Pregabalin add‐on for drug‐resistant focal epilepsy

Mariangela Panebianco; Rebecca Bresnahan; Karla Hemming; Anthony G Marson

doi:10.1002/14651858.CD005612.pub4

. 2019 Jul 9;2019(7):CD005612. doi: 10.1002/14651858.CD005612.pub4

Pregabalin add‐on for drug‐resistant focal epilepsy

Mariangela Panebianco ¹, Rebecca Bresnahan ^1,^✉, Karla Hemming ², Anthony G Marson ^1,^3,⁴

Editor: Cochrane Epilepsy Group

PMCID: PMC6614921 PMID: 31287157

Abstract

Background

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 which have been developed to improve outcomes.

This is an updated version of the Cochrane Review published in Issue 3, 2014, and includes three new studies.

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 Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), on 5 July 2018, MEDLINE (Ovid, 1946 to 5 July 2018), ClinicalTrials.gov (5 July 2018), and the World Health Organization International Clinical Trials Registry Platform (ICTRP, 5 July 2018), and contacted Pfizer Ltd, manufacturer of pregabalin, to identify published, unpublished, and ongoing trials.

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 and assessed trials for eligibility and extracted data. Analyses were by intention‐to‐treat. We presented results as risk ratios (RR) and odds ratios (OR) with 95% confidence intervals (CIs). Two review authors assessed the included studies for risk of bias using the Cochrane 'Risk of bias' tool.

Main results

We included nine industry‐sponsored randomised controlled trials (3327 participants) in the review. Seven 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 2.28, 95% CI 1.52 to 3.42, 7 trials, 2193 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 1.35, 95% CI 1.11 to 1.65, 7 trials, 2193 participants, moderate‐certainty evidence) and for adverse effects (RR 2.65, 95% CI 1.88 to 3.74, 7 trials, 2193 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 (RR 1.39, 95% CI 0.40 to 4.83) for seizure freedom, 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 found no significant differences between pregabalin and lamotrigine (RR 1.07, 95% CI 0.75 to 1.52), levetiracetam (RR 1.03, 95% CI 0.71 to 1.49), or gabapentin (RR 0.78, 95% CI 0.57 to 1.07) for treatment withdrawal due to any reason or due to adverse effects (pregabalin versus lamotrigine: RR 0.89, 95% CI 0.53 to 1.48; versus levetiracetam: RR 1.29, 95% CI 0.66 to 2.54; versus gabapentin: RR 1.07, 95% CI 0.54 to 2.11). Ataxia, dizziness, somnolence, weight gain, and fatigue were significantly associated with pregabalin.

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 rated the certainty of the evidence as very low to moderate using the GRADE approach.

Authors' conclusions

Pregabalin, when used as an add‐on drug for treatment‐resistant focal epilepsy, is 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, however issues with tolerability were noted at higher doses. The trials included in this review were of short duration, and longer‐term trials are needed to inform clinical decision making.

Plain language summary

Pregabalin add‐on for drug‐resistant focal epilepsy

Review question

This review aimed to assess the effectiveness and tolerability of pregabalin when used as an add‐on antiepileptic drug in treatment‐resistant focal epilepsy.

Background

Epilepsy is a common chronic neurological disease that affects approximately 1% of people in the UK. Approximately 1 in 400 people with epilepsy have seizures that continue despite antiepileptic drug treatment (drug‐resistant epilepsy). A number of new antiepileptic drugs have been developed to treat epilepsy, of which pregabalin is one. Use of pregabalin in combination with other antiepileptic drugs can reduce the frequency of seizures, but has some adverse effects.

Study characteristics

This review examined data from 9 trials including a total of 3327 participants. Study participants were assigned using a random method to take pregabalin, placebo, or another antiepileptic drug in addition to their usual antiepileptic drugs.

Key results

Participants taking pregabalin were more than twice as likely to have their seizure frequency reduced by 50% or more during a 12‐week treatment period compared to those taking placebo, and were nearly four times more likely to be completely free of seizures. Pregabalin was shown to be effective across a range of doses (150 mg to 600 mg), with increasing effectiveness at higher doses. There was also an increased likelihood of treatment withdrawal with pregabalin. Side effects associated with pregabalin included ataxia, dizziness, fatigue, somnolence, and weight gain. When pregabalin was compared to three other antiepileptic drugs (lamotrigine, levetiracetam, and gabapentin), participants taking pregabalin were more likely to achieve a 50% reduction in seizure frequency than those taking lamotrigine. We found no significant differences between pregabalin and levetiracetam or gabapentin as add‐on drugs.

