Course Content

Ideals in Brief

Migraine is thought to be one of the oldest known disease to humankind with treatment methods dating back to medieval times, and is considered the most prevalent neurological disease, affecting millions of Americans. Although there is no cure, there are treatment options available to manage the symptoms. Yet, migraine research to find a cure is grossly underfunded. This program will address treatment options, as well as probable prognoses for a migraine sufferer.

According to Lisa Jacobson, “It’s a real illness – it’s a neurological condition, but you don’t feel as though you’re even allowed to express what’s going on, because most people don’t take your symptoms seriously. That’s because it’s an invisible illness. No one can see your pain, nausea, or sensitivity to light, sound, smell, or touch.”1

Ellen, who first experienced a migraine at 26 thought she was having a stroke, and went straight to the emergency room/department, where she was quickly diagnosed with “common migraine.”2

Individuals who experience migraines often encounter misconceptions about what it means to have this condition. Those who have experienced migraines know it is no ordinary headache (Figure 1).3 Symptoms can last for days, and the misconception that migraines are just ordinary headaches is widespread and extends well beyond the physical symptoms that accompany a migraine attack. Those who have never experienced a migraine do not realize the significant psychological and social effects the condition has, nor how disabling it can be.

People who suffer with migraines have voiced nine statements that they want to be made known to confute the migraine stigma:1

• It is more than just a headache. “It is a disease of the brain”, says Shirley Kessel, a resident of Lafayette Hill, who is the executive director of Miles for Migraines, a nonprofit organization that organizes walking and running events to raise money for migraine research.
• Symptoms can last for days before, during, and after an attack. “It is a spectrum disease,” meaning there can be a mild or brutal attack or a multi-day attack that requires hospitalization, according to Paula Dumas, an Atlanta resident who is the founder of Migraine Again, an online wellness community for people who experience migraines and other forms of headache.
• For some, symptoms never end. A small population of individuals with migraines experience a chronic, rather than an episodic (comes and goes), form which means they have a migraine lasting four to 72 hours on 15 or more days each month for greater than three months, with at least eight of those days including additional symptoms, according to Dr. Robert Cowan, a professor of neurology and the director of headache program at Stanford University Medicine.
• Treatments for migraines are not perfect. It is important to understand that drugs do not work consistently for everyone.
• Migraine attacks often cannot be prevented. Even with self-care routines such as, sleeping, eating, and exercising on a regular schedule, migraines can still occur.
• It is often a very lonely experience. “Due to a lack of understanding from the public, family and friends, people with migraines often feel that nobody comprehends what they are going through,” says Kessel.
• It can be devastating on work, family and social life. Migraine sufferers fear the risk of losing family, friends, and employment.
• Finding the right health care provider can be difficult. “There are approximately 500 board-certified headache specialists in the United States, which means about one doctor for every 65,000 to 85,000 migraine patients, depending on the estimate used”, according to Cowan. Lisa Jacobson surmises that the lack of specialists in the country, as well as worldwide is due to migraines not being taken seriously as an illness.  Dumas notes, that most doctors “get little to no training in medical school in headaches and migraine.”
• Living with migraines takes tenacity, and resilience. “It takes courage to keep fighting,” according to Dumas. “Imagine how hard it is to drag yourself out of bed, in pain, day after day, and fight a disease that others think is stress-induced or imagined.”

Despite the discrimination, stigma, and social implications that can accompany migraine sufferers, several well-known people have been reported or even publicly spoken about their migraine attacks, including: Ben Affleck, Whoopi Goldberg, Kareem Abdul-Jabbar, Janet Jackson, Cindy McCain, Sigmund Freud, Vincent Van Gogh, Thomas Jefferson, Charles Darwin, and Marcia Cross, who has been a migraineur (migraine sufferer) since a teenager and is a spokeswoman for a migraine triptan medication. She has partnered with GlaxoSmithKline  to disseminate the word that migraine is not “just a headache”.4,5

There are other types of migraines that are rare, and extreme, but worth mentioning, and are named based on the body part that is affected. Most of these variants are very rare. Note: For the purpose of this CE program the focus will be migraines that affect the brain. Migraine variants include:6,7

