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Am Fam Physician. 2018;97(9):572-573

Author disclosure: No relevant financial affiliations.

Clinical Question

Which is the best antiepileptic drug monotherapy for adults and children with epilepsy?

Evidence-Based Answer

In patients with partial-onset (focal) seizures, levetiracetam (Keppra), lamotrigine (Lamictal), and carbamazepine (Tegretol) were associated with the longest time to treatment withdrawal (i.e., the recommended patient-oriented outcome measure that balances tolerability with effectiveness). In patients with generalized seizure disorder, valproic acid (Depakene) was associated with the longest time to treatment withdrawal.1 (Strength of Recommendation: A, based on consistent patient-oriented evidence.)

Practice Pointers

Approximately 1.2% of the U.S. population has active epilepsy, including 3 million adults and 470,000 children.2 Up to 70% of patients with epilepsy will attain remission with appropriate treatment, the majority with antiepileptic drug monotherapy.3,4 This analysis compared the effectiveness of 10 monotherapy antiepileptic drugs: carbamazepine, gabapentin (Neurontin), lamotrigine, levetiracetam, oxcarbazepine (Trileptal), phenobarbital, phenytoin (Dilantin), valproic acid, topiramate (Topamax), and zonisamide (Zonegran).

This Cochrane review included 36 randomized controlled trials with 12,391 patients. Patients of all ages were pooled for analyses; approximately 67% had partial-onset seizures, 25% had generalized-onset seizures, and 9% had unclassified seizures.1 The primary outcome was time to withdrawal of allocated treatment, with longer time to withdrawal indicating more successful therapy. Secondary outcomes were six- and 12-month remission of seizures, time to first seizure post-randomization, and treatment-related adverse effects. Outcomes were presented as Cox proportional hazard ratios (HRs), with HRs less than 1.0 being better and HRs greater than 1.0 being worse when compared with control drugs.1

In patients being treated for partial seizures, lamotrigine (HR = 0.75; 95% confidence interval [CI], 0.65 to 0.86) and levetiracetam (HR = 0.82; 95% CI, 0.69 to 0.97) had longer times to withdrawal than carbamazepine. Lamotrigine outperformed gabapentin (HR = 1.6; 95% CI, 1.31 to 1.96) and phenobarbital (HR = 2.08; 95% CI, 1.53 to 2.83). Although generally less tolerable, the older antiepileptic drugs including phenobarbital (HR = 0.61; 95% CI, 0.49 to 0.77), phenytoin (HR = 0.76; 95% CI, 0.64 to 0.91), and carbamazepine (HR = 0.78; 95% CI, 0.70 to 0.86) delayed the time to first seizure compared with lamotrigine.

In patients being treated for generalized seizures, valproic acid was superior to carbamazepine (HR = 1.42; 95% CI, 1.09 to 1.85), topiramate (HR = 1.76; 95% CI, 1.22 to 2.53), and phenobarbital (HR = 2.09; 95% CI, 1.17 to 3.75) in time to treatment withdrawal. There were no significant differences between agents in time to six- or 12-month remission for either partial or generalized seizures. Adverse effects associated with antiepileptic drugs included fatigue, headache, gastrointestinal disturbances, dizziness, and skin reactions. Adverse effects were described in narrative format because of variability among studies.

Current National Institute for Health and Care Excellence guidelines recommend carbamazepine or lamotrigine for patients diagnosed with partial seizures, with levetiracetam as a favorable alternative. For generalized seizures, valproic acid is recommended as first-line therapy, with lamotrigine and levetiracetam as alternative options and first-line therapy for women who are or could become pregnant.5

These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, assistant medical editor.

A collection of Cochrane for Clinicians published in AFP is available at

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