Certainty of the evidence

We rated all included studies as at low or unclear in risk of bias due to missing information about the methods used to conduct the trial and a suspicion of publication bias. Publication bias can occur when studies that report non‐significant findings are not published. We suspected publication bias because the majority of included studies showed significant findings and were sponsored by the same drug company. We assessed the certainty of the evidence for the primary outcome of reduction in seizure frequency as low, meaning that we cannot be certain that the finding reported is accurate. However, we rated the certainty of the evidence for the outcomes seizure freedom and treatment withdrawal as moderate, so we can be fairly confident that these results are accurate. There were no data regarding the longer‐term effectiveness of pregabalin, which should be investigated in future studies.

The evidence is current to 5 July 2018.

Summary of findings

Background

Description of the condition

Epilepsy is a common neurological chronic condition that affects approximately 1% of the UK population (Hauser 1990). A single antiepileptic drug (AED) (monotherapy) can induce remission for the majority of those diagnosed. However, up to 30% of people with epilepsy fail to respond to monotherapy (Cockerell 1995). Patients who have failed to respond to a minimum of two AEDs given as monotherapy are considered to be 'drug‐resistant'. The majority of those who are drug‐resistant have focal onset (also called focal‐ or localisation‐related) seizures. During focal‐onset seizures, abnormal electrical activity initiates in one part of the brain, and during the course of the seizure the abnormal electrical activity either remains localised or spreads to other parts of the brain (Ramaratnam 2016). For individuals with drug‐resistant focal epilepsy, recurrent seizures can reduce quality of life, and may also lead to injuries, social isolation, and depression (Villeneuve 2004). Individuals with this neurological condition pose a significant therapeutic problem, which has led to the development of new AEDs as well as exploration of non‐pharmacological treatment options, such as vagal nerve stimulation and epilepsy surgery (Panebianco 2015; West 2015). Over the past two decades, the introduction of several new antiepileptic drugs that often are better tolerated and more manageable than older AEDs has improved the ability to treat individuals with epilepsy. Recent studies have reported that 12% to 17% of treatment‐resistant individuals become seizure‐free with the addition of a previously untried, in most cases new‐generation, antiepileptic drug (Granata 2009).

Description of the intervention

Since the 1990s, numerous new AEDs have become available that aim to provide more potent and better‐tolerated treatments for epilepsy. Pregabalin is one of these new compounds with antiepileptic, analgesic, and anxiolytic (anxiety‐reducing) properties. Pregabalin has favourable pharmacokinetics: it is not protein bound, is 90% bioavailable, and reaches peak plasma concentrations within 1.5 hours of administration of an oral dose. With repeated doses, a steady state is achieved within 24 to 48 hours. Furthermore, 90% of the drug is eliminated, unmetabolised, by the kidneys, and it has no known drug interactions (Brodie 2005). Pregabalin was launched in the UK market in 2004 as an add‐on AED for focal‐onset seizures, as well as a treatment for neuropathic pain, and as an anxiolytic in 2006.

How the intervention might work

Pregabalin is structurally related to both the neurotransmitter γ‐aminobutyric acid (GABA), and the older antiepileptic drug, gabapentin. Similar to gabapentin, the primary mechanism underlying the pharmacological action of pregabalin does not appear to involve the GABA system. In particular, pregabalin does not bind to GABA‐A, GABA‐B, or benzodiazepine receptors. Pregabalin is neither metabolically converted to GABA or to a GABA agonist, nor does it have any effect on the uptake or degradation of GABA. In fact, the primary mode of action of pregabalin is via the inhibition of depolarisation‐induced calcium influx at P‐, Q‐, and N‐type voltage‐gated calcium channels, located at the nerve terminals. At the molecular level, this action is achieved by pregabalin binding to the α‐2‐δ subunit of voltage‐gated calcium channels (Ben‐Menachem 2004). As a consequence of the reduced calcium influx, less excitatory neurotransmitter, such as glutamate, is released from the presynaptic nerve terminals.This action is thought to mediate its antiepileptic, anxiolytic, and analgesic properties. In addition, by acting on AMPA (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid) receptors, pregabalin indirectly reduces synaptic noradrenaline release (Fink 2002).

