Lamotrigine add-on therapy for drug-resistant focal epilepsy

Key messages

1. Lamotrigine is an antiseizure medication used as an adjunctive treatment for focal seizures in people with drug-resistant epilepsy. Focal epilepsy is characterised by seizures arising from a specific area of the brain.
3. Lamotrigine is probably effective for reducing seizure frequency in children and adults, but further trials are needed to assess the long-term effects of lamotrigine and to compare lamotrigine with other add-on drugs.

What is epilepsy and how is it treated?

Epilepsy is a brain disorder that causes recurring seizures. Approximately one-third of people with epilepsy continue to have seizures despite using antiseizure medicines. Older antiseizure medicines can have many unwanted effects, so it is important to develop effective new therapies. Several new medicines have been developed as 'add-on' treatments (to be used in combination with other medicines). One of these new medicines is called lamotrigine.

What did we want to find out?

We wanted to find out if add-on lamotrigine was better than add-on placebo (dummy treatment) or no add-on treatment for reducing the frequency of seizures and withdrawal from treatment, and for improving cognition (ability to learn) and quality of life. We also wanted to know if lamotrigine had any unwanted effects.

What did we do?

We searched for studies that examined add-on lamotrigine compared with add-on placebo or no add-on treatment in people of any age who had focal epilepsy that had not responded to previous treatments (drug-resistant focal epilepsy). We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 14 studies that enroled a total of 1806 people (adults, children, and infants).

Lamotrigine, used in combination with other antiseizure medicines in people with drug-resistant focal epilepsy, is probably more effective than placebo for achieving a 50% or greater reduction in seizure frequency. In addition, people using add-on lamotrigine are probably no more likely to stop treatment than those using add-on placebo. However, adding lamotrigine to usual treatment probably leads to more unwanted effects such as unsteadiness (ataxia), dizziness, double vision (diplopia), and nausea.

Further high-quality research is needed to fully evaluate the benefits and harms of add-on lamotrigine compared with add-on placebo or no add-on treatment, and compared with other new antiseizure medicines.

What are the limitations of the evidence?

We have moderate confidence in the evidence, mainly because the studies reported few events (seizures, treatment withdrawal, unwanted effects).

How up to date is this evidence?

This review updates our previous review. The evidence is current to 3 October 2022.

Authors' conclusions: 

Lamotrigine as an add-on treatment for drug-resistant focal seizures is probably effective for reducing seizure frequency. Certain adverse effects (ataxia, dizziness, diplopia, and nausea) are probably more likely to occur with lamotrigine compared with placebo. There is probably little or no difference in the number of people who withdraw from treatment with lamotrigine versus placebo.

The trials were of relatively short duration and provided no long-term evidence. In addition, some trials had few participants.

Further trials are needed to assess the long-term effects of lamotrigine and to compare lamotrigine with other add-on drugs.

Read the full abstract...
Background: 

This is an updated version of a Cochrane Review last updated in 2020.

Epilepsy is a common neurological disorder, affecting 0.5% to 1% of the population. In nearly 30% of cases, epilepsy is resistant to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is a second-generation antiseizure medication. When used as an add-on (in combination with other antiseizure medications), lamotrigine can reduce seizures, but with some adverse effects.

Objectives: 

To evaluate the benefits and harms of add-on lamotrigine, compared with add-on placebo or no add-on treatment in people with drug-resistant focal epilepsy.

Search strategy: 

For this update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) on 3 October 2022 with no language restrictions. CRS Web includes randomised and quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups, including Epilepsy.

Selection criteria: 

We included randomised controlled trials (RCTs) that investigated add-on lamotrigine versus add-on placebo or no add-on treatment in people of any age with drug-resistant focal epilepsy. We used data from the first period of eligible cross-over trials.

Data collection and analysis: 

For this update, two review authors independently selected trials and extracted data. Our primary outcome was 50% or greater reduction in seizure frequency. Our secondary outcomes were treatment withdrawal, adverse effects, cognitive effects, and quality of life. Primary analyses were by intention-to-treat. We performed sensitivity best- and worse-case analyses to account for missing outcome data. We calculated pooled risk ratios (RRs) with 95% confidence intervals (95% Cls) for dichotomous outcomes.

Main results: 

We identified no new studies for this update, so the results and conclusions of the review are unchanged.

We included five parallel-group studies in adults or children, eight cross-over studies in adults or children, and one parallel study with a responder-enriched design in infants. In total, these 14 studies enroled 1806 eligible participants (38 infants, 199 children, 1569 adults). Baseline phases ranged from four to 12 weeks and treatment phases ranged from eight to 36 weeks. We rated 11 studies (1243 participants) at low overall risk of bias and three (697 participants) at unclear overall risk of bias due to lack of information on study design. Four studies (563 participants) reported effective blinding.

Lamotrigine compared with placebo probably increases the likelihood of achieving 50% or greater reduction in seizure frequency (RR 1.80, 95% CI 1.45 to 2.23; 12 trials, 1322 participants (adults and children); moderate-certainty evidence). There is probably little or no difference in risk of treatment withdrawal for any reason among people treated with lamotrigine versus people treated with placebo (RR 1.11, 95% CI 0.91 to 1.37; 14 trials; 1806 participants; moderate-certainty evidence).

Lamotrigine compared with placebo is probably associated with a greater risk of ataxia (RR 3.34, 99% Cl 2.01 to 5.55; 12 trials; 1525 participants; moderate-certainty evidence), dizziness (RR 1.76, 99% Cl 1.28 to 2.43; 13 trials; 1768 participants; moderate-certainty evidence), nausea (RR 1.81, 99% CI 1.22 to 2.68; 12 studies, 1486 participants; moderate-certainty evidence), and diplopia (RR 3.79, 99% Cl 2.15 to 6.68; 3 trials, 944 participants; moderate-certainty evidence). There is probably little or no difference in the risk of fatigue between lamotrigine and placebo (RR 0.82, 99% CI 0.55 to 1.22; 12 studies, 1552 participants; moderate-certainty evidence).