According to the American Headache Society guideline on the management of adults with acute migraine in the emergency department (ED) and based on four randomized controlled trials (RCTs), intravenous (IV) valproic acid 500-1,000 mg may deem to be an effective dose with minimal adverse events. However, it is not to be used as first-line therapy as other treatments have been shown to be more effective. [1]
A systematic review from the American Headache Society suggests that intravenous valproic acid has been shown to be effective as an acute treatment therapy for pediatric migraines. This recommendation is based on a retrospective review and a case series. The retrospective review included 31 children (mean age of 15 ± 2 years) who received 1,000 mg of IV valproic acid, with 6 (19%) requiring an extra 500 mg bolus of valproic acid. Pediatric patients who received one dose achieved a 40% reduction in pain, with a time to maximum relief of 63 ± 31 minutes. A limitation was that the patients had already received multiple medications including concomitant dexamethasone and ondansetron in prior that could have influenced the pain responses. A case series studied 12 pediatric patients (19 years, mean age 15) with migraine who received a single dose of either 500 mg or 1000 mg IV valproic acid in the emergency department. Mean pain reduction prior to valproic acid was 17%. Valproic acid administration led to another 36% ± 34.2% reduction in pain. Ten (83%) patients were discharged home after administration. As with the retrospective review, the case series was not able to completely separate other medication effects from the valproic acid. [2]
A 2008 review identified seven publications on the use of IV valproic acid for acute migraines. Available studies are small, mostly open-label, and not placebo-controlled. The doses used also vary. Two of the 3 comparative trials failed to show a significant difference between intravenous valproic acid and the comparator antimigraine treatments, and 1 trial showed the superiority of prochlorperazine over intravenous valproic acid. Valproic acid has not been shown to be superior to other drugs, but future trials are needed to produce high-quality data and a standardized dose. [3]
A 2020 meta-analysis included 7 RCTs encompassing 682 patients to evaluate the efficacy and safety of intravenous sodium valproate (iVPA) in patients with acute migraine in the emergency department. The dose of administered iVPA ranged from 1,000 mg to 400 mg diluted in normal saline (NS), with an administration rate ranging from 2 to 20 minutes. Overall, iVPA shown to be noninferior to the comparators (metoclopramide, ketorolac, prochlorperazine, and lysine-acetylsalicylic acid); however, iVPA recipients experienced less improvement of headache intensity (standardized mean differences [SMD] -0.39, 95% confidence interval [CI] -0.73 to -0.06, p= 0.02) and lower rate of headache relief (odds ratio [OR] 0.51; 95% CI 0.33 to 0.77; p= 0.002) than those who received comparator treatments. Moreover, the odds of rescue therapy associated with iVPA increased compared to other active comparators (OR 3.76; 95% CI 1.96 to 7.20; p<0.0001). Subgroup analysis revealed similar outcomes associated with iVPA compared to dexamethasone, with similar improvement of headache intensity and recurrence. Despite the heterogeneity across the included studies, the analysis suggests iVPA as a promising agent for acute migraine; however, the results have to be interpreted and applied with caution. [4]
A 2022 randomized clinical trial investigated the efficacy of intravenous ibuprofen versus sodium valproate for acute migraine attacks in an emergency department setting. This double-blinded, prospective study randomized patients aged 18 to 65 who presented with acute migraine, defined as migraine without aura according to the International Classification of Headache Disorders. The study involved two treatment groups where patients received either 800 mg of sodium valproate or 800 mg of ibuprofen. Each medication was administered through intravenous infusion in 150 mL of normal saline over a five-minute period. Pain levels were measured using the Numerical Rating Scale (NRS) over a two-hour period, and the primary endpoint was set as achieving a significant reduction in pain, specifically a decrease of ≥50% in the NRS score from baseline. The results from the investigation indicated a statistically significant greater mean decrease in NRS scores in the sodium valproate group compared to the ibuprofen group. The sodium valproate cohort experienced a mean NRS reduction difference of 1.69 points at 30 minutes and 3.61 points at 60 minutes, notably surpassing the ibuprofen group's outcomes. Furthermore, the number of patients achieving the primary pain relief endpoint was markedly higher with sodium valproate (p<0.001). Although the frequency of recurring migraine attacks and the need for rescue analgesics post-discharge did not differ significantly between groups, adverse events were minimal across both treatments. This trial underscores the superior analgesic potential of sodium valproate over ibuprofen in the clinical management of acute migraines in emergency settings. [5]
A 2005 retrospective chart review conducted over an 18-month period sought to describe the efficacy and tolerability of rapid intravenous VPA administration in a pediatric population experiencing severe migraine headaches. To evaluate these parameters, data from medical records were analyzed, focusing on children who received VPA for acute migraine relief. This included examining baseline headache intensity using a 10-point numerical pain scale, the duration until maximum relief was attained, the extent of pain reduction following VPA administration, as well as monitoring changes in vital signs such as heart rate, blood pressure, respiratory rate, and pulse oximetry. Adverse events potentially attributed to VPA infusions were also meticulously documented. Most children received a fixed VPA regimen consisting of 1,000 mg (first dose) infused at 50 mg/min. If pain reduction was not sufficient, a second VPA dose of 500 mg was provided. All VPA infusions were prepared by diluting with normal saline to a final volume of 60 mL. [6]
Results from this chart review encompassed 31 children, predominantly female (81%), with a mean age of 15 years, who underwent 58 clinic visits and received 71 VPA infusions. A significant proportion of these visits concluded with a single VPA dose, where an average dose of 976 mg was infused over approximately 12 minutes, resulting in a 39.8% reduction in pain. For cases requiring a second VPA dose, a reduction of 57% from baseline pain intensity was recorded, with the second dose delivered at 500 mg. Despite adverse events such as cold sensation, dizziness, nausea, a possible absence seizure, paraesthesia, and tachycardia occurring in a few instances, VPA infusions were generally well tolerated. Notably, the study observed no significant changes in vital signs, indicating the safety of rapid VPA infusions in this demographic. Further research, preferably prospective and controlled trials, is suggested to refine the understanding and clinical application of VPA in treating pediatric migraine. [6]