Lamotrigine add-on therapy for drug-resistant generalised tonic-clonic seizures.

This is an update of the Cochrane Review first published in 2010; it includes one additional study. Primary generalised tonic-clonic seizures are a type of generalised seizure. Other types of seizures include: absence, myoclonic, and atonic seizures. Effective control of tonic-clonic seizures reduces the risk of injury and death, and improves quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not, and require a combination of antiepileptic drugs. To assess the effectiveness and tolerability of add-on lamotrigine for drug-resistant primary generalised tonic-clonic seizures. For the latest update, we searched these databases on 19 March 2019: Cochrane Register of Studies (CRS) Web, MEDLINE Ovid, and the WHO International Clinical Trials Registry Platform (ICTRP). The CRS includes records from the Cochrane Epilepsy Group Specialized Register, CENTRAL, Embase, and ClinicalTrials.gov. We imposed no language restrictions. We also contacted GlaxoSmithKline, manufacturers of lamotrigine. Randomised controlled parallel or cross-over trials of add-on lamotrigine for people of any age with drug-resistant primary generalised tonic-clonic seizures. We followed standard Cochrane methodology; two review authors independently assessed trials for inclusion, evaluated risk of bias, extracted relevant data, and GRADE-assessed evidence. We investigated these outcomes: (1) 50% or greater reduction in primary generalised tonic-clonic seizure frequency; (2) seizure freedom; (3) treatment withdrawal; (4) adverse effects; (5) cognitive effects; and (6) quality of life. We used an intention-to-treat (ITT) population for all analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs); for adverse effects, we used 99% CIs to compensate for multiple hypothesis testing. We included three studies (total 300 participants): two parallel-group studies and one cross-over study. We assessed varied risks of bias across studies; most limitations arose from the poor reporting of methodological details. We meta-analysed data extracted from the two parallel-group studies, and conducted a narrative synthesis for data from the cross-over study. Both parallel-group studies (270 participants) reported all dichotomous outcomes. Participants taking lamotrigine were almost twice as likely to attain a 50% or greater reduction in primary generalised tonic-clonic seizure frequency than those taking a placebo (RR 1.88, 95% CI 1.43 to 2.45; low-certainty evidence). The results between groups were inconclusive for the likelihood of seizure freedom (RR 1.55, 95% CI 0.89 to 2.72; very low-certainty evidence); treatment withdrawal (RR 1.20, 95% CI 0.72 to 1.99; very low-certainty evidence); and individual adverse effects: ataxia (RR 3.05, 99% CI 0.05 to 199.36); dizziness (RR 0.91, 99% CI 0.29 to 2.86; very low-certainty evidence); fatigue (RR 1.02, 99% CI 0.13 to 8.14; very low-certainty evidence); nausea (RR 1.60, 99% CI 0.48 to 5.32; very low-certainty evidence); and somnolence (RR 3.73, 99% CI 0.36 to 38.90; low-certainty evidence). The cross-over trial (26 participants) reported that 7/14 participants with generalised tonic-clonic seizures experienced a 50% or greater reduction in seizure frequency with add-on lamotrigine compared to placebo. The authors reported four treatment withdrawals, but did not specify during which treatment allocation they occurred. Rash (seven lamotrigine participants; zero placebo participants) and fatigue (five lamotrigine participants; zero placebo participants) were the most frequently reported adverse effects. None of the included studies measured cognition. One parallel-group study (N = 153) evaluated quality of life. They reported inconclusive results for the overall quality of life score between groups (P = 0.74). This review provides insufficient information to inform clinical practice. Low-certainty evidence suggests that lamotrigine reduces the rate of generalised tonic-clonic seizures by 50% or more. Very low-certainty evidence found inconclusive results between groups for all other outcomes. Therefore, we are uncertain to very uncertain that the results reported are accurate, and suggest that the true effect could be grossly different. More trials, recruiting larger populations, over longer periods, are necessary to determine lamotrigine's clinical use.

