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Review Article

Acute Migraine Treatment Werner J. Becker, MD ABSTRACT Purpose of Review: This article provides a systematic, evidence-based approach to acute medication choices for the patient with migraine. Recent Findings: Recent clinical trials, meta-analyses, and practice guidelines have confirmed that four nonsteroidal anti-inflammatory drugs (NSAIDs) with randomized controlled trial evidence for efficacy in migraine (ibuprofen, naproxen sodium, diclofenac potassium, and acetylsalicylic acid) and seven triptans (sumatriptan, rizatriptan, eletriptan, zolmitriptan, almotriptan, frovatriptan, and naratriptan) are appropriate medications for acute migraine treatment. Dihydroergotamine (DHE) is also suitable for selected patients. Summary: NSAIDs and triptans are the mainstays of acute migraine therapy, and antiemetic drugs can be added as necessary. Opioids and combination analgesics containing opioids should not be used routinely. Patient-specific clinical features should help guide the selection of an acute medication for an individual patient. Acute medications can be organized into four treatment strategies for use in various clinical settings. The acetaminophen-NSAID strategy is suitable for patients with attacks of mild to moderate severity. The triptan strategy is suitable for patients with severe attacks and for those with attacks of moderate severity who do not respond well to NSAIDs. The refractory migraine strategies may be useful for patients who do not respond well to the NSAIDs or triptans alone and include using triptans and NSAIDs simultaneously in combination, DHE, and rescue medications (eg, dopamine antagonists, combination analgesics, and corticosteroids) when the patient’s usual medications fail. Strategies for patients with contraindications to vasoconstricting drugs include use of NSAIDs, combination analgesics, and dopamine antagonists. Acetaminophen is the safest acute migraine drug during pregnancy, and acetaminophen with codeine is also an option. Sumatriptan may be an option during pregnancy for selected patients and is compatible with breast-feeding.

Address correspondence to Dr Werner J. Becker, Foothills Hospital, Division of Neurology, 12th Floor, 1403 29th Street NW, Calgary, AB, T2N 2T9, Canada, [email protected]. Relationship Disclosure: Dr Becker has served on the medical advisory boards of Allergan, Inc; Amgen Inc; electroCore Medical LLC; and Tribute Pharmaceuticals Canada, Inc, and the clinical trial steering committee of St. Jude Medical, Inc. He has received personal compensation for speaking engagements from Allergan, Inc; EMD Serono, Inc; Teva Pharmaceutical Industries Ltd; and Tribute Pharmaceuticals Canada, Inc, and for the development of educational materials for Allergan, Inc. Unlabeled Use of Products/Investigational Use Disclosure: Dr Becker discusses the unlabeled/investigational use of butalbital, codeine, dexamethasone, dexketoprofen, dimenhydrinate, domperidone, ketorolac, metoclopramide, morphine, oxycodone, prednisone, prochlorperazine, and tramadol for the acute treatment of migraine. * 2015, American Academy of Neurology.

Continuum (Minneap Minn) 2015;21(4):953–972.

INTRODUCTION Pharmacologic migraine treatment can be divided into two categories: acute migraine drug treatment for individual attacks and prophylactic (preventive) drug treatment. It is critical that patients understand the differences between these two categories as the medications used are quite different. Also, while daily medication use is essential for successful preventive treatment, the frequency of use of acute medications must be limited to avoid medication-overuse headache. Continuum (Minneap Minn) 2015;21(4):953–972

Use of acute medications among individuals with migraine is almost universal. More than 90% of migraine sufferers in the general population use one or more acute migraine medications.1 Treating moderate or severe migraine attacks effectively is important. Migraine attacks cause significant disability. Based on ictal disability during the migraine attack alone, the World Health Organization (WHO) ranks migraine eighth among all disorders causing years of life lived with disability.2 Effective acute medication use should www.ContinuumJournal.com

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Acute Migraine Treatment KEY POINTS

h Patients need to understand the difference between acute and preventive migraine medications.

h The cost of migraine to society, considering both direct and indirect costs, is enormous. A European study found that the cost of headache to society exceeded the costs of many other neurologic disorders, including stroke, multiple sclerosis, and Parkinson disease.

have the potential to markedly reduce the disability caused by migraine attacks by shortening attack duration and reducing attack severity. The cost of migraine to society, considering both direct and indirect costs (eg, missed work) is enormous. A European study found that the cost of headache to society greatly exceeded the costs of many other neurologic disorders, including stroke, multiple sclerosis, and Parkinson disease.3 Good acute pharmacologic migraine treatment might be expected to reduce these costs. For some individuals, migraine appears to be a progressive disorder. Approximately 1% of the general population has chronic migraine, a disabling migraine syndrome in which individuals suffer from headache on 15 or more days per month for at least 3 months.4 Approximately 12% of the general population has migraine,5 and essentially all individuals with chronic migraine have a prior history of episodic migraine. Risk factors that predispose patients to the development of chronic migraine include obesity, snoring, caffeine use, allodynia, depression, stressful situations, acute medication overuse, head injury, and suboptimal acute treatment of individual attacks. Peripheral and central sensitization of pain pathways due to repeated migraine attacks may play a role in the pathophysiology of chronic migraine, and, indeed, a high migraine attack frequency is a major risk factor for its development.6 APPROACH TO ACUTE MIGRAINE TREATMENT Many medications are used for acute migraine treatment, and both the practitioner and the patient need to have an organized approach to medication choice. Three basic approaches or strategies have been identified based upon attack severity and migraine-related disability.7 Stratified Approach In the stratified approach, the medication chosen for a given patient is based

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on migraine attack severity and the resulting disability. Thus, a triptan might be prescribed as initial therapy for patients with severe disabling attacks that often render them unable to function, while a nonsteroidal anti-inflammatory drug (NSAID) might be chosen as initial therapy for a patient with less severe attacks. This approach attempts to try the ‘‘best’’ medication for the patient first. Neurologists should keep in mind that by the time patients with migraine consult, they have invariably tried multiple over-thecounter simple and combination analgesics, including NSAIDS. Therefore, a stratified approach will be necessary for patients who present to a neurologist. Step-Care-Across-Attacks Approach In the step-care-across-attacks approach, a less expensive medication or one with greater perceived safety or fewer side effects is chosen first for a patient. If this is ineffective, other medications are tried in turn for subsequent attacks as previously used medications fail. This approach may result in several failed therapeutic trials with simple analgesics and NSAIDs before an effective medication is found for the patient with relatively severe migraine attacks. It may also result in a patient becoming a ‘‘lapsed consulter’’ as patients may feel little can be done for them. They may then rely on overthe-counter nonprescription medications, often with poor therapeutic results. In practice, given the availability of many medications without prescription, many patients have already tried a number of medications before consulting a physician for their headaches. Thus, they may be well advanced along a step-care-acrossattacks approach at the time of consulting. Step-Care-Within-Attack Approach With the step-care-within-attack approach, a patient takes a simple analgesic (eg,

