Abstract and Introduction
Abstract
There are many options for acute migraine attack treatment, but none is ideal for all patients. This study aims to review current medical office-based acute migraine therapy in adults and provides readers with an organized approach to this important facet of migraine treatment. A general literature review includes a review of several recent published guidelines. Acetaminophen, 4 nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, acetylsalicylic acid [ASA], naproxen sodium, and diclofenac potassium), and 7 triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) have good evidence for efficacy and form the core of acute migraine treatment. NSAID–triptan combinations, dihydroergotamine, non-opioid combination analgesics (acetaminophen, ASA, and caffeine), and several anti-emetics (metoclopramide, domperidone, and prochlorperazine) are additional evidence-based options. Opioid containing combination analgesics may be helpful in specific patients, but should not be used routinely. Clinical features to be considered when choosing an acute migraine medication include usual headache intensity, usual rapidity of pain intensity increase, nausea, vomiting, degree of disability, patient response to previously used medications, history of headache recurrence with previous attacks, and the presence of contraindications to specific acute medications. Available acute medications can be organized into 4 treatment strategies, including a strategy for attacks of mild to moderate severity (strategy one: acetaminophen and/or NSAIDs), a triptan strategy for patients with severe attacks and for attacks not responding to strategy one, a refractory attack strategy, and a strategy for patients with contraindications to vasoconstricting drugs. Acute treatment of migraine attacks during pregnancy, lactation, and for patients with chronic migraine is also discussed. In chronic migraine, it is particularly important that medication overuse is eliminated or avoided. Migraine treatment is complex, and treatment must be individualized and tailored to the patient's clinical features. Clinicians should make full use of available medications and formulations in an organized approach.
Introduction
The acute therapy of migraine has a long history, as patients and their physicians have tried to relieve the pain of migraine attacks. Caffeine was recommended for acute migraine treatment for hundreds of years, and it was recognized over a century ago that patient response to medications for migraine attacks is idiosyncratic and that treatment must be tailored to the individual. This was based on the observation that measures that worked well in one case would fail in another apparently similar case.[1,2]
In the modern era in Western nations, acute medications for migraine attacks are used almost universally by migraine sufferers, with over 90% using some type of acute medication.[3] Medication choice for the acute treatment of migraine attacks is not a simple matter, given the multiple medications available, and as has been recognized for over a century, one cannot predict which medication will work best for any given patient.[2] Also, migraine attacks are generally treated in settings where the patient must usually act without outside assistance. The patient must therefore become an informed and knowledgeable member of the treatment team and partner with the health-care provider. The ability to take acute medications appropriately is an important skill which the patient must master, along with many other self-management skills, if migraine is to be managed as successfully as possible.
Pharmacological management is only one part of migraine management. It was pointed out over half a century ago that it was more important for a patient to live within his or her limitations, then to try an endless round of medications.[4] Acute migraine medications have improved a great deal since that time, but this statement is still largely true. While patients differ in how severe their migraine tendency is, lifestyle and other environmental factors are very significant for many patients. Dealing with these may be difficult, and not all patients are willing to make the personal adjustments necessary for optimal migraine management.[2] However, pharmacological management should be only one facet of a much broader approach to migraine management.[5]
Medication Choices
Many different medications have been used, but the mainstays of modern acute migraine treatment are the nonsteroidal anti-inflammatory drugs (NSAIDs) and the triptans. The evidence base for many acute migraine medications has recently been reviewed.[6]
Acetaminophen and NSAIDs
Acetaminophen is widely used, and has randomized controlled trial evidence for efficacy in migraine,[7,8] but is generally considered effective primarily for attacks of mild or moderate severity. As with the NSAIDs, it can be combined with an anti-emetic if the patient has significant nausea. A recent systematic review concluded that acetaminophen 1000 mg plus metoclopramide 10 mg had 2-hour headache relief rates similar to those of sumatriptan 100 mg (39% vs 42%, respectively).[9]
NSAIDs
The NSAIDs are generally a good starting point for acute migraine treatment, although acetaminophen can be tried if there are contraindications to NSAID use, and triptans are another option. Ibuprofen,[10] naproxen sodium,[11] acetylsalicylic acid (ASA),[12] and diclofenac potassium[13] all have double-blind randomized controlled trial evidence for efficacy that has been analyzed in systematic reviews. These NSAIDs have different pharmacokinetics, and this has implications for their usefulness in a specific patient. Ibuprofen and diclofenac potassium have very rapid absorption from the gastrointestinal tract, and therefore the potential for a rapid onset of action (Table 1). Although they may completely abort a migraine attack, their short half-life may make repeated dosing necessary for a single attack in some patients. Naproxen sodium, on the other hand, has slower absorption but a much longer half-life.
