Diagnostic criteria for migraine headache are listed in Table 422-3. A high index of suspicion is required to diagnose migraine: the migraine aura, consisting of visual disturbances with flashing lights or zigzag lines moving across the visual field or of other neurologic symptoms, is reported in only 20–25% of patients. It should be distinguished from the pan-field television static-like disturbance now recognized as the visual snow syndrome. The first phase of a migraine attack for most patients is the premonitory (prodromal) phase consisting of some or all of the following: yawning, tiredness, cognitive dysfunction, mood change, neck discomfort, polyuria, and food cravings; this can last from a few hours to days. Typically, the headache phase follows with its associated features, such as nausea, photophobia, and phonophobia as well as allodynia. When questioned, these typical migraine symptoms also emerge in the premonitory phase, and typical premonitory symptoms also continue into the headache phase. As the headache lessens many patients enter a postdrome, most commonly feeling tired/weary, having problems concentrating, and experiencing mild neck discomfort that can last for hours and sometimes up to a day. A headache diary can often be helpful in making the diagnosis; this is also helpful in assessing disability and the frequency of treatment for acute attacks. Patients with episodes of migraine on eight or more days per month and with at least 15 total days of headache per month are considered to have chronic migraine (see “Chronic Daily Headache” in Chap. 13). Migraine must be differentiated from TTH (discussed below), which is reported to be the most common primary headache syndrome. Migraine has several forms that have been defined (Table 422-1): migraine with and without aura and chronic migraine are the most important. Migraine at its most basic level is headache with associated features, and tension-type headache is headache that is featureless. Most patients with disabling headache probably have migraine.
TREATMENT Migraine Headache
Once a diagnosis of migraine has been established, it is important to assess the extent of a patient’s disease and disability. The Migraine Disability Assessment Score (MIDAS) is a well-validated, easy-to-use tool (Fig. 422-4).
Patient education is an important aspect of migraine management. Information for patients is available at websites such as the American Migraine Foundation (www.americanmigrainefoundation.org) and the Migraine Trust (www.migrainetrust.org). It is helpful for patients to understand that migraine is an inherited tendency to headache; that migraine can be modified and controlled by lifestyle adjustments and medications, but it cannot be eradicated; and that, except on some occasions in women on oral estrogens or contraceptives, migraine is not associated with serious or life-threatening illnesses.
NONPHARMACOLOGIC MANAGEMENT Migraine can often be managed to some degree by a variety of nonpharmacologic approaches. When patients can identify reliable triggers, their avoidance can be useful. A regulated lifestyle is helpful, including a healthy diet, regular exercise, regular sleep patterns, avoidance of excess caffeine and alcohol, and avoidance of acute changes in stress levels, being particularly wary of the let-down effect.
The measures that benefit a given individual should be used routinely because they provide a simple, cost-effective approach to migraine management. Patients with migraine do not encounter more stress than headache-free individuals; over-responsiveness to changes in stress appears to be the issue. Because the stresses of everyday living cannot be eliminated, lessening one’s response to stress by various techniques is helpful for many patients. These may include yoga, transcendental meditation, hypnosis, and conditioning techniques such as biofeedback. For most patients seen in clinical practice, this approach is, at best, an adjunct to pharmacotherapy. Nonpharmacologic measures are unlikely to prevent all migraine attacks. If these measures fail to prevent an attack, pharmacologic approaches are then needed.
ACUTE ATTACK THERAPIES FOR MIGRAINE The mainstay of pharmacologic therapy is the judicious use of one or more of the many medicines that are effective in migraine (Table 422-4). The selection of the optimal regimen for a given patient depends on a number of factors, the most important of which is the severity of the attack. Mild migraine attacks can usually be managed by oral agents; the average efficacy rate is 50–70%. Severe migraine attacks may require parenteral therapy. Most drugs effective in the treatment of migraine are members of one of three major pharmacologic classes: nonsteroidal anti-inflammatory drugs, 5-HT1B/1D receptor agonists, and dopamine receptor antagonists. Two new classes of therapeutic agents, CGRP receptor antagonists, such as rimegepant and ubrogepant, and 5-HT1F receptor agonists, such as lasmiditan, should soon be available.
In general, an adequate dose of whichever agent is chosen should be used as soon as possible after the onset of an attack. If additional medication is required within 60 min because symptoms return or have not abated, the initial dose should be increased for subsequent attacks or a different class of drug tried as first-line treatment. Migraine therapy must be individualized; a standard approach for all patients is not possible. A therapeutic regimen may need to be constantly refined until one is identified that provides the patient with rapid, complete, and consistent relief with minimal side effects (Table 422-5).
