Use of Intravenous Valproate Sodium in Status Migraine

Authors


Address all correspondence to Dr. John Norton, Director of Medical Psychiatry, University of Mississippi College of Medicine, 2500 North State Street, Jackson, MS 39216.

Abstract

Patients with migraines have typically been given one group of medications for abortive treatment and another for preventative. In the acute situation when the patient has severe nausea it is difficult to administer medications. Intravenous medications would avoid this problem but are limited to the opiates and dihydroergotamine. The following cases demonstrate the acute treatment of migraine with intravenous valproic acid (Depacon). The oral form of valproic acid has been used as a prophylactic agent, but the intravenous form may provide an alternative for abortive care as well. The ease of administration and lack of side effects are also important considerations. Double-blind studies will help clarify the situation.

As every clinician who works with patients with migraine is aware, they often do not obey the classic rules that are laid out by those who specialize in headache. Clinicians divide the medication management of migraine into those agents used for abortive and those used for prophylactic treatment. 1 This system is helpful and tends to work quite nicely. Many regimens have been developed, including dihydroergotamine, opiates, chlorpromazine, ergots, and benzodiazepines, to treat status migraine. 2 Each has its advocates, but there is still a need for agents that can be given rapidly and to patients who often are nauseated and cannot tolerate oral mediations. The following two cases involve the use of intravenous valproate sodium (Depacon) in patients with status migraine. While valproate is typically thought of as a prophylactic agent, the rapid infusion of this agent may have a place as an abortive migraine agent as well. This may be helpful in avoiding the more extensive use of opiates and other analgesics that can often lead to a cycle of addiction and have their own toxicity. It is hoped that these cases may serve as a catalyst for a double-blind, controlled study to clarify the issue.

CASE HISTORIES

Patient 1

A 34-year-old woman with a history of migraines with aura since her teenage years reports they occur once or twice per month and last between 1 and 3 days. She also has muscle contraction headaches between one and three times per month, often starting 1 to 2 days prior to a migraine. She has been treated with carbamazepine, 200 mg, twice a day and during a headache uses sumatriptan in either oral or subcutaneous forms depending on the severity of the headache. She also uses prochlorperazine as needed for control of nausea. She was diagnosed with unipolar depression for which she takes paroxetine, 40 mg per day.

The patient presented to the emergency department after having a migraine that persisted and actually worsened over the previous 3 days. The nature of the headache was typical for the patient, but the duration was protracted and persistent vomiting caused her to become dehydrated. She tried ergotamine/caffeine, sumatriptan, and prochlorperazine over the previous several days with no success. The patient's physical and neurological examination, complete blood count, electrolytes, and erythrocyte sedimentation rate were all within normal limits. Her blood urea nitrogen was 31 mg/dL, and her creatinine was 1.1 mg/dL, consistent with a prerenal azotemia. This was felt to be due to dehydration from ongoing vomiting. A noncontrast head computed tomography (CT) scan was within normal limits.

The patient was admitted and started on 5% dextrose normal saline at 100 mL per hour, and she was given a standard trial of dihydroergotamine but had no relief over the first 4 hours of hospitalization. The patient then received adjunctive merperidine and prochlorperazine with no improvement in her symptoms. The decision was made to initiate intravenous valproate sodium 1 g in 250 mL of normal saline given over 1 hour. This same dose was repeated 2 hours later. Within 1 hour after the second dose, the patient stated that her headache was distinctly improved and within another 2 hours had resolved, allowing her to sleep for the first time in 3 days. A valproic acid trough level the next day was 82 μg/mL. The patient was switched to 1 g of oral divalproic acid twice a day and was discharged on hospital day 2.

Patient 2

The second patient is a 28-year-old woman with a 5-year history of migraine with aura. Her headaches would occur two to four times per month. On average, they would last 1 day, and she would take the combination of isometheptene mucate, dichloralphenazone, and acetaminophen (Midrin) and usually experience relief. She was not on a prophylactic agent. She had no other medical problems, was on no standing medication, and had a completely normal physical and neurological examination. She presented to the emergency department after having a severe migraine that had lasted 2 days and was accompanied by nausea and vomiting. The patient had tried Midrin and sumatriptan at home without success.

Due to the change in the nature of her headache, a head CT without contrast and a lumbar puncture were performed. Both were within normal limits. Routine laboratory tests, including a complete blood count, electrolytes, serum pregnancy test, blood urea nitrogen, creatinine, and urinalysis were unremarkable. The patient was given merperidine in the emergency department with no improvement in her symptoms and was given several doses of prochlorperazine to control vomiting. Due to continued vomiting and no improvement in her headache, the patient was admitted to the hospital and given 1 g of valproate sodium intravenously in 250 mL of normal saline over 1 hour. This was followed by the same dose 4 hours later. Within 2 hours, the patient reported a marked lessening in her symptoms. She was able to sleep and awoke the next morning headache-free. Her trough valproic acid level was 68 μg/mL. On the second hospital day, the patient was switched to 1 g of divalproic acid twice a day by mouth.

COMMENTS

Valproic acid is increasingly used for the prophylactic treatment of migraine. It has not typically been used as an abortive agent, especially since the oral form may not be well absorbed in a patient with significant nausea and vomiting often with concurrent gastroparesis. The above cases demonstrate the use of the intravenous form of valproate sodium (Depacon) as an abortive agent. Oral divalproic acid was then continued as a prophylactic agent. Depacon has been used more frequently in patients who have epilepsy to achieve rapid titration of medication or who cannot take their medication orally. Depacon has the same indications as oral valproic acid and is approved for migraine prophylaxis, generalized and partial seizures, and bipolar illness. 3,4

The half-life of Depacon is 9 to 16 hours, and it has essentially 100% bioavailability. More than 2000 doses have been given to more than 300 patients with epilepsy, and Depacon produced no significant adverse effects. Depacon does not require telemetry because it does not adversely affect blood pressure, cardiac, or respiratory functions. It is recommended that Depacon not be given at a rate of more than 20 mg per minute, although up to 200 mg per minute have been given with no adverse side effects. There may be less nausea with the intravenous than the oral form of the medication. There is no difference in the conversion between the oral and intravenous forms of valproic acid. Therapeutic serum levels are achieved almost immediately, which is what makes it of value in epilepsy. 5,6

The side effects of Depacon are similar to the oral forms of valproic acid. Alopecia may be experienced in up to a quarter of patients, but it can be minimized if vitamins with zinc and selenium are taken concurrently. Weight gain is common and at times can be significant. This should be addressed at the outset and the patient given dietary counsel, put on an exercise program, and when needed, supplemented with topiramate, which has anorexic effects. Patients may develop sedation and ataxia, but this is usually at higher blood levels. Less common side effects include hyponatremia, pancreatitis, rash, thrombocytopenia, and polycystic ovary disease. 7-8

The exact mechanism of why Depacon was effective as an abortive agent in these patients is not clear. The rapid development of therapeutic levels may have had a role. With the morbidity involved with acute intractable migraine and the potential for dependence on opiate medications, it is essential to have as many tools as possible to quickly and effectively treat this condition. Depacon seems well suited to this role, given its route of administration, safety, and usually benign side effect profile. Further case reports and double-blind studies are required to evaluate Depacon's role in acute migraine treatment.

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