How migraines develop is not well known. It is believed that migraines are caused by activation of nerves in the face (trigeminal nerves). Specifically, nerves that sense pain (nociceptors) and also stimulate blood vessels in the head are activated. Stimulation of the blood vessels by these nerves then stimulates regions of the brain involved in pain perception, such as the thalamus and various regions in the cortex.

Causes of Migraines

Environmental Causes of Migraines
There are many environmental causes such as stress, bright lights, difficulty sleeping, ingredients in food and drinks, doing physically strenuous work and menstruation. Individuals can also be genetically predisposed to migraines due to mutations in specific genes.

Genetic Predisposition to Migraines
More than 100 genes have been shown to have at least one mutation that is associated with migraine development. Most genes that have been shown to contribute to migraines are involved in neuronal or vascular functions. Genome-wide analyses revealed that genes that encode a cation channel expressed in sensory neurons (TRPM8), a protein that influences how neurons relay messages to each other (LRP1) and a protein that may be involved in neurogenesis are also associated with migraines.

Non-HM MAs can also be caused by genetic mutation. A mutation in a gene (KCNK18) that codes a protein involved in potassium channel development (TRESK).

Treatments for Migraines

Preventative treatments for a migraine
There are few preventative treatments available for a migraine. However, several new therapies are also showing signs of potential as preventative treatments. One commonly used preventative pharmacological agent is flunarizine. Daily doses of this drug have been shown to be effective. However, they do have the side effect of sleepiness.

Another preventative medication worth mentioning is Topiramate. Topiramate is a derivative of D-fructose. It has several different effects on nerve cells including:

• Blocking the activity of voltage-gated sodium and calcium channels
• Refulating glutamate-mediated neurotransmission
• Enhancing GAABA receptor activity
• Blocking carbonic anhydrase

Topiramate inhibits excitatory neurotransmission and enhances inhibitory neurotransmission. Thus, it may work to improve pain by reducing the spread of pain signal transmission.

Topiramate is a derivative of D-fructose. It has several different effects on nerve cells including:

• Blocking the activity of voltage-gated sodium and calcium channels
• Refulating glutamate-mediated neurotransmission
• Enhancing GAABA receptor activity
• Blocking carbonic anhydrase

Topiramate inhibits excitatory neurotransmission and enhances inhibitory neurotransmission. Thus, it may work to improve pain by reducing the spread of pain signal transmission.

Acute Treatments for migraines
Acute treatments, such as non-steroidal anti-inflammatory drugs (NSAIDs), triptans (drugs designed to treat migraines and cluster headaches),  dihydroergotamine and antiemetics (drug treatment against nausea and vomiting), are often effective at treating episodic migraines. They are less effective for chronic migraines, and thus pose a risk of inducing headaches from medication overuse. Thus, single medications should be taken only for 15 days per month.

Non-steroidal anti-inflammatory drugs
These are the most commonly used treatments for mild and moderate migraines. Commonly used NSAIDS for a migraine include:

• Aspirin
• Other NSAIDs
• Paracetamol (acetaminophen)
• Paracetamol with caffeine

Other NSAIDs for consideration of temporary migraine relief include:

• Phenazone
• Metamizole (dipyrone)
• Tolfenamic acid
• Acetaminophen (for mild migraines)
• Acetylsalicylic acid (ASA)
• Ibuprofen
• Diclofenac
• Naproxen sodium
• Combination of ASA , paracetamol and caffeine
• Combination of indomethacin, caffeine and prochlorperazine
• Sumatriptan (particularly rectal formation)

There are also medications that are taken with NSAIDs to treat secondary effects of a migraine such as nausea and vomiting. These include:

• Antiemetics
• Prokinetics

While NSAIDs are taken primarily orally, they can be taken other ways such as intranasally, intravenously or topically.

Cox-2 inhibitors are a specific class of NSAIDs. They work by blocking the cyclooxygenase (COX) enzyme family. COX enzymes generate prostanoids (mediators of vasoconstriction and inflammation) such as thromboxane and prostaglandins. Cox2-inhibitors block the creation of prostanoids, which exacerbate migraines. Although a few Cox-2 inhibitors were taken off the market for treatment of migraines due to their potential cardiovascular risks, Celecoxib is still available and effective.

