Desdemona: Why is your speech so faint? Are you not well?
Othello: I have a pain upon my forehead here.
Desdemona: Let me but bind it hard; within this hour ‘twill be well.
Othello, Act III, scene iii
Migraine has no cure. Drug therapies are broadly divided into two groups: (1) those designed to treat acute occurrences and (2) those that are prophylactic (preventive) in nature. Many people with migraine use both forms of treatment. The goal is to treat migraine symptoms as soon as possible and to minimize the number of migraine occurrences by avoiding triggers.
The treatment of an individual migraine attack once it has occurred, or acute treatment, is commonly referred to as “abortive therapy.” Four major medications are used for abortive therapy: (1) the triptans; (2) ergotamine; (3) dihydroergotamine; and (4) Midrin, a combination of isometheptene mucate, dichloralphenazone, and acetaminophen. Other medications include CGRP receptor antagonists and, among herbals, feverfew.
Most drugs for acute migraine work best when taken right away, when symptoms first appear, followed by rest or sleep in a darkened room. Patients should always have their migraine medicine nearby in case of an attack. For people with extreme migraine pain, a powerful “rescue” drug containing opiates might be prescribed. Because not everyone responds the same way to migraine drugs, patients must work with their healthcare provider to find the treatment that is most effective.
For relatively mild migraine symptoms, over-the-counter pain medications such as aspirin, acetaminophen (Tylenol), or nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Advil, Motrin), may be sufficient. Some combination medicines are sold specifically for migraines (eg, Excedrin Migraine, which contains aspirin, acetaminophen, and caffeine) but these are usually not strong enough for severe migraines. The patient needs to understand that taking migraine medications more than 3 days a week may lead to rebound headaches—headaches that keep coming back, in part because of the medications.
It is essential to teach that acetaminophen can also be toxic to the liver, especially if combined with other medications, or in the presence of liver disease or alcohol abuse. Repeated doses of ibuprofen or aspirin may irritate the lining of the stomach or gut. If OTC treatments are not sufficient, prescription medicines may be helpful. Nasal sprays, suppositories, or injections are available if nausea and vomiting preclude an oral route of delivery.
Many migraine medicines work by narrowing blood vessels to counteract vasodilation in the vessels of the brain. Caution is advised if the patient has risk for heart attacks or has heart disease. Do not give ergots if the patient is pregnant or planning to become pregnant.
Classes of drugs that are used for abortive therapy of the more severe migraines include the following.
Triptans, the gold standard in acute migraine therapy, are potent 5-hydroxytryptamine (serotonin) subtypes 1B and 1D receptor agonists that, when delivered orally, are effective in 29% to 64% of patients, depending on the criteria used to define pain relief: (1) pain-free after 2 hours, and (2) moderate or severe pain to mild or no pain after 2 hours. However, clinical use can be limited by their potent vasoconstriction, especially in patients with cardiovascular disease.
Triptans are the most common drugs prescribed to alleviate acute attacks. Examples include:
Triptans are available as tablets that are swallowed, or tablets that dissolve on the tongue, nasal sprays, or by injection if nausea is a concern. They should be used as early as possible before, or with the onset of, migraine. Since 2008 a single-tablet combination of sumatriptan and the NSAID naproxen sodium (Treximet) has proved more effective in relieving migraine symptoms than either alone because the sumatriptan targets the nerves and blood vessels involved in a migraine while the naproxen sodium targets inflammation.
The side effect profiles of the triptans are similar and include occasional nausea, vomiting, and numbness or tingling of the fingers and toes. Clear contraindications to the use of triptans include a history of coronary artery disease or hypertension. If the patient has hemiplegia (one-sided paralysis) or blindness as an aura in a migraine attack, then triptans should not be used. Finally, these drugs should not be used for treatment until it has been confirmed that the patient has migraines.
Ergotamines (ergotamine tartrate and dihydroergotamine) work in the same way as triptans, causing vasoconstriction. Ergot derivatives are no longer preferred, due to less efficacy and more risks, though if patients fail triptans then ergotamines can be considered. Ergotamine and caffeine combination drugs (Cafergot, Migergot) are much less expensive and generally less effective than triptans. They seem most effective in those whose pain lasts for more than 2 days. Ergotamines should not be prescribed for chronic usage on a daily basis due to side effects.
