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By Michael J. Marmura, MD and Stephen Silberstein, MD

igraine is a common chronic and often disabling OTCs without substantial relief.2 Providers treating migraine neurological disorder characterized by attacks of must be familiar with different acute treatments, be comfortable moderate to severe headache. Migraineurs usually with individualizing treatment, and be able to combine treat- experience nausea and light and sound sensitivity ment modalities. Mduring their attacks, and many have aura. Most Acute attack include specific medications, such patients experience reduced ability to function with attacks and as , ergots and (DHE), and non-spe- many are bed-bound. Migraines can have multiple triggers such cific medications used for other pain disorders. In selecting acute as food, sleep changes, or hormonal factors.1 Often migraineurs migraine , patients need a treatment plan tailored to elect to treat their headaches without physician consultation their headache type. Mild or moderate intensity attacks often using rest or over-the-counter (OTC) medications. Patients who respond to treatment with non-steroidal anti-inflammatory present for evaluation with migraine have usually tried some medications (NSAIDs) or combination medications, while more

12 Practical Neurology February 2009 severe attacks may respond better to specific medications. If the or combination medications more than 10 days a month for initial treatments fail, rescue medication is needed. This review more than three months.11 Frequent and use discusses acute evidence-based and practical treatments for are risk factors for the development of CDH,12 and stopping migraine, and specifically focuses on the treatment of intractable these medications can result in increased headache and with- headaches such as status migrainosus. drawal symptoms. MOH requires overuse for at least three months and a history of headaches worsening with the overuse.13 Basic Principles MOH can cause adverse events (AEs) specific to the class of In migraine, there are two basic strategies for treatment of acute medication such as ergotism, constipation, gastrointestinal and headache: step care and stratified care. In the step care model, renal disease, or tardive dyskinesias. Treatment of MOH by with- patients usually progress through a sequence of medications— drawing the offending agent usually improves migraine after a usually starting with a simple analgesic, then perhaps an anti- period of increased headache lasting weeks to months. emetic, and then a specific medication if the initial treatments are Migraineurs should be aware of MOH and keep a headache cal- ineffective.3 This can mean escalating treatment across or within endar (diary) of headaches and acute medication use.14 attacks. Stratified care involves treating attacks based on migraine Frequent migraines or those that do not respond to acute severity. In this model, patients use non-specific medications for agents are an indication for prophylaxis. Preventative medications minimally disabling attacks, and specific are indicated in patients with 1.) attacks medications for severe attacks. more than once a week, 2.) acute med- Compared to step care, stratified care ication use more than two days per improves treatment outcomes,4 improves Compared to week, 3.) impairment of quality of life or quality of life,5 and reduces costs.6 disability despite acute medication use, Early treatment of migraine attacks step care, 4.) complicated migraine conditions improves outcomes. Patients taking such as hemiplegic migraine, and 5.) ad- triptans early, when the pain is still stratified care verse events or contraindications to mild, often have increased pain-free acute medication. For example, patients rates at two hours.7 When taken early, improves with a contraindication to triptans or triptans may prevent the development ergots, such as coronary artery disease, of central sensitization in migraine,8 as treatment may need migraine prophylaxis, as acute manifested clinically by cutaneous allo- agents might not be effective.15 Migraine dynia, which is pain in response to nor- outcomes, prophylaxis is indicated in about one- mally non-painful stimuli. Migraineurs third of all migraineurs, but only three to with cutaneous allodynia are less likely improves quality 13 percent of patients take them.16 to respond to triptans.9 When selecting acute migraine med- of life, and Non-specific Medications ication, individualize the treatment NSAIDs. NSAIDs are effective in the according to the headache characteris- reduces costs. acute treatment of migraine. They may tics. For rapidly escalating and disabling work by suppressing inflammation and attacks, consider injectable medications. preventing and treating central sensiti- Patients with significant nausea or vomiting should use non-oral zation by blocking glial production of prostaglandins. They may medications and . Migraineurs with attacks that do also treat non-traditional migraine symptoms, such as neck pain not respond to specific medication (often with frequent urgent and sinus pressure, that are commonly associated with acute physician or emergency room visits) need a rescue treatment. migraine attacks.17 NSAIDs are less likely to cause MOH than Before deciding a treatment is ineffective, patients should treat at other treatments,12 but frequent use can lead to undesired sys- least two attacks. Other strategies include changing the dose, giv- temic AEs such as peptic ulcers or renal disease. Multiple ing a different formulation or route of administration, or adding NSAIDS demonstrate effectiveness in migraine. (Table 1) They a second agent. can be combined with triptans or antiemetics for severe attacks. For patients with frequent headaches, it is important to avoid . Opioids provide therapeutic benefit in migraine but overuse of acute medication. Medication overuse impacts more are associated with a high risk of abuse and dependency. Opioids migraineurs than patients with other chronic pain disorders10and are most useful in patients with infrequent but disabling is one cause of chronic daily headache (CDH). Medication over- migraine, especially if there are contraindications to specific treat- use headache (MOH) is defined as the use of simple analgesics ments, such as cardiovascular disease or pregnancy. Although AEs more than 15 days per month or using triptans, ergots, opioids may include sedation or confusion, patients might use opioids as