Bresnahan R ，Panebianco M ，Marson AG 《Cochrane Database of Systematic Reviews》

Lamotrigine add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review previously published in 2016. Epilepsy is a common neurological disorder, affecting 0.5% to 1% of the population. For nearly 30% of these people, their epilepsy is resistant to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is one of the newer antiepileptic drugs. Lamotrigine, in combination with other antiepileptic drugs (add-on), can reduce seizures, but with some adverse effects. To determine the effects of lamotrigine on (1) seizures, (2) adverse-effect profile, and (3) cognition and quality of life, compared to placebo, when used as an add-on treatment for people with drug-resistant focal epilepsy. For the latest update of the review, we searched the following databases on 9 March 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to March 06, 2020). CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. No language restrictions were imposed. Randomised placebo-controlled trials of people with drug-resistant focal epilepsy of any age, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded, placebo-controlled. For cross-over studies, the first treatment period was treated as a parallel trial. Eligible participants were adults or children with drug-resistant focal epilepsy. 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 (RRs) with 95% confidence intervals (95% Cls) were estimated for the primary outcomes of seizure frequency and treatment withdrawal. For adverse effects, we calculated pooled RRs and 99% Cls. We did not identify any new studies for this update, therefore, the results and conclusions are unchanged. In previous updates of this review, the authors found five parallel add-on studies, eight cross-over studies in adults or children with drug-resistant focal epilepsy, and one parallel add-on study with a responder-enriched design in infants. In total, these 14 studies included 1806 eligible participants (38 infants, 199 children, 1569 adults). Baseline phases ranged from four to 12 weeks; treatment phases from eight to 36 weeks. Overall, 11 studies (1243 participants) were rated as having low risk of bias, and three (697 participants) had unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in four studies (563 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 trials, 1322 participants (adults and children); moderate-certainty evidence) 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 0.91 to 1.37; 14 trials; 1806 participants; moderate-certainty evidence). The adverse events significantly associated with lamotrigine were: ataxia, dizziness, diplopia (double vision), and nausea. The RR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; 12 trials; 1525 participants; high-certainty evidence); dizziness 2.00 (99% Cl 1.52 to 2.64;13 trials; 1768 participants; moderate-certainty evidence); diplopia 3.79 (99% Cl 2.15 to 6.68; 3 trials, 944 participants; high-certainty evidence); nausea 1.81 (99% Cl 1.22 to 2.68; 12 studies,1486 participants; moderate-certainty evidence). 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 certainty, due to incomplete data for some outcomes. Lamotrigine as an add-on treatment for drug-resistant focal 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 lamotrigine with other add-on drugs.

Panebianco M ，Bresnahan R ，Ramaratnam S ，Marson AG ... -  《Cochrane Database of Systematic Reviews》

