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  • Battling Migraine with Innovative Approaches and Emergent Therapies
    The intense pulsing, throbbing pain of migraines is unmistakable to those who suffer from them. Migraines are noted as the third most common illness worldwide, and nearly one in four US households has a family member suffering from the ailment. While most individuals who have them experience attacks once or twice a month, there are more than 4 million people who have recurrent daily migraines with at least 15 migraines per month. A patient would be classified as having chronic migraines if they have them with that frequency. More than 90% of people with migraines are unable to work or function normally during their migraine. Every year, acute migraine attacks result in 1.2 million ER visits. 

    There is currently no cure for migraines. Treatment should first start with lifestyle changes. This includes eliminating known triggers, getting sufficient sleep, not missing meals, and reducing stress. Medications for migraine treatment are categorized into two groups: pain-relieving medications (also known as acute or abortive treatments), which are taken during migraine attacks and aimed at stopping symptoms, and preventative medications. Treatment choices are based on the frequency and severity of the headaches, whether or not nausea and vomiting are involved, how disabling the headaches are, and any other medical conditions the individual has.

    First-line treatment options for mild-to-moderate migraine attacks are acetaminophen and oral NSAIDs (eg, aspirin, diclofenac, ibuprofen, naproxen). These drugs are considered to be first-line treatment options because they are effective, cheaper, and less likely to cause side effects than medications that are migraine-specific treatments (eg, triptans, ergots). Triptans have shown to be effective first-line treatment for moderate to severe migraines. There are currently seven triptans available today, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. As 5-hydroxytryptamine receptor agonists, these medications are pharmacologically specific for migraines. Although these drugs have the same mechanism of action, they differ in routes of administration, cost, and pharmacokinetics.

    Several medications are considered to be second-line treatment options for migraines, due to either adverse effects, route of administration, cost, or abuse potential. These drugs include dihydroergotamine, opioids, antiemetics, and other medications such as ketorolac.

    Dihydroergotamine is an alpha-adrenergic blocker with arterial vasoconstrictor and venoconstrictor properties. It is also a potent 5-HT 1b/1d receptor agonist. Opioids such as butorphanol, codeine, tramadol, and meperidine have shown moderate evidence of effectiveness for the treatment of migraines. However, they should only be used as a last alternative and are usually not as effective as migraine-specific medications. Also, the potential for tolerance, dependence, addiction, and overdose complicates the use of these drugs. It should also be noted that opioid use is associated with an increased risk of developing chronic migraine and medication overuse headache.

    Antiemetics also can be used for reducing migraine headache pain. Dopamine antagonists such as IV metoclopramide, IV or IM chlorpromazine, and prochlorperazine are antiemetics that can be used as monotherapy for acute migraines. Unfortunately, many of these drugs are associated with QT interval prolongation and torsades de pointes. In addition, dopamine antagonists may cause extrapyramidal adverse effects, and therefore patients should be warned about overuse.

    Droperidol and haloperidol are also therapies that appear to be effective in acute migraine treatment. However, these medications are not considered to be first-line options due to evidence of efficacy being derived from lower-quality clinical studies and because the incidence of adverse effects is high.

    Parenterally administered ketorolac is sometimes used in patients when other migraine treatments have not worked. However, due to the risk of developing serious side effects such as GI bleeding, perforating ulcers, and coagulation disorders, this drug should not be used for more than 5 days.

    Patients who are being treated in an emergency department or clinic setting for migraines are often given adjunctive treatment with IV or IM dexamethasone in combination with standard acute migraine treatment. This is done to reduce the risk of early headache recurrence. However, frequent use of adjunctive dexamethasone should be avoided due to the risk of glucocorticoid toxicity.

    In October 2019, the FDA approved a new therapy called Reyvow (lasmiditan) tablets for the treatment of migraines with or without aura in adults. Reyvow is a selective serotonin 1F receptor agonist. It does not have vasoconstrictive activity. Its use is likely most appropriate for individuals who have contraindications to taking triptans due to cardiovascular risk factors.