• Hemiplegic migraines – including two types, familial hemiplegic migraine (FHM) and sporadic hemiplegic migraine (SHM); and is characterized by paralysis or weakness on one side of the body, and other symptoms that mimic a stroke
• Ophthalmic migraine (ocular or retinal migraines) – characterized by repeated instances of visual disturbances
• Ophthalmoplegic migraine – characterized by intense migraine pain behind the eye.
• Menstrual migraine – related to a woman’s menstrual cycle and the fluctuations of hormones that precede it.
• Abdominal migraine – characterized by moderate to severe pain in the middle of the abdomen with a duration of one to 72 hours, with little or no headache. This type of migraine commonly affects young children.
• Basilar migraine (or Bickerstaff syndrome) – believed to be related to hormonal changes that primarily affect females during adolescence and young adulthood.
• Chronic migraine (or sometimes called transformed migraine) – characterized by repeated and ongoing head migraines for at least half of the days in a month or for many, daily or almost daily. Frequency of migraines will increase over time.
• Vertebrobasilar migraine – vertigo, which may be caused by an anomaly in the lower part of the brain.
• Status migrainosus – very rare, serious and prolonged migraine, usually lasting more than 72 hours. The migraineur must be hospitalized, due to associated complications, including dehydration  which requires intravenous treatment to remain hydrated.

Based on information provided from the Migraine Research Foundation, migraines affect 39 million women, men, and children in the United States, and one billion worldwide. 8 Migraine is the 3rd most prevalent illness the world, and the 6th most disabling.8

Migraines are more commonly identified in women than men, which is most likely hormonally-driven. Migraines initially appear between the ages of 10 and 45, and most commonly occur between the ages of 15 and 55, seen in lowest income populations, and in Caucasian people .9,10,11

Migraines have serious economic consequences, which makes it a public health issue. Healthcare and “hidden,” or indirect, costs such as, job absenteeism (lost productivity) associated with migraines are estimated to be as high as $36 billion annually in the United States.8,12 American employers lose more than $13 billion per year, due to 113 million lost work days.8

In 2015, the medical cost of treating chronic migraine was greater than $5.4 billion, and migraineurs spent over $41 billion on treating their overall condition.8 Like others who suffer from chronic illnesses, migraineurs experience the high costs of medical services and limited support and access to quality care; thereby, increasing the risk for other physical and psychological conditions.8

Migraine is one of the oldest known diseases to affect humankind.10

As early as 1200 B.C.E., headache with neuralgia was recorded in the medical documents of the ancient Egyptians noting descriptions of the clinical and medical symptoms in earliest writings; it appears that migraines are among the oldest known disease to humankind.10

In 400 B.C.E., Hippocrates described in detail the occurrence of migraine attacks, the visual disturbances during migraine aura, and the relief from vomiting (“to release the bad vapors”).10

The word migraine is derived from the Greek word “hemicrania”, which means half the skull or half-head. Galenus of Pergamon used the term; he thought there was a connection between the stomach and the brain, due to the nausea and vomiting that was often associated with an attack.10

Treatment of migraines date back to medieval times and based on limited medical understanding. Treatment or procedures were derived from superstition or witchcraft such as trepanning, a surgical procedure that involved non-fatal drilling of holes into the skull to release evil spirits. It was thought that this drastic step was taken in response to headaches.10

(973 – 1037), Ibn Sina, an Islamic philosopher-scientist, described migraine symptoms in his textbook On Medicine, as “…small movements, drinking and eating, and sounds provoke the pain…The patient cannot tolerate the sound of speaking and light. He would like to rest in darkness alone.”10

In 1938, Graham and Wolff published a paper promoting ergotamine tartrate to relieve migraines. This was considered perhaps the first true medicine providing relief by causing vasoconstriction in the brain blood vessels. Wolff later developed the experimental approach to the study of headache and elaborated the vascular theory of migraine, which is now surpassed by the genetic, neurogenic model of migraine.10

In the 1950s, the newer ergotamine-derived drug, dihydroergotamine (DHE) , was found to act   non-selectively on all serotonin receptor subtypes. This action results in a decrease in transmission of pain messages along nerve fibers and binds to dopamine leading to vasoconstriction.10,13,14

In 1988, migraine and other headache disorders were first comprehensively classified by the International Headache Society (HIS).9

The 1990s saw the development of triptans, such as the medication Imitrex (sumatriptan), a selective agonist specifically targeted for the serotonin 5-HT1 receptor, used for acute treatment of migraine attacks.10

Active Learning

As mentioned, Imitrex (sumatriptan) is a medication that is used to treat acute migraine attacks. List other triptan medications, and their route of administration that is used to abort migraines.  How does your list compare to the information provided in the program?

