Dopamine Antagonists Treat Migraine Effectively

STOWE, VT—Dopamine antagonists can be a beneficial adjunctive treatment for migraine, according to an overview provided at the 26th Annual Stowe Headache Symposium of the Headache Cooperative of New England. “We should consider dopamine antagonists as first-line IV treatments and second-line oral treatments for both acute treatment and prevention of headache,” said Lauren Natbony, MD. Among oral dopamine antagonists, olanzapine appears to be supported by the most compelling evidence, she added. Migraine treatment is an off-label use for most of these medications.

Lauren Natbony, MD

Dopamine modulates processes involved in migraine such as nociception, autonomic response, and vasoregulation. Dopamine also contributes to many of the symptoms of migraine, including nausea, vomiting, mood changes, and fatigue. Dopamine antagonists are appropriate for patients who have not responded to triptans and for patients who cannot use triptans, said Dr. Natbony, a headache fellow at the Icahn School of Medicine at Mount Sinai in New York. “For episodes of status migrainosus, these medications can be used continuously over a number of days. For prevention, we could consider these agents in patients who fail multiple medications.”

The three classes of dopamine antagonists used to treat headache are typical antipsychotics, atypical antipsychotics, and prokinetic agents. The typical antipsychotics tend to produce more sedation, have more anticholinergic effect, and entail a higher risk of extrapyramidal symptoms such as acute dystonia, compared with atypical antipsychotics. Because of concerns about side effects, the recommendation is to use typical antipsychotics for no more than 10 days per month. Atypical antipsychotics, on the other hand, are suitable for long-term treatment, said Dr. Natbony.

Typical Antipsychotics

Four studies have indicated that prochlorperazine is more effective for pain reduction than placebo, regardless of the route of administration. The drug also has proven more effective than ketorolac, magnesium, valproate, and sumatriptan. Data suggest that buccal prochlorperazine is more effective than oral ergotamine, but this formulation is not available in the United States. The best alternatives are oral prochlorperazine (5 mg to 10 mg) and rectal prochlorperazine (25 mg), said Dr. Natbony. “The dose can be used once for acute relief or can be repeated every six to eight hours for multiple days to abort status migrainosus.”

Data suggest that chlorpromazine effectively relieves migraine and associated symptoms, and prevents migraine recurrence more effectively than IV lidocaine or dihydroergotamine. “For acute migraine attacks, 25 mg orally can be used every six hours, for a total daily dose of 100 mg,” said Dr. Natbony. Neurologists can consider chlorpromazine for patients with cluster headache who are refractory to other treatments, but the study of the drug in this population had a small sample size and included a wide range of doses.

Researchers have studied promethazine as an adjunctive treatment, but not as a single agent. Intramuscular promethazine provides a similar level of pain relief whether given with meperidine or ketorolac. Oral promethazine plus sumatriptan provides a significant benefit, compared with sumatriptan alone. “Therefore, I would consider it an add-on medication to a triptan,” said Dr. Natbony. Promethazine is not administered IV or subcutaneously because of the risk of severe tissue injury such as gangrene.

Two studies indicate that droperidol is highly effective for intractable migraine. No oral formulation is available, but droperidol can be administered either IV or intramuscularly. For outpatient purposes, an intramuscular dose of 2.75 mg is effective and yields few side effects. Droperidol entails a risk of QT prolongation, however, and may be inappropriate for patients with cardiac disease.

In a study of 40 patients with migraine, 5 mg of IV haloperidol provided significantrelief, compared with placebo. Based on these data, Dr. Natbony and colleagues use 2 mg to 5 mg of oral haloperidol as an outpatient treatment to abort headache. No studies have examined oral haloperidol specifically, however.

Prokinetic Agents

Prokinetic agents can be used during a migraine prodrome to prevent an attack. Data suggest that IV metoclopramide is superior to placebo, but that intramuscular and rectal formulations are not. As a single agent, metoclopramide is inferior to prochlorperazine. Oral metoclopramide, when administered with an analgesic, is less effective than a triptan, “therefore it should only be considered in those who can’t use triptans,” said Dr. Natbony. A 10-mg tid oral dose is beneficial for prophylactic and abortive therapy. Metoclopramide is pregnancy category B and can be considered for pregnant and lactating women. The drug may stimulate gastrointestinal motility, and using it in combination with another agent (eg, a triptan) may improve absorption of that agent.