Both ibuprofen and diclofenac potassium have special formulations with more rapid absorption and therefore a more rapid onset of action that have been shown to have advantages over their oral tablet counterparts. Solubilized ibuprofen 400 mg has generally shown a higher response rate for headache relief (headache reduced from moderate or severe intensity to mild or no headache) at 1 hour as compared to the corresponding standard ibuprofen tablet.[14] Diclofenac potassium powder for oral solution (50 mg) has been compared directly to the corresponding oral tablet. For the pain free at 2 hours end point, the powdered formulation (sachets) was superior to the tablet, with 24.7% of patients pain free with the sachet, and 18.5% with the tablet (P = .0035). With the sachet, analgesic effects were noted within 15 minutes.[15]
ASA also has a relatively rapid absorption (Table 1), and an intermediate half-life of 5–6 hours if active metabolites are included. Effervescent ASA has a faster absorption than regular tablets.[16]
Ibuprofen is one of the most frequently used NSAIDs for migraine.[3] This may reflect its low cost, availability, and relatively good efficacy. In a large double-blind cross-over study, response rates for the headache relief end point at 2 hours were 60.2% for ibuprofen 400 mg, 55.8% for sumatriptan 50 mg, 52.5% for effervescent ASA, and 30.6% for placebo,[17] although ibuprofen has not been compared directly with sumatriptan 100 mg, a more optimal sumatriptan dose. It may produce less gastric irritation than ASA, and the proportion of patients with headache relief at 2 hours is at least as high with the ibuprofen 400 mg tablet[18] as with a dose of 900–1000 mg ASA.[12] Naproxen sodium has the advantage of a long half-life, but headache relief rates at 2 hours are lower than for ibuprofen.[11,19] Pharmacokinetics, dosages, and headache response rates (given as NNTs [number needed to treat]) for acetaminophen and the NSAIDs are shown in Table 1.[5,9,12,13,18,19]
Combination analgesics with both acetaminophen and ASA have also been investigated for efficacy in acute migraine treatment. A combination of acetaminophen, ASA, and caffeine has been shown to have greater efficacy than any one of its components in comparable doses alone.[20] Caffeine does appear to make a significant contribution to analgesia when included in combination tablets,[21] but this needs to be balanced with possible interference with sleep if rest is to be part of the treatment paradigm. Another study that compared an acetaminophen/ASA/caffeine (AAC) combination tablet to ibuprofen 400 mg found the AAC tablet to be superior on several end points.[22] Adding metoclopramide 10 mg to ASA improves relief of nausea and vomiting.[12]
Triptans and Triptan-NSAID Combinations
Triptans.—The triptans, unlike the NSAIDs, are serotonergic agonists that target primarily the 5HT1b and 5HT1d receptors. Although the ergotamines are agonists at the same receptors, these older drugs are much less specific and affect other receptor types as well. These older drugs therefore tend to have more side effects at therapeutically effective doses. All available triptans are vasoconstrictors and are therefore contraindicated in patients with cardiovascular disease. Although several head-to-head clinical trials have suggested that NSAIDs are as effective as the triptans,[23] and for some patients they no doubt are, clinical experience suggests that overall the triptans are the most effective acute migraine drugs available.