The conclusive etiology or cause of migraines is still unknown; however, it is believed to be due to environmental and genetic factors. Family history is indicative to a genetic predisposition. It is estimated that 70% of migraineurs have a close relative, like parent or sibling with a history of migraine. This genetic relationship is stronger for migraines with aura, than for migraines without aura.14,16 The nature of this genetic influence is not entirely understood.

Genetic implication was first observed and defined in individuals when a single-gene defect was isolated in familial hemiplegic migraine (FHM) , a type ofmigraine with aura, which is inherited in an autosomal matter.15,16

In 2012, genetic linkage to migraines was revealed.10 There are four gene loci (region of a chromosome occupied by a particular gene) that have been identified and appear to be involved in the underlying biology that results in migraine symptoms. The identified gene loci are: LRP1 Locus, TRPM8 Locus, MEF2D Locus, TGFBR2 Locus.10 Ongoing functional studies are needed to further examine the underlying molecular pathways to identify acceptable treatment targets for migraines.

Brain tissue itself lacks pain-sensitive nerves and does not feel pain.7 However, information about touch, pain, temperature, and vibration in the head and neck is sent to the brain by the trigeminal nerve (pair of cranial nerves at the base of the brain); therefore, headaches occur when pain-sensitive nerve endings called nociceptors (nerve fiber endings that receive and transmit pain signals) react to headache triggers (something that brings about a disease or condition), and send messages through the trigeminal nerve to the thalamus (brain “relay station” for pain sensation from all over the body).7

Headaches are defined as pain located in any area of the head, usually affecting both sides, and can vary from mild to moderate, which can last from 30 minutes for up to a period of one week.17,18 The pain is a result of pain-sensitive nerves in the scalp, blood vessels, and other brain tissues that send signals that register as pain in the brain cells.17 Areas that can be affected by headaches are: forehead, temples and back of the neck. Some factors that can provoke a headache are stress, anxiety and muscle strain.18

Migraines are complex, multi-factorial, disabling and considered a hereditary neurovascular (neural and vascular event that initiates a migraine) headache disorder.14,15 Migraine pain is most often unilateral (one side of the head), but can be bilateral (both sides of the head) and is characterized by recurrent attacks or is episodic (comes and goes). To be considered a migraine the pain must have at least a combination of three to five features:14,17

• Moderate to severe
• Throbbing/pulsating
• Accompanied by either nausea and/or vomiting
• Photophobia (sensitivity to light) and phonophobia (sensitivity to sound)
• Aggravated by physical activity

Due to the disease itself or a genetic predisposition  the migraine brain is structurally and functionally altered. The functional, molecular, and anatomical anomalies contribute to a neuronal substrate (specific substance or layer) for a hyper-sensitive fluctuation in homeostasis (equilibrium), which leads to a decreased ability to adapt, and the recurrence of headache.13,15

Migraine attacks are thought to originate from the following areas:15

• Hypothalamus/Thalamus
• Brainstem
• Cortex

With neurological complexities affecting the multiple cortical, subcortical, and brainstem areas that regulate autonomic, affective, cognitive, and sensory functions.15

The pathophysiology  of migraines (as mentioned previously) is believed to be neurovascular with evidence supporting the following:16

• Beginning with the brain and distributing to the blood vessels (vascular)
• Neuronal mechanism
• Intensified excitability of the cerebral cortex
• Abnormal control of pain neurons in the trigeminal nucleus of the brainstem

Migraine attacks are likely to begin centrally, in brain areas capable of generating the classical neurological symptoms, whereas the headache phase start with activation of meningeal nociceptors at the origin of the trigeminovascular system.15 This activation of the trigeminovascular pathway act as a precursor for explaining why the pain is restricted to the head and intensifies when intracranial pressure increases.15

The three main causes of migraines (vascular instability: vasoconstriction (can improve headache) – constriction/narrowing of blood vessels, increase of blood pressure, and vasodilation (provoke an attack) – dilation/expanding of blood vessels, decrease of blood pressure):19

