europe, Africa, and South America, where archaeologists have unearthed thousands of trepanned skulls dating back to the Neolithic period (10,000–4,500 BC). In a time when sterile technique and antimicrobials were unknown, the chances of surviving such a procedure were dismal. The technique was both medical – for pain – and spiritual – to release evil spirits that were erroneously blamed for severe psychiatric illnesses [Hobert, 2017]. 

The ancient Chinese were believed not to perform such an archaic method, relying on herbs and medicine instead. However, archaeological  evidence reveals that trepanation was practiced throughout China thousands of years ago [Hobert, 2017]. A considerable number of trepanned Chinese skulls have shown signs of healing to suggest that some patients survived the surgery.

Although ancient craniotomies are now considered crude and barbaric, they are still performed today under sterile conditions to access the brain. There are several types: [Kellicker, 2018]
Awake—Before removing any brain tissue, the patient is awakened, and the neurosurgeon creates a cortical map, using a small electrical stimulation device to observe the changes in the patient's condition when an area is stimulated [Shinoura, 2011]. If an area is stimulated and the patient moves or loses some ability, like speech, the surgeon knows that the area is vital and cannot be removed or cut through to access a tumor. 
Stereotactic—computer navigation is used to take images of the problem area, which then guide the surgeon to the precise location in the brain through one or more burr holes
Endoscopic— the neurosurgeon inserts a lighted scope with a camera into the brain through one or more burr holes.

Traditional medications for preventing migraines 
Table 1 – Medications for migraine prophylaxis [Silberstein, 2015]


Triptans in the acute treatment of migraine
The triptans are a class of anti-migraine medications that are also termed selective 5-hydroxytryptamine/serotonin1B/1D (5-HT1B/1D) agonists [Ferrari, 2002]. Although triptans are widely used in the acute management of migraine, uncertainty exists around the comparative efficacy of triptans among each other and versus non-triptan migraine treatments. 

Analyses of 133 randomized, controlled clinical trials compared the relative efficacy of triptans (alone or in combination with other drugs) for acute treatment of migraines. The studies compared them with other triptan agents, non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA), acetaminophen, ergots, opioids, or anti-emetics [Cameron, 2015]. Results included the following: 
Standard dose triptans relieved headaches within 2 hours in 42 to 76% of patients, and 2-hour sustained freedom from pain was achieved for 18% to 50% of patients. 
Standard dose triptans provided sustained headache relief at 24 hours in 29% to 50% of patients and sustained freedom from pain in 18% to 33% of patients. 
For 2-hour headache relief, standard dose triptan achieved better outcomes (42% to 76% response) than ergots (38%); equal or better outcomes than NSAIDs, ASA, and acetaminophen (46% to 52%); and equal or slightly worse outcomes than combination therapy (62% to 80%). 
Among individual triptans, sumatriptan subcutaneous injection, rizatriptan ODT (oral dissolving tablets), zolmitriptan ODT, and eletriptan tablets were associated with the most favorable outcomes. 
Use of triptans in combination with ASA or acetaminophen, or using alternative modes of administration such as injectables, may be associated with slightly better outcomes than standard dose triptan tablets.

The new kids on the block 
While the triptans (5-HT1B/1D agonists) have been the savior for many people who experience migraines, the drug class has two drawbacks:
They relieve pain at 2-hours and 24-hours in a relatively low fraction of patients [Cameron, 2015]. Approximately one-third of people with migraines do not respond to triptans; 30% to 40% have recurrent attacks [Denier, 2008]. Room for improvement exists. 
Concerns about their cardiovascular safety arise from the observation that 5HT-1B receptors are present on the coronary arteries. Thus, they are contraindicated in patients with coronary artery disease, cerebrovascular disease, peripheral vascular disease, and uncontrolled hypertension. [Pringsheim, 2014].
Also, while they can relieve migraine pain, the effectiveness of this drug class in preventing migraines is limited to several triptans. However, there are no approved indications for these drugs in migraine prophylaxis [Silberstein, 2012]. Because of these unmet needs in migraine pharmacotherapy, researchers have developed new molecular entities to either prevent or abort these headache types. 

CGRP blockers
CGRP stands for Calcitonin Gene-Related Peptides. They are short chains of amino acids and are produced by neurons in the body. CGRP is released during migraine attacks [Deen, 2017], and it may play a causative role in the induction of migraine attacks. CGRP blockers inhibit the peptides, therefore, preventing the occurrence of migraines. CGRP blockers are significantly more effective than placebo in preventing migraines, and their efficacy is on par with other prophylactic treatments [Deen, 2017]. Thus, blocking CGRP in migraine patients is seemingly both efficient and well-tolerated. However, CGRP and its receptor are plentiful in both the blood vessels and in the peripheral and central nervous systems. Therefore, CGRP blockade may pose a risk in subjects with comorbidities such as cardiovascular diseases. Also, long-term effects are still unknown. Whether blocking CGRP could potentially transform transient mild cerebral ischemia into a full-blown brain infarct is not yet known [MaassenVanDenBrink, 2016]. Future studies should include patients with preexisting cardiovascular conditions. However, based on current knowledge, the pros of blocking CGRP in migraine patients exceed the cons.

Three CGRPs have been approved for marketing: fremanezumab–vfrm (Ajovy®), erenumab-aooe (Aimovig®), and galcanezumab-gnlm (Emgality®). Ubrogepant (Ubrelvy®) is a medication used for the acute treatment of migraine with or without aura in adults [Dodick, 2019]. CGRPs are not indicated for the prevention of migraine. It is the first drug in the CGRP class approved for the acute treatment of migraine. [See Table 2]

Ditans
Ditans are serotonin receptor agonists that selectively bind to the 5-HT-1F receptor [Do, 2019], rather than binding to the 5-HT-1B and 1D receptors as the triptans do. The lack of affinity for these 1B and 1D receptors might result in fewer side effects related to vasoconstriction compared to triptans in susceptible people, such as those with ischemic heart disease, Reynaud’s phenomenon or after myocardial infarction. 

Table 2 – New migraine drugs

Conclusions
Therapy for migraines has improved dramatically since the days of the rusty, unsterile craniotomy. The clinician and patient have many options for both the prevention and treatment of migraine attacks, which can incapacitate the patient for hours and sometimes days.  

Ron Gasbarro, PharmD, is a registered pharmacist, medical writer, and principal at Rx-Press.com. 

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