February 2009 Practical Neurology 13 Acute Treatment for Migraine

Table 1: NSAIDs effective in migraine migraine and relatively well tolerated.23 Contraindications Medication Route Dose (mg) include glaucoma, renal failure, severe hypertension, heart or renal disease and MAO inhibitors. Naproxyn PO 500-1100 Butalbital-containing analgesics include combinations with Indomethacin PO 25-75 acetaminophen or aspirin with and with or without PR 50 . No clinical trial demonstrates that butalbital, a barbi- turate, adds to the effectiveness of the constituent components, IM 50 and the risk of dependency and MOH is high.24 As with opi- Indomethacin--caffeine PR 25-4-75 oids, use of butalbital-containing medication must be moni- Ketoprofen PO 75-150 tored closely and limited to situations when other treatments are ineffective or contraindicated. Piroxicam SL 40 Ketorolac IM 30-60 Specific Medications Triptans. The development and use of triptans, a class of med- IV 15-60 ications specifically designed to treat acute migraine attacks, Ibuprofen PO 200-400 has revolutionized migraine treatment. Triptans are selective Diclofenac PO 50-100 , and all have high affinity for 5- HT1B and 5-HT1D receptors, with variable activity at the 5- Aspirin PO 650-1000 HT1F receptor.25 Although initial research suggested Aspirin-acetominophen-caffeine PO 250-250-65 effectiveness occurred because of their vasconstrictive proper- PO 200-400 ties, their ability to block the transmission of pain signals from the trigeminal nerve to the TNC and prevent release of inflam- Celecoxib PO 400 matory neuropeptides is more important.26 Triptans are well PO – oral, SL – sublingual, IM – intramuscular, tolerated and effective, with an excellent safety profile and IV- intravenous, PR – suppository without the risk of dependence or addiction seen with barbitu- a rescue medication to avoid the distress of a visit to the emer- rate or opioid medications. Currently seven different triptans gency room. Codeine with acetaminophen is effective in are available for the treatment of migraine. Each triptan has migraine, and other opioids commonly used as different pharmacologic properties; some are available in differ- rescue treatments include fentanyl, hydromorphone, hydro- ent formulations, such as orally disintegrating tablets, nasal codone, methadone, , oxycodone, propoxyphene, and sprays (NS), or subcutaneous injection (SC).27 (Table 2) pentazocine. Meperdine IM and IV is commonly used18 but may Deciding which triptan to utilize is patient-dependant: how cause paradoxical reactions such as seizures. The -antago- they metabolize the medication, headache patterns, and what nist opioid butorphanol may have lower abuse potential and can adverse events they can experience. SC is the most be given IV (2-3mg) or as a nasal spray (NS) for migraine.19 effective and fastest-acting triptan but causes the most AEs.28 Treatment of frequent migraine with opioids is problematic. A recent meta-analysis of 53 trials evaluating oral triptans Do not use opioids in patients with addictive tendancies, a his- compared all oral triptans to sumatriptan 100mg. tory of substance abuse, severe psychiatric disorders, or MOH. 10mg had better efficacy and consistency. 80mg had Patients taking long-term daily opiates for CDH usually do not better efficacy but more AEs. 12.5mg had better improve, and many are non-compliant.20 When using opioids, pain-free response and fewer AEs. 2.5mg, frovatrip- prescribe with strict limits and monitor the patient closely. tan 2.5mg, and sumatriptan 25mg had lower response rates at Patients should not receive opioid prescriptions from multiple two hours, but naratriptan 2.5mg and sumatriptan 25mg were providers. better tolerated than sumatriptan 100mg. 2.5 and Other analgesics. Acetominophen is effective for migraine 5mg, rizatriptan 5mg and eletriptan 40mg had similar results at a dose of 1000mg21 and is useful for patients with con- compared with sumatriptan 100mg.29 In clinical practice, traindications to NSAIDs. Caffeine enhances the effect of patients vary in their characteristics and response patterns. Trial other migraine medications and has analgesic properties of its and error is often necessary to find the best treatment.30 If one own.22 Acetominophen and caffeine are often used in combi- triptan fails, it is worth trying another. nation medications. The combination of isometheptene (a Sumatriptan now is available in a fixed combination with na- sympathomimetic), dichoralphenazone (a choral hydrate proxyn. The combination, more effective for migraine than either derivative) and acetaminophen is modestly effective for sumatriptan or naproxyn alone,31 prevents headache recurrence.32

