Mariangela Panebianco1, Rebecca Bresnahan1,2, Anthony G Marson1,3,4. 1. Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. 2. Liverpool Reviews and Implementation Group, Department of Health Data Science, University of Liverpool, Liverpool, UK. 3. The Walton Centre NHS Foundation Trust, Liverpool, UK. 4. Liverpool Health Partners, Liverpool, UK.
Abstract
BACKGROUND: 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. OBJECTIVES: To assess the efficacy and tolerability of pregabalin when used as an add-on treatment for drug-resistant focal epilepsy. SEARCH METHODS: 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 We contacted the manufacturers of pregabalin and authors in the field to identify any relevant unpublished studies. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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, eventrate 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 eventrate (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 eventrate (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. AUTHORS' CONCLUSIONS: 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.
BACKGROUND: 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. OBJECTIVES: To assess the efficacy and tolerability of pregabalin when used as an add-on treatment for drug-resistant focal epilepsy. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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, eventrate 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 eventrate (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 eventrate (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. AUTHORS' CONCLUSIONS: 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.
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