Headache Drugs Logo
Home | About Dr. Robbins | Archived Articles | Headache Books | Topic Index  

Back to List


Third-Line Migraine Preventive Medication
Posted Sept 2000

The third line approaches for migraine prophylaxis are: (1) MAO inhibitors: (2) MAO inhibitor plus a first line preventive; (3) intravenous DHE; and (4) daily opioids. These third line therapies are not instituted without first attempting other, less problematic, options. Botox (Botulinum) injections are a promising new therapy that may prove helpful.

MAO Inhibitors
The use of MAOIs, such as phenelzine, poses potentially serious problems. However, they can be helpful in severe, refractive migraine, and are very effective when utilized for chronic daily headache. Their strong antianxiety and antipanic effects are useful for many patients, as are the beneficial effects on depression. Patients must be selected carefully since they need to be vigilant about what they eat and they cannot take OTC cold remedies. Given these restrictions, responsible patients can use the MAOIs with relative safety. The hypertensive crisis due to interactions with foods or drugs is a rare occurrence. (See Table 3.10). The MAOIs may be carefully combined with certain tricyclics, beta blockers, and calcium blockers. Sumatriptan cannot be used with the MAOIs. For any of the following medications, patients need to be informed of the side effects, as listed in the PDR and package insert.

Phenelzine (Nardil):
Nardil is the MAOI most frequently used for headache prevention. Nardil is often effective for refractive migraine, and is helpful for chronic daily headache. Nardil also relieves anxiety and depression.

Dosage: Beginning with one 15 mg. tablet each night, the dose may be increased over 1 week to three tablets each night. By taking the medication only at night, interactions are much less likely to occur with tyramine foods. The usual dosage is 45 mg. (3 tablets) each night. Some patients do well on 15 or 30 mg. nightly, and others require 75 mg. Minimal doses lessen the likelihood of side effects. If 75 mg. (5 pills) do not help, another medication should be employed and Nardil discontinued.

Side Effects: Side effects tend to be similar to those of the tricyclic antidepressants: dry mouth, constipation, insomnia, and weight gain. Tachycardia may occur. The major problems with Nardil are insomnia and weight gain. Switching to early morning dosing may help the insomnia. Agitation or other mood altering side effects may occur. Nardil is a very effective antidepressant and antianxiety drug. Hypotension may be a problem, and patients must have blood pressures checked both lying and standing (orthostatic). In very rare situations, where only Nardil has helped the patient but hypotension is a major problem, the hypotension may be counteracted by adding Florinef. Sedation can occur but is uncommon. Liver functions must be monitored via blood tests.

If water retention becomes a problem, careful use of diuretics may be helpful. Although it is not generally advisable to treat side effects of one medication with another medication, in situations where Nardil is the patient’s only effective therapy for headache, we may have no other option but to treat the side effects. The most serious adverse effect, the hypertensive crisis, is uncommon, but may occur with the ingestion of certain foods. Meperidine (Demerol), or decongestants may not be used with MAO inhibitors. Patients should contact their physician prior to taking other drugs or OTC preparations. Excessive amounts of caffeine should be avoided.

To counteract the hypertensive crisis, should it occur, patients should carry capsules of Procardia, 20 mg. They would bite or cut the capsule and put it under the tongue for the following circumstances: a headache that is much different than their usual one, nausea and vomiting, dilated pupils, palpitations, neck or occipital pain that is different than their usual headache, diaphoresis with either cold, wet extremities or with a fever. They then must go to the emergency room for a blood pressure check. Among reliable headache patients, this crisis occurs very rarely.

Foods to Avoid While on Nardil
Red wine or sherry, ale and beer
Tenderized meats, caviar, dried or salted fish, herring, liver, fermented meats, (pepperoni, summer sausage, salami, bologna)
Excessive caffeine, chocolate
Aged cheeses (only Velveeta is OK to eat)
Sour cream
Bananas, figs that are overripe, avocados
Yeast extracts
Soy sauce
Fava beans

Phenelzine plus Verapamil:
This very powerful combination for severe, refractive migraines must be monitored since hypotension is a problem. The usual dosage is two to four phenelzine pills (15 mg. each) plus 120 to 240 mg. of verapamil per day. Verapamil SR tablets are available in 120, 180 and 240 mg., allowing convenient once per day dosing. In addition to easing the migraines, verapamil minimizes the possibility of a hypertensive crisis. The dosages of both the phenelzine and the verapamil must be very slowly increased over 2 weeks, with frequent blood pressure checks. The usual precautions observed with the use of MAOIs must also be observed with this combination.

