Migraine is a common chronic and often disabling. By Michael J. Marmura, MD and Stephen Silberstein, MD

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1 By Michael J. Marmura, MD and Stephen Silberstein, MD Migraine is a common chronic and often disabling neurological disorder characterized by attacks of moderate to severe headache. Migraineurs usually experience nausea and light and sound sensitivity during their attacks, and many have aura. Most patients experience reduced ability to function with attacks and many are bed-bound. Migraines can have multiple triggers such as food, sleep changes, or hormonal factors. 1 Often migraineurs elect to treat their headaches without physician consultation using rest or over-the-counter (OTC) medications. Patients who present for evaluation with migraine have usually tried some OTCs without substantial relief. Providers treating migraine must be familiar with different acute treatments, be comfortable with individualizing treatment, and be able to combine treatment modalities. Acute attack medications include specific medications, such as triptans, ergots and dihydroergotamine (DHE), and non-specific medications used for other pain disorders. In selecting acute migraine medication, patients need a treatment plan tailored to their headache type. Mild or moderate intensity attacks often respond to treatment with non-steroidal anti-inflammatory medications (NSAIDs) or combination medications, while more 1 Practical Neurology February 009

2 severe attacks may respond better to specific medications. If the initial treatments fail, rescue medication is needed. This review discusses acute evidence-based and practical treatments for migraine, and specifically focuses on the treatment of intractable headaches such as status migrainosus. Basic Principles In migraine, there are two basic strategies for treatment of acute headache: step care and stratified care. In the step care model, patients usually progress through a sequence of medications usually starting with a simple analgesic, then perhaps an antiemetic, and then a specific medication if the initial treatments are ineffective. 3 This can mean escalating treatment across or within attacks. Stratified care involves treating attacks based on migraine severity. In this model, patients use non-specific medications for minimally disabling attacks, and specific medications for severe attacks. Compared to step care, stratified care improves treatment outcomes, 4 improves quality of life, 5 and reduces costs. 6 Early treatment of migraine attacks improves outcomes. Patients taking triptans early, when the pain is still mild, often have increased pain-free rates at two hours. 7 When taken early, triptans may prevent the development of central sensitization in migraine, 8 as manifested clinically by cutaneous allodynia, which is pain in response to normally non-painful stimuli. Migraineurs with cutaneous allodynia are less likely to respond to triptans. 9 When selecting acute migraine medication, individualize the treatment according to the headache characteristics. For rapidly escalating and disabling attacks, consider injectable medications. Patients with significant nausea or vomiting should use non-oral medications and antiemetics. Migraineurs with attacks that do not respond to specific medication (often with frequent urgent physician or emergency room visits) need a rescue treatment. Before deciding a treatment is ineffective, patients should treat at least two attacks. Other strategies include changing the dose, giving a different formulation or route of administration, or adding a second agent. For patients with frequent headaches, it is important to avoid overuse of acute medication. Medication overuse impacts more migraineurs than patients with other chronic pain disorders 10 and is one cause of chronic daily headache (CDH). Medication overuse headache (MOH) is defined as the use of simple analgesics more than 15 days per month or using triptans, ergots, opioids Compared to step care, stratified care improves treatment outcomes, improves quality of life, and reduces costs. or combination medications more than 10 days a month for more than three months. 11 Frequent opioid and barbiturate use are risk factors for the development of CDH, 1 and stopping these medications can result in increased headache and withdrawal symptoms. MOH requires overuse for at least three months and a history of headaches worsening with the overuse. 