A 31-year-old woman asks for help with frequent migraines. She gets good response from abortive medication but had no success with the two preventive medications she has tried. You consider trying an anticonvulsant.
Do anticonvulsant medications reduce headache frequency in patients with migraine headache?
Good evidence supports the use of anticonvulsants as a class with overall reduction in number of headaches per month and overall increase in patients achieving 50 percent reduction of headache frequency. Of the medications within this heterogeneous group, valproic acid and divalproex have the strongest evidence to support their use for this indication.
Background. Anticonvulsant drugs seem to be useful in clinical practice for the prophylaxis of migraine. This benefit may be explained by the actions of these drugs in the central nervous system; these actions probably are relevant to the pathophysiology of migraine.
Objectives. To assess the evidence from controlled trials on the efficacy and tolerability of anticonvulsants in preventing migraine attacks in adult patients.
Search Strategy. The authors1 searched MEDLINE (from 1966 on) and the Cochrane Central Register of Controlled Trials (CENTRAL). The most recent search was conducted in April 2003. Additional information was obtained from hand-searching specialist headache journals; correspondence with pharmaceutical companies, authors of reports, and experts in the field; and a variety of review articles and books.
Selection Criteria. Studies were required to be prospective, controlled trials of self-administered drugs taken regularly to prevent migraine attacks or to reduce the intensity of attacks.
Data Collection and Analysis. Studies were selected and data extracted by two independent reviewers. For migraine frequency data, standardized mean differences (SMDs) were calculated for individual studies and pooled across studies. For dichotomous data on significant reduction in migraine frequency, odds ratios (ORs) and numbers needed to treat (NNTs) were similarly calculated. Adverse events were analyzed by calculating numbers needed to harm (NNHs) for studies using similar agents.
Primary Results. Fifteen articles were included in the review. Of these, 14 reported on trials comparing anticonvulsants with placebo: four trials of divalproex sodium, three trials of topiramate, two trials of sodium valproate, two trials of gabapentin, and one trial each of carbamazepine, clonazepam, and lamotrigine. The other article reported on a trial comparing sodium valproate with an active comparator, flunarizine, and one trial of divalproex sodium versus placebo included a comparison against propranolol, also an active comparator. Data from 2,024 patients were considered. Analysis of data from eight trials (n = 841) found that as a class, anticonvulsants reduce migraine frequency by about 1.4 attacks per 28 days compared with placebo (SMD, −0.60; 95 percent confidence interval [CI], −0.93 to −0.26). Data from 10 trials (n = 1,341) show that anticonvulsants, as a class, also more than double the number of patients in whom migraine frequency is reduced by 50 percent or more, compared with placebo (OR, 3.90; 95 percent CI, 2.61 to 5.82; NNT, 3.8; 95 percent CI, 3.2 to 4.6). In seven trials of sodium valproate and divalproex sodium, NNHs for five clinically important adverse events ranged from 6.6 to 16.3. For the three trials of topiramate, NNHs for eight adverse events (100-mg dose) ranged from 2.4 to 32.9.
Reviewers’ Conclusions. Anticonvulsants appear to be effective in reducing migraine frequency and reasonably well-tolerated. There is noticeable variation among individual agents, but there are insufficient data to determine whether these discrepancies are a result of chance or variation in true efficacy. Neither clonazepam nor lamotrigine was superior to placebo (one trial each). Relatively few robust trials are available for agents other than sodium valproate/divalproex sodium. Two recently published large trials of topiramate demonstrated reasonable efficacy, and another trial of this agent is anticipated in the near future.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
Migraine headaches affect approximately 6 percent of men and 15 to 17 percent of women.2 It is difficult to determine which, if any, preventive medication may reduce the patient’s burden. Therefore, it is helpful to have a variety of drug classes to try.
The American Academy of Neurology and American Academy of Family Physicians3 reviewed the treatment of migraine, including the use of prophylactic drugs. Effective agents for migraine prevention include beta blockers, tricyclic antidepressants, selective serotonin reuptake inhibitors, calcium channel blockers, vitamins and supplements (e.g., riboflavin, feverfew, magnesium), nonsteroidal anti-inflammatory drugs, centrally acting antiadrenergic agents, and anticonvulsants.3,4
This Cochrane review should ease physicians’ concerns about using anticonvulsants for migraine prophylaxis. Statistically and clinically significant benefit was found for sodium divalproex, valproic acid, carbamazepine, gabapentin, and topiramate. Each drug was studied in one to five clinical trials, and the dosages used for migraine prevention were uniformly lower than antiepileptic dosages. Although side effects and withdrawal from treatment did occur, the rates were moderate.
The mnemonic STEPS can guide physicians in choosing from the many agents available for migraine prophylaxis:Safety, Tolerability, Efficacy, Price, and Simplicity. In a typical young, healthy patient with migraine, beta blockers, divalproex sodium, and tricyclic antidepressants (especially amitriptyline) are safe, inexpensive, and well tolerated, and have the best track record for efficacy. Vitamins and supplements have smaller bodies of evidence to support them and sometimes are hard to find in the recommended dosing forms, but they are effective. Generic fluoxetine also is inexpensive, well tolerated, and convenient.
Tolerability of anticonvulsants ranges from good to fair. Efficacy is similar to that of other drugs.3 Valproic acid and carbamazepine are less expensive than gabapentin and topiramate. All anticonvulsants have once- or twice-daily dosing, but safety is a distinguishing issue. Most patients with migraine are women of childbearing age. Like many of the options for migraine prophylaxis, valproic acid and carbamazepine are pregnancy category D agents; other agents used for migraine prophylaxis are category C. Hepatotoxicity also is a concern with valproic acid and carbamazepine. Although anticonvulsant medications are not the first choice for migraine prevention, they are a welcome option that broadens the options for treating patients with migraine.