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Meta-Analysis
. 2013 Jun 24;2013(6):CD010608.
doi: 10.1002/14651858.CD010608.

Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults

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

Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate 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 antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate (which are the subjects of separate Cochrane reviews) 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 antiepileptic drugs other than gabapentin, pregabalin, topiramate, and 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 antiepileptic drugs and comparators (placebo, active control, or same drug 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 numbers needed to treat (NNTs). We also summarised data on adverse events from placebo-controlled trials and calculated risk differences (RDs) and numbers needed to harm (NNHs).

Main results: Eleven papers describing 10 unique trials met the inclusion criteria. The 10 trials reported results for nine antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate. Six of the eight drugs investigated in placebo-controlled trials were not better than placebo in reducing headache frequency per 28-day period during treatment (clonazepam, lamotrigine, oxcarbazepine, and vigabatrin) and/or in the proportion of responders (acetazolamide, carisbamate, lamotrigine, oxcarbazepine). One prospective, randomised, double-blind, single cross-over trial of 48 patients demonstrated a significant superiority of carbamazepine over placebo in the proportion of responders (OR 11.77; 95% confidence interval (CI) 3.92 to 35.32). The NNT was 2 (95% CI 2 to 3). In a small prospective, randomised, double-blind, parallel-group trial, levetiracetam 1000 mg was significantly superior to placebo in reducing headache frequency per 28-day period during treatment (MD -2.40; 95% CI -4.52 to -0.28; 26 patients), as well as in the proportion of responders (OR 26.07; 95% CI 1.30 to 521.91; 26 patients). The NNT was 2 (95% CI 1 to 4). The same trial examined levetiracetam 1000 mg versus topiramate 100 mg and found a small but significant difference favouring topiramate in headache frequency per 28-day period during treatment (MD 1.40; 95% CI 0.14 to 2.66; 28 patients). There was no significant difference between levetiracetam and topiramate in the proportion of responders (OR 0.71; 95% CI 0.16 to 3.23; 28 patients). Finally, one trial with 75 participants examined zonisamide versus topiramate (200 and 100 mg, respectively) and found no significant difference between them in reduction of headache frequency from baseline during the third month of treatment. Adverse events for active treatment versus placebo were available for all investigated drugs except levetiracetam, vigabatrin, and zonisamide. A high prevalence of adverse events was noted for carbamazepine, with a NNH of only 2 (95% CI 2 to 4).

Authors' conclusions: Available evidence does not allow robust conclusions regarding the efficacy of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate in the prophylaxis of episodic migraine among adults. Acetazolamide, carisbamate, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin were not more effective than placebo in reducing headache frequency. In one trial each, carbamazepine and levetiracetam were significantly superior to placebo in reducing headache frequency, and there was no significant difference in proportion of responders between zonisamide and active comparator. These three positive studies suffer from considerable methodological limitations.

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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: Acetazolamide versus placebo, Outcome 1: Responders (patients with ≥ 50% reduction in headache frequency)
2.1
2.1. Analysis
Comparison 2: Carbamazepine versus placebo, Outcome 1: OR for responders (patients with ≥ 50% reduction in headache frequency)
2.2
2.2. Analysis
Comparison 2: Carbamazepine versus placebo, Outcome 2: RR for responders (patients with ≥ 50% reduction in headache frequency)
2.3
2.3. Analysis
Comparison 2: Carbamazepine versus placebo, Outcome 3: Any adverse event
2.4
2.4. Analysis
Comparison 2: Carbamazepine versus placebo, Outcome 4: Drowsiness
2.5
2.5. Analysis
Comparison 2: Carbamazepine versus placebo, Outcome 5: Nausea
2.6
2.6. Analysis
Comparison 2: Carbamazepine versus placebo, Outcome 6: Vertigo/giddiness
3.1
3.1. Analysis
Comparison 3: Carisbamate versus placebo, Outcome 1: Responders (patients with ≥ 50% reduction in headache frequency)
4.1
4.1. Analysis
Comparison 4: Carisbamate dose comparisons, Outcome 1: Responders (patients with ≥ 50% reduction in headache frequency)
5.1
5.1. Analysis
Comparison 5: Clonazepam versus placebo, Outcome 1: Headache frequency (post‐treatment; headache days per month)
6.1
6.1. Analysis
Comparison 6: Lamotrigine versus placebo, Outcome 1: Headache frequency (change from baseline to post‐treatment, or post‐treatment alone)
6.2
6.2. Analysis
Comparison 6: Lamotrigine versus placebo, Outcome 2: Responders (patients with ≥ 50% reduction in headache frequency)
7.1
7.1. Analysis
Comparison 7: Lamotrigine versus topiramate, Outcome 1: Headache frequency (change from baseline to post‐treatment)
7.2
7.2. Analysis
Comparison 7: Lamotrigine versus topiramate, Outcome 2: Responders (patients with ≥ 50% reduction in headache frequency)
8.1
8.1. Analysis
Comparison 8: Levetiracetam versus placebo, Outcome 1: Headache frequency (post‐treatment; headache days per month)
8.2
8.2. Analysis
Comparison 8: Levetiracetam versus placebo, Outcome 2: OR for responders (patients with ≥ 50% reduction in headache frequency)
8.3
8.3. Analysis
Comparison 8: Levetiracetam versus placebo, Outcome 3: RR for responders (patients with ≥ 50% reduction in headache frequency)
9.1
9.1. Analysis
Comparison 9: Levetiracetam versus topiramate, Outcome 1: Headache frequency (post‐treatment; headache days per month)
9.2
9.2. Analysis
Comparison 9: Levetiracetam versus topiramate, Outcome 2: Responders (patients with ≥ 50% reduction in headache frequency)
10.1
10.1. Analysis
Comparison 10: Oxcarbazepine versus placebo, Outcome 1: Headache frequency (change from baseline to post‐treatment)
10.2
10.2. Analysis
Comparison 10: Oxcarbazepine versus placebo, Outcome 2: Responders (patients with ≥ 50% reduction in headache frequency)
11.1
11.1. Analysis
Comparison 11: Vigabatrin versus placebo, Outcome 1: Headache frequency (post‐treatment)
12.1
12.1. Analysis
Comparison 12: Zonisamide versus topiramate, Outcome 1: Headache frequency (change from baseline to post‐treatment)
See this image and copyright information in PMC

References

References to studies included in this review

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