Notably, the mechanism of action of pregabalin does not appear to differ from that of gabapentin. The affinity of pregabalin for the α‐2‐δ modulatory site, however, is much greater than that of gabapentin. This explains why pregabalin is three‐ to six‐fold more potent than gabapentin in animal models of seizures and epilepsy, and also in models of anxiety and neuropathic pain.

Why it is important to do this review

This review is an update of a previous Cochrane Review (Pulman 2014) and aims to summarise existing data regarding the effects of add‐on pregabalin for people with drug‐resistant focal‐onset seizures. Clinical trials published on the antiepileptic properties of pregabalin have so far focused on people with drug‐resistant focal‐onset epilepsy. In these randomised placebo‐controlled trials, study participants are randomised to have either pregabalin or placebo added to their existing AED treatment. This is in keeping with international guidelines on the development of AEDs (ILAE Commission 1989). Once a drug has confirmed efficacy and safety as an add‐on therapy, it can be tested as monotherapy. The use of pregabalin as monotherapy has been addressed in a separate Cochrane Review by Zhou 2012.

Objectives

To assess the efficacy and tolerability of pregabalin when used as an add‐on treatment for drug‐resistant focal epilepsy.

Methods

Criteria for considering studies for this review

Types of studies

To be included in the review, studies had to meet the following criteria:

randomised controlled trials;
double‐blind or single‐blinded trials;
placebo controlled or active controlled;
parallel‐group or cross‐over studies.

Types of participants

People of any age with drug‐resistant focal epilepsy (i.e. experiencing simple focal, complex focal, or secondary generalised tonic‐clonic seizures).

Types of interventions

The active‐treatment group received pregabalin in addition to an existing AED regimen taken at time of randomisation.
The control group received a matched placebo or an active comparator control in addition to an existing AED regimen taken at time of randomisation.

Types of outcome measures

Primary outcomes

50% or greater reduction in seizure frequency

We chose the proportion of people with a 50% or greater reduction in seizure frequency in the treatment period compared to the pre‐randomisation baseline period as the primary outcome. We chose this because it is a commonly reported outcome, and can be calculated for studies that do not report this outcome provided that baseline seizure data were recorded.

Secondary outcomes

Seizure freedom

The proportion of participants with a complete cessation of seizures during the treatment period.

Treatment withdrawal

We used the proportion of participants having treatment withdrawn for any reason during the course of the treatment period as a measure of global effectiveness. Treatment is likely to be withdrawn due to adverse effects, lack of efficacy, or a combination of both, and this is an outcome to which the individual makes a direct contribution. In trials of short duration, it is likely that adverse effects will be the most common reason for withdrawal. We also assessed the proportion of participants having treatment withdrawn for adverse effects.

Adverse effects

The proportion of participants experiencing the following five adverse effects (we considered these adverse effects to be common and important adverse effects of AEDs):
1. ataxia (co‐ordination problems);
2. dizziness;
3. fatigue;
4. nausea;
5. somnolence (unusual drowsiness).
The proportion of participants experiencing the five most common adverse effects mentioned in the included trials if these differed from those listed in (1) above.

Search methods for identification of studies

Electronic searches

We ran searches for the original review in 2007, and subsequent searches in March 2010, September 2011, May 2012, January 2014, September 2015, and September 2016. For the latest update we searched the following.

Cochrane Register of Studies (CRS Web, 5 July 2018), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), using the search strategy outlined in Appendix 1.
MEDLINE (Ovid, 1946 to 5 July 2018) using the search strategy outlined in Appendix 2.
ClinicalTrials.gov (5 July 2018) using the search strategy outlined in Appendix 3.
World Health Organization International Clinical Trials Registry Platform (ICTRP, 5 July 2018) using the search strategy outlined in Appendix 4.

We did not impose any language restrictions.

Searching other resources

We reviewed the reference lists of retrieved studies to check for additional reports of relevant studies. We also contacted Pfizer Ltd (manufacturer of pregabalin) and colleagues in the field.

Data collection and analysis

Selection of studies

For the update, two review authors (RB and MP) independently assessed trials for inclusion. Any disagreements were resolved by discussion with a third review author (AM). Two review authors (RB and MP) extracted data and assessed risk of bias; again, disagreements were resolved by discussion.