Pregabalin add-on for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review last published in Issue 7, 2019; it includes two additional studies. Epilepsy is a common neurological disease that affects approximately 1% of the UK population. Approximately one-third of these people continue to have seizures despite drug treatment. Pregabalin is one of the newer antiepileptic drugs that has been developed to improve outcomes. In this review we summarised the current evidence regarding pregabalin when used as an add-on treatment for drug-resistant focal epilepsy. To assess the efficacy and tolerability of pregabalin when used as an add-on treatment for drug-resistant focal epilepsy. For the latest update we searched the following databases on 16 November 2020: Cochrane Register of Studies (CRS Web), and MEDLINE (Ovid, 1946 to 16 November 2020). CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organisation International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups, including Epilepsy. We imposed no language restrictions. We contacted the manufacturers of pregabalin and authors in the field to identify any relevant unpublished studies. We included randomised controlled trials comparing pregabalin with placebo or an alternative antiepileptic drug as an add-on for people of any age with drug-resistant focal epilepsy. Double-blind and single-blind trials were eligible for inclusion. The primary outcome was 50% or greater reduction in seizure frequency; secondary outcomes were seizure freedom, treatment withdrawal for any reason, treatment withdrawal due to adverse effects, and proportion of individuals experiencing adverse effects. Two review authors independently selected trials for inclusion and extracted the relevant data. Primary analyses were intention-to-treat (ITT). We presented summary risk ratios (RRs) and odds ratios (ORs) with 95% confidence intervals (CIs). We evaluated dose response in regression models. We carried out a risk of bias assessment for each included study using the Cochrane risk of bias tool and assessed the overall certainty of evidence using the GRADE approach. We included 11 randomised controlled trials (3949 participants). Nine trials compared pregabalin to placebo. For the primary outcome, participants randomised to pregabalin were significantly more likely to attain a 50% or greater reduction in seizure frequency compared to placebo (RR 1.95, 95% CI 1.40 to 2.72, 9 trials, 2663 participants, low-certainty evidence). The odds of response doubled with an increase in dose from 300 mg/day to 600 mg/day (OR 1.99, 95% CI 1.74 to 2.28), indicating a dose-response relationship. Pregabalin was significantly associated with seizure freedom (RR 3.94, 95% CI 1.50 to 10.37, 4 trials, 1125 participants, moderate-certainty evidence). Participants were significantly more likely to withdraw from pregabalin treatment than placebo for any reason (RR 1.33, 95% CI 1.10 to 1.60; 9 trials, 2663 participants; moderate-certainty evidence) and for adverse effects (RR 2.60, 95% CI 1.86 to 3.64; 9 trials, 2663 participants; moderate-certainty evidence). Three trials compared pregabalin to three active-control drugs: lamotrigine, levetiracetam and gabapentin. Participants allocated to pregabalin were significantly more likely to achieve a 50% or greater reduction in seizure frequency than those allocated to lamotrigine (RR 1.47, 95% CI 1.03 to 2.12; 1 trial, 293 participants) but not those allocated to levetiracetam (RR 0.94, 95% CI 0.80 to 1.11; 1 trial, 509 participants) or gabapentin (RR 0.96, 95% CI 0.82 to 1.12; 1 trial, 484 participants). We found no significant differences between pregabalin and lamotrigine for seizure freedom (RR 1.39, 95% CI 0.40 to 4.83). However, significantly fewer participants achieved seizure freedom with add-on pregabalin compared to levetiracetam (RR 0.50, 95% CI 0.30 to 0.85). No data were reported for this outcome for pregabalin versus gabapentin. We detected no significant differences in treatment withdrawal rate for any reason or due to adverse effects, specifically, during either pooled analysis or subgroup analysis. Ataxia, dizziness, somnolence, weight gain, headache and fatigue were significantly associated with pregabalin than in active control. We rated the overall risk of bias in the included studies as low or unclear due to the possibility of publication bias and lack of methodological details provided. We assessed all the studies to be at a high risk of funding bias as they were all sponsored by Pfizer. We rated the certainty of the evidence as very low to moderate using the GRADE approach. For people with drug-resistant focal epilepsy, pregabalin when used as an add-on treatment was significantly more effective than placebo at producing a 50% or greater seizure reduction and seizure freedom. Results demonstrated efficacy for doses from 150 mg/day to 600 mg/day, with increasing effectiveness at 600 mg doses, although there were issues with tolerability at higher doses. However, the trials included in this review were of short duration, and longer-term trials are needed to inform clinical decision-making. This review focused on the use of pregabalin in drug-resistant focal epilepsy, and the results cannot be generalised to add-on treatment for generalised epilepsies. Likewise, no inference can be made about the effects of pregabalin when used as monotherapy.

Panebianco M ，Bresnahan R ，Marson AG 《Cochrane Database of Systematic Reviews》

Pregabalin add-on for drug-resistant focal epilepsy.

Panebianco M ，Bresnahan R ，Hemming K ，Marson AG ... -  《Cochrane Database of Systematic Reviews》

Lamotrigine add-on therapy for drug-resistant focal epilepsy.

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. 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. 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. 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. 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. 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). 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.

Panebianco M ，Bresnahan R ，Marson AG 《Cochrane Database of Systematic Reviews》