14 Practical Neurology February 2009 Table 2: Seratonin 5-HT 1b/1d agonists (triptans) however, the rate of MedicationFormuations Doses (mg) Tmax (hours) Half-life (hours) cardiovascular events was very low Almotriptan PO 6.25, 12.5 2.1 3.1 and most chest pain Eletriptan PO 20, 40 1.8 5 related to triptan PO 2.5 ~2.5 ~26 use is not serious or related to Naratriptan PO 1, 2.5 2 6 ischemia.36,37 Rizatriptan PO (tablet or dissolvable) 5, 10 2-3 2 Neuroleptics. Sumatriptan PO 25, 50, 100 1.5 2 Neuroleptics and antiemetics used in NS 20 1.5 1.8 migraine are anti- SC 4, 6 0.17 2 dopinergic medica- Sumatriptan/naproxyn PO 85/500 tions that block at D2 Zolmitriptan PO (tablet or dissolvable) 2.5, 5 receptors in the NS 5 3 3 brain. They are usu- PO – oral, SL – sublingual, IM – intramuscular, IV- intravenous, PR – suppository ally effective both for improving the DHE and . Ergotamine and dihydroergotamine nausea or vomiting associated with migraine and treating pain. (DHE) are older treatments for moderate-severe migraine that Neuroleptics are often effective even in severe migraine and are serotonin agonists with vasoconstrictive and α-adrenergic many are available as PR, IM or IV treatments. They are effec- activity. Ergotamine has more arterial vasoconstriction than tive as rescue medication, and studies suggest neuroleptics are DHE, which is a more potent α- with less underutilized in the emergency room for the treatment of acute emetic effect. Ergotamine causes more AEs, especially nausea migraine.38,39 and vomiting, compared to triptans, which limits its usefulness.33 Multiple antidopaminergic medications are useful in Ergotamine is available as suppositories or tablets with and with- migraine. (Table 3) Oral is effective as an adju- out caffeine. DHE is available as NS, SC or IM injection, and vant medication with NSAIDs or triptans and decreases gastric IV. Nausea is less common with the NS, SC or IM forms of stasis and enhances absorption of other medications.40 DHE than with IV treatment.34 To avoid the nausea with IV , , prochlorperazine, and DHE treat together with an anti-emetic. DHE is particularly are all useful in acute migraine, even in refractory cases such as useful for patients with frequent severe migraine and may be less CDH.41-43 Sedation and extrapyramidal AEs are common. likely to produce MOH than ergots or triptans. and are treatments for nausea that are Triptans, ergotamine and DHE are contraindicated in less likely to cause extrapyramidal AEs. Seratonin receptor (5- patients with ischemic heart disease, vasospasm, uncontrolled HT3) antagonists may also help treat nausea but do not appear hypertension or transient ischemic attacks.35 In triptan trials, effective for the treatment of migraine pain.44 Looking Forward: Needle-free “Injections” A new drug-device combination under consideration by the FDA would deliver sumatriptan subcutaneously with- out a needle. Sumatriptan Dose-Pro (Zogenix) is described by the developer as a pre-filled, single-use disposable, nee- dle-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 report- ed by Zogenix, DosePro was bioequivalent to the needle-based autoinjector; healthy volunteers achieved maximum plasma concentrations of sumatriptan within approximately 12 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 2009 Practical Neurology 15 Acute Treatment for Migraine

