Management of Migraine: Part II
Author: James R. Couch, MD, PhD, Professor and Chair, Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, Okla.
Editor’s Note—This is the second in a two-part series on the management of migraine headaches. Part I discussed the definition of the primary headaches, the pathophysiology of migraines, diagnosis and medical therapies, as well as the background and pharmacology of triptans.
Use of Triptans
Table 1 provides the usual dose and the usual maximum daily dose of the 6 available triptans, and one whose release is anticipated soon. Sumatriptan has the widest range of dosage forms with oral, nasal spray, and subcutaneous formulations. All are available as tablets. With oral administration, onset of response within 30-60 minutes is usual with 80+% of response at 2 hours and peak response at 4 hours. Repeat dosing in 1+ hours can be done and the usual limit is 2 doses/d although more can be used at times (see maximum daily dose).
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The rapidly disintegrating (melt) tablet forms for rizatriptan and zolmitriptan have achieved good acceptance due to convenience. These "melt" tablets do not necessarily have faster onset of action than the standard tablet. The sumatriptan nasal spray may be used when the patient is too nauseated to take a pill. The response to nasal spray is similar in time course to sumatriptan tablets.
Subcutaneous sumatriptan (6 mg/dose) has the fastest onset of effect with initial relief in 10-20 minutes; 70-75% respond by 1 hour and 80% at 2 hours. For patients who awaken with severe headache or who have very rapid onset of headache, this is a very useful preparation.
DHE. Dihydroergotamine mesylate (DHE, or DHE 45) is an agonist for most aminergic receptors, including the 5HT-1, 5HT-2, catecholamine, and dopamine receptors. It is most potent at the 5H%-1B and 1-D receptors being equipotent to sumatriptan here. DHE is relatively less potent at other receptors.
Given intravenously, 1 mg of DHE is as potent as subcutaneous sumatriptan in migraine relief. Table 2 outlines the protocol used by Raskin. Given IV, DHE can produce relief in 15-30 minutes in 70-80% of acute migraine (pain-free in 50%). DHE has so far not been found to produce habituation-withdrawal or rebound-withdrawal headache.
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DHE has a half-life of 10 hours. There is accumulation of metabolites over time with repeated dosing. Coronary vasoconstriction is a potential problem and DHE should not be used in subjects with coronary disease. DHE can also be used as a 1-mg intramuscular or subcutaneous injection. Studies have shown a slower onset of action but 50-60% good headache relief. Patients may be trained to give their own injections and thus use the medication at home.
Isometheptene (Midrin) is a combination of 65 mg of isometheptene mucate, a weak catecholamine agonist; 100 mg of dichloralphenazone, an antihistamine; and 325 mg of acetaminophen. Receptor pharmacology has not been studied, but this medication appears to have an abortive antimigraine action. The dosage schedule is listed in Table 2. Side effects are very few, and tolerance has not been studied. Some patients respond to isometheptene very well. As with other abortive medications, this should not be used for daily therapy but use should be limited to no more than 2-3 d/wk.
Ergotamine has the same spectrum of action as DHE but is a more potent arterial vasoconstrictor. The side effects and risks are very similar to those of DHE and the triptans. Ergotamine tends to have a greater incidence of side effects than the triptans, perhaps because of the wider range of receptors it affects. Dosage is given in Table 2.
The cost of the triptans and other symptomatic medication is given in Table 3.
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Migraine Therapies
Prophylactic Antimigraine Therapy
The concept of preventive therapy assumes that migraine is triggerable and relates to a cascade of events. Interruption of the trigger or the cascade prevents occurrence of the symptomatic headache.
General Principles of Preventive Therapy
The decision of whether to use preventive medication is based on how much the migraine problem interferes with the patient’s life. This consideration is based on: 1) frequency; 2) intensity; 3) duration of headache; 4) the patient’s willingness or desire to try the prophylactic approach; and (5) extent and tolerability of side effects of the medication. Typically, occurrence of 3 or 4 headaches per month or more than 8 days per month with headache are reasonable thresholds for consideration of prophylactic therapy. Two severe headaches lasting 4 days each per month would prompt many patients to consider prophylactic therapy. On the other hand, 4 headaches of 4 hours each per month would likely result in a request for symptomatic therapy.