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August 2015

acetaminophen or an NSAID) at migraine attack onset and then ‘‘steps up’’ later in the course of the attack to another medication class (eg, a triptan) if the initial medication fails to provide adequate relief. This approach may be effective for patients with attacks that build up slowly or for patients with attacks of variable severity, but all acute medications for migraine generally work better when taken early in the attack. The second moreeffective medication may also not work well for the patient if it is taken later in the attack. Patients using the step-carewithin-attack approach need to monitor their success rate with their initial medication, preferably with a headache diary, and if the success rate is low, they would be well advised to go directly to the more effective medication early in their attacks. GENERAL PRINCIPLES OF ACUTE MIGRAINE TREATMENT Practitioners need to consider several principles of acute migraine treatment when recommending an acute medication for a specific patient, which include the following: 1. Early treatment in the attack should be a goal for most patients. All acute medications, including triptans,8 tend to be more effective if taken early in the attack compared to when the attack has progressed or is fully established. 2. The response of a patient to an acute medication cannot be predicted with certainty. The physician’s first recommendation may not be effective, and patients need to understand that other options are available. Patient follow-up is often critical in achieving a successful outcome. 3. An appropriate treatment approach needs to be chosen, as discussed above. Some patients have attacks of differing severity and may need more than one acute treatment option for best results. Continuum (Minneap Minn) 2015;21(4):953–972

4. An appropriate medication formulation should be chosen based on the characteristics of the patient’s migraine attacks. Some patients may require more than one formulation. Attack features to consider include: & For patients without significant nausea, regular oral tablets may be a good choice, but orally disintegrating tablets (wafers), nasal sprays, and injections may all be appropriate options. Among the triptans, subcutaneous sumatriptan has the highest response rate,9 but also produces the most discomfort and is associated with the highest rate of side effects. The triptan nasal sprays, because of partial absorption through the nasal mucosa, particularly with zolmitriptan nasal spray, may have a faster onset of action than the tablets. & The triptan orally disintegrating tablets (wafers) can be helpful for patients with mild nausea, or when nausea is exacerbated by taking fluids, and allow for early treatment even if water is not available. They are not absorbed through the buccal mucosa and, therefore, do not have a faster onset of action than regular tablets. & For patients with greater degrees of nausea and for those who may vomit later in the attack, the triptan nasal sprays can be very useful. However, the dysgeusia associated with nasal sprays may exacerbate nausea and should be monitored. & For migraine attacks that build up very rapidly and for those that are fully developed upon awakening, an injectable formulation (eg, injectable sumatriptan) often has the greatest chance of providing

KEY POINTS

h For patients with relatively severe and disabling migraine attacks, a stratified approach to acute medication choice, which tries the best drug first, is often the best approach.

h When migraine attacks usually build up to a moderate or severe intensity, acute medications are generally more effective when taken early in the attack while the pain is still mild, but care must be taken to avoid medication overuse in patients with frequent attacks.

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Acute Migraine Treatment KEY POINTS

h Although most patients prefer an oral medication, a nonoral formulation, particularly subcutaneous sumatriptan, may be much more effective for attacks with early vomiting.

h Opiate-containing combination analgesics should not be used routinely for migraine treatment, as better options are available for most patients.

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relief. This is particularly true if the patient tends to vomit early in the attack. & For less severe attacks that build up rapidly or if patients desire a faster onset of action, several oral formulations that are designed to deliver a fast onset of action can be recommended. These include diclofenac powder for oral solution,10 solubilized (liquid-containing) NSAID formulations (eg, ibuprofen), effervescent acetylsalicylic acid (ASA), and the sumatriptan fast-dissolving tablet. 5. Two or more acute medications can be combined if necessary. The most studied combination has been sumatriptan and naproxen, and the combination is more effective than either drug alone.11 Metoclopramide can also be added to a triptan or NSAID or a combination of both to treat nausea and may also enhance absorption of the acute migraine drug. Caffeine enhances the effectiveness of analgesics, but needs to be balanced against negative effects such as interference with sleep and caffeine-withdrawal headache caused by excessive use. 6. Acute medication overuse needs to be avoided. Individuals with migraine appear to be particularly susceptible to exacerbation of their headache syndrome by the frequent use of analgesics. Frequent ergotamine and triptan use can also lead to increased headache frequency. Use of acetaminophen or NSAIDs on 15 or more days per month, or combination analgesics, opioids, ergotamines, or triptans on 10 or more days per month are considered to place patients at risk for medication-overuse headache.12 7. Opiates and opiate-containing combination analgesics should not be used for the routine

treatment of migraine. These medications, although helpful for some patients, are less effective than many of the other medications available and tend to lead to escalation in frequency of use and medication-overuse headache. MEDICATION CHOICE Randomized, double-blind controlled-trial evidence exists that a number of medications are effective for acute migraine treatment. When choosing an appropriate acute medication for a specific patient, an organized approach is important. Organizing the available medications into a small number of strategies that can be applied to a specific clinical situation may be helpful (Table 1-1).13 This approach is discussed further below. Antiemetics Metoclopramide (usual dose 10 mg, may be used up to 4 times a day) has the strongest evidence for efficacy in migraine, and some evidence exists for the use of domperidone (not available in the United States; usual dose 10 mg, may be used up to 4 times a day). Although metoclopramide poses some risk of extrapyramidal side effects and domperidone has been reported to cause QT prolongation, these are uncommon with the intermittent oral dosing used to treat migraine attacks. Many patients use dimenhydrinate because of its availability without prescription, but dimenhydrinate is a complex formulation and contains both an antihistamine (H1 antagonist) and a stimulant (theophylline derivative) The medication has abuse potential, and its efficacy in treating migraine-related nausea lacks evidence. Metoclopramide and domperidone are better choices. For refractory patients, prochlorperazine can also be used, both orally (usual dose 10 mg, may be given up to 4 times a day) or by suppository (dosage range 10 mg to 25 mg, maximum daily dose 50 mg), but

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KEY POINTS

h When an antiemetic is

TABLE 1-1 Acute Migraine Treatment Strategies Strategy

Medications

Acetaminophen and nonsteroidal anti-inflammatory drug strategy for attacks of mild to moderate severity

Acetaminophen (primarily for milder attacks)

necessary, a dopamine antagonist, in particular metoclopramide, is often the best choice.

h The nonsteroidal

Acetylsalicylic acid

anti-inflammatory drugs with the best evidence for efficacy for acute migraine treatment are acetylsalicylic acid, ibuprofen, naproxen sodium, and diclofenac potassium.