Data extraction and management

The same two review authors extracted the following information from the included trials. Any disagreements were resolved by mutual discussion.

Methodological/trial design

Method of randomisation and concealment.
Method of double‐blinding.
Whether any participants had been excluded from the reported analyses.
Duration of baseline period.
Duration of treatment period.
Dose(s) of pregabalin tested.

Participant/demographic information

Total number of participants allocated to each treatment group.
Age/sex.
Number with focal/generalised epilepsy.
Seizure types.
Seizure frequency during the baseline period.
Number of background drugs.

For all trials sponsored by Pfizer Ltd, confirmation of the following information

Method of randomisation.
Total number randomised to each group.
Number of participants in each group achieving a 50% or greater reduction in seizure frequency.
Number of participants in each group having treatment withdrawn postrandomisation.
For excluded participants:
1. the reason for exclusion;
2. whether any of those excluded completed the treatment phase;
3. whether any of those excluded had a 50% or greater reduction in seizure frequency during the treatment phase.

Outcomes

We recorded the number of participants experiencing each outcome (see Types of outcome measures) per randomised group.

Assessment of risk of bias in included studies

For the update, two review authors (RB and MP) independently assessed risk of bias for each trial using the Cochrane 'Risk of bias' tool as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreements were discussed and resolved. We judged each included study to be at low, high, or unclear risk of bias for the six domains applicable to randomised controlled trials: randomisation method, allocation concealment, blinding methods, incomplete outcome data, selective outcome reporting, and other sources of bias.

Measures of treatment effect

We presented the primary outcome of seizure reduction as a risk ratio. We also presented the secondary outcomes, including seizure freedom, treatment withdrawal, and adverse effects, as risk ratios.

Unit of analysis issues

The inclusion of cross‐over studies in meta‐analyses introduces unit of analysis issues because each patient contributes data to both treatment groups. We had planned to extract data from the first treatment period of any eligible cross‐over studies, had any been identified for inclusion. Essentially, we would have regarded the first treatment period as a parallel study, thus preventing data from the same patient being considered twice whilst simultaneously avoiding any issues of carry‐over effect. We did not include any cross‐over studies in this current review update, hence there were no unit of analysis issues to consider.

Dealing with missing data

We sought any missing data from the study authors. We carried out intention‐to‐treat (ITT), best‐case, and worst‐case analysis on the primary outcome to account for any missing data. All analyses are presented in the main report.

Assessment of heterogeneity

We assessed clinical heterogeneity by comparing the distribution of important participant factors amongst trials (e.g. age, seizure type, duration of epilepsy, number of antiepileptic drugs taken at the time of randomisation) and trial factors (e.g. allocation concealment, blinding, losses to follow‐up). We examined statistical heterogeneity using a Chi² test and the I² statistic for heterogeneity and, providing no significant heterogeneity was present (P > 0.10), we employed a fixed‐effect model. In the event that we found heterogeneity (P < 0.10), we planned to use a random‐effects model analysis employing the inverse‐variance method.

Assessment of reporting biases

We requested protocols from study authors to enable a comparison of outcomes of interest. We investigated outcome reporting bias using the Outcome Reporting Bias in Trials (ORBIT I) matrix system for benefit outcomes, Kirkham 2010, and ORBIT II matrix system for harm outcomes (Saini 2014). We examined the asymmetry of funnel plots to detect any publication bias.

Data synthesis

We employed a fixed‐effect model meta‐analysis to synthesise the data. Comparisons we expected to carry out included:

pregabalin intervention group versus placebo control group;
pregabalin intervention group versus active‐comparator control group.

We planned to stratify each comparison by study characteristics, such as dose of pregabalin used, during subgroup analysis to ensure the appropriate combination of study data.

Our preferred estimator was the Mantel‐Haenszel risk ratio (RR). For the outcomes 50% or greater reduction in seizure frequency and treatment withdrawal, we used 95% confidence intervals (CIs). For individual adverse effects, we used 99% CIs to make an allowance for multiple testing.

Our analyses included all participants in the treatment group to which they had been allocated. For the efficacy outcome (50% or greater reduction in seizure frequency), we undertook three analyses:

Primary (ITT) analysis: participants not completing follow‐up or with inadequate seizure data were assumed to be non‐responders. Analysis by ITT was reported by all of the included studies.
Worst‐case analysis: participants not completing follow‐up or with inadequate seizure data were assumed to be non‐responders in the intervention group, and responders in the placebo group.
Best‐case analysis: participants not completing follow‐up or with inadequate seizure data were assumed to be responders in the intervention group, and non‐responders in the placebo group.