It is not uncommon for patients to have significant side effects. Weight gain, sedation, and impaired thinking can occur as side effects with most of these agents. In each patient, the therapeutic benefit must be balanced against the extent of side effects to maximize the overall therapeutic result.
The drugs that have been most successful in migraine prevention are the antiserotonin drug methysergide, beta-adrenergic blocking agents, tricyclic antidepressant agents, and valproic acid. Other drugs for this purpose include newer anticonvulsants (Gabapentin, Topiramate), atypical antidepressants (Trazodone, Nefadozone, SSRIs), cyproheptadine, and calcium channel blocking agents.
Most of these medications have a "window" type of effect with no effect if the dose is too low, and worsening of headache if the dose is too high. For example, doses of Depakote > 2000 mg/d or amitriptyline > 300 mg/d frequently are associated with no further improvement and even worsening of headache. The preventive medications have multiple side effects and are not well tolerated by all patients. The usual procedure is to start with a small dosage and build up the dosage gradually until either a therapeutic effect or limiting side effects are observed. Monotherapy should be attempted and explored before combinations of prophylactic medications are tried.
The effective prophylactic antimigraine agents are outlined in Table 4. These agents will be considered by classes.
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To determine if therapy is effective, use a calendar. Have the patient record their worst headache for each day they have a headache in a mild, moderate, or severe format or on a 0-10 scale. The calendar will allow the physician to know if the patient is improving or worsening.
Specific Agents
The beta-adrenergic blocking agent propranolol was approved for migraine prophylaxis in 1974. The beta-adrenergic blocking agents without intrinsic sympathomimetic activity (ISA) appear to have a preventive antimigraine effect. Propranolol will be discussed as the representative of this group.
The pharmacology of propranolol is complex. As a nonspecific beta-adrenergic blocking agent, it has many pharmacologic effects, including decrease in blood pressure, heart rate, and cardiac contraction; inhibition of bronchodilation; and decrease in the gluconeogenic response in diabetics on insulin. Propranolol also has an anti-anxiety effect in small doses and has been used to diminish panic attacks and to control stage fright.
Propranolol has been found to be most effective in patients with intermittent migraine. In propranolol studies that were controlled and blinded, approximately 50-55% of patients were improved by more than 50%.
The side effects of propranolol include fatigue or a lack of energy sedation and weight gain. Orthostatic hypotension and syncope can result if the hypotensive effect is too great. The slowing of heart rate is occasionally significant enough that the patient develops a heart rate below 50 beats per minute. At this rate, the patient may have great difficulty carrying on usual activities.
Because of the negative chronotropic and inotropic effects of propranolol, patients may find their capability for exercise diminished. Usually this is a problem only when maximum exercise tolerance is tested. Some patients, however, find fatigue or dyspnea with just carrying out activities of daily living. In patients with limited cardiac reserve, propranolol can induce cardiac failure or worsen existing failure. If these side effects are intolerable or dangerous, propranolol should be discontinued.
The dosage of propranolol may vary from as little as 20-30 mg/d to as much as 480 mg/d. In most patients who respond to propranolol, dosages of 80-240 mg/d provide good headache prophylaxis. There is not a dose-response relationship but rather an apparently idiosyncratic relationship between dosage and headache relief. Typically propranolol can be safely started at 20 mg/d. The dose can be advanced by 20 mg every third day to a maximum of 40 mg t.i.d. The dosage usually can then be increased by 40 mg every week or every month until optimal effect is reached.
Three contraindications should be stressed: 1) propranolol should not be given to diabetics, because it masks the response to hypoglycemia; 2) propranolol may precipitate asthmatic reactions in patients with actual or latent asthma; and 3) propranolol may enhance or precipitate depression and this may be very significant and serious. Additionally, if patients develop significant hypotension, slowing of heart rate, or heart block, propranolol should be discontinued.