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Both the severity and duration of a migraine attack can be reduced significantly by NSAIDs (Table 422-4). Indeed, many undiagnosed migraineurs self-treat with nonprescription NSAIDs. A general consensus is that NSAIDs are most effective when taken early in the migraine attack. However, the effectiveness of these agents in migraine is usually less than optimal in moderate or severe migraine attacks. The combination of acetaminophen (paracetamol), aspirin, and caffeine has been approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate migraine. The combination of aspirin and metoclopramide has been shown to be comparable to a single dose of oral sumatriptan. Important side effects of NSAIDs include dyspepsia and gastrointestinal irritation.
5-HT1B/1D RECEPTOR AGONISTS Oral Stimulation of 5-HT1B/1D receptors can stop an acute migraine attack. Ergotamine and dihydroergotamine are nonselective receptor agonists, whereas the triptans are selective 5-HT1B/1D receptor agonists. A variety of triptans—sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan—are available for the treatment of migraine.
Each drug in the triptan class has similar pharmacologic properties but varies slightly in terms of clinical efficacy. Rizatriptan and eletriptan are, on a population basis, the most efficacious of the triptans currently available in the United States. Sumatriptan and zolmitriptan have similar rates of efficacy as well as time to onset, with an advantage of having multiple formulations, whereas almotriptan has a similar rate of efficacy to sumatriptan and is better tolerated, and frovatriptan and naratriptan are somewhat slower in onset and are also well tolerated. Clinical efficacy appears to be related more to the tmax (time to peak plasma level) than to the potency, half-life, or bioavailability. This observation is consistent with a large body of data indicating that faster-acting analgesics are more effective than slower-acting agents.
Unfortunately, monotherapy with a selective oral 5-HT1B/1D receptor agonist does not result in rapid, consistent, and complete relief of migraine in all patients. Triptans are generally not effective in migraine with aura unless given after the aura is completed and the headache initiated. Side effects are common, although often mild and transient. Moreover, 5-HT1B/1D receptor agonists are contraindicated in individuals with a history of cardiovascular and cerebrovascular disease. Recurrence of headache, within usual time course of an attack, is another important limitation of triptan use and occurs at least occasionally in most patients. Evidence from randomized controlled trials shows that coadministration of a longer-acting NSAID, naproxen 500 mg, with sumatriptan will augment the initial effect of sumatriptan and, importantly, reduce rates of headache recurrence.
Ergotamine preparations offer a nonselective means of stimulating 5-HT1 receptors. A nonnauseating dose of ergotamine should be sought because a dose that provokes nausea is too high and may intensify head pain. Oral (excluding sublingual) formulations of ergotamine also contain 100 mg caffeine (theoretically to enhance ergotamine absorption and possibly to add additional analgesic activity). The average oral ergotamine dose for a migraine attack is 2 mg. Because the clinical studies demonstrating the efficacy of ergotamine in migraine predated the clinical trial methodologies used with the triptans, it is difficult to assess the comparative efficacy of ergotamine versus the triptans. In general, with use of ergotamine there appears to be a much higher incidence of nausea than with triptans but less headache recurrence.
Nasal Nasal formulations of dihydroergotamine, zolmitriptan, or sumatriptan can be useful in patients requiring a nonoral route of administration. The nasal sprays result in substantial blood levels within 30–60 min. Although in theory nasal sprays might provide faster and more effective relief of a migraine attack than oral formulations, their reported efficacy is only ~50–60%. Studies with a new inhalational formulation of dihydroergotamine indicate that its absorption problems can be overcome to produce rapid onset of action with good tolerability.
Parenteral Administration of drugs by injection, such as dihydroergotamine and sumatriptan, is approved by the FDA for the rapid relief of a migraine attack. Peak plasma levels of dihydroergotamine are achieved 3 min after IV dosing, 30 min after IM dosing, and 45 min after SC dosing. If an attack has not already peaked, SC or IM administration of 1 mg of dihydroergotamine is adequate for about 80–90% of patients. Sumatriptan, 4–6 mg SC, is effective in ~50–80% of patients, and can now be administered by a needle-free device.
DOPAMINE RECEPTOR ANTAGONISTS Oral Oral dopamine receptor antagonists can be considered as adjunctive therapy in migraine. Drug absorption is impaired during migraine because of reduced gastrointestinal motility. Delayed absorption occurs even in the absence of nausea and is related to the severity of the attack and not its duration. Therefore, when oral NSAIDs and/or triptan agents fail, the addition of a dopamine receptor antagonist, such as metoclopramide 10 mg or domperidone 10 mg (not available in the United States), should be considered to enhance gastric absorption. In addition, dopamine receptor antagonists decrease nausea/vomiting and restore normal gastric motility.
Parenteral Dopamine receptor antagonists (e.g., chlorpromazine, prochlorperazine, metoclopramide) by injection can also provide significant acute relief of migraine; they can be used in combination with parenteral 5-HT1B/1D receptor agonists. A common IV protocol used for the treatment of severe migraine is the administration over 2 min of a mixture of 5 mg of prochlorperazine and 0.5 mg of dihydroergotamine.