Domperidone, another prokinetic agent, effectively prevents migraine if taken in a 30-mg dose during the prodromal phase. Research also indicates that the oral formulation shortens the duration of a migraine attack without provoking adverse events. Domperidone is not available in the US, however, thus in this class of drugs, metoclopramide is the abortive treatment of choice, said Dr. Natbony.

Atypical Antipsychotics

Atypical antipsychotics are effective in migraine prophylaxis and generally are less sedating and less likely to produce movement disorders. Olanzapine has the best evidence in migraine among the atypical antipsychotics. The drug decreased the number of headache days and pain intensity in a study of chronic migraineurs who were refractory to more than four preventive agents. The study was retrospective and unblinded and had no placebo control, however. In practice, 5-mg to 10-mg doses are used at bedtime as a preventive treatment. A second study supported olanzapine’s efficacy as an abortive agent in daily doses of 2.5 mg to 5 mg. Neurologists may repeat dosing as needed to a daily maximum of 20 mg. “We have used 2.5 mg to 5 mg nightly for five to 10 nights to help break status migrainosus,” said Dr. Natbony.

Compared with olanzapine, quetiapine is less potent and entails a lower risk of movement disorders. In two studies of migraineurs who had failed standard preventive agents, quetiapine reduced headache frequency and severity, as well as the use of rescue medications. Doses administered in the study ranged from 25 mg to 75 mg daily.

The literature contains only case studies of aripiprazole in migrain­eurs. Three patients who received aripiprazole for psychiatric conditions reported spontaneous relief of migraine. One patient with medication overuse headache was treated successfully with aripiprazole. Doses range from 10 mg to 20 mg daily.

Like aripiprazole, ziprasidone has not been studied in randomized controlled trials. One case report described three patients with chronic daily headache who had improvements in headache frequency and severity with ziprasidone. For migraine prevention, neurologists can start with a dose of 20 mg bid and increase it to 80 mg bid, said Dr. Natbony. For acute treatment, doses range from 40 mg to 80 mg, with a maximum of 160 mg daily.

Comparative Efficacy

“The most beneficial oral medication appears to be olanzapine, followed by chlorpromazine” for acute treatment, said Dr. Natbony. IV prochlorperazine is also more effective than IV metoclopramide for acute treatment, “though metoclopramide should be considered as first-line treatment for prevention of a migraine attack and given during a prodrome,” she concluded.

—Erik Greb

STOWE, VT—Dopamine antagonists can be a beneficial adjunctive treatment for migraine, according to an overview provided at the 26th Annual Stowe Headache Symposium of the Headache Cooperative of New England. “We should consider dopamine antagonists as first-line IV treatments and second-line oral treatments for both acute treatment and prevention of headache,” said Lauren Natbony, MD. Among oral dopamine antagonists, olanzapine appears to be supported by the most compelling evidence, she added. Migraine treatment is an off-label use for most of these medications.

Lauren Natbony, MD

Dopamine modulates processes involved in migraine such as nociception, autonomic response, and vasoregulation. Dopamine also contributes to many of the symptoms of migraine, including nausea, vomiting, mood changes, and fatigue. Dopamine antagonists are appropriate for patients who have not responded to triptans and for patients who cannot use triptans, said Dr. Natbony, a headache fellow at the Icahn School of Medicine at Mount Sinai in New York. “For episodes of status migrainosus, these medications can be used continuously over a number of days. For prevention, we could consider these agents in patients who fail multiple medications.”

The three classes of dopamine antagonists used to treat headache are typical antipsychotics, atypical antipsychotics, and prokinetic agents. The typical antipsychotics tend to produce more sedation, have more anticholinergic effect, and entail a higher risk of extrapyramidal symptoms such as acute dystonia, compared with atypical antipsychotics. Because of concerns about side effects, the recommendation is to use typical antipsychotics for no more than 10 days per month. Atypical antipsychotics, on the other hand, are suitable for long-term treatment, said Dr. Natbony.