There are side effects associated with NSAID use such as an increased risk for heart attack and stroke and stomach bleeding. Other side effects include:

• Heartburn
• Stomach ulcer
• Stomach pain
• Increased bleeding
• Headaches
• Dizziness
• Ringing in the ears
• Liver problems
• Kidney problems
• High blood pressure
• Leg swelling

Patients with peptic ulcer and haemorrhagic diathesis should also not take NSAIDs for migraines as it may irritate these conditions.

Triptans
Triptans were introduced over 25 years ago. They are used to treat moderate to severe migraines, mild to moderate migraines that are unresponsive to NSAIDs or that occur in patients with a contraindicated condition, and other headaches. Triptans have replaced ergot derivatives as the drug of choice for treating migraines.

As previously mentioned, they function by activating serotonin receptors. Through activation of these receptors they induce vasoconstriction in the brain and block release of neurotransmitters in a subset of pain nerves in the central and peripheral nervous system.

It is particularly effective when injected or taken intranasally. Examples include injectable and intranasal therapy, sumatriptan, and oral zolmitriptan. However, oral treatments are also highly effective.

Sumatriptan
Sumatriptan is the original tripatan, introduced in the early 1990s. Though it has a relatively short half-life, it is still considered the gold standard of triptains. Sumatriptan can be taken in many forms including subcutaneously, intranasally, orally and even transdermally. It is most effective and effective faster when delivered subcutaneously. However, this method of administration has several side effects.  Oral consumption is also effective and can be better tolerated at lower doses.

Second Generation Triptans

• Zolmitriptan
• Naratriptan
• Rizatriptan,
• Almotriptan
• Eletriptan
• Frovatriptan

Zolmitriptan and Naratriptan are effective at treating migraines at low doses (starting at 2.5mg). Naratriptan also appeared to have very few adverse events in clinical trials.  Rizatriptan is also very effective at treating a multitude of migraine symptoms. It is also has a relatively short time to onset compared to other triptans (1h). However, it also has a very short half-life. Eletriptan is also effective. The higher the dose, the greater the effects.

While Frovatriptan is not more effective than the previously mentioned triptans, it is better tolerated. However, it is not as strong as the original triptan, Sumatriptan. However, it is more effective when taken early than late in a migraine attack. It is primarily prescribed for women with a menstrual migraine or menstrual-related migraine.

Almotriptan
Almotriptan has proven to be one of the more fast acting and well-tolerated triptans. It not only reduces pain, and migraine-related symptoms, but reduces the number of reoccurring migraines. Like frovatriptan, it is more effective when taken early during the migraine attack compared to late administration.

Patients do not develop a tolerance to triptans and so they do not become less effective over time. There is no way to predict which triptan is best for an individual. Triptans tend to have similar side effects. These side effects include unusual sensations like tingling, pressure, numbness or pressure, flushing, neck pain, and chest pressure. Dizziness and sedation may also occur with the injectable form. Triptans are contraindicated for patients with untreated high blood pressure, coronary heart disease, Raynaud’s disease, a history of stroke, pregnancy, breastfeeding, liver damage, kidney damage, old age (greater than 64 years) and hemiplegic migraine.

Only one triptan can be used at a time. However, the FDA has approved use of triptans in combination with specific NSAIDs. For example, the combination of sumatriptan and naproxen sodium is more effective than either treatment alone. However, combinations can lead to medication overuse headaches and thus should be restricted to 10 days per month.

Ergot derivatives
Ergot derivatives work by activating receptors of the neurotransmitter serotonin. Triptans also work by activating serotonin receptors. Ergot derivatives include ergotamine tartrate and dihydroergotamine. While effective, they can induce headaches due to frequent use.

Ergotamine tartrate
Ergotamine was the first drug used to treat migraines in the short ter. It first entered the market in the 1920s. It was and remains a drug of choice for migraines due to its long period of efficacy and cost-effectiveness. It can be taken as an oral medication, suppository or inhalant. The suppository may even be combined with caffeine.

However, because it functions as a vasoconstrictor, it cannot be used by individuals with high blood pressure, coronary heart disease, peripheral vascular diseases, stroke, impaired hepatic or renal function, or individuals that are pregnant.

One of its benefits, its long lasting effects, also comes at a price. Ergotamine is also associated with several side effects such as nausea, vomiting, cramps, sleepiness and lower limb pain. This treatment can not be used within a few (6-24hours of triptains).