Other beta-blocking agents without ISA appear to be equivalent to propranolol in their potency and range of effectiveness. Although some of these agents may have desirable properties such as longer half-life, there has been very little evidence that use of one beta-blocking agent without ISA is better than any other. Typically, if one beta-blocking agent fails, better results are seldom obtained with trials of other beta-blockers.
Tricyclic Antidepressants (TCAs)
TCAs have been generally favored for chronic tension-type headache and chronic daily headache with migraine and tension features, whereas the beta-adrenergic blocking agents have typically been more effective in the patient with pure intermittent migraine. TCAs may be effective for intermittent migraine as well. In my experience, amitriptyline and doxepin are the 2 most effective TCAs in migraine prevention. Some patients, however, are found to respond to other tricyclic agents when amitriptyline and doxepin have failed. Although there are no studies on this subject, anecdotal experience suggests that some patients may respond better to doxepin than to amitriptyline, or vice versa. If only a modest response is obtained to one of the agents, it is usually worthwhile to give the other a try to see if it has better therapeutic efficacy.
The pharmacology of TCAs is complex. These agents inhibit reuptake of 5HT and norepinephrine at nerve endings and also have anticholinergic, beta-adrenergic blocking, and sedative effects.
For amitriptyline, a starting dosage of 10-25 mg at bedtime is usually tolerated. The optimum dosage may be increased by 10-25 mg every 1-2 weeks to a maximum of 300 mg/d. The optimum dosage is determined by either good headache relief or occurrence of unacceptable side effects. The response to TCAs, like that to propranolol, is more idiosyncratic and not closely related to blood levels. If the patient has no side effects and no relief, continue to increase the dosage. At dosages above 200 mg/d, an amitriptyline level should be obtained. If the tricyclic level of amitriptyline plus nortriptyline or doxepin plus nordoxepin exceeds 300 mg/mL, the dosage should be decreased. Above 300 ng/mL, the blood level may not remain stable at a given dose and may tend to drift upward producing toxicity. Typically, the dosage should be divided, with 50% at bedtime and the remainder in divided doses during the day. Giving the entire dose at bedtime may work well in some subjects, but others may have recurrence of headache in afternoon or evening with a once-a-day regimen.
The typical side effects of the tricyclics are drowsiness along with the anticholinergic effects of a dry mouth, constipation, difficult or slowed urination, blurred vision, and weight gain. The majority of patients will accommodate well to the drug with dose adjustment and slow progression of dose. Anxiety and paradoxical stimulation with difficulty sleeping occurs in 2-5% of patients. Tardive dyskinesia has been reported rarely. TCAs may lower seizure threshold and should not be used in subjects with history of seizure unless they are taking adequate antiepileptic medication.
Amitriptyline and imipramine have been associated with sudden death in rare cases. These drugs have rarely been associated with fatal arrhythmias. To date, doxepin has not been reported to have cardiac side effects. For patients older than age 50 or who have significant risk factors for cardiac disease, an ECG is recommended before these agents are administered. This precaution is also recommended for most of the preventive antimigraine agents listed in Table 4.
Combinations of amitriptyline in dosages of 75-150 mg/d and propranolol at 80-160 mg/d have been used by headache experts in treating migraine. In some patients, a significant additive effect is observed.
Valproic Acid
Valproic acid (VPA) was first reported to be effective in treating migraine in 1987. This led to several controlled trials in which approximately 50% of subjects treated with VPA were improved more than 50%. VPA has now become a major preventative antimigraine agent.
The formulation of divalproex sodium (Depakote) has a higher tolerability than valproic acid per se. The latter formulation had a significant incidence of nausea and gastric irritation, which occurs much less often with Depakote. The major side effects of VPA as divalproex sodium are weight gain, tremor, and hair loss. These symptoms remit when VPA is discontinued. Sedation and difficulty thinking may be seen in occasional patients.