Phenelzine plus Amitriptyline:
This powerful combination of drugs for migraine, chronic daily headache, and depression is actually much less of a problem than was previously thought. Some evidence exists that the amitriptyline decreases the risk of a hypertensive crisis with the phenelzine. This combination is particularly helpful in cases where phenelzine is effective for the headaches but causes a severe sleep disorder. The same cautions must be followed with this combination as with phenelzine alone, but with this combination hypotension is more likely to occur than the hypertensive crises, and blood pressure must be closely watched.

The usual dosage of phenelzine is two to four pills (15 mg. per pill) per day, and 10 to 50 mg. of amitriptyline per night.

Repetitive IV DHE:
For patients with severe, frequent migraines or severe chronic daily headaches, repetitive IV DHE therapy has been very successful. Although usually performed in the hospital over 3 days, giving nine doses of DHE, the procedure may be done in the office without difficulty. Outpatient DHE allows this treatment to be available for those patients who do not wish to be hospitalized. IV DHE has proven very safe; serious side effects are rare, with only a few reported cases of claudication (that was reversible) and angina. The pharmacology of DHE is different than that of the other ergot preparations. It does not greatly constrict arteries, but is primarily a venoconstrictor. Serotonergic effects are most likely the mechanism of action. Although DHE is relatively safe for patients over the age of 50, caution must be used and lower doses given to those in older age ranges. Patients with peripheral vascular disease or heart disease must not be given DHE. DHE should be used with caution in patients with hypertension.

For the majority of patients, IV DHE has been successful in decreasing the intensity and frequency of headaches for a period of time. I have found that the effects of a course of DHE therapy usually last 1 or 2 months, with an occasional 6 or 8 month hiatus in the headaches. It is extremely effective for halting an acute migraine, as well as for preventing migraine attacks. Daily IM DHE is sometimes effective in preventing migraine.

Side Effects: The usual side effects are nausea, a hot feeling in the head, tightness in the throat or chest, leg and muscle cramps, and a transient rise in blood pressure. Because of the nausea, which is common, an antiemetic pill or injection is given half an hour prior to the DHE. The tightness in the throat or chest rapidly stops and does not present a serious problem, for it is of muscular or GI origin. An EKG should be done if this occurs. A transient muscle tension headache may ensue following the DHE, and diarrhea is occasionally a problem.

Office Protocol for IV DHE: The office protocol is as follows: give Reglan, one-half or one 10 mg. pill, with several Tums. One-half hour later, slowly give ½ mg. IV DHE. If well tolerated, give another ½ mg., for a total of 1 cc as the first dose. I do not usually utilize a hep-lock. If the first dose is well tolerated, as it usually is, the entire 1 mg. of DHE can be given at the next treatment. Patients may take the Reglan pill at home, prior to arriving for the DHE. Reglan is not usually very sedating, so that patients can drive, which is a tremendous advantage. The patient must be alert prior to driving after the DHE. If nausea is a problem, the dose is either lowered to ½ or ¾ mg., or stronger antiemetic medications are utilized. Phenergan, 25 mg. PO or IM, may be utilized. Alternatively, Vistaril, 25 mg. PO or IM, may be effective and is less sedating that Phenergan. Compazine, 10 to 25 mg. PO or 5 mg. IM, is a very effective antiemetic. Compazine may induce severe side effects (agitation or extrapyramidal reactions). Thorazine is a very effective medication to combat nausea, but with an increased incidence of side effects. Most patients are able to tolerate DHE with the Reglan as an antiemetic.

Blood pressure and pulse must be monitored before and after the DHE is given, and it is not unusual for the blood pressure to rise slightly after the DHE.

The office protocol is usually performed twice per day for 2 or 3 days, or a total of four to six doses.

Hospital Protocol for IV DHE: In the hospital, more doses may be administered in 1 day than in the office. We attempt to give a total of nine doses of DHE. The protocol is the same as in the office, beginning with only one pill of Reglan and, if necessary, progressing to stronger antiemetic medications. The goal is to utilize doses of DHE that are subnauseating. Detoxification from analgesics is somewhat easier in the hospital than as an outpatient. If needed, IV fluids may be given in the hospital. However, the overwhelming majority of patients greatly appreciate receiving DHE as outpatients.