13 MOH can cause adverse events (AEs) specific to the class of medication such as ergotism, constipation, gastrointestinal and renal disease, or tardive dyskinesias. Treatment of MOH by withdrawing the offending agent usually improves migraine after a period of increased headache lasting weeks to months. Migraineurs should be aware of MOH and keep a headache calendar (diary) of headaches and acute medication use. 14 Frequent migraines or those that do not respond to acute agents are an indication for prophylaxis. Preventative medications are indicated in patients with 1.) attacks more than once a week,.) acute medication use more than two days per week, 3.) impairment of quality of life or disability despite acute medication use, 4.) complicated migraine conditions such as hemiplegic migraine, and 5.) adverse events or contraindications to acute medication. For example, patients with a contraindication to triptans or ergots, such as coronary artery disease, may need migraine prophylaxis, as acute agents might not be effective. 15 Migraine prophylaxis is indicated in about onethird of all migraineurs, but only three to 13 percent of patients take them. 16 Non-specific Medications NSAIDs. NSAIDs are effective in the acute treatment of migraine. They may work by suppressing inflammation and preventing and treating central sensitization by blocking glial production of prostaglandins. They may also treat non-traditional migraine symptoms, such as neck pain and sinus pressure, that are commonly associated with acute migraine attacks. 17 NSAIDs are less likely to cause MOH than other treatments, 1 but frequent use can lead to undesired systemic AEs such as peptic ulcers or renal disease. Multiple NSAIDS demonstrate effectiveness in migraine. (Table 1) They can be combined with triptans or antiemetics for severe attacks. Opioids. Opioids provide therapeutic benefit in migraine but are associated with a high risk of abuse and dependency. Opioids are most useful in patients with infrequent but disabling migraine, especially if there are contraindications to specific treatments, such as cardiovascular disease or pregnancy. Although AEs may include sedation or confusion, patients might use opioids as February 009 Practical Neurology 13

3 Acute Treatment for Migraine Table 1: NSAIDs effective in migraine Medication Naproxyn Indomethacin Indomethacin-prochlorperazine-caffeine Ketoprofen Piroxicam Ketorolac Route SL Dose (mg) Ibuprofen Diclofenac Aspirin Aspirin-acetominophen-caffeine Tolfenamic acid Celecoxib oral, SL sublingual, intramuscular, - intravenous, suppository a rescue medication to avoid the distress of a visit to the emergency room. Codeine with acetaminophen is effective in migraine, and other opioids commonly used as rescue treatments include fentanyl, hydromorphone, hydrocodone, methadone, morphine, oxycodone, propoxyphene, and pentazocine. Meperdine and is commonly used 18 but may cause paradoxical reactions such as seizures. The agonist-antagonist opioid butorphanol may have lower abuse potential and can be given (-3mg) or as a nasal spray (NS) for migraine. 19 Treatment of frequent migraine with opioids is problematic. Do not use opioids in patients with addictive tendancies, a history of substance abuse, severe psychiatric disorders, or MOH. Patients taking long-term daily opiates for CDH usually do not improve, and many are non-compliant. 0 When using opioids, prescribe with strict limits and monitor the patient closely. Patients should not receive opioid prescriptions from multiple providers. Other analgesics. Acetominophen is effective for migraine at a dose of 1000mg 1 and is useful for patients with contraindications to NSAIDs. Caffeine enhances the effect of other migraine medications and has analgesic properties of its own. Acetominophen and caffeine are often used in combination medications. The combination of isometheptene (a sympathomimetic), dichoralphenazone (a choral hydrate derivative) and acetaminophen is modestly effective for migraine and relatively well tolerated. 3 Contraindications include glaucoma, renal failure, severe hypertension, heart or renal disease and MAO inhibitors. Butalbital-containing analgesics include combinations with acetaminophen or aspirin with caffeine and with or without codeine. No clinical trial demonstrates that butalbital, a barbiturate, adds to the effectiveness of the constituent components, and the risk of dependency and MOH is high. 4 As with opioids, use of butalbital-containing medication must be monitored closely and limited to situations when other treatments are ineffective or contraindicated. Specific Medications Triptans. The development and use of triptans, a class of medications specifically designed to treat acute migraine attacks, has revolutionized migraine treatment. Triptans are selective serotonin receptor agonists, and all have high affinity for 5- HT1B and 5-HT1D receptors, with variable activity at the 5- HT1F receptor. 5 Although initial research suggested triptan effectiveness occurred because of their vasconstrictive properties, their ability to block the transmission of pain signals from the trigeminal nerve to the TNC and prevent release of inflammatory neuropeptides is more important. 