    There is a new class of drugs called calcitonin gene-related peptide (CGRP) antagonists that contain two recent FDA approvals for the treatment of migraines. These drugs are Ubrelvy (ubrogepant), an oral tablet approved in December 2019, and Nurtec ODT (rimegepant), an orally disintegrating tablet approved in February 2020. This drug class is designed to treat migraines by targeting CGRP, a substance that is elevated in the serum during migraine attacks. These medications are considered treatment options when either an insufficient response or contraindication to triptans is present.

    There is limited clinical trial data that shows that various forms of neuromodulation may be beneficial for the treatment of acute migraine pain. These therapies stimulate the central or peripheral nervous system with an electric current or a magnetic field. They are considered to be possible choices for individuals who would like non-pharmacological treatment options and in those who have a poor response to, are unable to tolerate, or have contraindications to migraine medications. Examples of neuromodulation include transcutaneous supraorbital nerve stimulation, remote electrical neuromodulation, transcranial magnetic stimulation, and noninvasive vagus nerve stimulation.

    Nerve blocks targeting the occipital nerve, sphenopalatine ganglion, and trigeminal nerve are considered options for acute migraine treatment in people who have severe and prolonged migraine attacks, and in people who are refractory to or have contraindications to standard treatments. Important contraindications to peripheral nerve blocks include known allergy to a local anesthetic, open skull defect, and overlying skin infection. Pregnancy is a relative contraindication. It should be noted that evidence of peripheral nerve blocks being efficacious is limited to mostly small, low-quality clinical trials.

    Preventative treatment should be considered in individuals with the following situations: if the migraine attacks significantly interfere with the person’s daily routine despite taking acute treatment; if the patient has frequent attacks (>4 monthly headache days); if the individual has contraindication to, failure with, or overuse of acute treatments; if the individual is experiencing adverse events with acute treatment, or if the individual prefers to be on preventative medication. Prevention medications should also be considered in individuals who have certain rare migraine types such as hemiplegic migraine, migraine with brainstem aura, and migraine with prolonged aura. In addition, migraine prevention medications should be given to patients who previously experienced a migrainous infarction, even if there is a low attack frequency.

    Anti-seizure medications currently have the most support in clinical data for migraine prevention treatment. Topiramate is considered to be the top choice because it has Class I evidence supporting its efficacy and because it is usually tolerated well by patients. Valproate is another option that has shown efficacy in preventing migraines. However, it should be noted that valproate and topiramate might cause side effects, including dizziness, weight changes, and nausea. Divalproex is another anti-seizure medication that has shown to be very effective in preventing migraines. However, this medication is a less desirable option due to possible side effects, including weight gain, hair loss, tremor, teratogenicity, increased liver function tests, and increased risk for pancreatitis.

    Antihypertensive medications may also be used for migraine prevention. There has been data from clinical trials that have established efficacy in migraine prevention with metoprolol, propranolol, and timolol. Calcium channel blockers such as verapamil may also be helpful in migraine prevention. In addition, antidepressants amitriptyline and venlafaxine may also be effective in migraine prevention.

    In October 2010, the FDA approved Botox (onabotulinumtoxinA) for the prophylaxis of headaches in adults with chronic migraines (>15 days per month, with headache lasting four or more hours a day). Botox injections are usually administered about every 12 weeks.

    In recent years, there have been four CGRP antagonists approved by the FDA for the prevention of migraines, Aimovig (erenumab-aooe) in May 2018, Emgality (galcanezumab-gnlm) and Ajovy (fremanezumab-vfrm) in September 2018, and Vyepti (eptinezumab-jjmr) in February 2020. The drugs in this class are metabolized differently, have fewer adverse reactions reported in clinical trials, and have fewer warnings and precautions compared to other migraine therapies.

    Although there is no cure for migraines, new therapies continue to emerge that help prevent and treat migraines. Hopefully, as advancements in migraine therapies continue, patients will experience less debilitating and less frequent migraines, and consequently, the quality of their lives will improve.