Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults
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.
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.
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.
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).
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).
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.
Mattias Linde, Wim M Mulleners, Edward P Chronicle, Douglas C McCrory
Plain language summary
Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for preventing migraine attacks in adults
Various medicines, collectively termed 'antiepileptics', are used to treat epilepsy. For several years, three antiepileptics have also been recommended as drugs of first choice (topiramate and valproate) or third choice (gabapentin) for preventing migraine attacks. These three drugs, along with one other (pregabalin), are the subject of separate Cochrane reviews. For the present review, researchers in The Cochrane Collaboration reviewed the evidence about the effect of other antiepileptics in adult patients (≥ 16 years of age) with 'episodic' migraine (headache on < 15 days per month). They examined research published up to 15 January 2013 and found 10 studies of nine different antiepileptics. The majority of these drugs were no better than placebo for migraine prophylaxis (acetazolamide, carisbamate, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin). In one study each, carbamazepine and levetiracetam were better than placebo, and there was no significant difference between zonisamide and topiramate (a drug proven to be effective for migraine prophylaxis). None of these studies was of high methodological quality. The quantity and quality of the evidence were such that no firm conclusions could be drawn about the effect or lack of effect of any of the antiepileptics studied.
Mattias Linde, Wim M Mulleners, Edward P Chronicle, Douglas C McCrory
Implications for practice
Bearing in mind the limitations invoked by the methodological and reporting issues mentioned above, this review nevertheless helps to provide a rational framework for the application of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate for the preventive management of migraine headache in clinical practice. There is, at present, either insufficient or no evidence to warrant their use in clinical practice.
It must be stressed, however, that this review does not provide definite evidence for the management of other aspects of the condition (eg, prodromal symptoms, aura symptoms), either because these aspects were not considered in the selected trials or were not adequately reported. Likewise, the conclusions in this review cannot be extrapolated to chronic migraine, transformed migraine, or chronic daily headache. None of these conditions was considered for this review, as properly validated definitions are as yet lacking.
Implications for research
At present, there is an inadequate number of trials of antiepileptic drugs other than topiramate and valproate in the prophylaxis of migraine. Based on the identified evidence, carbamazepine, levetiracetam, and zonisamide are drugs that could be considered for further investigation in methodologically stringent trials. However, the fact that a drug has antiepileptic activity should not, per se, be considered good reason to expect antimigraine activity or sufficient reason to subject patients to a clinical trial. Little is definitely known about the mechanism of action of the antiepileptics that are effective in migraine prophylaxis, eg, topiramate and valproate. A considerable amount of basic science research in both animal models and human neuroscience laboratories will be necessary in order to discover which of the many potential actions of antiepileptic drugs are causative in the reduction of headache frequency or severity. A programme of research aimed at improving efficacy and tolerability by designing prophylactic drugs targeted at known migraine mechanisms would be worthwhile.
In general, we feel that the quality of both methods and reporting is disappointing in this area of investigation. In particular, investigators wishing to report intention‐to‐treat analyses should carefully consider the recommendations of medical statisticians (eg, Hollis 1999). Future trialists should also be encouraged to follow the recommendations of the International Headache Society (Tfelt‐Hansen 2012) with regard to both trial design and reporting of data.