6 Triptans are well tolerated and effective, with an excellent safety profile and without the risk of dependence or addiction seen with barbiturate or opioid medications. Currently seven different triptans are available for the treatment of migraine. Each triptan has different pharmacologic properties; some are available in different formulations, such as orally disintegrating tablets, nasal sprays (NS), or subcutaneous injection (SC). 7 (Table ) Deciding which triptan to utilize is patient-dependant: how they metabolize the medication, headache patterns, and what adverse events they can experience. SC sumatriptan is the most effective and fastest-acting triptan but causes the most AEs. 8 A recent meta-analysis of 53 trials evaluating oral triptans compared all oral triptans to sumatriptan 100mg. Rizatriptan 10mg had better efficacy and consistency. Eletriptan 80mg had better efficacy but more AEs. Almotriptan 1.5mg had better pain-free response and fewer AEs. Naratriptan.5mg, frovatriptan.5mg, and sumatriptan 5mg had lower response rates at two hours, but naratriptan.5mg and sumatriptan 5mg were better tolerated than sumatriptan 100mg. Zolmitriptan.5 and 5mg, rizatriptan 5mg and eletriptan 40mg had similar results compared with sumatriptan 100mg. 9 In clinical practice, patients vary in their characteristics and response patterns. Trial and error is often necessary to find the best treatment. 30 If one triptan fails, it is worth trying another. Sumatriptan now is available in a fixed combination with naproxyn. The combination, more effective for migraine than either sumatriptan or naproxyn alone, 31 prevents headache recurrence Practical Neurology February 009

4 Table : Seratonin 5-HT 1b/1d agonists (triptans) Medication Formuations Doses (mg) Tmax (hours) Half-life (hours) Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Sumatriptan/naproxyn Zolmitriptan (tablet or dissolvable) NS SC (tablet or dissolvable) NS oral, SL sublingual, intramuscular, - intravenous, suppository DHE and Ergotamine. Ergotamine and dihydroergotamine (DHE) are older treatments for moderate-severe migraine that are serotonin agonists with vasoconstrictive and α-adrenergic activity. Ergotamine has more arterial vasoconstriction than DHE, which is a more potent α-adrenergic antagonist with less emetic effect. Ergotamine causes more AEs, especially nausea and vomiting, compared to triptans, which limits its usefulness. 33 Ergotamine is available as suppositories or tablets with and without caffeine. DHE is available as NS, SC or injection, and. Nausea is less common with the NS, SC or forms of DHE than with treatment. 34 To avoid the nausea with DHE treat together with an anti-emetic. DHE is particularly useful for patients with frequent severe migraine and may be less likely to produce MOH than ergots or triptans. Triptans, ergotamine and DHE are contraindicated in patients with ischemic heart disease, vasospasm, uncontrolled hypertension or transient ischemic attacks. 35 In triptan trials, 6.5, 1.5 0, ,.5 5, 10 5, 50, , 6 85/500.5, 5 5 Looking Forward: Needle-free Injections however, the rate of cardiovascular events was very low and most chest pain related to triptan use is not serious or related to ischemia. 36,37 Neuroleptics. Neuroleptics and antiemetics used in migraine are antidopinergic medications that block dopamine at D receptors in the brain. They are usually effective both for improving the nausea or vomiting associated with migraine and treating pain. Neuroleptics are often effective even in severe migraine and many are available as, or treatments. They are effective as rescue medication, and studies suggest neuroleptics are underutilized in the emergency room for the treatment of acute migraine. 38,39 Multiple antidopaminergic medications are useful in migraine. (Table 3) Oral metoclopramide is effective as an adjuvant medication with NSAIDs or triptans and decreases gastric stasis and enhances absorption of other medications. 40 Chlorpromazine, droperidol, prochlorperazine, and haloperidol are all useful in acute migraine, even in refractory cases such as CDH Sedation and extrapyramidal AEs are common. Promethazine and hydroxyzine are treatments for nausea that are less likely to cause extrapyramidal AEs. Seratonin receptor (5- HT3) antagonists may also help treat nausea but do not appear effective for the treatment of migraine pain. 44 A new drug-device combination under consideration by the FDA would deliver sumatriptan subcutaneously without a needle. Sumatriptan Dose-Pro (Zogenix) is described by the developer as a pre-filled, single-use disposable, needle-free drug delivery system designed to deliver 6mg of sumatriptan in 0.5mL of sterile liquid. Patients simply snap off the cap, press the device to a fold of abdominal skin, and depress the plunger. According to data presented at the 50th Annual American Headache Society Meeting in Boston last year and reported by Zogenix, DosePro was bioequivalent to the needle-based autoinjector; healthy volunteers achieved maximum plasma concentrations of sumatriptan within approximately 1 minutes. A second study involving migraine patients demonstrated that 98 percent of patients correctly used the three-step DosePro technology on the first try ~ ~ PN Staff February 009 Practical Neurology 15

