Adjunctive Treatment for Focal-Onset Seizures: Which Medication Has the Best Efficacy and Tolerability?

November 2022

For patients taking an antiseizure medication who do not achieve freedom from seizures, another antiseizure medication is often prescribed as an adjunctive therapy. However, no head-to-head randomized clinical trials have been conducted comparing antiseizure medications as adjunctive therapies that can inform the choice of adjunctive therapy.

To help clinicians decide which antiseizure medications to select as adjunctive therapies, investigators recently conducted a network meta-analysis to compare the efficacy and safety of the 5 third-generation antiseizure medications that have been approved by the US Food and Drug Administration. The study included data from adult patients who had been enrolled in randomized clinical trials for uncontrolled focal epilepsy. The medications tested in the trials were brivaracetam, cenobamate, eslicarbazepine acetate, lacosamide, and perampanel.

Outcomes for efficacy were seizure response, defined as the percentage of patients with ≥50% reduction in monthly seizures, and seizure freedom, defined as the percentage of patients who had no seizures during the maintenance or treatment period. The investigators identified 16 randomized clinical trials that together included 4507 patients who received an adjunctive antiseizure medication and 2246 patients who received a placebo.

The analysis showed that, as expected, patients had significantly better seizure responses to all 5 antiseizure medications compared with placebo. The seizure response and seizure freedom rates were highest for cenobamate. The investigators also found that brivaracetam, cenobamate, eslicarbazepine acetate, and perampanel were associated with significantly higher rates of seizure freedom compared with placebo, but lacosamide was not more efficacious for achieving seizure freedom compared with placebo.

A hierarchical rank of the medications and doses showed that the option with the highest probability of having the best efficacy was 400 mg daily of cenobamate.

Outcomes for safety and tolerability were the percentage of patients who had a treatment-related adverse event (TRAE) and the percentage of patients who discontinued the adjunctive antiseizure medication due to a TRAE. Of the 16 trials selected for the analysis, 14 contained safety and tolerability data.

Lacosamide was the only antiseizure medication not associated with an increase in TRAEs compared with placebo. Conversely, cenobamate had the greatest risk of a TRAE, which the investigators suggested might be caused by the higher doses used. All 5 antiseizure medications were associated with higher risks of discontinuation due to TRAEs compared with placebo.

The hierarchical analysis showed that brivaracetam and lacosamide were most likely to be well-tolerated. The lowest risk of any TRAE was for 200 mg daily of lacosamide. Medications with the lowest risk of discontinuation due to a TRAE was 200 mg daily of lacosamide or 4 mg daily of perampanel.

Some limitations of the analysis were the relatively short maintenance periods, use of only 1 trial for cenobamate, and lack of information about cost-effectiveness and quality of life.

The investigators concluded, “Although network meta-analyses cannot replace studies directly comparing two or more drugs, they may offer reliable evidence of the relative efficacy and safety, provide useful information about the hierarchy of competing interventions, and may inform and guide physicians in clinical decision making.”


Lattanzi S, Trinka E, Zaccara G, et al. Third-generation antiseizure medications for adjunctive treatment of focal-onset seizures in adults: a systematic review and network meta-analysis. Drugs. 2022;82(2):199-218.

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