Emergency Medicine

Understanding Migraine: Treatment Options

A decade after the first triptan drug was introduced, what do we know about this therapeutic class? Which migraineurs should not take a triptan? What are the advantages of one triptan over another and one mode of delivery over another? Do the ergotamines still have a role to play, and what other options does a clinician have when triptans fail? In the second of three parts, the authors examine these and other treatment issues.

By Jeff Unger, MD, Roger K. Cady, MD, and Kathleen Farmer-Cady, PsyD

Dr. Unger is director of the Chino Medical Group Headache Intervention Center in Chino, California. Dr. Cady is the director and Dr. Farmer-Cady the administrator of the Headache Care Center at Primary Care Network, Inc., in Springfield, Missouri. They are also co-founders of the Primary Care Network.

Last month, we reviewed the definition and causes of migraine headaches, the underlying biological mechanisms, and key diagnostic considerations. We also discussed the five phases of the migraine process.

In this second article in our three-part series, we will review appropriate therapeutic strategies for acute migraine. We will also discuss specific migraine medications—namely, the triptans, ergotamines, and rescue medications.

ACUTE TREATMENT OF MIGRAINE

The treatment of migraine involves three important strategies: behavioral and educational intervention (see table below), symptomatic (acute) therapies, and preventive considerations. All three approaches need to be employed for successful management of migraine.

Behavioral Approach to Migraine Management

• Go to bed and wake up at the same time seven days a week. Get 8 to 9 hours of uninterrupted sleep each night. Instead of sleeping in on weekends, awaken at the usual time, get out of bed, walk around the house for 10 minutes, drink some juice, and then go back to bed. People who sleep in on weekends will likely develop "hangover headaches" from excessive sleep. Avoid working long hours or irregular shifts.

• Limit caffeine consumption to less than 240 mg a day. This is equivalent to two cups of coffee or two caffeinated sodas daily. Consumption should be progressively reduced at a rate of one cup a day per week. Thus, if one is drinking 10 cups of caffeine a day, it will take eight weeks to reduce caffeine consumption to two cups daily. Caffeine is also found in certain drugs, such as Excedrin. Taking two Excedrin migraine tablets is the equivalent of drinking two cups of coffee. Many weekend headaches are due to caffeine withdrawal. If one drinks coffee on weekdays, drinking a cup of coffee on weekends may stop caffeine withdrawal headaches.

• Do not skip or delay meals. Eat three meals daily, all at a scheduled time. Most migraineurs do not wake up hungry. During the migraine prodrome, patients may lose their appetite, but hunger may trigger a migraine.

• Do not smoke.

• Exercise five days a week by walking 30 minutes each day. This stabilizes pain receptors in the brain and may limit the weight gain experienced by patients taking some preventive medications.

• Use symptomatic headache medications only twice weekly. Patients with menstrual migraine may use daily symptomatic medications as described below.

• Avoid known headache triggers, especially during a prodrome. For example, if drinking red wine triggers migraine, avoid drinking wine during a prodrome or during a vulnerable time such as menstruation.

• Practice relaxation exercises, such as biofeedback or yoga, on a regular basis, especially during a prodrome. For thermal biofeedback, a thermometer is taped on the index finger and the temperature of the finger is recorded. Migraineurs usually have a finger temperature below 80°F, whereas non-migraineurs typically have a finger temperature around 85°F. (Many migraineurs complain about chronically cold hands and feet.) By relaxing, practicing deep breathing, and listening to soft music for 10 minutes twice daily, a migraineur can increase his or her finger temperature. A goal of 96°F should be set. Once this has been attained, the body will have learned to replace the fight-or-flight response with the relaxation response. In this way, the number and severity of headaches decrease significantly. Research has indicated that thermal biofeedback is as effective in preventing migraine attacks as propranolol.

• Have a written plan for treating your migraine attacks. Do not vary from the plan unless authorized to do so by your physician.

• Keep a detailed headache diary, which is useful in assessing the efficacy of treatment and identifying specific migraine triggers.

Sources: Holroyd KA and Penzien DB, 1990; Lemstra M, et al., 2002; Richardson NJ, et al., 1995; Unger J, 2002 (see Suggested Reading)

Acute intervention strategies vary, depending on the severity of the headaches. Mild, intermittent headaches may respond well to over-the-counter medications or anti-inflammatory drugs such as naproxen and ibuprofen. For best efficacy, these drugs should be used as early as possible after the onset of mild headache. Patients may prevent their acute migraine by recognizing their prodrome and treating themselves with naproxyn 500 to 750 mg. In addition, relaxation therapy and thermal biofeedback may be practiced during the prodrome.