Seven triptans are currently available in oral form, and all have good evidence for efficacy in acute migraine therapy. Although all share a relatively similar molecular structure, individual patients respond to different triptans in profoundly different ways, both in terms of effectiveness for pain relief and side effects. The response of an individual patient's response to one triptan compared to another cannot be predicted with certainty, although in terms of patient groups some generalizations can be made based at least in part on pharmacokinetic differences. Not all the factors which govern a specific patient's response to the different triptans are understood, however, and the clinical implications of this are that if the patient's response to one triptan is not excellent, another triptan should be tried to see if a better response can be obtained.
The 7 triptans currently available in North America along with their various formulations are shown in Table 2. In general, 2 triptans, frovatriptan and naratriptan, both with relatively long plasma half-lives, tend to have a slow onset of action and a low headache recurrence rate in the following 24 hours if relief occurs. Oral rizatriptan and eletriptan have a fast onset of action, although differences in this respect between them and the remaining 3 triptans, sumatriptan, almotriptan, and zolmitriptan, are not marked. Tablet formulation can play a significant role, and a systematic review found that the onset of action of the fast-dissolving sumatriptan tablet was comparable to rizatriptan, an oral triptan with a recognized very fast onset of action.[24] The differences between patients are in general considered to be greater than the efficacy differences between the oral triptans, and side effect profiles and headache recurrence rates are additional factors to be considered when deciding which triptan to use. A recent meta-analysis found that eletriptan 40 mg and rizatriptan 10 mg provided the highest pain-free rates at 2 hours, and eletriptan provided in addition the highest 24-hour sustained-free rate with no recurrence of headache for 24 hours after treatment.[25] Pharmacokinetics, 2-hour pain-free rates (given as NNTs), and dosages are given in Table 2 for commonly used formulations for the 7 available triptans.[5,26]
Triptan–NSAID Combinations.—There is good evidence that combining sumatriptan with naproxen provides greater efficacy than using either drug alone. The combination provides a higher 2-hour headache relief rate than either drug alone, with a 65% rate for a combination of sumatriptan 85 mg/naproxen sodium 500 mg as compared to 55% for sumatriptan monotherapy (P = .009) in one study, and 57% vs 50% in another (P = .02).[27] The combination also has been shown to provide a higher 24-hour sustained pain response (no more than mild pain and no rescue medication at 2 hours and for 24 hours post-dose) than either drug alone. Twenty-four hour sustained-pain responses were seen in 46% of subjects with a combination of sumatriptan 50 mg and naproxen 500 mg, in 29% of those who took sumatriptan 50 mg alone, in 25% with naproxen 500 mg alone, and in 17% of those who took placebo.[28] Headache attacks meeting criteria for probable migraine also respond to a sumatriptan 85 mg/naproxen sodium 500 mg combination tablets as compared to placebo (29% pain free at 2 hours with the combination vs 11% with placebo).[29]
It might be expected that similar results should be obtained with other triptan/NSAID combinations, although few trials have been done. A combination of frovatriptan 2.5 mg and dexketoprofen (an NSAID with a short half-life) has been compared to use of frovatriptan alone. The combination therapy resulted in higher pain-free rates at 2 hours than with frovatriptan alone (51% vs 29%).[30]
Combining an NSAID with a triptan would therefore appear to be a good strategy for patients who do not respond well to a triptan alone. Most of the available evidence for this strategy has come from studies using a sumatriptan–naproxen sodium combination.
Ergot Alkaloids
The ergotamines, although effective for some patients, have been largely replaced by the triptans, which have the advantage of greater pharmacological specificity and fewer side effects.[31] Dihydroergotamine is still a very useful drug and can be used intranasally and subcutaneously,[32,33] but is not available in an oral form for acute treatment because of poor absorption.