OTHER OPTIONS FOR ACUTE MIGRAINE Oral The combination of acetaminophen, dichloralphenazone, and isometheptene, one to two capsules, has been classified by the FDA as “possibly” effective in the treatment of migraine. Because the clinical studies demonstrating the efficacy of this combination analgesic in migraine predated the clinical trial methodologies used with the triptans, it is difficult to compare the efficacy of this sympathomimetic compound to other agents.
Parenteral Opioids are modestly effective in the acute treatment of migraine. For example, IV meperidine (50–100 mg) is given frequently in the emergency room. This regimen “works” in the sense that the pain of migraine is eliminated. Importantly, it is clear from a recent randomized controlled trial that prochlorperazine is superior to hydromorphone in the emergency room setting. However, opioids are clearly suboptimal for patients with recurrent headache. Opioids do not treat the underlying headache mechanism; rather, they act to alter the pain sensation, and there is evidence their use may decrease the likelihood of a response to triptans in the future. Moreover, in patients taking oral opioids, such as oxycodone or hydrocodone, habituation or addiction can greatly confuse the treatment of migraine. Opioid craving and/or withdrawal can aggravate and accentuate migraine. Therefore, it is recommended that opioid use in migraine be limited to patients with severe, but infrequent, headaches that are unresponsive to other pharmacologic approaches or who have contraindications to other therapies. A trial of an infusion of the anti-GGRP antibody during an acute migraine attack demonstrated benefit compared with placebo in achieving freedom from pain and elimination of the patient's most bothersome symptom during the attack.
Neuromodulation Single pulse transcranial magnetic stimulation (sTMS) is FDA-approved for the acute treatment of migraine. Two pulses can be applied at the onset of an attack and this can be repeated. The use of sTMS is safe where there is no cranial metal implant, and offers an option to patients seeking non-pharmaceutical approaches to treatment. Similarly, a noninvasive vagus nerve stimulator (nVNS) is FDA-approved for the treatment of migraine attacks in adults. One to two 120-second doses may be applied for attack treatment.
MEDICATION-OVERUSE HEADACHE Acute attack medications, particularly opioid or barbiturate-containing compound analgesics, have a propensity to aggravate headache frequency and induce a state of refractory daily or near-daily headache called medication-overuse headache. This condition is likely not a separate headache entity but a reaction of the migraine patient’s biology to a particular medicine. Migraine patients who have two or more headache days a week should be cautioned about frequent analgesic use (see “Chronic Daily Headache” in Chap. 13).
PREVENTIVE TREATMENTS FOR MIGRAINE Patients with an increasing frequency of migraine attacks or with attacks that are either unresponsive or poorly responsive to abortive treatments are good candidates for preventive agents. In general, a preventive medication should be considered in patients with four or more attacks a month. Significant side effects are associated with the use of many of these agents; furthermore, determination of dose can be difficult because the recommended doses have been derived for conditions other than migraine. The mechanism of action of these drugs is unclear; it seems likely that the brain sensitivity that underlies migraine is modified. Patients are usually started on a low dose of a chosen treatment; the dose is then gradually increased, up to a reasonable maximum, to achieve clinical benefit.
Treatments that have the capacity to stabilize migraine are listed in Table 422-6. Most treatments must be taken daily, and there is usually a lag of between 2 and 12 weeks before an effect is seen. The drugs that have been approved by the FDA for the preventive treatment of migraine include propranolol, timolol, sodium valproate, and topiramate. In addition, a number of other drugs appear to display preventive efficacy. This group includes amitriptyline, nortriptyline, flunarizine, phenelzine, and cyproheptadine. Placebo-controlled trials of onabotulinum toxin type A in episodic migraine were negative, whereas, overall, placebo-controlled trials in chronic migraine were positive. The FDA has approved sTMS for the preventive treatment of migraine. It offers a well-tolerated, effective option for patients. Phenelzine is a monoamine oxidase inhibitor (MAOI); therefore, tyramine-containing foods, decongestants, and meperidine are contraindicated, and it is reserved for only very recalcitrant cases. Methysergide is now of historical interest only, since it is no longer manufactured. Melatonin has been reported to be useful, with controlled trial evidence but is not approved in the U.S. Monoclonal antibodies to the CGRP receptor (erenumab) or to the peptide (eptinezumab, fremanezumab, and galcanezumab) have all proven effective and well-tolerated in migraine and some are now available as novel, migraine-specific preventative agents.
The probability of success with any one of the antimigraine drugs is 50%. Many patients are managed adequately with well-tolerated doses of candesartan, propranolol, amitriptyline, topiramate, or valproate. If these agents fail or produce unacceptable side effects, neuromodulation approaches, such as sTMS, or related agents from the above classes, can be used (Table 422-6). Once effective stabilization is achieved, the drug is continued for ~6 months and then slowly tapered to assess the continued need. Many patients are able to discontinue medication and experience fewer and milder attacks for long periods, suggesting that these drugs may alter the natural history of migraine.