Patients who recognize a prodrome may also use naratriptan or frovatriptan to preempt a migraine attack. If they use naratriptan in advance of the onset of headache, during the prodrome, patients can usually abort the headache before the pain begins or they may experience a headache of much less intensity.

The first migraine-specific drug, sumatriptan, was released in 1993. Until that time, migraine was treated with a variety of drugs, including ergotamines, which had many side effects and were difficult to use. The triptans are all excellent drugs. They rapidly eliminate pain while restoring patients to normal function. Studies have consistently demonstrated that triptans are the preferred symptomatic drug class of migraine patients. The table below lists the currently available triptans, their maximum daily doses, and the period of time that must elapse before the dose can be repeated for headache recurrence.

Guide to Triptan Therapy
	Drug	Dose	Repeat dose	Maximum dose/24 hrs
	sumatriptan oral tabs	50-100 mg	2 hrs	200 mg
	sumatriptan nasal spray	5 and 20 mg	2 hrs	40 mg
	sumatriptan injection	6 mg	1 hr	12 mg
	zolmitriptan tabs	2.5-5 mg	2 hrs	10 mg
	zolmitriptan ZMT	2.5 mg	2 hrs	10 mg
	zolmitriptan nasal spray	2.5 mg	2 hrs	10 mg
	rizatriptan tabs*	5 and 10 mg	2 hrs	30 mg
	naratriptan	1 and 2.5 mg	4 hrs	5 mg
	almotriptan	6.25 and 12.5 mg	2 hrs	25 mg
	frovatriptan	2.5 mg	4 hrs	5 mg
	eletriptan	20 and 40 mg	2 hrs	80 mg
	*If patient is taking propranolol, only a 5-mg dose should be used.

Triptans are believed to alleviate migraine by several mechanisms. By binding to 5HT-1D receptors, triptans stop the release of neuropeptides at the trigeminal vascular junction. The cerebral meningeal vessels contain 5HT-1B receptors, which when triggered will produce sterile inflammation. The triptans bind to these receptors and stop the sterile inflammation of meningeal arteries. In addition, triptans may act on central 5HT-1D receptors to limit pain transmission and associated migraine symptoms, such as nausea, vomiting, light and sound sensitivity, and cognitive impairment.

The most common side effects with the triptans are tingling, flushing, fatigue, and feeling warm. Chest tightness occurs occasionally and is thought to be noncardiac in origin. The table below lists "triptan pearls" that will improve the clinical efficacy of these drugs.

Triptan Pearls

• Early intervention with a triptan will often result in a more rapid reduction of headache pain and return to normal function. Treating headache during the mild pain phase will allow the patient to become pain-free within two hours 80% of the time versus only 36% of the time if a triptan is used during the moderate to severe headache phase. Mild-phase treatment also will lessen the likelihood of headache recurrence and limit the drug's side effects (such as paresthesias, throat discomfort, flushing, fatigue, and chest pain). Once allodynia develops, triptans may be less effective in stopping a migraine attack.

• Patients should experience significant pain relief within two hours of taking a triptan. The exceptions to this rule are naratriptan and frovatriptan, which may not reduce headache for four hours after dosing. Redosing of a triptan is advised if the headache is not improved after two hours (after four hours with naratriptan and frovatriptan) or if the headache resolves and then recurs within 24 hours. If a second dose is used, 90% of patients will have complete relief within four hours.

• Triptans should be used to treat at least three migraines before trying a different drug. Failure with one triptan does not imply that the patient will not find relief with one of the other triptans.

• Patients taking propranolol for migraine prophylaxis should reduce a single dose of rizatriptan to 5 mg and a total dose in 24 hours to 15 mg. Individuals taking a different beta blocker need not reduce the dose.

• If a patient's headache worsens after taking a triptan, try reducing the initial dose by 50%.

• Patients who are most disabled by their headaches should be prescribed a triptan before trying drugs that are not as migraine-specific (such as combination drugs, OTC analgesics, NSAIDs, and ergotamines).

• A headache diary is very helpful in assessing the efficacy of triptan therapy during the course of multiple migraine attacks.

• Migraineurs who experience nausea may add metoclopramide 10 mg to their oral treatment regimen.

• Adding an NSAID to a triptan may improve the efficacy of the triptan and prevent a postdrome phase during which the patient feels fatigued and has memory problems for 24 hours after the migraine resolves.