Other Medication Combinations
Combination analgesics with isometheptene, a vasoconstrictor, are also used for migraine,[34] but there is little evidence for the effectiveness of isometheptene alone. Combination analgesics with opioids including codeine should not be used routinely in migraine because of poor evidence for efficacy beyond that provided by NSAIDs and risk of overuse with resultant medication overuse headache. When their use is necessary because of unresponsiveness or contraindications to other medications, combination analgesics with tramadol may be the preferred option.[35] Use of barbiturate-containing analgesics and stronger opioids like morphine and butorphanol should be limited to exceptional cases because of risk of addiction and medication overuse headache.[36]
Medications containing barbiturates in particular appear to place patients at risk for overuse and medication overuse headache, and the evidence suggests that they are no more effective than less detrimental medication combinations. A randomized double-blind controlled cross-over trial compared a butalbital–acetaminophen–caffeine combination analgesic to a sumatriptan–naproxen sodium combination. There was no significant difference in the primary study end point, but the sumatriptan–naproxen combination was superior on most secondary end points.[37] There is also concern that using opioids may make patients more refractory to other acute medications including the triptans. A post hoc analysis of a rizatriptan clinical treatment trial found that recent opioid use was associated with a lower response rate to rizatriptan, but current data cannot differentiate whether this was an effect of the prior opioid use or whether opioid use was a marker for patients with more refractory migraine.[38]
Clinical use of Acute Medications
There are a large number of pharmacological options available for acute migraine treatment, and none of them are ideal for all patients. The art and science of headache neurology involves recommending the best option for a specific patient.[36,39] The clinical features of both of the patient's general medical condition and of the attacks themselves need to be woven into the decision-making process.
Headache Intensity.—Headache intensity is an important factor in medication choice. If headaches are usually of mild to moderate intensity, acetaminophen, or an NSAID may give good relief. If headaches are more severe, this is less likely although an NSAID may still be effective. A post hoc analysis that examined the response of patients who treated migraine when the headache intensity was severe with acetaminophen/ASA/caffeine (AAC), ibuprofen, or placebo found that 2-hour headache response rates (headache reduced to mild or none) were 62% for AAC vs 54% for ibuprofen (P = .036). This study suggests that many patients with severe migraine attacks do respond to NSAIDs, and that the AAC combination is an effective acute migraine medication.[40] The ACC combination studied, which contained 500 mg ASA, 500 mg acetaminophen, and 130 mg of caffeine, was significantly superior to ibuprofen 400 mg on a number of study end points (P < .04).
With a stratified approach to care, the acute medication is chosen according to the degree of disability caused by migraine. There is evidence that this is the most effective approach.[41] In this approach, patients with greater disability are started on a triptan initially, while those with attacks of lesser intensity may be given an NSAID first, and escalated to a triptan in later attacks if the NSAID does not produce satisfactory results. The stratified approach is based on the principle that the triptans are more effective for severe migraine attacks than the NSAIDs, an assumption that is based more on clinical experience than on good randomized controlled head-to-head trial data.
The alternative to the stratified approach is the step care across attacks approach, where all patients are tried on an NSAID or other nonspecific analgesic first, and then escalated to a triptan for later attacks if the first medication is not satisfactory. One of the main reasons for this approach is to avoid the costs involved with using triptans. A disadvantage of this approach is that it may delay finding an effective medication for the patient, and thereby lead to increased patient disability, disillusionment with the health-care system, and the patient may stop consulting for migraine. In a clinical trial that compared stratified care to the step care across attacks approach, disability time (from 0–4 hours after treatment) averaged across all 6 attacks was significantly lower for stratified care than for the step care across attacks strategy.[41]
The question of whether to use stratified vs step care across attacks care is somewhat academic, in that most patients who see physicians for migraine have already usually tried a number of analgesics prior to consultation, so the step care across attacks approach has already been started. The step care across attacks approach would seem the most appropriate one for most patients with migraine, assuming that the patient is also educated with regard to other treatment options. For those with severe attacks that often require bed rest, however, a stratified approach would seem more appropriate. This has been termed the combined acute medication treatment approach[5] and is discussed in the Canadian Headache Society Guideline: Acute Drug Treatment for Migraine Headache.