Ibuprofen Naproxen sodium Diclofenac potassium Triptan strategy for moderate and severe attacks

Sumatriptan Rizatriptan Eletriptan Zolmitriptan Almotriptan Frovatriptan Naratriptan

Refractory migraine strategies

Triptan and nonsteroidal anti-inflammatory drug combinations Dihydroergotamine Various rescue medications (eg, dopamine antagonists) Combination analgesics without opioids Combination analgesics with opioids (not for routine use)

Strategies for patients with contraindications to vasoconstricting drugs

Nonsteroidal anti-inflammatory drugs Dopamine antagonists Combination analgesics without opioids Combination analgesics with opioids (not for routine use)

has more extrapyramidal side effects. Metoclopramide, domperidone, and prochlorperazine can each be added to all the acute treatment strategies discussed below.13 Acetaminophen–Nonsteroidal Anti-Inflammatory Drug Strategy for Attacks of Mild to Moderate Intensity Acetaminophen and four NSAIDs (ASA, ibuprofen, naproxen sodium, and diclofenac Continuum (Minneap Minn) 2015;21(4):953–972

potassium) have good evidence supporting their use for migraine. Oral ketorolac does not have randomized controlled trial evidence, although parenteral ketorolac has been studied in the emergency department setting. The preferential use of oral medications with a sound evidence base is prudent. Acetaminophen has the advantage of less gastric irritation, and because it does not block prostaglandin synthesis in platelets, it does not affect platelet www.ContinuumJournal.com

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Acute Migraine Treatment KEY POINT

h Specialized nonsteroidal anti-inflammatory drug formulations with a more rapid onset of action than regular tablets are available.

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function. Acetaminophen is considered less effective than the NSAIDs and suitable for relatively mild migraine attacks. The recommended dose of acetaminophen for migraine is 1000 mg per dose, and, because of its short half-life (2 to 3 hours), patients may need to repeat this dose. It is important that the daily dose be kept below 4000 mg in a 24-hour period to avoid hepatotoxicity. Ibuprofen is likely the most commonly used NSAID by individuals with migraine. Good evidence for efficacy exists, with a number needed to treat of 3.2 for headache relief at 2 hours (pain reduced to mild or no pain) and 7.2 for pain free at 2 hours.14 A solubilized form (liquid-containing capsules) has a somewhat faster onset of action as compared to regular tablets. Ibuprofen also suffers from a short half-life (2 hours), so repeated dosing may be necessary. In controlled trials, higher doses were no more effective than the 400-mg dose, which is the most appropriate dose (maximum daily dose 2400 mg). Ibuprofen may cause less gastric irritation than ASA and is at least as effective. Although the response of an individual patient to any particular drug cannot be predicted, ibuprofen appears to be preferable to ASA for most patients. Diclofenac potassium is another NSAID with a rapid onset of action. Maximal plasma concentrations are achieved in under an hour with the tablet and in less than 15 minutes with the powdered formulation for oral solution.10 Numbers needed to treat for the 2-hour painfree end point (at least for the powder formulation) are similar to ibuprofen. Like ibuprofen, the half-life is short (2 hours). The usual dose of diclofenac potassium is 50 mg; the maximum daily dose for diclofenac potassium tablets is 150 mg. For diclofenac powder, one dose per day is recommended. Naproxen sodium, with its long duration of action (half-life of 14 hours) is

unique among the NSAIDs commonly used for acute migraine treatment. However, naproxen sodium has a slower onset of action, and the number needed to treat for the 2-hour pain-free end point is 15, which is higher than for the other NSAIDs. It has a favorable cardiovascular risk profile compared to ibuprofen and diclofenac potassium, although the relevance of this to the intermittent dosing used by patients with migraine is unclear. The usual dose is 500 mg or 550 mg, although one study suggested the 825-mg dose was more effective.15 Total daily dose should not exceed 1375 mg. The naproxen sodium salt should be used for faster absorption. ASA is usually used in doses of 975 mg to 1000 mg (maximum daily dose 4000 mg). Effervescent ASA has a faster onset of action than regular tablets and has shown efficacy similar to that of sumatriptan 50 mg.16 Including its active salicylate metabolite, ASA has a relatively long half-life of 6 hours. Like all the NSAIDs and acetaminophen, the medication can be combined with metoclopramide 10 mg. Other NSAIDs may also be effective, but cannot be recommended because of a lack of good randomized controlled trials. This includes ketorolac, although ketorolac is of some interest because it combines rapid absorption (maximum plasma levels occur in less than 1 hour) with a relatively long half-life (5 hours). The usual dose is 10 mg, and the maximum daily dose 40 mg; it is recommended that patients not use ketorolac for more than 5 to 7 consecutive days because of potential renal and gastrointestinal toxicity. Clinical trials suggest that the NSAIDs can be effective even in severe migraine attacks, which has been recognized by several guidelines.17,18 However, clinical experience indicates that for many patients with severe migraine attacks, the triptans are often a better choice. For a

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summary of the acetaminophen-NSAID strategy, see Table 1-2. Triptan Strategy for Moderate and Severe Attacks The triptans are considered second line by some, after the NSAIDs, but perhaps the only reason for this approach is that they are considerably more expensive than the NSAIDs. The triptans have been proven to be very safe in patients free of vascular disease and are generally well tolerated.19 For many patients with severe migraine attacks, these medications

should be considered first line. When patients are usually NSAID responsive but have occasional treatment failures, a triptan can be prescribed as a rescue medication. In fact, when an NSAID is prescribed for a patient with relatively severe migraine attacks, a triptan could be preemptively prescribed as a rescue medication in case the NSAID is not satisfactory. If necessary, the triptan could become the patient’s primary acute medication. The triptans have become the most used migraine-specific medications because of their pharmacologic specificity,

TABLE 1-2 Acetaminophen and Nonsteroidal Anti-inflammatory a,b Drug Strategy for Attacks of Mild to Moderate Severity