Dihydroergotamine (DHE)
DHE can be used to stop migraines in the short term. While its side effects are less severe than ergotamine, it is not as effective. The best method of administration is intravenously, although it can take a while before it is effective. DHE can also be administered subcutaneously or intramuscularly. It is often also taken with metoclopramide to prevent nausea. DHE is also contraindicated for vascular diseases, and liver or kidney dysfunction. DHE side effects include numbness, tingling, cramps, heart palpitations, pain and tightness.

New Treatments for Migraines
Monoclonal Antibodies Targeting Calcitonin gene-related peptide (CGRP) (Gepants)
The calcitonin gene-related peptide (CGRP) is one of many peptides released by trigeminal nerve fibers that initiate migraine pain. CGRP and other peptides promote inflammation by further widening dilated blood vessels which further activates trigeminal fibers, and enhances release of these proteins. CGRP also promotes migraine by causing certain cells to release substances that promote inflammation and by transmitting pain signals from the blood vessels to the nervous system.

CGRP antagonists are known as gepants or monoclonal antibodies. They are currently being developed as both acute treatments and preventative migraine therapies. This group of therapies is unique in that it does not cause vasoconstriction, and can target specific migraine mechanism. This opens up the use of migraine therapies to individuals with vascular diseases. There are currently five effective CGRP treatments that are effective:

• Telcagepant
• MK-3207,
• Olcagepant
• BMS-927711
• BI44370TA
• NCT01613248

Unfortunately, all of the clinical trials for these therapies were ended early due to various concerns related to liver toxicity. Anti-GCRP antibodies have also been developed to remove excess CGRPs and to block activation of the CGRP receptor.  Anti-GCRP includes:

• ALD-403
• LY-2951742
• LBR-101

Serotonin 5HT1F agonists (ditans)
A serotonin agonists known as lasmiditan (COL-144) has been shown to be effective against short-term treatment of migraines and few side effects when taken intravenously or orally. Ditans work by reducing the expression of c-Fos, a protein that activates pain neurons. It does this without impacting vessel constriction. While it was found to be effective in a clinical trial, many participants also experienced dizziness.

Glutamate receptor antagonists</b
Glutamate receptor antagonists have been found to be effective in treating migrates in the short-term. However, because of liver toxicity issues, clinical trials of some glutamate receptors were discontinued. Still, there are other mechanisms of blocking glutamate receptor activity that remain to be explored for their potential in treating or preventing migraines.

Onabotulinumuntoxin A
Botulinum toxin (BT) is a fatal toxin produced by the anaerobic bacterium Clostridium botulinum. Treatment with the toxin leads to chemical denervation by inhibiting the release of acetylcholine from nerve fibers, and thus indirectly blocking muscle contraction. However, despite its lethality, BT has become an increasingly valuable tool in the clinical field. When administered in therapeutic doses, the properties of BT can be effectively controlled to produce paralysis in targeted muscles. The most well-known application of BT is for treatment of glabellar and other facial lines. A recent clinical trial investigating the effects of BT on migraine pain found that treatment reduced the frequency of headaches and headache related disability, while also improving function and quality of life. It was also found to be as effective as topiramate. However, more people continued treatment with BT than topiramate.

Neurostimulation and modulation
Occipital nerve stimulation (ONS) Occipital nerve stimulation or ONS is an invasive treatment requiring the stimulation of leads inserted under the skin above the occipital nerves. Three clinical trials were performed on this treatment. One found no difference in migraine pain. However, another found that treatment reduced the frequency of migraines by 50%, as well as their intensity. A third study only saw a reduction in migraine frequency by 30%. However, disability due to migraines and migraine-related pain were reduced. When combined with supraorbital stimulation, headache frequency decreased by more than 90%.

Neurostimulation
Another stimulating device that has shown promise is the  Cefaly . It stimulates the supraorbital in a transcutaneous manner to prevent migraines. Not only has it been shown to be effective in humans, but it is very well-tolerated with few side effects. Treatment improves severity in individuals with infrequent migraines. This is a great alternative for individuals that cannot take medications daily or that does not have migraines frequently enough to take medication.

Single ‑ pulse transcranial magnetic stimulation
The application of single pulses of transcranial magnetic stimulation (TMS) to the back of the head may also be an effective treatment for migraines. The FDA approved the use of TMS devices, such as the  Cerena Transcranial Magnetic Stimulator , to treat migraines a few years ago in 2013. These devices can be large. However, smaller devices are being approved for adults with specific forms of a migraine such as a migraine with aura. These devices can be used for treatment of migraines or as preventative measures.