Table 3: Neuroleptics in migraine (“thunderclap headache”), systemic illness such as fever or immunosupression, older age of onset (over 50 in a patient with- Medication Route Dose (mg) out a history of headache) or neurological deficits. Patients with Metoclopramide PO 5-10 SM often require intense treatment, including parenteral thera- IM 10 py. Truly refractory patients with severe disability, medical prob- lems, or MOH should be admitted into the hospital. IV 10-20 Prochlorperazine PO 5-10 Principles in the treatment of status migrainosus include: PR 25 1. Exclude secondary causes of headache. 2. Treat intravenously if needed. IV 5-10 3. If medication overuse exists, stop the offending agent. Droperidol IM 2.5 4. Monitor and treat drug withdrawal. IV 0.625-2.5 5. IV fluids and electrolyte replacement as needed. 6. Treat concurrent nausea and vomiting. Chlorpromazine PO 25-100 7. Place the patient in a quiet environment with little ambi- PR 50-100 ent lighting. 8. Frequent ECGs to monitor QTc (depending on medica- IV 10-25 tion) Haloperidol IM 5 9. Start migraine prophylaxis. IV 2-5 PO – oral, SL – sublingual, IM – intramuscular, Treatment of SM in the hospital usually begins with IV flu- IV- intravenous, PR – suppository ids and anti-emetics (Table 3) with or without diphenhy- dramine. This is usually followed by DHE, maximum 3mg Special Situations per day in three divided doses for up to one week, if there are Prodrome and Aura. Treatment of migraine during the no contraindications.43 Adjunctive treatments helpful in some prodrome of premonitory symptoms, such as hunger, neck patients include IV magnesium, IV sodium valproate 15- pain, thirst or drowsiness before headache begins, is occa- 20mg/kg rapidly infused,51 and steroids such as dexametha- sionally effective. Dromperidone 20-40mg and metoclo- sone or hydrocortisone.52 pramide may help prevent attacks,45 and triptans46 may be useful, especially in the setting of menstrual migraine.47 No Future Directions medication is proven to reverse the neuronal dysfunction of Although many treatment options are available in migraine, prolonged migraine aura, but case reports suggest IV mag- some patients will still experience profound disability due to nesium 1000mg,48 NS 25mg,49 carbon dioxide, their migraine despite treatment. Advances in our understand- and cranial transmagnetic stimulation may be effective in ing of migraine pathophysiology will lead to new treatments some patients. in the next few years. Calcitonin gene-related peptide (CGRP) Status migrainosus. Status migrainosus (SM) is defined as is important in migraine, and CGRP antagonists will soon a severe migraine attack lasting more than 72 hours.11 Patients become available. Initial studies suggest they are effective and are often debilitated and have used acute medication without well-tolerated.54 Other potential targets may include adeno- relief. Occasionally they will present to emergency depart- sine receptor agonists, glutamate receptor antagonists, and ments (EDs) for evaluation and treatment. Treatment out- nitric oxide synthase inhibitors.55 Carbon dioxide nasal spray comes and practices in EDs suggest the current treatment of appears promising based on early clinical observations,56 and migraine is often poor. Patients are much more likely to there may even be a role for non-medication alternatives such receive opioids than migraine-specific medication such as as repetitive transcranial magnetic stimulation for acute DHE, and most still have headache and impaired function 24 migraine with aura. PN hours after treatment.50 Most patients presenting to EDs with headache meet established criteria for migraine, but only a Stephen Silberstein, MD is professor of Neurology at Thomas Jefferson minority receive a migraine diagnosis.37 University in Philadelphia and on staff at the Jefferson Headache Center. The first goal of treatment in the ED is to establish the diag- Michael Marmura, MD is assistant professor of Neurology at Thomas nosis. Common “red flags” that indicate a secondary headache Jefferson University in Philadelphia and on staff at the Jefferson Headache include new-onset headache, headache with sudden onset Center.

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