Medication

Usual Dose and Maximum Dose per Dayc

Acetaminophen (primarily for milder attacks)d

1000 mg

Ibuprofen tablets

400 mg

Maximum 4000 mg/d

Maximum 2400 mg/d Ibuprofen solubilized (liquid) tablets

400 mg Maximum 2400 mg/d

Diclofenac potassium tablets

50 mg Maximum 150 mg/d

Diclofenac powder for oral solution

50 mg Maximum single dose/d recommended

Naproxen sodium

500Y550 mg (up to 825 mg) Maximum 1375 mg/d

Acetylsalicylic acid

975Y1000 mg Maximum 4000 mg/d

Effervescent acetylsalicylic acid

975Y1000 mg Maximum up to 2000 mg/d recommended

a

For acetaminophen and all nonsteroidal anti-inflammatory drugs, limit use to 14 days a month or fewer to avoid medication-overuse headache. Patients may experience gastrointestinal irritation, increased blood pressure, and renal toxicity with excessive use of all nonsteroidal anti-inflammatory drugs. Avoid the use of these drugs if gastrointestinal ulcers are present or if the patient has asthma with acetylsalicylic acid. c Dosages are for adults. For acute migraine treatment, only one or two doses are usually recommended. d Liver toxicity with excessive dose or concomitant use of alcohol. b

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Acute Migraine Treatment KEY POINTS

h Because they are highly specific medications, the triptans offer an excellent clinical benefit-to-side-effect ratio for many patients.

h Despite the pharmacologic similarities among the various triptans, individual patients may respond much better to one triptan than another.

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which usually allows them to be used in adequate doses without major side effects. They are 5-hydroxytryptamine (5-HT1B, 5-HT1D) receptor agonists, and their antimigraine actions are mediated mainly through these receptors. Triptans have a great advantage over ergotamine and dihydroergotamine (DHE) in that these older drugs affect a number of other receptor types that often produce side effects, in particular nausea, at therapeutic doses. All seven triptans currently available have strong evidence for efficacy. Although they largely share a common mechanism of action, some patients will greatly prefer one triptan over another because of greater effectiveness, fewer side effects, or both. This phenomenon remains unexplained, although it may relate to the different genetic factors that may underlie the migraine disorder in different patients. In general, there is no ‘‘best’’ triptan overall, and for any given patient, the best triptan in the one that is most effective and best tolerated by that patient. If a patient’s response to a specific triptan is not optimal, then several other triptans should be tried for subsequent attacks as they may work much better. However, not all patients with migraine respond to the triptans, and some will need other options. Triptan choice. Despite their similarities, pharmacokinetic and other differences exist between the various triptans and their formulations, which have significant clinical implications. Sumatriptan 6 mg administered by subcutaneous injection has the lowest number needed to treat for any triptan formulation (2.3 for 2 hours pain free). Among the oral triptans, a recent meta-analysis found that eletriptan 40 mg and rizatriptan 10 mg provided the highest pain-free rates at 2 hours, and eletriptan also provided the highest 24-hour sustained painfree rate (no recurrence of headache for 24 hours).20

Some attempt can be made to tailor triptan choice to the characteristics of the patient’s migraine attacks. If patients awaken with full-blown attacks or if they tend to vomit early in the attack, subcutaneous sumatriptan 6 mg may be the best choice; it is also a good choice for patients who do not respond well to other triptan formulations (Case 1-1). For patients with lesser degrees of nausea, sumatriptan nasal spray 20 mg or zolmitriptan nasal spray 5 mg may be good choices. The nasal sprays may also be helpful for any patients who do not respond well to the oral triptans. If taking oral fluids exacerbates nausea, the orally dissolving tablets (wafers) (rizatriptan 10 mg and zolmitriptan 2.5 mg) may be a good choice. The wafers also allow for early treatment when water is not readily available. The wafers are not absorbed through the oral mucosa, however, and do not have a faster onset of action than the standard oral tablets. For most patients, the standard oral tablets work well. For patients with attacks that build up rapidly to a high intensity, speed of action and a high response rate are important. For these, rizatriptan 10 mg and eletriptan 40 mg might be the most useful oral triptans. Zolmitriptan nasal spray 5 mg should also be considered, particularly if significant nausea is present. Of the zolmitriptan administered intranasally, 30% is absorbed through the nasal mucosa and, therefore, enters the blood stream very rapidly. Zolmitriptan nasal spray 5 mg provides pain relief in some patients (superiority over placebo) within 15 minutes, and pain-free responses exceed placebo at 30 minutes.21 If frequent headache recurrence after initial successful treatment is an issue, eletriptan 40 mg and frovatriptan 2.5 mg are good choices as both have a longer half-life than most triptans and a lower headache recurrence rate.22 If side effects are an issue, almotriptan 12.5 mg may be better tolerated but still offers a good response

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Case 1-1 A 34-year old-woman who had experienced episodic migraine attacks since her teenage years presented for a neurologic evaluation, where she reported having about four attacks per month, most of which occurred during the day and responded well to oral rizatriptan 10 mg if treated shortly after attack onset. She reported waking once a month with a fully developed migraine attack and vomiting within an hour of awakening. These attacks did not respond to oral rizatriptan, and she was unable to go to work on those days. She had no significant past medical history. Neurologic examination was normal. She was advised to use sumatriptan 6 mg by subcutaneous self-injection for the severe attacks that were present on awakening and to continue with oral rizatriptan for other attacks. She was prescribed oral metoclopramide 10 mg tablets and advised to take one tablet with the sumatriptan to assist in managing her nausea. She was also advised that if nausea and vomiting remained a problem, another option for treatment of her nausea would be prochlorperazine suppositories (10 mg to 25 mg). Comment. Subcutaneous sumatriptan remains the triptan with the highest response rate in treating migraine attacks and is particularly useful for patients with early vomiting during the attack. Most patients prefer an oral medication if possible; thus, it can be useful both in terms of patient convenience and cost to make more than one formulation available. Patients can then tailor their treatment to the nature of the migraine attack being treated. Although an antiemetic may not be necessary if the triptan works well, antiemetics can be a useful addition to the triptan in patients with significant nausea or vomiting. Prochlorperazine has more extrapyramidal side effects than metoclopramide, but the suppository formulation can be very helpful, particularly if patients vomit with some of their attacks.