Alterations of liver function due to changes in carnitine metabolism occur and may result in elevated blood ammonia. Hepatoxicity may occur and is a greater risk in the setting of polytherapy. Children are at greater risk than adults, and the extent of potential hepatoxicity in adults is unknown. Obtaining baseline SGOT, SGPT, and GGTP is advisable when VPA is started and these should be checked yearly. VPA should not be used in patients with liver disease. VPA has rarely been associated with bone marrow suppression.
The dosage for divalproex sodium is 250 mg once or twice per day initially and then is increased by 250 mg/d per week. The maximum dose for headache prophylaxis is usually 500 mg t.i.d. Higher dosages only rarely improve the response and may make the headache problem worse.
Methysergide
Methysergide is a serotonin receptor-blocking agent, although it also has significant potency for blocking norepinephrine receptors. Methysergide is seldom used now due to risks and side effects and should be used only by those who take time to become very familiar with it.
Comment: For migraine prophylaxis, the 4 medications listed (propranolol, amitriptyline, valproic acid, and methysergide) have typically been the most effective. In a compilation of studies carried out to determine the extent to which patients were improved by at least 50%, the results showed 58% of a group of 1500 patients taking methysergide, 55% of a group of 100 patients on amitriptyline, 51% of a group of 210 patients on propranolol, and 48% of a group taking divalproex, and reached this criterion in various double-blind studies in a comparison of medication vs. placebo. No definite dosage-response relationship has been found for any prophylactic antimigraine medication. The prophylactic antimigraine response appears idiosyncratic as far as is currently known.
Other Prophylactic Agents
Antiepileptic Drugs (AED)
Most of the newer AEDs have been tested in migraine prophylaxis. Of these, Gabapentin and Topiramate have been most useful. Gabapentin in doses of 300-1800 mg/d and Topiramate in doses of 50-250 mg/d have been useful with efficacy similar to VPA. Side effects of sedation, agitation, and difficulty thinking are seen with both. Topiramate may actually decrease appetite and induce weight loss of 3-7% of body weight. Other new AEDs are under investigation.
Calcium Channel Blocking Agents
These generally have been disappointing in their effects on migraine prophylaxis. Initial expectations for these agents were high, but the calcium channel blocking agents have shown very poor effectiveness in double-blind studies against placebos. There appears, however, to be a smaller group of patients who respond very well to calcium channel blocking agents. These patients often develop tachyphylaxis after 2-3 months on the medication and require a period of at least 1 month off the medication to restore responsiveness.
The representative of this group is verapamil. When it is effective, it is usually at dosages of 80-480 mg/d. Verapamil is typically more effective when used as the regular formulation and less effective as a slow-release agent or long-acting agent. Usually 80 mg t.i.d. is a reasonably effective dosage. The dosage may be increased to 120 mg q.i.d. if tolerated.
Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) have been studied primarily in an anecdotal fashion. Phenelzine has been used most commonly. Because of the risk of paradoxical hypertension and the need for a special diet low in tyramine, MAOIs are used only when other drugs have failed. Occasionally, patients may respond to phenelzine at 15-30 mg t.i.d. The reader is referred to drug compendia for pharmacology and side effects.
Cost of Therapy
The preventive or prophylactic antimigraine medications vary widely in cost. Table 5 reviews the costs of 1-month supplies of these medications at their usual daily dosages. The average wholesale price is presented.
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Tension-Type Headache and Chronic Daily Headache
Acute Intermittent Tension-Type Headache
For the acute, intermittent tension-type headache, use of analgesic or nonsteroidal anti-inflammatory agents such as ibuprofen, naproxen, or acetaminophen usually suffices. For more intense tension headaches a combination of butalbital (50 mg) and an analgesic such as aspirin (Fiorinal) or acetaminophen (Fioricet) may be very helpful. At times, addition of a muscle relaxant in a low dosage, such as 2 mg of diazepam or 50 mg of orphenadrine, may be helpful. Very often, however, the patient with pure tension headache does not see a physician for medication unless the tension headache develops into a migraine. Use of butalbital compounds or benzodiazepines must be undertaken with great care. These are potentially habituating compounds and can easily be overused leading to a drug-induced, rebound withdrawal headache.