• Inflammation – inflammation influences the endocrine (glands that secrete hormones) and neurotransmitter levels, which can modulate or change inflammation. Inflammation contributes to migraines because it causes changes in the trigeminal nerve (mediates pain). Specifically, a cytokine called IL-1b increases cyclooxygenase (COX-2), an enzyme responsible for the formation of prostaglandin, which control processes, such as inflammation. The COX-2 causes the trigeminal nerve to release calcitonin gene-related peptide (CGRP); this released CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation. This CGRP release is perhaps the most significant cause of migraines.
• Endocrine Dysregulation – hormones contribute in modulating the vascular system, and a dysfunction in the endocrine system can result in an unbalanced level of the following (causing either vasoconstriction or vasodilation):

• Angiotensin II – Vasoconstriction 
• Cortisol – vasoconstriction
• Epinephrine and norepinephrine – vasoconstriction
• Estrogen – vasodilation
• Melatonin – vasoconstriction
• Neuropeptide Y – vasoconstriction
• Substance P – vasoconstriction
• Testosterone – vasoconstriction
• Vasopressin – vasoconstriction

Substance P causes neurogenic inflammation, and pain perception. Substance P is released with glutamate where if too much glutamate is released, the result may be an increase in pain perception.

• Neurotransmitter Dysregulation – inflammation causes glutamate excitotoxicity
• Glutamate – vasodilation
• GABA – vasodilation
• Acetylcholine – vasoconstrictor, deficiency causes vasodilation
• Serotonin – vasoconstrictor, deficiency causes vasodilation

Serotonin (vasoconstrictor) levels tend to decrease during a migraine. This may cause the         trigeminal nerve to release neuropeptides (neurokinin A, Substance P, CGRP) which   travel to the meninges (outer covering of brain), producing a migraine.20

Migraines can occur in four phases/stages, although a migraineur may not experience all phases. The phases consist of Prodrome (Premonitory), Aura, Headache (Attack), Postdrome:14,16,20,21

• Prodrome (Premonitory) – approximately 60% of migraineurs experience this phase, which occurs 24 to 48 hours before the migraine. There may be subtle early signs, symptoms, or changes that precede the upcoming migraine, and although the features vary, they tend to be consistent for a given individual.
• Aura – a transient focal neurological phenomenon, which can occur before or during a migraine.
• Headache (Attack) – varies from person to person. Approximately 40% of cases have pain that is bilateral, and is accompanied with neck pain, lasting three to four days.
• Postdrome – final phase or the after effect of the migraine attack. The migraineur may feel exhausted or very tired, while others feel exhilarated. This phase can last up to 24 hours. Figure 4 depicts of the four phases/stages.22

There are two major types of migraine,with and without aura.7

• Migraine with aura (classic migraine) – often associated as a warning sign before any pain manifests but may occur during or afterward. Also, an aura can occur without headache pain, which can occur at any time. Pre-clinical and clinical studies suggest that migraine aura is caused by cortical spreading depression (CSD).15 In 1944, Leao proposed the theory of CSD to explain the mechanism of migraine with aura as a wave of depolarization/excitation followed by hyperpolarization/inhibition in the cortical gray matter (neurons and glia). This depolarization causes the aura phase, which activates trigeminal fibers, causing the headache. The neurochemical basis of CSD is the release of potassium or the excitatory amino acid glutamate from neural tissue. The release depolarizes the adjacent tissue, releasing more neurotransmitters, facilitating the spreading depression.14,15
• Auras typically appear slowly over five to 20 minutes and last up to an hour. They can consist of visual disturbances and other neurological symptoms (sensory/motor effects). Visual auras include:23
• Blind spots

• Colored spots
• Flashes of light
• Light sparks and stars
• Tunnel vision
• Zigzag vision

Other symptoms that can affect the senses and movement include:20,23

• Paresthesia (abnormal sensation), such as, tingling, numbness, pins and needles that start in the fingers or arm and move to face
• Confusion and cognitive impairment
• Hearing noises or music that are not actually there
• Loss of appetite
• Nausea
• Muscle weakness
• Photophobia and phonophobia or increased sensitivity to noise
• Speech impairment, such as the inability to form words, but still knowing what is to be said
• Sudden jerk or uncontrollable movements
• Sweating

Sometimes an aura can occur without any other symptoms or sensations, often called a silent migraine this type of migraine is commonly seen in migraineurs 50 years or older.23

Migraine without aura (common migraine) – More frequent form of migraine, in which headache pain occurs without warning and is usually unilateral, with pain worsening with movement.  Symptoms include:7,11,18,20,23

• Blurred vision or temporary loss of vision
• Changes in mood (moodiness)
• Confusion
• Fatigue
• Nausea/vomiting
• Photophobia, phonophobia or increased sensitivity to noise
• Pain behind the ear or eye or periorbital area
• Stiffness in shoulders or neck

Even when a migraineur executes preventive measures to avoid a migraine, triggers can still be elicited. Triggers can result from emotional, environmental, medication/diet (food and food additives), and biological/sleep/physical changes.