rate and a low headache recurrence rate. Four triptans contain a sulfonyl group or a sulfonamide moiety (sumatriptan, almotriptan, eletriptan, and naratriptan). Although patients with a sulfonamide allergy usually tolerate these triptans well, if previous allergic reactions to sulfonamides have been severe, a sulfur-free triptan can be chosen (eg, rizatriptan, frovatriptan, or zolmitriptan). For a summary of the triptan strategy, see Table 1-3. Much of the data on which triptan comparisons are based derive from metaanalyses of studies in which patients were treated when the pain was moderate or severe in intensity, but fewer data exist on how the various triptans compare when they are taken early in the migraine attack. When triptans are taken earlier while pain is still mild, headache relief and pain-free response rates are higher23 and headache recurrence rates may also be lower. Taking a triptan early while pain is still mild is advantageous for most patients if past experience has shown Continuum (Minneap Minn) 2015;21(4):953–972

that such attacks are likely to progress to moderate or severe intensity and respond less well when a triptan is taken later in the attack. Caution must be exercised in patients with relatively frequent migraine attacks, as medication overuse needs to be avoided. If patients are at risk for medication-overuse headache, preventive medications and behavioral interventions should be considered. Headache recurrence within 24 hours of initial successful treatment is usually best treated with a second dose of the same triptan that was taken initially. Several options are available to reduce the recurrence rate in patients prone to headache recurrence after triptan treatment (Case 1-2). Naproxen sodium 500 mg to 550 mg can be added to the triptan, as headache recurrence after sumatriptan has been shown to be reduced when naproxen is added to the sumatriptan.11 Alternatively, another triptan with a relatively low recurrence rate (eg, eletriptan, frovatriptan, or naratriptan) can be tried, www.ContinuumJournal.com

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a,b,c TABLE 1-3 Triptan Strategy for Moderate and Severe Attacks

Medication

Usual and Maximum Daily Dosed

Almotriptan tabletse

12.5 mg Maximum 25 mg/d

Eletriptan tablets

40 mg Maximum 80 mg/d

Frovatriptan tablet

2.5 mg Maximum 5 mg/d

Naratriptan tablets

2.5 mg Maximum 5 mg/d

Rizatriptan tabletse,f

10 mg Maximum 20 mg/d e,f

Rizatriptan wafers (orally dispersible tablets)

10 mg Maximum 20 mg/d

e

Sumatriptan tablets

100 mg (50 mg also used) Maximum 200 mg/d e

20 mg

Sumatriptan intranasal

Maximum 40 mg/d Sumatriptan injection

e

4Y6 mg Maximum 12 mg/d

Zolmitriptan tablets

e

2.5Y5 mg Maximum 10 mg/d

Zolmitriptan wafers (orally dispersible tablets)

e

2.5 mg Maximum 10 mg/d

Zolmitriptan intranasal

e

5 mg Maximum 10 mg/d

a

Selected side effects of triptans include flushing, hot or warm sensation, paresthesia, and chest or jaw discomfort or tightness. Limit the use of triptans to fewer than 10 days per month to avoid medication-overuse headache. c Triptans are contraindicated in cerebrovascular, cardiovascular, and peripheral vascular disorders; in uncontrolled hypertension and ischemic bowel disease; and in concomitant use within 24 hours of ergot-containing medications. d Dosages are for adults. For acute migraine treatment, only one dose is usually recommended, followed by a second dose (2 hours or more after the first dose) if the headache reoccurs after initial relief. e Avoid the use of almotriptan, rizatriptan, sumatriptan, and zolmitriptan with monamine oxidase inhibitors and within 2 weeks after discontinuation of monamine oxidase inhibitors. f For rizatriptan, reduce the dose to 5 mg (maximum 10 mg per day) if the patient is also on propranolol. b

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KEY POINTS

Case 1-2

h Headache recurrence

A 28-year-old man with a long history of severe migraine attacks, which increased rapidly in intensity after onset, was concerned because, although his headaches responded well to oral sumatriptan 100 mg taken early in the attack, his headaches usually recurred after 8 to 12 hours. He took acetaminophen with codeine for these recurrent headaches, but obtained only partial relief from this approach. Several therapeutic options were discussed with him, and it was decided to switch his triptan to eletriptan 40 mg as this triptan has a longer half-life than sumatriptan, and evidence exists that it has a lower headache recurrence rate than sumatriptan. He tried this strategy, but he continued to experience frequent headache recurrence with the eletriptan and often needed to take a second dose later in the day for the recurrent headache. At this point, he was advised to take naproxen sodium 550 mg simultaneously with the eletriptan when treating his initial migraine attack. Comment. Headache recurrence after triptan treatment is not uncommon. A second dose of the triptan is very useful in treating headache recurrence, in contrast to headache persistence (no or little relief after initial triptan treatment) where a second triptan dose is of questionable benefit. The triptans appear to differ in their recurrence rates, but this is hard to assess as a headache can only recur if it responds to the initial triptan treatment. Frovatriptan, which has the longest half-life of all the triptans, has a low recurrence rate and can be useful in patients with headache recurrence. However, frovatriptan has lower response rates at early time points after dosing as compared to eletriptan and therefore was not considered for this patient. Adding a nonsteroidal anti-inflammatory drug can also improve responsiveness to triptans, and naproxen sodium, with its long half-life, appears especially well suited for reducing headache recurrence. Treatment with the triptan early in the attack also has the potential to reduce headache recurrence.

but frovatriptan and naratriptan have a slower onset of action and higher numbers needed to treat for pain free at 2 hours (8.5 for frovatriptan and 8.2 for naratriptan). DHE also has a long halflife and a low headache recurrence rate. Headache persistence is said to occur when the initial triptan dose fails to provide a clinically meaningful response. In contrast to headache recurrence, clinical trials suggest that a second triptan dose is no more helpful than placebo under these circumstances.24 Some patients do indicate that a second triptan dose is helpful to them, but this is difficult to interpret given the high placebo response to medication taken for headache persistence in clinical trials, perhaps Continuum (Minneap Minn) 2015;21(4):953–972

can be minimized by treatment early in the migraine attack, choosing a triptan with a relatively longer half-life (eg, eletriptan, frovatriptan), combining a long half-life nonsteroidal anti-inflammatory drug with the triptan (eg, naproxen sodium), or using dihydroergotamine.

h For headache recurrence after initial relief, a second triptan dose is often the best treatment option. In contrast, for headache persistence (no response to the initial triptan dose), another rescue medication is usually the best option.

because the initial triptan dose is still active. It may be prudent to use another rescue medication if the initial triptan dose fails. Although early treatment is recommended for patients with migraine without aura, data from several small clinical trials do not support triptan treatment during the migraine aura, at least for subcutaneous sumatriptan and oral eletriptan. As a result, it has been recommended that patients experiencing migraine with aura take their triptan at the onset of the pain phase of the migraine attack. Nevertheless, some patients do report success with triptan treatment during the aura.25 Triptan treatment during typical aura appears to be safe,26 and if www.ContinuumJournal.com

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Acute Migraine Treatment KEY POINT

h Triptan effectiveness can be enhanced by taking the triptan early in the attack and, if necessary, by taking a nonsteroidal anti-inflammatory drug (eg, naproxen sodium) with the triptan.

