Headache Division, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Headache. 2020 Mar;60(3):617-620. doi: 10.1111/head.13756. Epub 2020 Jan 27.
This is a small pilot study to evaluate the effectiveness of an intravenous (IV) valproate sodium therapy protocol for migraine prevention in a population of patients with chronic migraine refractory to multiple preventive medications.
Valproate sodium is an anti-epileptic and mood stabilizer that has been shown to prevent migraine when used daily in oral form. The specific mechanism of action in migraine is unknown, but it may be related to suppressing inflammation and increasing brain Gamma-aminobutyric acid levels. It also may relate to its ability to suppress cortical spreading depression. Multiple studies have suggested that valproic acid and its derivatives may inhibit Calcitonin gene-related peptide. In the present work, we undertook a small pilot study to evaluate the effectiveness of an IV valproate sodium therapy for migraine prevention in a population of patients with chronic migraine refractory to multiple preventive medications.
Fourteen adult patients with chronic migraine were admitted for a 4-day course of IV valproate sodium. Patients received 250 mg of valproate sodium over a standard infusion time of 60 minutes every 8 hours. Most patients received 9 doses over the 4-day course of treatment. One patient had to discontinue after 1 dose of 250-mg valproate sodium, as this patient experienced an increase in his previous symptoms of nausea, vomiting, and vertigo with his first dose. To avoid positive selection bias, we evaluated the first admission for valproate IV therapy in patients with multiple admissions; there was 1 patient with 2 admissions and 1 with 3 admissions for IV valproate sodium. Of note - all admission outcomes for these patients were similar. Headache diaries were reviewed from 1 month before, during, and approximately 2 months after their admission.
Due to the observational nature of the study and small sample size, we did not think that quantitative statistical analysis would add more meaning to this pilot study. Formal quantitative statistical analysis was not performed in this study and descriptive statistical analysis was used due to this being a pilot proof of concept study. Physician clinical judgment in combination with patient reports were used to assign a dichotomous conclusion on clinical improvement for each patient. In the future, we plan to create a larger study, including additional treatment groups for control, such as IV Dihydroergotamine or IV Chlorpromazine, in order to quantify improvement of symptoms.
A total of 9 out of 13 (69%) patients had an improvement in their headache post-admission and reported a reduction in headache frequency, intensity, and/or use of acute medications 4-6 weeks following their admissions. A total of 5 out of 13 (38%) patients also reported an improvement in headache intensity during the 4-day period of inpatient admission. The other 8 out of 13 (62%) patients reported stable headache pattern. One patient had feelings of restlessness, which improved with prolongation of infusion time to 120 minutes.
These results indicate that this repetitive dosing valproate sodium protocol is a safe and well-tolerated intervention for the treatment of chronic migraine resistant to oral medications. Given the promising outcomes on patient headache improvement with this small pilot study, studies to confirm this benefit in a larger cohort of chronic migraine patients are warranted, preferable with the addition of a blinded control group for comparison.
这是一项小型先导研究，旨在评估静脉内（IV）丙戊酸钠疗法预防慢性偏头痛患者对多种预防药物耐药的偏头痛的有效性。
丙戊酸钠是一种抗癫痫药和情绪稳定剂，已证明以口服形式每天使用可预防偏头痛。偏头痛中特定的作用机制尚不清楚，但它可能与抑制炎症和增加大脑γ-氨基丁酸水平有关。它还可能与抑制皮质扩散性抑制有关。多项研究表明，丙戊酸及其衍生物可能抑制降钙素基因相关肽。在本工作中，我们进行了一项小型先导研究，以评估静脉内丙戊酸钠治疗预防慢性偏头痛患者对多种预防药物耐药的偏头痛的有效性。
14 名慢性偏头痛成年患者入院接受为期 4 天的 IV 丙戊酸钠治疗。患者每 8 小时接受 250mg 丙戊酸钠静脉滴注 60 分钟。大多数患者在 4 天的治疗过程中接受了 9 次剂量。一名患者在接受 250mg 丙戊酸钠 1 剂后不得不停药，因为该患者在首次剂量后出现先前恶心、呕吐和眩晕症状加重。为避免阳性选择偏倚，我们评估了在多次入院的患者中首次接受 IV 丙戊酸钠治疗的入院情况；有 1 名患者有 2 次入院和 1 名患者有 3 次入院接受 IV 丙戊酸钠。值得注意的是-所有这些患者的入院结局都相似。在入院前 1 个月、入院期间和入院后约 2 个月回顾头痛日记。
由于研究的观察性质和样本量小，我们认为定量统计分析不会为这项先导研究增加更多意义。由于这是一项先导性概念验证研究，因此未进行正式的定量统计分析，而是使用描述性统计分析。医生的临床判断结合患者的报告用于对每位患者的临床改善情况进行二分法结论的赋值。将来，我们计划进行更大的研究，包括为对照组创建额外的治疗组，例如 IV 二氢麦角胺或 IV 氯丙嗪，以量化症状的改善。
共有 13 名患者中的 9 名（69%）在入院后头痛得到改善，并报告在入院后 4-6 周内头痛发作频率、强度和/或急性药物使用减少。13 名患者中有 5 名（38%）在住院期间的 4 天内头痛强度也有所改善。其余 13 名患者中的 8 名（62%）报告头痛模式稳定。1 名患者出现烦躁不安，延长输液时间至 120 分钟后症状改善。
这些结果表明，这种重复剂量丙戊酸钠方案是一种安全且耐受良好的慢性偏头痛治疗方法，适用于对口服药物耐药的偏头痛。鉴于这项小型先导研究在改善患者头痛方面的良好结果，有必要在更大的慢性偏头痛患者队列中进行研究以证实这种益处，最好添加一个盲法对照组进行比较。