Table 1 lists some specific known triggers.14,17,21,24

Table 1. Triggers
Emotional	Environmental	Medication/diet (food and food additives)	Biological/sleep/physical factors
Anxiety	Loud noises	Medications (e.g., nitroglycerin, estrogen)	Hormonal changes in women (menstruation, ovulation, oral contraceptives, or hormone replacement therapy (HRT)
Stress	Bright/flashing lights	Migraine medication overuse	Changes in wake-sleep pattern (too much or too little sleep), including jet lag.
Depression	Strong smells (perfumes/cologne, industrial compounds	Cured or processed meats (containing nitrates)	Overexertion (too much physical activity, including sexual activity)
	Sudden environmental or barometric/climate changes	Artificial sweeteners/Monosodium glutamate (MSG)
	Tobacco/smoking	Aged cheese (tyramine)
	Motion sickness	Yeast
	Allergies	Some fruits (citrus) or nuts
	Head trauma	Alcohol (e.g. red wine)
	Tension in neck and shoulders	Caffeine
	Eye strain	Dehydration
	Hypertension (uncommon)	Skipped meals

In 2013, the International Classification of Headache Disorders, 3rd edition (IHCD-3) beta was published and recognized by the World Health Organization (WHO). Researchers and clinicians refer to its diagnostic criteria.9

When compared to other chronic diseases, migraines continue to be poorly understood, and often undiagnosed. Almost 50% of migraineurs have not been diagnosed.11

There is no specific test to diagnose a migraine headache, but ruling out other medical conditions is of importance when diagnosing migraines. Diagnosis is determined by symptoms, medical history, physical/neurological exam, and applying the ICHD-3 criteria.14,21 The criteria for diagnosing migraines without aura are depicted below, with these indications not attributable to another disorder.14

Note: For migraines with aura, two attacks suffice for diagnosis.

Currently, there is no cure for migraines. Therefore, the two primary goals for migraine therapy is to terminate (abort) acute attacks, and to prevent (prophylactic) the next attack from occurring, which consists of acute and preventative therapy.

Acute therapy is an attempt to stop the progression of a headache that has begun, and preventative therapy (in the absence of a headache) is to reduce the severity, frequency, and/or duration of an attack, improve responsiveness to abortive therapy, and possibly improve the migraineur’s quality of life (reduce disability). Overall, management entails: trigger avoidance, acute symptomatic control and preventative medication.

Migraine treatment types may be based on whether attacks are mild, moderate or severe. Acute treatment (abortive) are classified as:7,10,14,25

• Selective serotonin receptor (5-HT1) agonist or triptans – increase levels of serotonin (neurotransmitter) in the brain by constricting the dilated blood vessels, and relaxing the pain (reduce pain threshold), and associated symptoms. Preferred treatment for moderate to severe pain. Table 214,26 lists triptans dosage form, route of administration, and duration of action.
• Ergot alkaloids (derivatives) – include drugs such as Ergomar (ergotamine tartrate) and Migranal DHE (dihydroergotamine).Mechanism of actions for this class were discussed earlier in the program.
• Analgesics – these medications demonstrate pain and antipyretic (fever) reducing properties and are used to treat mild to moderate pain, including acetaminophen, aspirin, and Excedrin Migraine.
• Nonsteroidal anti-inflammatory drugs (NSAID) – these medications demonstrate anti-inflammatory, analgesic, and antipyretic effects and are used for mild to moderately-severe pain. These medications work by blocking the enzyme COX-2, which is responsible for prostaglandin synthesis, and include Naprosyn (Naproxen), and Motrin (Ibuprofen), Orudis (Ketoprofen), Toradol/Sprix (Ketorolac). Ketorolac is a short-term (up to five days) NSAID used for moderate to moderately severe acute pain requiring analgesia at the opioid level.
• Combination analgesics/products – combination of drugs such as, butalbital, acetaminophen/aspirin plus caffeine (Fioricet, Fiornal), and Midrin (Isomethephene/vasoconstrictor, dichloralphenazone/muscle relaxant, and acetaminophen/analgesic).
• Narcotics/Opioids – prescribed when a migraine attack may be resistant to simple analgesics. Only prescribed briefly to relieve pain, and should not be used to treat chronic headaches. Medication can include: Tylenol#3 and 4 (acetaminophen and codeine), Demerol (Meperidine), Dilaudid (Hydromorphine), MS Contin, Avinza, Kadian (Morphine sulfate), Oxycontin (Oxycodone), Percocet (Oxycodone and acetaminophen), Norco (hydrocodone and acetaminophen).
• Antiemetics – dopamine antagonists used to treat nausea and vomiting. Medications include: Thorazine (Chlorpromazine), Compro suppository/Compazine (Prochlorperazine), and Reglan (Metochlopramide).