patients report success with treatment during the aura, there is no need to discourage this strategy. Triptans taken alone will often relieve migraine-related nausea satisfactorily, but metoclopramide or domperidone can be added to any triptan if necessary. The prokinetic effect of metoclopramide may also promote triptan absorption. In one study it was found that patients who did not receive adequate relief from sumatriptan 50 mg alone had better headache relief with the addition of metoclopramide.27 Refractory Migraine Strategies Several options are available for patients who do not respond adequately to either NSAIDs or triptans (Case 1-3). Clinical trials have clearly shown that when naproxen sodium is combined with sumatriptan, migraine attack response rates are better than with either drug alone.11 Despite a lack of evidence, extending these observations to other triptan/

NSAID combinations appears reasonable. Most triptans have a relatively short half-life, and, because of its long half-life, naproxen sodium may be particularly well suited for triptan/NSAID combination therapy as compared to other NSAIDs, particularly in reducing the rate of migraine recurrence. If the intent is to improve headache relief at 2 hours, a faster-acting NSAID, such as ibuprofen or diclofenac, might be more effective. A recent clinical trial that compared a combination of frovatriptan 2.5 mg (a long half-life triptan) to a combination of frovatriptan and a fast-acting, short half-life NSAID (dexketoprofen) supported this concept in that the combination resulted in higher pain-free rates at 2 hours than frovatriptan alone (51% versus 29%).28 For patients who usually, but not always, respond to a triptan/NSAID combination, it may be helpful to provide a rescue medication to use when their usual medication fails. However, the options

Case 1-3 A 44-year-old woman reported that her sumatriptan 100 mg tablets provided only incomplete relief from her migraine attacks. Early treatment of her attacks reduced their severity, but she was still left with a mild headache, which remained troublesome for another 12 hours. She had also tried rizatriptan, eletriptan, almotriptan, and frovatriptan in the past and felt that, of all of the triptans she had tried, sumatriptan provided her with the best overall relief. She was advised to take naproxen sodium 550 mg simultaneously with her sumatriptan to enhance the efficacy of her acute treatment. Comment. Adding naproxen to sumatriptan has been shown to improve efficacy. Many clinicians will use naproxen sodium with other triptans based on these findings or use triptans with other nonsteroidal anti-inflammatory drugs (NSAIDS), which seems reasonable, although the sumatriptan/naproxen combination is the only one that has been well studied. Although there have not been randomized controlled trials to address all these issues, if an NSAID is being added in a patient with migraine attacks that build up rapidly and more rapid complete relief is desired, use of a rapidly acting NSAID such as ibuprofen or diclofenac may be most useful. If headache recurrence or long-lasting lower level pain is being addressed, then naproxen with its long half-life may be a more reasonable choice. Naproxen sodium is preferred over other forms of naproxen because of faster absorption.

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August 2015

are limited if vomiting reduces the usefulness of oral medications. If a triptan has already been used, further vasoconstrictors need to be avoided. Dopamine antagonists are options, including prochlorperazine orally (10 mg, with up to four doses in 24 hours) or by suppository (10 mg to 25 mg, maximum daily dose 50 mg), and chlorpromazine orally (10 mg to 50 mg, with up to four doses in 24 hours) or intramuscularly (25 mg to 50 mg, with up to four doses in 24 hours). Both are powerful antiemetics, and the sedation they provide may also be helpful. NSAIDs for rescue may be problematic if the patient has already taken naproxen sodium. Ketorolac 60 mg by IM selfinjection can be used safely at home if patients are adequately trained.29 Indomethacin orally (50 mg to 75 mg) or by suppository (50 mg to 100 mg) can be used, but evidence for efficacy is limited. A short course of prednisone (60 mg on the first day with a rapid taper over 3 or 4 days) or dexamethasone (8 mg on the first day with a rapid taper over 3 or 4 days) can be considered for occasional use. Dexamethasone 4 mg plus rizatriptan 10 mg in a single-dose study resulted in a higher proportion of patients achieving a 24-hour sustained pain-free end point (50.7%) than rizatriptan alone (32.2%) in a menstrually related migraine study.30 Therefore, steroids may be of some use in patients in whom triptan therapy occasionally fails, but the evidence is very limited. Combination analgesics containing isometheptene have been widely used in the past for migraine, although little evidence exists for the effectiveness of isometheptene alone. Isometheptene is a sympathomimetic amine that is thought to exert its effects through vasoconstriction and is often combined with acetaminophen and caffeine. Physicians should be aware that in some combination analgeContinuum (Minneap Minn) 2015;21(4):953–972

sics, isometheptene is combined with dichloralphenazone. Dichloralphenazone is a mixture of antipyrine (an NSAID) and chloral hydrate (a hypnotic) and may not be an ideal medication for the modern treatment of migraine. A recent review of combination analgesics and migraine treatment summarized the evidence for the use of isometheptene combination analgesics for migraine, but did not provide conclusions with regard to the place of these treatments in migraine therapy.31 Combination analgesics with codeine or tramadol are additional options for rescue mediations when triptans occasionally fail or for patients who do not respond to triptans. Opiates should not be used routinely in migraine therapy, but occasional use when necessary in selected patients is a potential option. There is concern that opioid use can lead to receptor changes, which may make patients with migraine less responsive to other drugs, and opioid use may escalate over time and lead to medication-overuse headache. Intranasal butorphanol is best avoided because of risk of addiction and dependence, although it may be useful in selected cases as it can be used even if patients are vomiting. Frequency of use of all opioids should be carefully monitored. Combination analgesics with barbiturates (eg, butalbital) should be avoided and used only under very exceptional circumstances, if at all, as barbiturate-containing combination analgesics are a potent cause of medication-overuse headache. A large, randomized, double-blind crossover trial demonstrated that a sumatriptan/ naproxen combination was superior to a butalbital, acetaminophen, caffeine combination tablet on most end points.32 Some patients who do not respond well to triptans will respond to ergotamine or DHE. DHE is the preferred drug, and can be given by nasal spray (one 0.5-mg spray in each nostril, repeated after 15 www.ContinuumJournal.com

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Acute Migraine Treatment KEY POINTS

h For patients who do not respond to nonsteroidal anti-inflammatory drugs or the triptans, dihydroergotamine, metoclopramide, prochlorperazine, and a number of combination analgesics (with and without tramadol or codeine) are potential therapeutic options.

h Medication use should be minimized as much as possible during pregnancy, but acetaminophen, acetaminophen with codeine, and metoclopramide are considered safe acute treatments for migraine. Available data indicate sumatriptan is also relatively safe and could be considered for use during pregnancy where warranted.