Among the triptans, subcutaneous sumatriptan (6 mg) has shown the highest headache response rates in patient groups,[42] and is an option that should be considered in patients with severe migraine attacks, particularly if they have not had a satisfactory response to oral triptans. Intranasal zolmitriptan 5 mg can also be a helpful option for these patients.[43] Intranasal zolmitriptan 5 mg has shown a significantly higher 2-hour headache relief rate (70.3%) as compared to the 2.5 mg zolmitriptan tablet (61.3%) (P < .05).[43]
Nausea.—Nausea is one of the most common associated symptoms of the migraine attack. Not only can it be significantly disabling in its own right, it can affect the effectiveness of oral medications. Depending on the severity of the nausea, and whether vomiting is present, one of several treatment options can be pursued.
1. If nausea is mild, but exacerbated by taking fluids, patients may find the orally dissolving tablets (wafers) helpful.[44] These include rizatriptan and zolmitriptan, and melt in the mouth. They are not absorbed trans-buccally, but rather drug is swallowed with saliva. Because liquids are not required, they may exacerbate nausea less, and can also be taken early in the attack even when fluids are not available.
2. If nausea is moderate in degree, an anti-emetic given with the NSAID or oral triptan can be helpful. The anti-emetic with the greatest evidence for efficacy in migraine is oral metoclopramide (10 mg).[12,45–47] Although it may produce extrapyramidal side effects, these are rare with intermittent oral use for migraine attacks. Prochlorperazine 10 mg orally is another option, although it may have more extrapyramidal side effects. Domperidone 10 mg can also be used.[48,49] It has less evidence for efficacy than metoclopramide but has the advantage that it does not cross the blood–brain barrier and therefore does not cause extrapyramidal side effects. There are concerns about the cardiac safety of domperidone,[50] although the risks with intermittent use in otherwise healthy individuals with migraine are likely very low.
Promethazine 25 mg, a phenothiazine, has been shown to improve efficacy when combined with sumatriptan 50 mg as compared to sumatriptan alone (39% pain free at 2 hours as compared to 26%, P = .038).[51] Somnolence was a common side effect, however, and 4.3% of patients reported extrapyramidal symptoms as compared to no extrapyramidal symptoms in the sumatriptan plus placebo group. Parenteral use of promethazine should be avoided where possible because of its association with severe local adverse events.[52] Ondansetron has not been investigated for efficacy in migraine related nausea, and has been reported to cause migraine-like headache in children.[53]
3. If patients have severe nausea or vomiting, subcutaneous sumatriptan 6 mg should be considered, especially if vomiting occurs early in the migraine attack. Intranasal zolmitriptan 5 mg, which has good evidence for significant absorption through the nasal mucosa,[54] can also be considered, particularly if vomiting occurs later in the attack. Intranasal sumatriptan and intranasal dihydroergotamine are also available, but have less evidence for significant amounts of trans-nasal absorption. Anti-emetics can be used with these medications, and for patients with vomiting, prochlorperazine suppositories 10–25 mg may be helpful.[55]
Rapidity of Pain Increase After Onset.—For migraine attacks where the pain intensity builds up rapidly, several medication formulations designed for a rapid onset of action may be helpful. These include diclofenac powder for oral solution 50 mg,[15] solubilized ibuprofen 400 mg,[14] and effervescent ASA 1000 mg.[56] Several oral triptans also have a fast onset of action, including rizatriptan, eletriptan, and the fast-dissolving sumatriptan tablet.[24,25] Sumatriptan 6 mg subcutaneously, nasal sumatriptan 20 mg, and nasal zolmitriptan 5 mg are also good choices, with subcutaneous sumatriptan having a particularly fast onset of action.[42] Of note, the orally dissolving rizatriptan and zolmitriptan tablets (wafers) have no advantage over the regular oral tablets in terms of rapidity of onset of action.