Table 2. Triptans
Drug name (brand/generic)	Dosage form	Route of administration	Duration of Action (Half-life)
Amerge (Naratriptan)	Tablet	Oral	6 hours
Axert (Almotriptan)	Tablet	Oral	3 to 4 hours
Frova (Frovatriptan)	Tablet	Oral	26 to 30 hours
Imitrex  (Sumatriptan)	Tablet	Oral	~ 2.5 hours
Imitrex (Sumatriptan)	Spray	Nasal	~ 2 hours
Imitrex StatDose	Pen	Subcutaneous (under the skin)	1.7 to 3.1 hours
Onzetra Xsail (Sumatriptan)	Powder	Nasal	3 hours
Sumavel Dosepro (sumatriptan)	injection	Subcutaneous (under the skin)	1.7 to 3.1 hours
Zembrace-SymTouch (Sumatriptan)	Injection	Subcutaneous (under the skin)	1.7 to 3.1 hours
Treximet (Sumatriptan and Naproxen)	Tablet	Oral	2 hours and 19 hours accordingly
Maxalt, Maxalt-MLT (Rizatriptan)	Tablet and Rapid dissolving Tablet	Oral	2- 3 hours
Relpax (Eletriptan)	Tablet	Oral	4 hours
Zomig, Zomig ZMT (Zolmitriptan)	Tablet, rapid dissolving tablet, Spray	Oral, Nasal	3 hours

Preventative treatment is considered based on the migraineur experiencing the following:14

• Attacks greater than two months
• Attack duration longer than 24 hours
• Attacks that disrupt migraineurs life style, with significant disability that last three or more days
• Failed or overused abortive therapy
• Symptomatic medication is ineffective or contraindicated
• Use abortive medication more than twice daily

Several preventative treatments consist of medications initially marketed or targeted to treat other conditions. These medications include:14,16,25,27

• Antihypertensives (Ace-inhibitor, Beta-blockers, Calcium Channel Blockers)
• Ace-inhibitor – useful in reducing the severity of migraines.
• Beta-blockers – can reduce the frequency and severity of migraines.
• Calcium Channel Blockers – appear to work by preventing the blood vessels from either narrowing or widening, which affects blood flow to the brain. Also, may be useful in preventing migraine with aura.
• Anticonvulsants/antiepileptics (seizure medication) – increase levels of certain neurotransmitters and lessen pain impulses, drugs include: Topamax (Topiramate, Depacon (Valproate), Depakote (Divalproex), and Lamictal (Lamotrigine)
• Antidepressants (Tricyclics, Selective Serotonin-Reuptake Inhibitors or SSRI, Selective Norepinephrine-Reuptake Inhibitor or SNRI) – help prevent migraines by working on different chemicals in the brain. They increase the productions of serotonin and possibly other chemicals, such as, norepinephrine and dopamine.
• Botox (Botulinum Toxin) – OnabotulinumtoxinA, neuromuscular blocking agent.
• Calcitonin Gene-Related peptide (CGRP) Inhibitor – inhibits CGRP; CGRP concentrations decreases following administration of triptans. Inhibition is a new pathway to prevent acute migraine attacks.
• Almovig (Erenumab – first in a new class of drugs) – human monoclonal antibody that binds to CGRP receptor and antagonizes CGRP receptor function.

