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Intravenous Valproate Sodium Injection For
Prolonged Migraine Headache
Lawrence Robbins, MD
Posted February 2000
 

Abstract
The object of this study was to assess efficacy and tolerability of intravenous (IV) sodium valproate injection (VPA) for the acute treatment of migraine headache. Oral divalproex sodium is widely utilized as a headache preventive. The IV form (Depacon) has appeal as an abortive because of its lack of sedation, cardiovascular effect, and addiction potential.

32 female patients with moderate to severe headache of at least 48 hours duration were treated at the Robbins Headache Clinic. These patients had a long history of refractive migraine headaches. Duration of the headache ranged from 48 to 105 hours. The patients received 500mg of IV VPA, diluted in 5ml of normal saline, over 5 minutes. Only 4 patients were valproate naive. All treatment was outpatient. Relief was assessed at 1, 3, and 24 hours post-injection. Zero to 25% improvement was categorized as no relief, 25% to 80% mild or moderate relief, and complete relief was 80% to 100% improvement.

At one hour, 8(25%) had no relief, 16(50%) mild or moderate relief, and 8(25%)complete relief. After 3 hours, 7(22%) had no relief, 16(50%) mild or moderate relief, and 9(28%) complete relief. After 24 hours, 13(40%) had no relief, 7(22%) mild or moderate relief, and 12(37%) complete relief.

Valproate sodium injection was generally well tolerated. The following side effects were described: Unusual taste sensation (4 pts), somnolence (2), burning at injection site (2), nausea (1), increased headache (1), dizziness (1). Side effects were ransient, except for one patient with somnolence for 8 hours.

For the treatment of prolonged moderate or severe headache, IV VPA is a useful option. This group of patients is often refractive to multiple medications. Valproate is not addicting, and is without significant cardiovascular or respiratory effects. This therapy may also be used in conjunction with other migraine abortives such as triptans, dihydroergotamine, analgesics, or cortisone. 

Descriptors: Valproate, migraine, Depacon, Divalproex

Introduction
Oral divalproex sodium (VPA) is utilized widely as a preventive for migraine and for chronic daily headache^1,2. Divalproex sodium has proven to be a safe and effective medication. The intravenous (IV) form of VPA has appeal as an abortive medication because of its’ relative lack of sedation and cardiorespiratory effects. VPA does not produce euphoria, and is not addicting.

Many patients suffer prolonged, moderate or severe migraines. These long headaches, which sometimes are menstrually related, often prove difficult to treat. Medication approaches include triptans, dihydroergotamine (DHE), corticosteroids, and analgesics³. Intravenous VPA offers another weapon against these prolonged migraines.

Methodology
Thirty-two female patients, ages 24-58, with moderate to severe migraine of at least 48-hours duration, were treated as outpatients at the Robbins Headache Clinic. These patients had a long history of prolonged, refractory migraine headaches. In the past, their headaches had lasted days to weeks. Duration of the headaches treated in this study ranged from 48 to 105 hours prior to the IV VPA treatment.

Each patient received 500mg of IV VPA, diluted in 5ml of normal saline injected slowly over a five-minute period. Only four patients were valproate naïve.

Relief was assessed at one, three, and twenty-four hours post-injection. The post-treatment assessments were accomplished via phone interview. Relief was categorized according to the following scale: 0-25% = no relief, 25-80% = mild/moderate relief, and 80-100% = complete relief.

Results

Discussion
Prolonged, severe headache often proves difficult to treat. In the current study, IV VPA produced complete relief in 25% of patients after one hour, 28% at three hours, and 37% of the patients had complete relief after twenty-four hours. Many patients with prolonged migraine will improve for a number of hours with any particular therapy, and then relapse. In this study, IV VPA appears to have a lasting effect for at least twenty-four hours in certain patients.

A minority of migraine patients suffers chronically from severe, prolonged, refractory headache. The pain may last days to weeks, and often is associated with menstrual cycling. Triptans (sumatriptan, naratriptan, rizatriptan, zolmitriptan) often help, but the headache may recur. Corticosteroids may stop the headache, but it is necessary to limit the dose due to side effects. Repetitive IV DHE^3,4,5 does help a number of patients, as does intramuscular (IM) ketorolac. Some analgesics produce sedation, and some are potentially addicting. Intravenous VPA is well tolerated, and may be used alone or as an adjunct with other medication approaches. Because VPA does not affect cardiorespiratory function, it is compatible with triptans and DHE. The relative lack of sedation allows many patients to receive VPA and function effectively for the remainder of the day.

Oral divalproex sodium is a widely utilized, effective preventive medication for migraine⁶. However, as a migraine abortive, the oral form has been used with very limited success. The IV VPA achieves effective blood levels more rapidly than the oral form⁷. Several previous studies indicated that IV VPA may be useful for the acute treatment of migraine. In one study of twenty-four patients, eighteen of whom were valproate naïve, 300mg of IV valproate sodium was given in 100ml of normal saline⁸. Significant headache relief occurred in 88% of those patients. Onset of pain relief occurred in less than ten minutes in those who responded. Ten of the twenty-four patients reported complete relief within ten to twenty minutes. The authors state that rapid infusion of IV VPA yielded better results.

A second study with twenty patients was accomplished giving either 500mg of IV VPA over fifteen to thirty minutes, or DHE IM, with metoclopramide⁹. In the IV VPA group, headache relief after one hour was 60%, versus 40% in the DHE plus metoclopramide group. After four hours, IV VPA produced headache relief in 70% of patients versus 60% in the DHE group.

Intravenous valproate sodium should result in comparable C_max and C_min when compared to the oral formulation. The T_max of IV VPA occurs at the end of infusion, compared to about four hours after oral administration. The oral and intravenous forms are roughly bioequivalent⁷. The liver metabolizes valproate, and monitoring of the drug level and liver function tests is done on maintenance oral valproate therapy. It also is prudent to monitor platelets. However, with single dose IV administration, this should not be necessary. Valproate generally should not be given in any form to patients with compromised liver function. Valproate should not be given during pregnancy. Women of child-bearing age should be screened for pregnancy before use of the drug, and cautioned about the teratogenic potential of the drug if pregnancy should occur during maintenance therapy.

Intravenous valproate sodium was well tolerated in the current study. Previous studies, n=463, recorded the following more common adverse reactions: dizziness (5.2%), headache (4.3%), injection-site reactions (2.4%), injection-site pain (2.6%), taste perversion (1.9%), and somnolence (1.7%) ⁷. Intravenous valproate sodium may be effective for certain patients in the acute treatment of prolonged, severe migraine headache. Double blind studies, with controls, are necessary to assess this therapy more fully.

This study was supported by a grant from Abbott Laboratories.

Acknowledgements: The author wishes to thank Charles Ludmer, MD, and Halleh Akbarnia, MD, for their editorial help.

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