Typical Antipsychotics

Four studies have indicated that prochlorperazine is more effective for pain reduction than placebo, regardless of the route of administration. The drug also has proven more effective than ketorolac, magnesium, valproate, and sumatriptan. Data suggest that buccal prochlorperazine is more effective than oral ergotamine, but this formulation is not available in the United States. The best alternatives are oral prochlorperazine (5 mg to 10 mg) and rectal prochlorperazine (25 mg), said Dr. Natbony. “The dose can be used once for acute relief or can be repeated every six to eight hours for multiple days to abort status migrainosus.”

Data suggest that chlorpromazine effectively relieves migraine and associated symptoms, and prevents migraine recurrence more effectively than IV lidocaine or dihydroergotamine. “For acute migraine attacks, 25 mg orally can be used every six hours, for a total daily dose of 100 mg,” said Dr. Natbony. Neurologists can consider chlorpromazine for patients with cluster headache who are refractory to other treatments, but the study of the drug in this population had a small sample size and included a wide range of doses.

Researchers have studied promethazine as an adjunctive treatment, but not as a single agent. Intramuscular promethazine provides a similar level of pain relief whether given with meperidine or ketorolac. Oral promethazine plus sumatriptan provides a significant benefit, compared with sumatriptan alone. “Therefore, I would consider it an add-on medication to a triptan,” said Dr. Natbony. Promethazine is not administered IV or subcutaneously because of the risk of severe tissue injury such as gangrene.

Two studies indicate that droperidol is highly effective for intractable migraine. No oral formulation is available, but droperidol can be administered either IV or intramuscularly. For outpatient purposes, an intramuscular dose of 2.75 mg is effective and yields few side effects. Droperidol entails a risk of QT prolongation, however, and may be inappropriate for patients with cardiac disease.

In a study of 40 patients with migraine, 5 mg of IV haloperidol provided significantrelief, compared with placebo. Based on these data, Dr. Natbony and colleagues use 2 mg to 5 mg of oral haloperidol as an outpatient treatment to abort headache. No studies have examined oral haloperidol specifically, however.

Prokinetic Agents

Prokinetic agents can be used during a migraine prodrome to prevent an attack. Data suggest that IV metoclopramide is superior to placebo, but that intramuscular and rectal formulations are not. As a single agent, metoclopramide is inferior to prochlorperazine. Oral metoclopramide, when administered with an analgesic, is less effective than a triptan, “therefore it should only be considered in those who can’t use triptans,” said Dr. Natbony. A 10-mg tid oral dose is beneficial for prophylactic and abortive therapy. Metoclopramide is pregnancy category B and can be considered for pregnant and lactating women. The drug may stimulate gastrointestinal motility, and using it in combination with another agent (eg, a triptan) may improve absorption of that agent.

Domperidone, another prokinetic agent, effectively prevents migraine if taken in a 30-mg dose during the prodromal phase. Research also indicates that the oral formulation shortens the duration of a migraine attack without provoking adverse events. Domperidone is not available in the US, however, thus in this class of drugs, metoclopramide is the abortive treatment of choice, said Dr. Natbony.

Atypical Antipsychotics

Atypical antipsychotics are effective in migraine prophylaxis and generally are less sedating and less likely to produce movement disorders. Olanzapine has the best evidence in migraine among the atypical antipsychotics. The drug decreased the number of headache days and pain intensity in a study of chronic migraineurs who were refractory to more than four preventive agents. The study was retrospective and unblinded and had no placebo control, however. In practice, 5-mg to 10-mg doses are used at bedtime as a preventive treatment. A second study supported olanzapine’s efficacy as an abortive agent in daily doses of 2.5 mg to 5 mg. Neurologists may repeat dosing as needed to a daily maximum of 20 mg. “We have used 2.5 mg to 5 mg nightly for five to 10 nights to help break status migrainosus,” said Dr. Natbony.