Chronic Tension-Type Headache
Chronic daily headache with migraine and tension features. For chronic tension headache, a different situation exists. Chronic tension headaches typically have combined symptoms of tension and migraine headaches and fit into the category of combination tension-migraine or mixed chronic daily headache (or transformed migraine). This is the most common and most treatable type of chronic daily headache. Typically, the first-approach therapy is to use tricyclic antidepressant agents. Any of the other preventive antimigraine agents can also be used. The antimigraine, anticonvulsant agents, Divalproex, Gabapentin, and Topiramate have also been used frequently. Not infrequently, combination therapies combining a tricyclic with one of the other medications may be attempted, although there are relatively few standard data on response to these combination regimens. For this type of patient, it is necessary to limit access to habituating medication. Because of the chronicity of the pain problem, patients are very likely to overuse medications that are potentially habituating. This overuse may lead to a rebound-withdrawal (habituation-withdrawal) type of headache. In this situation, the medication is taken and gives relief, but as it is metabolized and excreted, the drop in level triggers another headache. In this way, the overused medication drives the headache and becomes part of the problem instead of part of the solution.
Pure Chronic Tension-Type Headache
Pure chronic tension-type headache with no associated migrainous features of photophobia, phonophobia, nausea, vomiting, diarrhea, or neurologic symptoms: These patients typically have a continuous mild-to-moderate headache that is worrisome, nagging, and uncomfortable but does not limit activity. Some patients with pure chronic tension type headache may respond to the preventive antimigraine agents but usually do not. Tizanidine in a dose of 8-24 mgs/d may be helpful in some patients. A q.i.d. schedule is usually used. Physical measures such as biofeedback or physical therapy may work occasionally. Studies are in progress evaluating botulinum toxin injections, but it is too early to predict success here.
Guidelines for Referring Headache Patients
Many headache patients are treated very capably by primary care physicians, but additional opinions and specialized care are sometimes required. One of the questions often asked is when a patient should be referred to a headache specialist. Situations that may require referral include:
1. a new, unexplained headache;
2. development of new, unexplained neurologic findings;
3. poor response to the treatments with which the physician is comfortable;
4. a situation in which the referring physician is uncomfortable with the patient for medical or psychological reasons; and
5. presence of comorbid medical or psychiatric conditions whose therapy is beyond the physician’s expertise.
The first area of consideration is a new, unexplained headache. If the patient has a headache that is severe enough to cause continual complaints and the treating physician is unable to find an adequate etiology, the patient probably should be referred to a specialist with greater knowledge of headaches.
If the patient develops new and progressive neurologic findings that cannot be explained on the basis of available testing and insight, the patient should be seen by a headache specialist.
The third situation deals with treatment of the headache. If the primary physician is unable to provide the patient with adequate relief, referral should be considered. If the pain can be relieved only by increasing the dosage of an analgesic/narcotic medication and the possibility looms that the patient may develop a habituation-withdrawal headache in response to that medication, the patient should be referred.
Finally, if the physician simply feels uncomfortable with the situation and believes that his or her skills may be inadequate to help the patient, referral is advised. The difficult headache patient usually has a very chronic pain problem, which may be exacerbated by psychological factors. If the patient is manifesting a significant degree of chronicity and if communication and trust between the patient and the physician begin to break down, referral is indicated.
Patients with chronic diseases often "doctor shop" to see if some other physician can provide a better level of treatment. If a patient asks for a referral, it is best to proceed with the referral. The patient will respect the physician for assisting the patient to continue searching for pain relief. The physician’s ready agreement to refer the patient demonstrates to the patient that the doctor’s first concern is the patient’s well-being.
There are several specialized headache centers throughout the country. The American Headache Society and the American Council of Headache Education can provide patients with information about these centers. The address for both organizations is 19 Mantua Road, Mt. Royal, NJ 08061.
Recommended Readings
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4. Ferrari MD, et al. Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet. 2001;358(9293):1668-1675.
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