5 Acute Treatment for Migraine Table 3: Neuroleptics in migraine Medication Metoclopramide Prochlorperazine Droperidol Chlorpromazine Haloperidol Route oral, SL sublingual, intramuscular, - intravenous, suppository Dose (mg) Special Situations Prodrome and Aura. Treatment of migraine during the prodrome of premonitory symptoms, such as hunger, neck pain, thirst or drowsiness before headache begins, is occasionally effective. Dromperidone 0-40mg and metoclopramide may help prevent attacks, 45 and triptans 46 may be useful, especially in the setting of menstrual migraine. 47 No medication is proven to reverse the neuronal dysfunction of prolonged migraine aura, but case reports suggest magnesium 1000mg, 48 ketamine NS 5mg, 49 carbon dioxide, and cranial transmagnetic stimulation may be effective in some patients. Status migrainosus. Status migrainosus (SM) is defined as a severe migraine attack lasting more than 7 hours. 11 Patients are often debilitated and have used acute medication without relief. Occasionally they will present to emergency departments (EDs) for evaluation and treatment. Treatment outcomes and practices in EDs suggest the current treatment of migraine is often poor. Patients are much more likely to receive opioids than migraine-specific medication such as DHE, and most still have headache and impaired function 4 hours after treatment. 50 Most patients presenting to EDs with headache meet established criteria for migraine, but only a minority receive a migraine diagnosis. 37 The first goal of treatment in the ED is to establish the diagnosis. Common red flags that indicate a secondary headache include new-onset headache, headache with sudden onset ( thunderclap headache ), systemic illness such as fever or immunosupression, older age of onset (over 50 in a patient without a history of headache) or neurological deficits. Patients with SM often require intense treatment, including parenteral therapy. Truly refractory patients with severe disability, medical problems, or MOH should be admitted into the hospital. Principles in the treatment of status migrainosus include: 1. Exclude secondary causes of headache.. Treat intravenously if needed. 3. If medication overuse exists, stop the offending agent. 4. Monitor and treat drug withdrawal. 5. fluids and electrolyte replacement as needed. 6. Treat concurrent nausea and vomiting. 7. Place the patient in a quiet environment with little ambient lighting. 8. Frequent ECGs to monitor QTc (depending on medication) 9. Start migraine prophylaxis. Treatment of SM in the hospital usually begins with fluids and anti-emetics (Table 3) with or without diphenhydramine. This is usually followed by DHE, maximum 3mg per day in three divided doses for up to one week, if there are no contraindications. 43 Adjunctive treatments helpful in some patients include magnesium, sodium valproate 15-0mg/kg rapidly infused, 51 and steroids such as dexamethasone or hydrocortisone. 5 Future Directions Although many treatment options are available in migraine, some patients will still experience profound disability due to their migraine despite treatment. Advances in our understanding of migraine pathophysiology will lead to new treatments in the next few years. Calcitonin gene-related peptide (CGRP) is important in migraine, and CGRP antagonists will soon become available. Initial studies suggest they are effective and well-tolerated. 54 Other potential targets may include adenosine receptor agonists, glutamate receptor antagonists, and nitric oxide synthase inhibitors. 55 Carbon dioxide nasal spray appears promising based on early clinical observations, 56 and there may even be a role for non-medication alternatives such as repetitive transcranial magnetic stimulation for acute migraine with aura. PN Stephen Silberstein, MD is professor of Neurology at Thomas Jefferson University in Philadelphia and on staff at the Jefferson Headache Center. Michael Marmura, MD is assistant professor of Neurology at Thomas Jefferson University in Philadelphia and on staff at the Jefferson Headache Center. 16 Practical Neurology February 009

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