Compared with olanzapine, quetiapine is less potent and entails a lower risk of movement disorders. In two studies of migraineurs who had failed standard preventive agents, quetiapine reduced headache frequency and severity, as well as the use of rescue medications. Doses administered in the study ranged from 25 mg to 75 mg daily.

The literature contains only case studies of aripiprazole in migrain­eurs. Three patients who received aripiprazole for psychiatric conditions reported spontaneous relief of migraine. One patient with medication overuse headache was treated successfully with aripiprazole. Doses range from 10 mg to 20 mg daily.

Like aripiprazole, ziprasidone has not been studied in randomized controlled trials. One case report described three patients with chronic daily headache who had improvements in headache frequency and severity with ziprasidone. For migraine prevention, neurologists can start with a dose of 20 mg bid and increase it to 80 mg bid, said Dr. Natbony. For acute treatment, doses range from 40 mg to 80 mg, with a maximum of 160 mg daily.

Comparative Efficacy

“The most beneficial oral medication appears to be olanzapine, followed by chlorpromazine” for acute treatment, said Dr. Natbony. IV prochlorperazine is also more effective than IV metoclopramide for acute treatment, “though metoclopramide should be considered as first-line treatment for prevention of a migraine attack and given during a prodrome,” she concluded.

—Erik Greb

STOWE, VT—Dopamine antagonists can be a beneficial adjunctive treatment for migraine, according to an overview provided at the 26th Annual Stowe Headache Symposium of the Headache Cooperative of New England. “We should consider dopamine antagonists as first-line IV treatments and second-line oral treatments for both acute treatment and prevention of headache,” said Lauren Natbony, MD. Among oral dopamine antagonists, olanzapine appears to be supported by the most compelling evidence, she added. Migraine treatment is an off-label use for most of these medications.

Lauren Natbony, MD

Dopamine modulates processes involved in migraine such as nociception, autonomic response, and vasoregulation. Dopamine also contributes to many of the symptoms of migraine, including nausea, vomiting, mood changes, and fatigue. Dopamine antagonists are appropriate for patients who have not responded to triptans and for patients who cannot use triptans, said Dr. Natbony, a headache fellow at the Icahn School of Medicine at Mount Sinai in New York. “For episodes of status migrainosus, these medications can be used continuously over a number of days. For prevention, we could consider these agents in patients who fail multiple medications.”

The three classes of dopamine antagonists used to treat headache are typical antipsychotics, atypical antipsychotics, and prokinetic agents. The typical antipsychotics tend to produce more sedation, have more anticholinergic effect, and entail a higher risk of extrapyramidal symptoms such as acute dystonia, compared with atypical antipsychotics. Because of concerns about side effects, the recommendation is to use typical antipsychotics for no more than 10 days per month. Atypical antipsychotics, on the other hand, are suitable for long-term treatment, said Dr. Natbony.

Typical Antipsychotics

Four studies have indicated that prochlorperazine is more effective for pain reduction than placebo, regardless of the route of administration. The drug also has proven more effective than ketorolac, magnesium, valproate, and sumatriptan. Data suggest that buccal prochlorperazine is more effective than oral ergotamine, but this formulation is not available in the United States. The best alternatives are oral prochlorperazine (5 mg to 10 mg) and rectal prochlorperazine (25 mg), said Dr. Natbony. “The dose can be used once for acute relief or can be repeated every six to eight hours for multiple days to abort status migrainosus.”

Data suggest that chlorpromazine effectively relieves migraine and associated symptoms, and prevents migraine recurrence more effectively than IV lidocaine or dihydroergotamine. “For acute migraine attacks, 25 mg orally can be used every six hours, for a total daily dose of 100 mg,” said Dr. Natbony. Neurologists can consider chlorpromazine for patients with cluster headache who are refractory to other treatments, but the study of the drug in this population had a small sample size and included a wide range of doses.