For migraine attacks that build up more slowly but that have a relatively long duration, some of the slower but longer acting treatment options may be more helpful when treatment is taken early in the attack, including naproxen and frovatriptan. If patients have migraine attacks of different intensities, and these tend to build up slowly, an NSAID can be tried first by the patient early in the attack, and then a fast-acting triptan later if the NSAID fails. However, if patients find that they have to go on to the triptan for most attacks, then it is usually best if they use a triptan as their first-line medication, as essentially all acute migraine medications do work best if taken early in the attack.
Headache Recurrence.—For patients who experience initial headache relief with treatment but who experience the return of moderate to severe headache within 24 hours, several options are available. These include:
Most patients with headache recurrence after triptan therapy will respond well to a second dose of the same triptan.[57] Although there is less research, clinical experience indicates that the same is also true for NSAIDs.
Early treatment of the attack may reduce the tendency for headache recurrence.
For recurrence after triptan therapy, the patient may find that they have less frequent headache recurrence if they switch to another triptan for future attacks. Eletriptan and frovatriptan appear to have relatively low recurrence rates.[25,58]
Naproxen sodium 500–550 mg can be taken simultaneously with the patient's triptan for initial attack therapy.[27]
For patients with major headache recurrence problems on triptan therapy, dihydroergotamine, either by nasal spray or by subcutaneous self-injection, can be used. Dihydroergotamine has a low headache recurrence rate.[33] A new inhaled form of dihydroergotamine has shown therapeutic promise and may soon be available.[59]
Headache Persistence.—If patients do not respond to their triptan for some attacks, with persistence of the head pain as opposed to initial relief followed by recurrence, a second dose of a triptan is unlikely to be of additional benefit.[60] A rescue medication from another drug class is usually recommended in this situation.
Migraine With Aura.—The available evidence from clinical trials suggests that both subcutaneous sumatriptan and oral eletriptan are not as effective as might be expected when taken during the migraine aura.[61,62] The recommendation is therefore that patients take their triptan at pain onset. More data are needed on this question, however. Many patients do have their pain onset during the aura.[63] Anecdotally, patients in the clinic do report success with triptan use during the aura, and triptan use during a typical migraine aura is considered safe. Finally, a recent open-label trial reported good success with sumatriptan taken during the aura.[64]
Refractory Migraine.—If patients are having difficulty finding an acute medication that works well for them, several factors should be considered.
Is the diagnosis correct, or is a secondary headache a possibility? Further investigation may be needed.
Are there lifestyle factors such as excessive stress which might be contributing to the patient's intractability? These may need to be addressed.
Is the patient treating too late in the migraine attack? For most drugs, including the triptans, early treatment when pain is still mild is usually more effective than treatment later in the attack.[65–67]
Medication combinations may be more effective for the patient. Triptan–NSAID combinations, and triptan–NSAID–metoclopramide combinations can be tried.
Medication overuse may contribute to intractability. Use of NSAIDs or acetaminophen on 15 days a month or more, or use of triptans or combination analgesics including those with codeine on 10 days a month or more, is considered to place patients at risk for medication overuse headache.[68] The above limits are based largely on expert opinion, and there is some evidence that even lower frequencies of use of opioid and/or barbiturate containing analgesics may predispose to medication overuse headache in individuals with migraine.[69] If present, medication overuse needs to be stopped, and the patient educated with regard to acceptable frequency of use limits for any acute medications used in the future.
Dihydroergotamine may be a useful acute treatment option in patients who do not respond well to more commonly used medications including the triptans.
Some patients do not respond well to any of the available acute migraine medications. For these patients, pharmacological migraine prophylaxis and behavioral approaches need to be maximized.