In the hospital, doses of DHE are given at 8 hour intervals. If nausea is extreme and the other nausea medications have proved ineffective, Thorazine, 25 to 50 mg. IM, is administered prior to the DHE. Alternatively, Reglan or Compazine may be given intravenously for severe nausea. IV DHE is extremely effective for a variety of headache types, including migraine, tension, and cluster.

Daily Opioids:
As a last resort, patients with frequent severe migraines and chronic daily headache at times respond to the administration of daily long-acting opioids. The prototype in this group is methadone; it is inexpensive, and the tablets are easy to break in half, rendering dosage adjustments very easy. However, particularly in opioid-naïve patients, methadone in overdose is more dangerous. Methadone is very unevenly distributed in the tissues, and it is easy for toxic levels to build up. Thus, it is crucial to keep the doses of methadone low. Sedation and constipation, while common with all opioids, are seen more with methadone. The usual dose is 5 or 10 mg. per day, sometimes as low as 2.5 mg., and occasionally increasing up to 30 or 40 mg. per day. In treating nonmalignant pain with opioids, it is very important to keep the doses low. There is a different set of rules in treating malignant cancer pain.

A long-acting form of morphine,is available in 20-, 50-, and 100 mg. doses. The usual dose is 20 or 50 mg. once per day. While well tolerated, morphine may not be quite as effective as methadone for chronic daily headache patients. Oxycontin, a long-acting type of oxycodone, is helpful because we see less sedation than with methadone. Oxycontin is available in 10-, 20-, and 40-mg. doses. The usual dose is 10 or 20 mg. twice per day. I generally will not increase past these levels. Ina recent study where we looked at over 300 patients treated over a 6-year period with long-acting opioids, only 13% did extremely well long-term. However, for those patients that did well, quality of life was greatly enhanced. While the opioids are effective anxiolytics, they should not be used for this purpose. Patients who tend to overuse these medications include those with severe anxiety; certain personality disorders such as histrionic, narcissistic, or borderline; and patients with a past history of opioid or alcohol abuse.

Botox Injections:
This is a promising, but still experimental, approach. Low doses (12 injections of 2 units each, or 24 units in total) of Botox are injected in the forehead and temple area. Side effects are minimal, particularly with these low doses. After the injections, headaches may improve for 2 to 4 months. Botox is expensive. Larger doses (50 units) may be necessary. The effect may diminish with the 2nd or 3rd treatments because of antibody production.

QuickReference Guide: Third Line Migraine Prevention

Phenelzine (Nardil):
This MAO inhibitor (MAOI) is a powerful migraine and daily headache preventive medication. Phenelzine may be used alone, or in combination with amitriptyline, verapamil, or propranolol. Phenelzine is very helpful for depression, anxiety, and panic attacks. The risk of a hypertensive crisis is small but is a major drawback to the MAOIs. Dietary restrictions render MAOIs difficult for the patient. Side effects include insomnia and weight gain, both of which are often major problems. Dry mouth, fatigue, constipation, and cognitive effects may also occur. Patients need to be aware of the symptoms of hypertensive reactions. The usual dose is 45 mg. each night (3 of the 15 mg. tablets). This is adjusted up or down, and the range varies from one to five tablets per day.

Repetitive IV DHE Therapy:
Helpful for patients with frequent migraine, severe daily headache, status migraine, and cluster headache. Weeks of headache improvement is often seen. IV DHE is useful in patients withdrawing from analgesics. The protocol can be done in the office or hospital. In the office, the protocol consists of metoclopramide, 5 or 10 mg. and 2 Tums, followed in ½ hour by the DHE. For the first dose, ½ mg. is given, and if it is well tolerated the subsequent doses are 1mg. Three or four doses are given in the office, and up to nine in the hospital. Side effects include nausea, heat flashes, muscle contraction headache, leg cramps, diarrhea, and GI pain. The IV DHE is usually well tolerated and effective. After the DHE, patients are continued on prevention medication. Daily IM DHE may prevent migraines.

Daily Opioids:
In patients with migraine and chronic daily headache, long-acting daily opioids are occasionally useful. Addiction, legal, or regulatory problems render these difficult to use. However, certain patients respond only to this class of medications. Long-acting opioids include methadone, long-acting forms of morphine such as MSContin, Kadian, Oxycontin (a long-acting form, oxycodone), and Duragesic (fentanyl) patches. The idea is to dose medications once or twice per day and not on a PRN basis. Sedation and constipation, along with other cognitive side effects, are common. For a small group of severe refractive headache patients, daily opioids can greatly enhance quality of life.