Adding lamotrigine for drug-resistant partial epilepsy

Background

Epilepsy is a disorder in which unexpected electrical discharges from the brain cause seizures. Approximately one-third of patients with epilepsy continue to have seizures, despite treatment with presently used (older) antiepileptic drugs (AEDs). In addition, the older AEDs have a lot of adverse effects.

Therefore, the development of effective new therapies for the treatment of refractory seizures is of considerable importance. As a result, a range of new AEDs has been developed as 'add-on' treatments. Lamotrigine is one of these.

Aims of the review

This review aimed to determine the effects of lamotrigine on seizures, adverse effects, cognition (ability to learn and understand) and quality of life compared to placebo controls, when used as an add-on treatment for people with partial epilepsy that would not respond to existing AEDs.

For this update, we did not identify any new studies to add, and thus, the conclusions remain unchanged. The review included 14 randomised controlled trials with a total number of 1958 participants.

Results

Lamotrigine, used in combination with other AEDs in patients who have drug-resistant partial epilepsy can decrease the frequency of seizures further. However, adding lamotrigine to the usual treatment is more often associated with an increase in adverse effects such as unsteadiness (ataxia), dizziness, double vision (diplopia), and nausea.

Quality of the evidence

We assessed the trials with regards to risk of bias. Overall, we rated the quality of the evidence as high.

Conclusions

Further high-quality research is needed to fully evaluate the efficacy and tolerability of lamotrigine and compare it with other newer AEDs.

The evidence is current to 28 May 2015.

Authors' conclusions: 

Lamotrigine as an add-on treatment for partial seizures appears to be effective in reducing seizure frequency, and seems to be fairly well tolerated. However, the trials were of relatively short duration and provided no evidence for the long-term. Further trials are needed to assess the long-term effects of lamotrigine, and to compare it with other add-on drugs.

Since we did not find any new studies, our conclusions remain unchanged.

Read the full abstract...
Background: 

This is an updated version of the Cochrane review published in The Cochrane Library 2010, Issue 1.

Epilepsy is a common neurological disorder, affecting almost 0.5% to 1% of the population. For nearly 30% of these people, their epilepsy is refractory to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is one of the newer antiepileptic drugs and is the topic of this review. Lamotrigine in combination with other antiepileptic drugs (add-on) can reduce seizures, but with some adverse effects. The aim of this systematic review was to overview the current evidence for the efficacy and tolerability of lamotrigine when used as an adjunctive treatment for people with refractory partial epilepsy.

Objectives: 

To determine the effects of lamotrigine on (1) seizures, (2) adverse effect profile, and (3) cognition and quality of life, compared to placebo controls, when used as an add-on treatment for people with refractory partial epilepsy.

Search strategy: 

For the previous version of the review, the authors searched the Cochrane Epilepsy Group Specialized Register (January 2010), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 1), MEDLINE (1950 to January 2010), and reference lists of articles.

For this update, we searched the Cochrane Epilepsy Group Specialized Register (28 May 2015), CENTRAL (The Cochrane Library 2015, Issue 4), MEDLINE (Ovid, 1946 to May 2015), and reference lists of articles. We also contacted the manufacturers of lamotrigine (GlaxoSmithKline). No language restrictions were imposed.

Selection criteria: 

Randomised placebo-controlled trials of people with drug-resistant partial epilepsy of any age, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded. For cross-over studies, the first treatment period was treated as a parallel trial. Eligible participants were adults or children with drug-resistant partial epilepsy.

Data collection and analysis: 

For this update, two review authors independently assessed the trials for inclusion, and extracted data. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal (any reason), adverse effects, effects on cognition and quality of life. Primary analyses were by intention-to-treat. Sensitivity best and worse case analyses were undertaken to account for missing outcome data. Pooled Risk Ratios (RR) with 95% confidence intervals (95% Cl) were estimated for the primary outcomes of seizure frequency and treatment withdrawal. For adverse effects, pooled RRs and 99% Cls were calculated.

Main results: 

We did not identify any new studies for this update, therefore, the results are unchanged.

For the previous version of the review, the authors found five parallel add-on studies and eight cross-over studies in adults or children with refractory focal epilepsy, and one parallel add-on study with a responder-enriched design in infants. In total, these 14 studies included 1958 participants (38 infants, 199 children, and 1721 adults). Baseline phases ranged from 4 to 12 weeks; treatment phases from 8 to 36 weeks. Overall, eleven studies (n = 1243 participants) were rated as having a low risk of bias, and three (n = 715 participants) had un unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in three studies (n = 504 participants). The overall risk ratio (RR) for 50% or greater reduction in seizure frequency was 1.80 (95% CI 1.45 to 2.23; 12 RCTs) for twelve studies (n = 1322 participants, adults and children) indicating that lamotrigine was significantly more effective than placebo in reducing seizure frequency. The overall RR for treatment withdrawal (for any reason) was 1.11 (95% CI 0.90 to 1.36; 14 RCTs) for fourteen studies (n = 1958 participants). The adverse events significantly associated with lamotrigine were: ataxia, dizziness, diplopia, and nausea. The RR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; 12 RCTs; n = 1524); dizziness 2.00 (99% Cl 1.51 to 2.64;13 RCTs; n = 1767); diplopia 3.79 (99% Cl 2.15 to 6.68; 3 RCTs; n = 943); nausea 1.81 (99% Cl 1.22 to 2.68; 12 RCTs; n = 1486). The limited data available precluded any conclusions about effects on cognition and quality of life. No important heterogeneity between studies was found for any of the outcomes. Overall, we assessed the evidence as high to moderate quality, due to incomplete data for some outcomes.

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