• If a patient receives a limited number of triptans per month from a third-party payer for frequent migraines, using an NSAID, such as naproxen 500 to 750 mg, at the onset of mild headache may stop the pain within two hours. If the headache persists or worsens, a triptan can then be used. This "staged-care approach" may reduce the number of triptans a patient needs each month.

Sources: Bedell AW, et al., 2000; Goldberg MR, et al, 2001; Lipton RB, et al., 2000; Sheftell FD and Tepper SJ, 2002 (see Suggested Reading)

Triptans are contraindicated in pregnancy and should be used with extreme caution to treat basilar migraine and migraine with prolonged aura. Patients with cardiac risk factors (such as uncontrolled hypertension, obesity, hyperlipidemia, diabetes, or a family or personal history of coronary artery disease) may use a triptan after a medical workup similar to that performed for preoperative clearance. High-risk patients should consider using alternative analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics. Triptans are known to constrict coronary blood vessels as well as meningeal arteries. However, the constriction of the coronary vessels is less than 10% of the narrowing that occurs in the meningeal blood vessels.

SPECIFIC MIGRAINE MEDICATIONS

All of the triptans are highly effective in the acute treatment of migraine and are similar in their mechanism of action. However, some triptans have qualities that distinguish them from other drugs in their class. When prescribing a triptan, one should keep in mind certain objectives for treatment outcome:

• Patients should be pain-free within two hours of using the triptan.

• Patients should not experience a headache recurrence within 24 hours once they have become pain-free.

• Patients should be able to return to full function within two to four hours after taking the triptan.

• Patients should be able to use the triptan without experiencing any significant adverse effects.

All of these objectives can be achieved by having patients take their triptan when the headache is in the mild phase. However, patients should also be advised against using triptans more than three times a week, unless the drugs are being used specifically for menstrual migraine prophylaxis.

Sumatriptan. This drug comes in three different formulations—oral tablets, a nasal spray, and as an injection. The injectable form of sumatriptan has the fastest onset of action of all the triptans. Sumatriptan nasal spray may have a faster onset of action than the oral preparation. Sumatriptan oral tablets come in three different doses—25, 50, and 100 mg. The 50- and 100-mg doses eliminate migraine pain in over 60% of migraineurs within two hours. Sumatriptan not only stops migraine pain but also improves migraine-induced cognitive impairment. The fast-acting injectable sumatriptan is very useful for treating acute-onset migraine associated with severe nausea and vomiting or when circumstances demand prompt intervention.

Zolmitriptan. This drug comes in two different preparations—oral tablets and the "melt" form (ZMT), which dissolves when placed on the tongue. A nasal spray formulation is expected to be released this year. Patients using zolmitriptan nasal spray may experience improvement in their headache within 15 minutes, with minimal side effects. Effectively treating a migraine within 90 minutes may reduce the patient's risk of developing allodynia, a painful response to a nonpainful stimulus. Patients with allodynia may experience peripheral pain in their scalp while combing their hair, or they may feel pain in an arm, leg, or even the groin as the headache pain worsens. Although triptans are effective at any time during a migraine attack, they work far better when used prior to the onset of allodynia.

In several studies, migraineurs felt that the ZMT and the oral tablets were similar in stopping their pain within two hours. The unpleasant taste associated with the sumatriptan nasal spray appears to be less of an issue with the zolmitriptan nasal formulation. Patients who are concomitantly using cimetidine should reduce their dose of zolmitriptan by 50%. Co-administration of cimetidine and zolmitriptan doubles the half-life of both zolmitriptan and its active metabolite.

Rizatriptan. This drug is rapidly absorbed as an oral tablet or an orally disintegrating disc, which may be convenient for patients who find it difficult or inconvenient to take an oral tablet without water. Rizatriptan is very useful in managing rapid-onset migraine associated with early nausea. Patients taking concomitant propranolol should use the 5-mg dose because of a potential doubling of circulating rizatriptan levels. Other beta blockers do not have a similar effect on rizatriptan.

Almotriptan. This drug has few drug interactions and a low adverse event profile. The 12.5-mg dose is preferred. Almotriptan is the least expensive triptan. In addition, it has a 39% sustained pain-free response rate over multiple attacks. This means that after a patient becomes pain-free within two hours of taking the drug, headaches rarely recur. The drug's onset of action is similar to sumatriptan's.