Table 3. Antihypertensives and Antidepressants specific classes with associated drug
Ace-Inhibitor	Beta-Blocker	Calcium Channel Blocker		Tricyclic	SSRIs	SNRIs
Zestril (Lisinopril)	(Propranolol) (Timolol) (Metoprolol)	Calan (Verapamil)		Elavil (Amitriptyline) Pamelor (Nortriptyline) Silenor (Doxepin) Vivactil (Protriptyline)	Paxil/Paxil CR (Paroxetine) Prozac (Fluoxetine) Zoloft (Sertraline)	Cymbalta (Duloxetine) Effexor (Venlafaxine)

Adverse effects while treating migraines can occur, including:20

• Gastrointestinal (GI) problems from prolonged NSAID use, or if taken in large doses, such as abdominal pain, GI bleeding and/or ulcers.
• Rebound headache caused by medication overuse occurs when medications stop relieving pain and begin to contribute to causing pain, leading the migraineur use more medication, thereby perpetuating the cycle.
• Serotonin syndrome – a rare and potentially life-threatening condition that results from the body having excessive serotonin.

The prognosis or course of the disease varies from person-to-person. Prolonged remission is common because the condition is fairly benign, and not associated with an increased risk of death. The severity and frequency of migraine attacks tend to lessen with increasing age.

One study showed that during childhood, 62% migraineurs were migraine free for greater than two years during puberty/adolescence and as young adults.14 Only 40% were still migraine free at 30 years of age.14 After 15 years, an estimated 40% women and 30% of men no longer have migraines.14

There are four main models of disease are:16

• Symptoms completely resolve
• Symptoms continue, but decrease overtime
• Symptoms may continue at same severity and frequency
• Attacks may worsen and become more frequent

Risk factors include:16

• Ischemic stroke (migraine with aura)
• Cervical artery dissection (migraine with aura)
• Migraineurs, particularly women, may develop higher than average number of white matter brain lesions of uncertain significance.

Annually, beginning the first Sunday of September, the Migraine Trust promotes Migraine Awareness Week to raise general awareness of migraine as a serious public health issue, and to lessen the stigma associated with the disease. As well as, bring awareness to the condition, its impact and the important necessary work involved to support millions of migraineurs affected.28

Migraine research is detrimentally underfunded compared to other chronic diseases to find a cure. Even though the ultimate goal is to find a cure, the Migraine Trust Fund supports research towards greater comprehension of migraine and its underlying pathophysiology. Research goals include improved management and treatment.29

Projects funded objectives by the Migraine Trust aim to:30

• Analyze how changes in the brain actually cause migraines
• Examine the biology of the condition
• Improve the management and treatment of migraine

Current research projects include funded by the Migraine Trust include:31

• Neuromodulation in migraine and other headaches which “aims to further understand migraine pathophysiology and to identify the mechanism of action of neuromodulation techniques in migraine”.
• Circadian biology of migraine which “investigates how circadian rhythms/daily body cycles( e.g., sleep-wake cycle) impact migraine triggering and susceptibility, as disruption in circadian regulation, such as jet lag and shift work, can trigger migraine attacks”.
• Migraine postdrome MRI study which “aims to study brain activity during postdrome phase of a migraine.”

Because of research, understanding the biology and pathophysiology of migraines has resulted in major classes of therapeutics being identified, with more anticipated in the future: triptans, serotonin 5-HT18/1D  receptor agonists, gepants, Calcitonin Gene-Related Peptide (CGRP) receptor antagonists, ditans, 5-HT1F   receptor agonists, CGRP mechanisms monoclonal antibodies, glurants, and mGLu5 modulators.32

As pharmacy professionals it is important to acknowledge and understand that migraines are a concerning neurological disorder that extends beyond a typical or ordinary headache, and that the condition has a physical, psychological, and economical impact on society. Pharmacy technicians are usually the first persons to encounter patients, so awareness, empathy and education is critical in providing quality patient care and outcome.

References:

1. Phillips, Quinn. “9 Things People with Migraines Want You to Know.” Every Day Health, 14 Sept. 2017, www.everydayhealth.com/hs/managing-migraines/wish-you-knew/. Accessed 14 Aug. 2018.
2. Ellen. Migraine Research Foundation, migraineresearchfoundation.org/our-community/migraine-stories/ellen/. Accessed 14 Aug. 2018.
3. Migraines More Than Just A Headache . Positive Health, 1 Dec. 2017, www.positivehealth.net/pain/migraines/. Accessed 14 Aug. 2018.
4. 50 Famous People With Migraine. Migrainepal, July 2018, migrainepal.com/famous-with-migraine. Accessed 15 Aug. 2018.
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