A particularly intractable migraine may respond to intramuscular or intravenous dihydroergotamine (DHE, Migranal). The initial dose of DHE is given intravenously, with metoclopramide or prochlorperazine to alleviate nausea, if needed. If the headache improves, the dosage of DHE plus metoclopramide is repeated. Nasal DHE can be used in the abortive treatment of migraine for some patients, to replace intramuscular or intravenous routes.
Ergot derivatives should not be used if the patient has heart disease or high blood pressure.
Midrin is a combination of isometheptene mucate, dichloralphenazone, and acetaminophen that provides both abortive and prophylactic therapy. The drug consists of an analgesic (acetaminophen), a muscle relaxant (dichloralphenazone), and a vasoconstrictor (isometheptene mucate). If Midrin is used for abortive migraine pain, patients are to take 2 tablets at the onset of a headache or aura, then 1 tablet hourly for 3 additional doses (5 tablets total). Midrin can also be used as a prophylactic agent for muscle tension headaches, taking 1 tablet twice a day, and then a third pill for a breakthrough headache during that day.
CGRP receptor antagonists include Olcegepant and Telcagepant. A significant recent advance in acute treatments relates to calcitonin gene-related peptide (CGRP) receptor antagonists to block CGRP action. Stimulation of trigeminal (TG) neurons results in the release of pro-inflammatory peptides such as CGRP, leading to local inflammation, vasodilation, and pain. High levels of CGRP are found in external jugular venous blood during migraine attacks, and infusion of CGRP can cause migraine.
Telcagepant (the first orally administered CGRP antagonist) has been shown to possess pain relief efficacy similar to that of zolmitriptan (Zomig) as acute therapy. It also shows improved safety and tolerability, although it associated with elevated levels of liver transaminase enzymes in a minority of patients (Weir and Cader, 2011). In 2011 Merck announced it will not continue to develop Telcagepant for the treatment of acute migraine. The decision was based on an assessment of data across the clinical program, including findings from a recently completed six-month Phase III study.
Olcegepant is another of several CGRP antagonists in development as a potential treatment for acute migraine attacks. This new class of drugs is designed to block and/or reverse CGRP-mediated dilation of intracranial vessels induced by activation of the main sensory nerves in the brain without the risks to heart patients inherent in triptans and ergots.
Feverfew (pictured earlier) is a popular herb for migraines. Several studies, but not all, support using feverfew for treating migraines. If you are interested in trying feverfew, check with your healthcare provider. Herbal remedies sold in drugstores and health food stores are not regulated for dosage, quality, lot reproducibility, or efficacy. Work with a trained herbalist when selecting herbs. Butterbur (see below) is another herbal remedy that has gained approval through clinical trials (NINDS, 2012).
Some migraine medicines should not be used during pregnancy because they can cause birth defects, premature contractions, and other problems. This includes over-the-counter medicines such as aspirin and ibuprofen. For most women, migraines improve or stop after the first trimester.
Rescue medications are those taken if abortives fail or cannot be taken. Most rescue medications are for pain. Other types of medications are used to help get through a migraine by reducing nausea and helping the patient to relax. They don’t have the ability to abort a migraine, but are hoped to mask the pain for a few hours while the migraine runs its course. They may be used alone or with other drugs. Rescue medications include the following.
Because migraines often include nausea and may include vomiting, drugs for nausea—metoclopramide (Reglan), prochlorperazine (Compro), promethazine (Phenergan), or prochlorperazine (Compazine)—can be combined with other medications.
Sedatives containing butalbital, combined with other pain relievers such as acetaminophen, aspirin, or narcotics (eg, codeine), are used to help relax the patient while the therapies begin to act. These can be addictive and should not be combined with alcohol.
Narcotic pain relievers include opiates, acetaminophen with codeine, oxycodone, or hydrocodone (e.g., Vicodin, Percocet). Medications containing narcotics, particularly codeine, are sometimes used to treat migraine headache pain if triptans or ergots are not possible, though they are addictive and must be used sparingly. Patients should be warned about the combinations that include acetaminophen so that they do not take additional Tylenol and risk damage to the liver.
Muscle relaxants, centrally acting—carisoprodol (Soma), metaxalone (Skelaxin), or tizanidine (Zanaflex)—may be of value in early stages.
Some patients may experience multiple migraines per month. If they have frequent migraines, 1 or more per week, or medications for acute attacks are relatively ineffective, there are prescription medicines to help to reduce the number of attacks. For it to be effective as prophylaxis, this medication must be taken every day for an indefinite period. Many of these drugs were originally designed to treat other health conditions, such as epilepsy or depression.
