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NIHR Signal A range of anti-epilepsy drugs are effective as first-line treatment

Published on 12 September 2017

doi: 10.3310/signal-000476

Lamotrigine and levetiracetam are emerging as first-line treatments for epilepsy, which people may be more likely to keep taking than carbamazepine. Reducing the risk of adverse events and treatment withdrawal is important when selecting an anti-epilepsy drug as it usually will need to be taken long-term.

This study reviewed evidence on anti-epilepsy drugs in adults and children. The drugs were compared directly or indirectly with each other. The main outcome of interest was time to withdrawal from treatment, which indicates effectiveness and tolerability.

The findings support NICE recommendations to use carbamazepine or lamotrigine as first-line therapies for epilepsy with partial seizures, with levetiracetam as an alternative. Sodium valproate or lamotrigine are recommended for people with generalised tonic-clonic seizures, and levetiracetam is an alternative option.

  •   Medicines, Nervous system disorders, Acute and general medicine
A range of anti-epilepsy drugs are effective as first-line treatment

Why was this study needed?

Epilepsy is common, affecting around one in every hundred people in the UK. People with epilepsy experience seizures due to abnormal electrical activity in the brain. Some types of epilepsy occur in one part of the brain (partial seizures) while others are more widespread (generalised seizures).

Drug treatments can reduce the number or the severity of seizures, or stop them completely. They usually need to be taken long-term, but some people stop taking them because of side effects. In the UK, an estimated 400 deaths due to epilepsy could be avoided each year through optimum treatment.

Up to 70% of people have good long term control of seizures after being prescribed their first anti-epilepsy drug, but others may need to try several different drugs.

This research from the Cochrane Epilepsy Group combines direct and indirect comparisons of drugs to inform which are best for first-line use in different types of epilepsy.

What did this study do?

This was a systematic review and network meta-analysis using individual participant data from many trials. It included randomised and quasi-randomised controlled trials which had compared 10 different anti-epilepsy drugs with each other: carbamazepine, phenobarbitone, phenytoin, sodium valproate, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam and zonisamide.

The study identified 77 eligible trials from which the authors obtained data on at least one outcome from 12,391 adults and children in 36 trials. The main outcome was time to withdrawal from treatment - a mixture of how effective and tolerable the drug was.

Evidence was of moderate to high quality, but the absence of individual data from over half of the eligible trials may introduce selection bias.

What did it find?

For partial seizures:

  • Compared to carbamazepine, people were less likely to stop treatment if taking lamotrigine (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65 to 0.86) or levetiracetam (HR 0.82, 95% CI 0.69 to 0.97). Those on phenobarbitone were more likely to stop (HR 1.55, 95% CI 1.18 to 2.04) and there was no difference for the other drugs.
  • Compared to lamotrigine, only people on levetiracetam were as likely to stop treatment (HR 1.10, 95% CI 0.89 to 1.35). People taking any of the other drugs were more likely to stop treatment, such as those on carbamazepine (HR 1.34, 95% CI 1.17 to 1.54) and phenobarbitone (HR 2.08, 95% CI 1.53 to 2.83).

For generalised seizures:

  • Compared to sodium valproate, people were as likely to stop taking lamotrigine (HR 0.90, 95% CI 0.60 to 1.35) or levetiracetam (HR 1.05, 95% CI 0.58 to 1.90). Results were less clear for gabapentin, phenytoin or oxcarbazepine due to wide confidence intervals.
  • Compared to sodium valproate, people were more likely to stop taking carbamazepine (HR 1.42, 95% CI 1.09 to 1.85), topiramate (HR 1.76, 95% CI 1.22 to 2.53) and phenobarbitone (HR 2.09, 95% CI 1.17 to 3.75).

Adverse events:

  • Side effects the drugs included stomach upsets, dizziness, faintness, skin disorders (including rashes), headaches, migraines, drowsiness and fatigue.

What does current guidance say on this issue?

NICE 2016 guidelines recommend carbamazepine or lamotrigine as first-line treatment for children, young people and adults with newly diagnosed partial seizures. If not tolerated then levetiracetam, oxcarbazepine or sodium valproate can be used.

For generalised tonic-clonic seizures, sodium valproate is recommended as first-line treatment. If this is unsuitable, lamotrigine is recommended. Carbamazepine and oxcarbazepine can be considered as alternatives.

Because of risks to the unborn baby sodium valproate should not be given to women or girls of childbearing age unless all other treatment options have failed.

What are the implications?

Using time to withdrawal from treatment, this analysis indicates that lamotrigine may be preferable to carbamazepine for initial treatment of partial seizures. Levetiracetam at its current price may now be the next best choice before carbamazepine in the UK. The results for generalised seizures are in line with NICE guidelines, to use sodium valproate or lamotrigine. Levetiracetam could now be an alternative option.

Though time to withdrawal of treatment is a good indicator of effectiveness and tolerability, factors such as side effects, compatibility with other medication, child-bearing potential and personal preference will be important when deciding on which anti epilepsy drug to try first.

Citation and Funding

Nevitt SJ, Sudwell M, Weston J, et al. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database Syst Rev. 2017;(6):CD011412.

Cochrane UK and the Epilepsy Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

NHS Choices. Epilepsy. London: Department of Health; 2014.

NICE. Epilepsies: diagnosis and management. GC137. London: National Institute for Health and Care Excellence; 2016.

Expert commentary

In general, epilepsy treatment is long-term, so minimisation of adverse effects is key. The composite outcome measure of time remaining on treatment takes efficacy and adverse effects into account. This meta-analysis supports NICE evaluations (2004, 2012) that carbamazepine and lamotrigine are suitable for focal seizures and levetiracetam is an alternative. Also, valproate is effective for generalised tonic-clonic seizures, with lamotrigine and levetiracetam alternatives, particularly if pregnancy is contemplated.

The availability of many medications that suppress seizures brings choice and the ability to minimise adverse-effects, but these have not affected remission rates. We await therapies that prevent the development of epilepsy and alter its natural history.

John Duncan, Professor of Neurology, UCL; Divisional Clinical Director, National Hospital for Neurology and Neurosurgery

Definitions

Network meta-analysis allows interventions to be compared which have never been directly compared in previous studies, as long as they have both been compared to something else in common.