Researchers have studied promethazine as an adjunctive treatment, but not as a single agent. Intramuscular promethazine provides a similar level of pain relief whether given with meperidine or ketorolac. Oral promethazine plus sumatriptan provides a significant benefit, compared with sumatriptan alone. “Therefore, I would consider it an add-on medication to a triptan,” said Dr. Natbony. Promethazine is not administered IV or subcutaneously because of the risk of severe tissue injury such as gangrene.

Two studies indicate that droperidol is highly effective for intractable migraine. No oral formulation is available, but droperidol can be administered either IV or intramuscularly. For outpatient purposes, an intramuscular dose of 2.75 mg is effective and yields few side effects. Droperidol entails a risk of QT prolongation, however, and may be inappropriate for patients with cardiac disease.

In a study of 40 patients with migraine, 5 mg of IV haloperidol provided significantrelief, compared with placebo. Based on these data, Dr. Natbony and colleagues use 2 mg to 5 mg of oral haloperidol as an outpatient treatment to abort headache. No studies have examined oral haloperidol specifically, however.

Prokinetic Agents

Prokinetic agents can be used during a migraine prodrome to prevent an attack. Data suggest that IV metoclopramide is superior to placebo, but that intramuscular and rectal formulations are not. As a single agent, metoclopramide is inferior to prochlorperazine. Oral metoclopramide, when administered with an analgesic, is less effective than a triptan, “therefore it should only be considered in those who can’t use triptans,” said Dr. Natbony. A 10-mg tid oral dose is beneficial for prophylactic and abortive therapy. Metoclopramide is pregnancy category B and can be considered for pregnant and lactating women. The drug may stimulate gastrointestinal motility, and using it in combination with another agent (eg, a triptan) may improve absorption of that agent.

Domperidone, another prokinetic agent, effectively prevents migraine if taken in a 30-mg dose during the prodromal phase. Research also indicates that the oral formulation shortens the duration of a migraine attack without provoking adverse events. Domperidone is not available in the US, however, thus in this class of drugs, metoclopramide is the abortive treatment of choice, said Dr. Natbony.

Atypical Antipsychotics

Atypical antipsychotics are effective in migraine prophylaxis and generally are less sedating and less likely to produce movement disorders. Olanzapine has the best evidence in migraine among the atypical antipsychotics. The drug decreased the number of headache days and pain intensity in a study of chronic migraineurs who were refractory to more than four preventive agents. The study was retrospective and unblinded and had no placebo control, however. In practice, 5-mg to 10-mg doses are used at bedtime as a preventive treatment. A second study supported olanzapine’s efficacy as an abortive agent in daily doses of 2.5 mg to 5 mg. Neurologists may repeat dosing as needed to a daily maximum of 20 mg. “We have used 2.5 mg to 5 mg nightly for five to 10 nights to help break status migrainosus,” said Dr. Natbony.

Compared with olanzapine, quetiapine is less potent and entails a lower risk of movement disorders. In two studies of migraineurs who had failed standard preventive agents, quetiapine reduced headache frequency and severity, as well as the use of rescue medications. Doses administered in the study ranged from 25 mg to 75 mg daily.

The literature contains only case studies of aripiprazole in migrain­eurs. Three patients who received aripiprazole for psychiatric conditions reported spontaneous relief of migraine. One patient with medication overuse headache was treated successfully with aripiprazole. Doses range from 10 mg to 20 mg daily.

Like aripiprazole, ziprasidone has not been studied in randomized controlled trials. One case report described three patients with chronic daily headache who had improvements in headache frequency and severity with ziprasidone. For migraine prevention, neurologists can start with a dose of 20 mg bid and increase it to 80 mg bid, said Dr. Natbony. For acute treatment, doses range from 40 mg to 80 mg, with a maximum of 160 mg daily.

Comparative Efficacy

“The most beneficial oral medication appears to be olanzapine, followed by chlorpromazine” for acute treatment, said Dr. Natbony. IV prochlorperazine is also more effective than IV metoclopramide for acute treatment, “though metoclopramide should be considered as first-line treatment for prevention of a migraine attack and given during a prodrome,” she concluded.

—Erik Greb