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. 2013 Jun 24;2013(6):CD010611.
doi: 10.1002/14651858.CD010611.

Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults

Mattias Linde  1 , Wim M Mulleners, Edward P Chronicle, Douglas C McCrory
Affiliations

Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults

Mattias Linde et al. Cochrane Database Syst Rev. .

Abstract

Background: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007.

Objectives: To describe and assess the evidence from controlled trials on the efficacy and tolerability of valproate (valproic acid or sodium valproate or a combination of the two) for preventing migraine attacks in adult patients with episodic migraine.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013.

Selection criteria: Studies were required to be prospective, controlled trials of valproate taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both.

Data collection and analysis: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between valproate and comparator (placebo, active control, or valproate in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with ≥ 50% reduction in headache frequency), we calculated odds ratios (ORs) and, in select cases, risk ratios (RRs); we also calculated numbers needed to treat (NNTs). We calculated MDs for Migraine Disability Assessment (MIDAS) scores. We also summarised data on adverse events from placebo-controlled trials and calculated risk differences (RDs) and numbers needed to harm (NNHs).

Main results: Ten papers describing 10 unique trials met the inclusion criteria. Analysis of data from two trials (63 participants) showed that sodium valproate reduced headache frequency by approximately four headaches per 28 days as compared to placebo (MD -4.31; 95% confidence interval (CI) -8.32 to -0.30). Data from four trials (542 participants) showed that divalproex sodium (a stable combination of sodium valproate and valproic acid in a 1:1 molar ratio) more than doubled the proportion of responders relative to placebo (RR 2.18; 95% CI 1.28 to 3.72; NNT 4; 95% CI 2 to 11). One study of sodium valproate (34 participants) versus placebo supported the latter findings (RR for responders 2.83; 95% CI 1.27 to 6.31; NNT 3; 95% CI 2 to 9). There was no significant difference in the proportion of responders between sodium valproate versus flunarizine (one trial, 41 participants) or between divalproex sodium versus propranolol (one trial, 32 participants). Pooled analysis of post-treatment mean headache frequencies in two trials (88 participants) demonstrates a slight but significant advantage for topiramate 50 mg over valproate 400 mg (MD -0.90; 95% CI -1.58 to -0.22). For placebo-controlled trials of sodium valproate and divalproex sodium, NNHs for clinically important adverse events ranged from 7 to 14.

Authors' conclusions: Valproate is effective in reducing headache frequency and is reasonably well tolerated in adult patients with episodic migraine.

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Conflict of interest statement

Prof Linde: During the process of preparing this review the author received a travel grant from Allergan in Sweden and was involved as an investigator in a clinical trial in Norway sponsored by AstraZeneca and comparing candesartan, propranolol, and placebo in the prophylaxis of migraine.

Dr Mulleners: The author was a paid consultant for the Merck Dutch Migraine Advisory Board and received a speaker's fee from Merck Sharp & Dohme Corp.

Prof Chronicle: Author deceased. During the process of preparing the original review the author was a paid consultant for Johnson & Johnson and NPS Pharmaceuticals in the USA.

Assoc Prof McCrory: During 2008, the author was a paid expert witness for the plaintiffs in a legal action against the manufacturer of Neurontin (gabapentin). In this capacity, he prepared a systematic review examining previously confidential research reports obtained from the manufacturer (through discovery), along with published trial reports of gabapentin for migraine prophylaxis, and testified at trial.

Figures

1
1
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Divalproex sodium versus placebo, Outcome 1 ORs for responders (patients with ≥ 50% reduction in headache frequency).
1.2
1.2. Analysis
Comparison 1 Divalproex sodium versus placebo, Outcome 2 RRs for responders (patients with ≥ 50% reduction in headache frequency).
2.1
2.1. Analysis
Comparison 2 Sodium valproate versus placebo, Outcome 1 Headache frequency (post‐treatment).
2.2
2.2. Analysis
Comparison 2 Sodium valproate versus placebo, Outcome 2 ORs for responders (patients with ≥ 50% reduction in headache frequency).
2.3
2.3. Analysis
Comparison 2 Sodium valproate versus placebo, Outcome 3 RRs for responders (patients with ≥ 50% reduction in headache frequency).
3.1
3.1. Analysis
Comparison 3 Sodium valproate dose comparisons, Outcome 1 Headache frequency (post‐treatment).
4.1
4.1. Analysis
Comparison 4 Sodium valproate versus flunarizine, Outcome 1 Responders (patients with ≥ 50% reduction in headache frequency).
5.1
5.1. Analysis
Comparison 5 Divalproex sodium versus propanolol, Outcome 1 Responders (patients with ≥ 50% reduction in headache frequency).
6.1
6.1. Analysis
Comparison 6 Sodium valproate versus topiramate, Outcome 1 Headache frequency (post‐treatment).
6.2
6.2. Analysis
Comparison 6 Sodium valproate versus topiramate, Outcome 2 MIDAS score.
7.1
7.1. Analysis
Comparison 7 Safety of sodium valproate and divalproex sodium versus placebo, Outcome 1 Any adverse event.
7.2
7.2. Analysis
Comparison 7 Safety of sodium valproate and divalproex sodium versus placebo, Outcome 2 Asthenia/fatigue.
7.3
7.3. Analysis
Comparison 7 Safety of sodium valproate and divalproex sodium versus placebo, Outcome 3 Dizziness/vertigo.
7.4
7.4. Analysis
Comparison 7 Safety of sodium valproate and divalproex sodium versus placebo, Outcome 4 Nausea.
7.5
7.5. Analysis
Comparison 7 Safety of sodium valproate and divalproex sodium versus placebo, Outcome 5 Tremor.
7.6
7.6. Analysis
Comparison 7 Safety of sodium valproate and divalproex sodium versus placebo, Outcome 6 Weight gain.
See this image and copyright information in PMC

References

References to studies included in this review

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