As more of the genetic components of migraine are found and understood, the reasons behind the effectiveness of the following groups of drugs should become clear and then they can probably be improved.
Tricyclic antidepressants include amitriptyline (Elavil), venlafaxine (Effexor), duloxetine (Cymbalta), and nortriptyline (Pamelor). Certain tricyclic antidepressants, irrespective of depression, help to prevent headaches, including migraines, by affecting the level of serotonin and other neurotransmitters, though amitriptyline is the only one shown to be useful for migraines.
Other classes of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs)—for example, fluoxetene (Prozac)—and serotonin-norepinephrine reuptake inhibitors (SNRIs), have not been shown effective for migraine prevention. However venlafaxine (Effexor), an SNRI, may be preventive.
Blood pressure medicines such as the beta blockers, propranolol (Inderal) or timolol (Blocadren), that are commonly used to reduce high blood pressure and coronary artery disease, can reduce the frequency and severity of migraines. The antihypertensive medication lisinopril (Zestril) is useful in minimizing the severity of migraines, though the mechanisms are not yet understood. Side effects can include drowsiness, depression, dizziness, fatigue, alopecia, bradycardia (slow heart rate), and cold extremities due to reduced blood flow. Beta blockers are often difficult to tolerate and are used when other groups of medications have failed.
Calcium channel blockers such as verapamil (Verelan, Calan), Cardizem, and Plendil, are another class of antihypertensive cardiovascular drugs that may be helpful in preventing migraines with aura.
Anticonvulsant seizure medicines such as topiramate (Topamax), divalproex sodium (Depakote), valproic acid (Depacon), and gabapentin (Neurontin), are neuronal stabilizing agents. The most common drug now prescribed to prevent migraines is the anticonvulsant topiramate (Topamax). Side effects include sleepiness, numbness and tingling in the fingers and toes, and increased intraocular pressure. Divalproex (Depakote) has also been used successfully to prevent migraine, with side effects including alopecia and tremor. Lamotrigine (Lamictal) may be helpful for migraines with aura. Anti-seizure drugs may have side effects such as nausea, vomiting, diarrhea, alopecia, cramps, and dizziness (Goodman and Gilman, 2011).
Botulinum toxin (Botox) injections may help reduce migraine attacks. The Food and Drug Administration (FDA) has approved botulinum toxin type A for treatment of chronic migraine headaches in adults. Injections of Botox are made in muscles of the forehead and neck. The treatment is expensive and typically needs to be repeated every 3 months.
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For most people, preventive medications do not eliminate headaches completely, and some cause serious side effects. Therefore if the migraines have been well controlled by the preventive medicines for months, it may be worthwhile to try to reduce the preventive medication gradually over time, until or unless the migraine headaches return.
Insights gleaned from genetic studies offer novel drug targets and potential prophylactic agents through alterations in neuronal excitability. Indeed, current prophylactics such as valproate, verapamil, topiramate, and lamotrigine are known to have effects on migraine-associated ion channels.
Several drugs that block glial cell activation are also available and have approved clinical safety profiles. These drugs include naltrexone, naloxone (these first two are effective opioid receptor antagonists), minocycline, and ibudilast, and some have already been shown to be effective as prophylactics for migraine (Weir and Cader, 2011).
Use of these drugs may not prevent all migraines, but they can be useful. Hormone therapy may help prevent attacks in women whose migraines seem to be linked to their menstrual cycle. In a few cases, triptans are used for migraine prevention. Of the triptans, Amerge and Frova have been studied and proven effective for the prevention of menstrually triggered migraines when taken twice a day for 5 to 7 days beginning 2 days before the onset of the menstrual period. These options may be of value if:
Healthcare providers can help to distinguish migraine headaches from other types of headache, which is critical for the appropriate use of therapeutic drugs, by asking questions about symptoms and family history of migraines. Usually, recurrent severe headaches, presence of aura, family history, or nausea are telltale signs of migraine. A physical exam should be done to determine if headaches are due to muscle tension, sinus problems, or a much more rare and serious brain disorder. There is no specific test to prove that a headache is actually a migraine. However, a brain MRI or CT scan can be used to follow unusual symptoms with potential migraines, including weakness, memory problems, or loss of alertness. An EEG may be performed to rule out seizures, or a lumbar puncture (spinal tap) might be done to check for infections (NIH Medline Plus, 2011).