Naratriptan and frovatriptan. These drugs are longer-duration triptans with half-lives of 6 and 25 hours, respectively. Both appear to have a lower headache recurrence rate than other triptans. However, their onset of action may be slightly slower than that of the shorter-duration triptans. Thus, these triptans are best suited for migraines that develop more slowly and last longer. Both products are well tolerated and have minimal potential for interactions with other drugs. Naratriptan has been shown to be effective in aborting migraine when taken during the prodrome. There is evidence that both naratriptan and frovatriptan are effective in preventing migraine associated with menstruation. Naratriptan has also been useful in treating patients with transformed migraine that has not responded to traditional pharmacologic and behavioral interventions.

Eletriptan. This drug is an oral triptan, approved by the Food and Drug Administration in 2002 and available on the market in 2003. The conventional tablet is 40 mg. Clinical trials have demonstrated that eletriptan is significantly superior to placebo for the acute treatment of migraine, with an onset of action of less than 30 minutes. Eletriptan is metabolized by the CYP3A4 hepatic degradation system. This important enzymatic system also is responsible for the metabolism of drugs that may significantly increase eletriptan levels in the brain. Both the peripheral and central nervous system effects of eletriptan can be increased. Although limited data are available to assess the true potential risk, a 50% reduction in eletriptan dosage when it is administered within three days of using a potent CYP3A4 inhibitor is advised. Such drugs would include macrolide antibiotics (such as erythromycin and clarithromycin), certain antifungals (such as ketoconazole and itraconazole), and antiretrovirals (such as indinavir, nelfinavir, and ritonavir). A 20-mg dose should be used when eletriptan is taken concomitantly with verapamil. Patients should be advised that drinking grapefruit juice while taking eletriptan can increase cerebral blood levels of the drug. Eletriptan does not interact with monoamine oxidase inhibitors.

Ergotamines. The ergotamine drugs were first used for acute migraine management in the 1950s. These drugs come in many different formulations, including nasal spray, injections, suppositories, and oral tablets. Although effective in treating migraine, the ergotamines are often more difficult to use than the triptans and have more side effects.

The injectable ergotamine is DHE-45, an excellent drug that treats many types of headaches, including migraine and cluster headaches. It can also be used in patients who have status migrainosus (severe migraine lasting more than three days associated with nausea, vomiting, and dehydration), as well as in the hospitalized patient being treated for analgesic-induced rebound headaches.

Patients who do not respond to triptans may do very well with ergotamines. Caution must be used in patients with heart disease because these drugs can narrow coronary vessels 100 times more than triptans. When used more than twice weekly, one of the oral forms (Caffergot) may cause problems such as hypertension, kidney failure, cold hands and feet, and rebound headaches. The ergotamines may also be used on a daily basis to treat menstrual migraine.

RESCUE MEDICATIONS

Rescue medications can be given to patients who for whatever reason fail to find relief from acute migraine with triptans or ergotamines. Commonly used rescue medications and dosages are listed in the table below. These medications can also be used as an alternative to migraine treatment in the emergency department.

Migraine Rescue Medications
	Drug	Dose/Route
	sumatriptan	6 mg subcutaneously
	chlorpromazine	12.5 mg slow IV push q 20 min (maximum 50 mg)
	prochlorperazine	10 mg slow IV push
	droperidol	2.5 mg slow IV push q 30 min (maximum 7.5 mg)
	depakon	1 gram IV push over 1 min
	magnesium sulfate	1 gram IV push over 1 min
	DHE45 + prochlorperazine	Mix DHE45 1 mg plus prochlorperazine 10 mg. Give 1.5 ml slow IV push over 1-3 min.
	dexamethasone	6-8 mg IV push
	methylprednisolone	250-500 mg IV push
	olanzapine	5-10 mg PO

Patients may also respond to an occipital nerve block, in which bupivacaine 0.5% 4 ml and triamcinolone 40 mg (1 ml) are injected into the occipital notch. The injection is performed using a 21-gauge needle at the ipsilateral occipital notch. Palpation of the occipital notch may be very uncomfortable for the patient. After the injection, the patient's scalp may become numb for four to six hours, after which the pain begins to subside. An occipital nerve block can be useful in post-traumatic migraine (from whiplash, for example), pregnancy, occipital neuritis, chronic daily headache due to analgesic abuse, new daily persistent headache, and status migrainosus.

Intravenous (IV) magnesium sulfate can also be given to patients with intractable migraine. We recommend using 1 gram, given IV push, over 30 to 60 seconds. Patients will develop a significant hot flash lasting up to a minute. However, as the hot flash ends, patients often note that their headache intensity is much improved and their symptoms are reduced. Up to 80% of patients note immediate improvement in their headaches, which often lasts for 24 hours or longer.

Part I: Pathophysiology and Presentation

Part III: Strategies for Prevention