The purpose of the best‐case and worst‐case analyses is to test the whether the assumption that all participants not completing follow‐up or with inadequate seizure data are non‐responders, made during ITT analysis, affects the estimated effect size.

Dose regression analysis

Dose‐response analysis was evaluated using a generalised linear mixed model (i.e. a model including both fixed and random effects) with the logit link function, as described in Turner 2000, and estimated using the command xtmelogit in STATA SE version 14 (Stata statistical software 2015). Study and dose were included as fixed effects within the mixed model whilst treatment was included as a random‐effect within the mixed model (no random‐effect was included for the constant term of the mixed model). Dose was standardised by its standard deviation (245 mg). This method estimated an odds ratio (OR) as opposed to a RR.

Subgroup analysis and investigation of heterogeneity

We undertook subgroup analysis for all of the outcomes included in this review. For the comparison pregabalin versus placebo, subgroup analysis was stratified by dose of pregabalin. Dose of pregabalin was chosen because it was the most striking clinical difference identified between the included studies and was thus anticipated to be the cause of any observed heterogeneity. For the comparison pregabalin versus active comparator, subgroup analysis was stratified by active comparator in order to determine whether pregabalin might be advantageous or disadvantageous compared to a specific alternative AED. If deemed appropriate, we intended to investigate heterogeneity using sensitivity analysis.

Sensitivity analysis

We also intended to carry out sensitivity analysis if peculiarities were found between study quality, characteristics of participants, interventions, and outcomes. We did not find any peculiarities between the studies, therefore no sensitivity analyses were conducted.

Summarising and interpreting results

We used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to interpret findings, and GRADEpro GDT software (which imports data from Review Manager 5 software (GRADEpro GDT 2015)), to create a 'Summary of findings' table for both comparisons: pregabalin versus placebo and pregabalin versus active comparator. We GRADE‐assessed the following outcomes, deemed to be the most important: 50% of greater reduction in seizure frequency (intention‐to‐treat, best‐case, and worst‐case analysis), seizure freedom, treatment withdrawal for any reason and treatment withdrawal due to adverse effects. We assessed the evidence across eight criteria (risk of bias, inconsistency, indirectness, imprecision, publication bias, effect size, presence of plausible confounding factors, and dose‐response gradient) to determine its certainty.

Results

Description of studies

Results of the search

The searches conducted (September 2015, September 2016 and July 2018), subsequent to the previously published search in January 2014, retrieved a total of 134 new records (see Figure 1). We removed 50 duplicates and 59 obviously irrelevant records, prior to any screening. This left 25 records to be evaluated based on title and abstract. We removed 21 records, based on their title and abstract, and subsequently assessed four records as full‐text articles. We excluded one record that was ineligible for inclusion (Taghdiri 2015). The other three studies (French 2014, French 2016 and Zaccara 2014), however, satisfied all inclusion criteria and were therefore included in the review.

Study flow diagram showing the screening results from the searches conducted in: September 2015, September 2016, and July 2018.

Included studies

We included nine randomised controlled trials (3327 participants) with parallel‐group design in the review, all of which were sponsored by the drug manufacturer Pfizer Ltd. All nine of the included studies recruited participants with drug‐resistant focal‐onset seizures. Participants were taking between one and four AEDs and had at least three, four, or six focal seizures per month in the pre‐randomisation baseline period. Further details are given below and are summarised in the Characteristics of included studies tables.

Arroyo and colleagues published a multicentre (45 sites in Europe, Australia, and Africa) trial in 2004 that included 288 participants (Arroyo 2004). Inclusion criteria were defined as people aged 18 years or older with focal‐onset seizures. As an electroencephalogram (EEG) was not required to confirm the diagnosis, some of the 18 participants who were stated as having "generalised seizures", rather than secondary generalised, may have had primary generalised epilepsy. Participants were randomised to either 50 mg pregabalin three times daily (n = 99); 200 mg pregabalin three times daily (n = 92); or placebo three times daily (n = 97). After a baseline assessment of eight weeks, the treatment period was conducted over 12 weeks (including a titration period of four and eight days). During the treatment period, participants were assessed weekly for the first two weeks and fortnightly thereafter. Median follow‐up was 12 weeks (range one day to 12 weeks). Three time points were reported in the study, each at four‐weekly intervals.