to 30 minutes [maximum dose 4 mg per day]) or by subcutaneous or IM selfinjection (usual dose 1 mg, preceded by metoclopramide 10 mg orally [maximum daily dose for parenteral DHE 3 mg per day]). Nausea is a common side effect. If leg cramps or coldness and tingling of the hands and feet occur, DHE should be reduced or discontinued. A new orally inhaled formulation of DHE has shown promise of good efficacy (28.4% pain free at 2 hours) but is not yet available.33 DHE is not available in oral formulations. Ergotamine tartrate is not recommended for routine use, and triptans are a better option for most patients. Ergotamine tartrate may be helpful in patients with prolonged attacks who do not respond well to the triptans. Patients need to find a subnauseating dose that is effective for their migraine attacks (usual dosage range is 0.5 mg to 2 mg).34 Refractory migraine strategies are summarized in Table 1-4 and Table 1-5. Strategies for Patients With Contraindications to Vasoconstricting Drugs Acute treatment options for patients with contraindications to vasoconstricting drugs (Table 1-6) include the NSAIDs and most of the rescue medications previously discussed (eg, dopamine antagonists, ketorolac injections, indomethacin, steroids, and combination analgesics with codeine or tramadol). If acute medications are used frequently, however, it should be kept in mind that many NSAIDs have been associated with an increased risk of cardiovascular events. Naproxen sodium may be an exception and may be the preferred NSAID in patients with cardiovascular disease.35 Nonopioid combination analgesics may also be helpful. Combination analgesics containing acetaminophen, ASA, and caffeine have been found superior to the combination of acetaminophen

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and ASA without caffeine, to ASA alone, and to acetaminophen alone.36 Combination analgesics without opiates may be helpful when triptans are contraindicated or ineffective. A combination of acetaminophen 400 mg per day, ASA 500 mg per day, and caffeine 100 mg given as a single dose was found to be effective even in patients with severe headache attacks compared to placebo.37 Combination analgesics containing isometheptene are considered contraindicated in patients with vascular disease because of its vasoconstrictor properties. Pharmacologic prophylactic therapy and behavioral treatment approaches should be maximized for all patients where acute pharmacologic therapy is problematic or ineffective. MIGRAINE DURING PREGNANCY No drug has been proven to be safe during pregnancy, so drug use should be avoided as much as possible and behavioral approaches maximized. Acetaminophen and metoclopramide are considered safe, while acetaminophen with codeine is also considered relatively safe, although caution should be observed toward the end of pregnancy because of potential withdrawal symptoms in the neonate and because of a slight association with acute cesarean delivery and postpartum hemorrhage.38 Other opioids may also cause harmful effects on the fetus or neonate without causing malformations. ASA should be avoided in pregnancy. Other NSAIDs are preferable because of less prolonged effects on platelet function. All NSAIDs should be avoided after the 32nd week of gestation because of effects on the ductus arteriosus, and it may be best to avoid NSAIDs in the first trimester because of a possible increased risk of spontaneous abortion, although in a recent historical cohort study, exposure to NSAIDs during pregnancy was not an independent risk factor for spontaneous abortion.39

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TABLE 1-4 Refractory Migraine Strategies Usual and Maximum Daily Dosea

Medication Sumatriptan and naproxen sodium taken simultaneously

Sumatriptan 100 mg, naproxen sodium 500Y550 mg (other doses are also used in combination tablets)

Selected Side Effects

Comments

See Table 1-2 and Table 1-3

The combination is more effective than either drug alone See Table 1-2 and Table 1-3

Maximum two doses Other triptans and other nonsteroidal anti-inflammatory drug combinations

See Table 1-2 and Table 1-3 for individual drugs

See Table 1-2 for individual drugs

Randomized clinical trials not available for most combinations

Dihydroergotamine intranasal

0.5 mg in each nostril, repeat dose in 15 minutes; may repeat four-spray sequence in 6 hours if necessary

Nausea, vomiting, muscle cramps, paresthesia, and other side effects related to vasoconstriction; rhinitis and taste disturbance

Contraindicated in vascular disease

Maximum 4 mg/d

Limit use to under 10 days a month for most patients, but relationship to medication-overuse headache uncertain. Avoid dihydroergotamine with CYP3A inhibitors (eg, clarithromycin, ketoconazole, ritonavir)

Dihydroergotamine subcutaneous or IM injection

0.5Y1 mg, dose may be repeated in 3 hours if necessary Maximum 3 mg/d

Nausea, vomiting, muscle cramps, paresthesia, and other side effects related to vasoconstriction

Contraindicated in vascular disease Limit use to under 10 days a month for most patients, but relationship to medication-overuse headache uncertain. Avoid dihydroergotamine with CYP3A inhibitors (eg, clarithromycin, ketoconazole, ritonavir)

Ergotamine tartrate sublingual tablets

0.5Y2 mg Maximum 6 mg/d

Nausea, vomiting, muscle cramps, paresthesia, and other side effects related to vasoconstriction

Contraindicated in vascular disease Limit use to fewer than 10 days a month to avoid medication-overuse headache

IM = intramuscular. a Dosages are for adults.

Although ergotamines must be avoided owing to uterotonic effects, triptans appear much safer during pregnancy. A large observational study found no asContinuum (Minneap Minn) 2015;21(4):953–972

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a TABLE 1-5 Refractory Migraine Strategies: Rescue Medications

Medication

Usual Doseb

Selected Side Effects

Comments

Prochlorperazine tablets

10 mg

Extrapyramidal symptoms, drowsiness

Dopamine antagonist

Prochlorperazine suppositories

10Y25 mg

Extrapyramidal symptoms, drowsiness

Dopamine antagonist, helpful if severe nausea or vomiting

Chlorpromazine tablets

10Y50 mg

Extrapyramidal symptoms, drowsiness

Limited evidence for efficacy

Ketorolac by IM self-injection

60 mg

Gastrointestinal disturbance, renal toxicity, injection site pain

Patients must be adequately trained

Indomethacin tablets

50Y75 mg

Indomethacin suppositories

50Y100 mg

Prednisone tablets

60 mg on the first day, with rapid taper over several days

Insomnia, behavioral change, other steroid side effects

Only for occasional use for prolonged attacks

Dexamethasone tablets

8 mg on the first day, with rapid taper over several days

Insomnia, behavioral change, other steroid side effects

Only for occasional use for prolonged attacks

Maximum 40 mg/d Maximum 50 mg/d

Maximum 200 mg/d Maximum 120 mg/d

Maximum 200 mg/d Maximum 200 mg/d

Combination analgesics Individualized dosing with isometheptene

See nonsteroidal anti-inflammatory Limited evidence drugs in Table 1-2 for efficacy See nonsteroidal anti-inflammatory Limited evidence for efficacy drugs in Table 1-2

