AEDs: Which Work Best as Monotherapy in Epilepsy?

November 27, 2017

Which antiepileptic drugs work best as monotherapy? A new Cochrane meta-analysis scrutinizes the evidence.

Which AEDs work best as monotherapy?A new Cochrane review scrutinizes the efficacy and tolerability of various agents.Â Â

Which antiepileptic drugs (AEDs) are best as monotherapy? Before the updated Cochrane review, first-line therapy in adults and children with partial onset seizures was with carbamazepine or lamotrigine. And first-line therapy for generalized seizure onset was with sodium valproate.

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60%-70% of people with epilepsy reach remission from seizures shortly after starting AED treatment. Most are treated with AED monotherapy. The National Institute for Health and Care Excellence (NICE) guidelines in the UK recommend carbamazepine or lamotrigine as first-line-therapy in adults and children with partial onset seizures and sodium valproate as first-line for generalized onset seizures. A 2007 network meta-analysis of AED monotherapy generally agreed with these recommendations.[1]

The Cochrane Review of AED monotherapy, which updates previous meta-analysis with studies published since 2007, adds levetiracetam and zonisamide.[2]

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Individual participant data (IPD) approach were used; considered gold standard for time-to-event pooled network meta-analysis. Combined IPD data from 12,391 people in 36 studies and compared 10 AEDS: carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide. ooled data from trials that did head-to-head comparisons were analyzed; a second analysis combined all data from trials to compare drugs that had not been previously compared.

For partial seizures, levetiracetam was found to be significantly better than carbamazepine and lamotrigine. Lamotrigine was significantly better than all other AEDs (except levetiracetam). And carbamazepine was significantly better than gabapentin and phenobarbitone. For generalized onset seizures, valproate was significantly better than carbamazepine, topiramate and phenobarbitone. For both partial and generalized onset seizures: phenobarbitone, the earliest licensed treatment, performed worse in terms of treatment failure than all other treatments.

There were few notable differences for partial or generalized seizure types, except fpr 12-month remission: Carbamazepine was significantly better than levetiracetam for partial seizures; and 6-month remission: Sodium valproate was significantly better than lamotrigine for generalized seizures. Regarding time to bot partial and generalized seizures: the oldest AEDs (phenytoin and phenobarbitone) were generally better than newer AEDs. The most commonly reported adverse events across all drugs: drowsiness/fatigue, headache/migraine, GI disturbances, dizziness/faintness, rash/skin disorders.

IPD data were available for just 69% of total participants from 47% of eligible trials, leaving out 31% of eligible participants. Methodological inadequacies in some trials could have biased results

1. Phenobarbitone and phenytoin are better for seizure control, but at the expense of earlier treatment failure. 2. Carbamazepine and lamotrigine are suitable as first-line monotherapy for partial onset seizures; levetiracetam may be a suitable alternative. 3. Sodium valproate is suitable as first-line monotherapy for generalized seizures; lamotrigine and levetiracetam may be suitable alternatives, especially for women of child-bearing age given the potential teratogenicity of sodium valproate 4. Zonisamide may effective in partial onset seizures: evidence is limited and more research is needed.

1. Tudur Smith C, Marson AG, Chadwick DW, Williamson PR. Multiple treatment comparisons in epilepsy monotherapy trials. Trials. 2007;5(8):34
2. Nevitt SJ, Sudell M, Weston J, Tudur Smith C, Marson AG. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database of Systematic Reviews. 2017, Issue 6. Art. No. CD011412.