Patients Must be Evaluated for Contraindications.—NSAIDs are contraindicated in patients with peptic ulcer disease, renal disease, and in patients on anticoagulants. Triptans are vasoconstrictors and are contraindicated in patients with coronary artery disease, peripheral vascular disease, and stroke. It is important to note that use of selective serotonin reuptake inhibitor antidepressants is not considered a contraindication to triptans by most clinicians, and although clinicians should be vigilant for the possibility of serotonin syndrome with this combination, current evidence does not support limiting the use of triptans with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors.[70] There are no data showing serious side effects, but triptans are listed as contraindicated in hemiplegic migraine by their manufacturers based on theoretical considerations. They have not been proven safe in hemiplegic migraine, and their use is controversial. A study of 76 patients with hemiplegic migraine treated with triptans concluded that they were safe and effective,[71] but this study was too small to exclude potentially serious side effects. Others have indicated that triptans may be safe in hemiplegic migraine,[72] are often used in hemiplegic migraine,[73] or have listed them as treatment options if NSAIDs and other analgesics have failed.[74]
Organizing Acute Migraine Medication Treatment Options
Given the many options for acute migraine treatment, it is helpful to organize them into a logical framework of strategies. Then an appropriate strategy can be chosen for a specific patient, depending on the clinical circumstances. For most patients with migraine, one of the 4 strategies shown in Table 3 would be appropriate, depending on patient history and clinical features. The first 2 strategies are based primarily on attack severity and on whether or not the patient responds satisfactorily to acetaminophen and/or NSAIDs. If strategy 1 (acetaminophen/NSAIDs) fails, then strategy 2 (triptan strategy) should be tried. For some patients with severe attacks, the choice may be made to go to the triptan strategy directly as a first line option.
Some patients with migraine have attacks of differing severity[75] and may benefit from having medications from more than one strategy available to them. This can be helpful particularly if they are able to predict the severity of the attack soon after it starts. For example, they may find it best to take an NSAID for their milder attacks, and a triptan for their more severe attacks.
For patients that are refractory to the first 2 strategies, a number of options exist, as shown in Table 3 (strategy 3 for refractory migraine attacks). This strategy may involve various rescue medications to be used by the patient for occasional failures of their usual medications (for example, they may be taking a triptan–NSAID combination as their usual medication, and may occasionally use a prochlorperazine suppository for rescue when their usual acute medication fails). A complete discussion of possible rescue medications is beyond the scope of this review, and it is suggested the reader consult the Canadian Headache Society Guideline: Acute Drug Therapy for Migraine Headache.[5]
Strategy 4 lists options available for acute migraine attack treatment for patients with contraindications to vasoconstricting drugs. Many NSAIDs have been associated with an increased risk of cardiovascular disease, but it is unclear how significant this is with intermittent use as in acute migraine treatment. Naproxen sodium appears to have a relatively good cardiovascular safety profile as compared to many other NSAIDs.[76,77] Patients with contraindications to vasoconstricting drugs who do not respond to NSAIDs may be one group in whom the use of opioid-containing analgesic combination tablets becomes necessary.[78] It is important to educate the patient regarding medication overuse headache and to monitor frequency of use in this circumstance.
Using the Acute Migraine Treatment Strategies
In summary, the strategies summarized in Table 3 can be applied quite easily to the individual patient. For most patients, presenting with migraine for the first time, the acetaminophen–NSAID strategy will be appropriate, unless the patient has already sufficiently tried this strategy with over-the-counter medications. If patients have severe attacks that usually render them bedridden for a time, it may be best to omit the acetaminophen–NSAID strategy and go directly to the triptan strategy.
For most patients, if the acetaminophen–NSAID strategy has failed, the triptan strategy is the next logical choice if there are no contraindications. If patients do not do well on the triptan strategy, strategy 3 for refractory patients should be initiated. If there are contraindications for vasoconstrictor drugs, then strategy 4 should be initiated instead of strategies 2 and 3.
Each strategy has a number of options, and decisions need to be made in conjunction with the patient as to how many options to try in each strategy. For strategy 2, example, it would usually be appropriate to try several triptans before moving on to strategy 3 (refractory patient strategy).