Depends on tablet ingredients Isometheptene is a vasoconstrictor; avoid in vascular disease

Combination analgesics with tramadol or codeine

Individualized dosing

Drowsiness, constipation

Monitor frequency of use as a risk of medication overuse-headache exists

Butorphanol intranasal

1 mg (1 spray) in one nostril, repeat once in 60 to 90 minutes if necessary; repeat two-dose sequence in 6 hours if necessary

CNS depression, sedation, respiratory depression, dependence, abuse, possible addiction

Use only in exceptional circumstances and limit use to fewer than 8 days per month to avoid medication-overuse headache

Butalbital-containing Avoid if possible combination analgesics Strong opiates (eg, Avoid if possible morphine, oxycodone) IM = intramuscular; CNS = central nervous system. a Rescue medications to be used when primary medication fails; consider whether related drugs have been used in past 24 hours. With migraine, most rescue medications are meant for occasional use, and some are potential options for primary medications in patients who are unresponsive to nonsteroidal anti-inflammatory drugs and vasoconstrictors. b Dosages are for adults.

third trimester was associated with atonic uterus and blood loss of greater than 500 mL during labor and delivery.40 Much fewer data exist with regard to the other triptans. Although still controver-

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sial, sumatriptan may be an option for pregnant women with difficult migraine that often renders them incapable of carrying out tasks of daily living or results in dehydration.

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a TABLE 1-6 Strategies for Patients With Contraindications to Vasoconstricting Drugs

Medication

Usual Dose

Selected Side Effects

Comments

Acetylsalicylic acid, acetaminophen, and caffeine combination analgesics

Individualized dosing

Gastric irritation (acetylsalicylic acid), liver toxicity at high doses (acetaminophen), insomnia (caffeine)

Combinations may be more effective than individual drugs alone

Combination analgesics with tramadol or codeine

Individualized dosing

Drowsiness, constipation, others according to ingredients

Limit use to fewer than 10 days per month to avoid medication-overuse headache

a

Nonsteroidal anti-inflammatory drugs including indomethacin, dopamine antagonists, and many of the rescue medications discussed in the refractory migraine strategies are also options for patients with contraindications to vasoconstricting drugs. Please see previous tables in this article for dosing and side effects.

Lidocaine is safe in pregnancy, so occipital nerve blocks can be considered. Prochlorperazine and other phenothiazines are not considered to be teratogenic, but their use near term may be associated with extrapyramidal effects in the newborn. Short courses of steroids given after 10 weeks gestation appear not to pose a risk to the fetus.41 MIGRAINE DURING LACTATION Acetaminophen is considered safe during breast-feeding. Among the NSAIDs, ibuprofen is preferred. Occasional use of diclofenac and ketorolac is considered compatible with breast-feeding, but ASA in analgesic doses should be avoided. The amount of infant exposure from maternal use of sumatriptan appears to be small, and sumatriptan use is considered compatible with breast-feeding.42 Metoclopramide, domperidone, prochlorperazine, and dimenhydrinate are all considered safe.43 If an opioid must be used, morphine is the opioid of choice, but the milk should be discarded if the mother experiences significant sedation. Caution should be exercised, particularly with premature infants and infants under 1 month of age. Because of variable maternal metabolism, codeine should be avoided as exposure of the infant to morphine (a metabolite of Continuum (Minneap Minn) 2015;21(4):953–972

codeine) may be much higher than expected if the mother is a fast metabolizer of codeine (5% to 40% of individuals, depending on ethnic background).44 CONCLUSION Many drugs have shown efficacy for acute migraine treatment in doubleblind, randomized controlled trials. However, choosing the best medication for a specific patient remains a complex task and requires careful consideration of the patient’s clinical features and preferences. Adequate patient education and an organized approach to medication choice is important. Patients may have more options for acute migraine treatment in the future, including single-pulse transcranial magnetic stimulation, which has shown promise for acute treatment of migraine with aura,45 and noninvasive vagal nerve stimulation, which is under investigation.46 New delivery systems for sumatriptan, which may eventually be applied to other drugs as well, are either becoming available or are under active investigation and include a needle-free injection system,47 transdermal drug delivery systems,48 and breath-powered devices for better drug delivery through the nasal mucosa.49 Research in these areas and others bodes well for the treatment of acute migraine www.ContinuumJournal.com

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attacks in the near future. An updated assessment of the evidence for the available pharmacologic therapies for acute migraine treatment has also recently been published.50

6. Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004;62(5):788Y790. doi:10.1212/ 01.WNL.0000113747.18760.D2.

USEFUL WEBSITES Scottish Intercollegiate Guidelines Network (SIGN). SIGN provides a clinical guideline for the diagnosis and management of headache in adults, including assessment tools and treatment recommendations. www.sign.ac.uk/pdf/sign107.pdf

7. Lipton RB, Stewart WF, Stone AM, et al. Disability in Strategies of Care Study group. Stratified care vs step care strategies for migraine: the Disability in Strategies of Care (DISC) Study: a randomized trial. JAMA 2000;284(20): 2599Y2605. doi:10.1001/jama.284.20.2599.

Toward Optimized Practice (TOP). TOP provides a variety of resources for headache management, including guidelines and assessment tools.

9. Treatment of migraine attacks with sumatriptan. The Subcutaneous Sumatriptan International Study Group. N Engl J Med 1991;325(5):316Y321.

www.topalbertadoctors.org/cpgs/10065 Motherisk, published by The Hospital for Sick Children, University of Toronto. Motherisk provides links to published studies on the safety or risk of specific drugs during pregnancy. www.motherisk.org/women/drugs.jsp REFERENCES 1. Cooke LJ, Becker WJ. Migraine prevalence, treatment and impact: the canadian women and migraine study. Can J Neurol Sci 2010;37(5):580Y587. 2. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990Y2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380(9859):2163Y2196. doi:10.1016/S0140-6736(12)61729-2. 3. Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. Eur J Neurol 2005;12(suppl 1):1Y27. doi:10.1111/j.1468-1331.2005.01202.x. 4. Buse DC, Manack AN, Fanning KM, et al. Chronic migraine prevalence, disability, and sociodemographic factors: results from the American Migraine Prevalence and Prevention Study. Headache 2012;52(10):1456Y1470. doi:10.1111/j.1526-4610.2012.02223.x. 5. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy.

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