Finally, if patients have attacks of differing severity, they may need medications from 2 different strategies. They may use, for example, an NSAID for milder attacks and a triptan for more severe attacks. Some patients may need to have available more than one agent from a single strategy. For example, patients may need injectable sumatriptan for severe headache attacks that are present on awakening, but they may prefer to use an oral triptan for attacks that occur during the day when they can treat early in the attack.
Special Situations
Pregnancy.—Acetaminophen and metoclopramide are considered safe, although no drug has been proven to be safe in pregnancy, and drug exposure should be minimized as much as possible. Acetaminophen with codeine is relatively safe,[79] 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 section and postpartum hemorrhage.[80] Although not known to cause malformations, other opioids may also produce harmful effects on the fetus or neonate.
ASA should be avoided in pregnancy as 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. There is concern that in the first trimester, they may cause an 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.[81]
Ergotamines must be avoided due to uterotonic effects, but triptans appear much safer during pregnancy. No association between sumatriptan use in the first trimester and fetal malformations or adverse pregnancy outcomes was found in a large observational study, although sumatriptan use in the second and third trimester was associated with atonic uterus and blood loss >500 mL during labor and delivery.[82] A pregnancy registry that included 528 pregnant women with first trimester sumatriptan exposure concluded that no signal of teratogenicity associated with major birth defects was detected.[83] There are much less data with regard to other triptans. It might be concluded, therefore, that for pregnant women with difficult migraine that greatly interferes with tasks of daily living or results in dehydration, sumatriptan may be an option during pregnancy.
Migraine During Lactation.—During breast feeding, acetaminophen is considered safe, and among the NSAIDs, ibuprofen is preferred. ASA in analgesic doses should be avoided, but occasional use of diclofenac and ketorolac is compatible with breast feeding.[79] Infant exposure after maternal use of sumatriptan would appear to be small, and sumatriptan use is considered compatible with breast feeding.[84] Metoclopramide, domperidone, prochlorperazine, and dimenhydrinate are all considered safe.[5]
Morphine is the opioid of choice if an opioid must be used, but if the mother experiences significant sedation the milk should be discarded, and it is important to be cautious with infants under 1 month of age and premature infants. Codeine should be avoided during lactation because of variable maternal metabolism.[85]
Chronic Migraine
Patients with chronic migraine represent the more severe end of the migraine spectrum. To meet diagnostic criteria for chronic migraine, patients must have a history of migraine, and have had headache on more than 14 days a month for at least 3 months. Importantly, at least 8 of these headache days must meet diagnostic criteria for migraine or have responded well to migraine specific medication.[68] The acute medications used for migraine attacks in chronic migraine are the same as the ones used in episodic migraine (migraine with headache on 14 days a month or less). Acute migraine treatment in chronic migraine, however, presents a difficult challenge for both the patient and the physician because of the high headache frequency, as it is important to avoid acute medication overuse and resultant medication overuse headache. Patient education is vital to meet this challenge, and migraine prophylactic therapy and behavioral treatment modalities should be maximized.[5,86] Use of combination analgesics containing opioids and barbiturates should be avoided if possible or minimized because of their propensity to cause medication overuse headache.
Comprehensive Migraine Management and New Directions
For many patients, acute medications are only part of the overall treatment plan, which must also include a number of other modalities. These include lifestyle modification and management of migraine triggers specific for that patient, behavioral treatment modalities like relaxation techniques, pacing,[87] and stress management,[88] and pharmacological prophylaxis.[89]
Fortunately, new acute therapies are under active investigation or becoming available. These include new treatment modalities like non-invasive vagal nerve stimulation[90] for migraine attacks and single-pulse transcranial magnetic stimulation for migraine with aura.[91] New drug delivery systems including transdermal drug delivery systems[92,93] and breath-powered devices for better drug delivery through the nasal mucosa[94] also hold promise for the future.
Headache. 2015;55(6):778-793. © 2015 Blackwell Publishing