Baulac and colleagues conducted a multicentre (97 sites in Europe, Canada, and Australia) trial, comprising 434 participants (Baulac 2010). Randomised participants were between 16 and 82 years of age and had undergone an EEG within two years prior to randomisation. Treatment arms were 150 mg to 300 mg pregabalin twice daily (n = 152); 150 mg to 200 mg lamotrigine twice daily (n = 141); and placebo (n = 141). Following a six‐week baseline period, there was a 17‐week double‐blind treatment period comprising two phases. The first phase (phase I) spanned 11 weeks and included an up‐titration period (one week for pregabalin and five weeks for lamotrigine). During phase I, participants randomised to pregabalin and lamotrigine were both up‐titrated to 300 mg/d of their respective treatment drugs and were then maintained on this dose. Participants who were seizure‐free for the duration of phase I continued to be maintained on 300 mg/d active treatment for the duration of phase II (six weeks). Participants randomised to pregabalin who continued to have seizures were further up‐titrated to 600 mg/d pregabalin during phase II, whereas participants randomised to lamotrigine who continued to have seizures were up‐titrated to 400 mg/d lamotrigine for the remaining six weeks of the treatment period. Participant review time points and follow‐up were not reported.

Beydoun and colleagues randomised 313 participants, aged 17 to 82 years, from 43 US and Canadian centres in a randomised placebo‐controlled trial (Beydoun 2005). Treatment groups included 200 mg pregabalin three times daily (n = 111); 300 mg pregabalin twice daily (n = 104); and placebo (n = 98). After a baseline assessment of eight weeks, the treatment period was conducted over 12 weeks (including a one‐week titration period). Follow‐up occurred on weeks two, four, eight, and 12. Median follow‐up was 12 weeks (range not reported). During the trial an interim analysis was carried out on 129 participants, which led to an alteration of the subsequent statistical analysis.

Elger and colleagues reported a multicentre (53 sites in Canada and Europe) trial of 341 participants, aged 17 to 78 years (Elger 2005). Treatment arms were 150 mg to 600 mg pregabalin (n = 131), titrated with respect to clinical response and adverse effects in 150 mg daily increments; fixed‐dose pregabalin of 300 mg twice daily (n = 137); and placebo (n = 73). Participants were randomised to one of the three treatments using a 2:2:1 ratio, respectively. The treatment period ran over 12 weeks and followed a six‐week baseline period. Participants were reviewed at two, four, eight, and 12 weeks into the study. Median follow‐up was 12 weeks, and over 58% of participants completed the study in each arm. The range of follow‐up was not reported.

French and colleagues published a multicentre (76 sites in US and Canada) trial that included 455 participants (French 2003). Randomised participants were between 12 and 70 years of age, but not all had EEG and imaging data. Those with absence seizures and Lennox‐Gastaut syndrome were excluded; however, the inclusion of some patients with primary generalised epilepsy could not be ruled out. Participants were randomised into one of five treatment arms: 50 mg/day (n = 88), 150 mg/day (n = 88), 300 mg/day (n = 90), and 600 mg/day (n = 89) pregabalin in a twice‐daily regimen, and placebo (n = 100). Baseline assessment occurred over eight weeks, and treatment duration was 12 weeks with no titration period. Follow‐up occurred on weeks two, four, eight, and 12. Median follow‐up was 12 weeks (range one day to 12 weeks). Around 83% of participants completed the study.

French and colleagues published a multicentre (66 centres in the USA, Europe, and Asia) trial that included 325 participants, aged 18 to 75 years (French 2014). Participants were randomised 1:1:1 to controlled‐release pregabalin 165 mg (n = 101), 330 mg (n = 114), or placebo (n = 110). The trial ran over 23 weeks including an eight‐week baseline phase, a two‐week double‐blind dose escalation, a 12‐week double‐blind maintenance phase, and a one‐week taper. The mean overall compliance was 99.2% for all three treatment arms, as demonstrated by participant‐completed diaries.

French and colleagues conducted a multicentre (56 centres in Eastern and Western Europe, Asia, South and Central America) trial that included 484 participants between 18 and 80 years of age (French 2016). Participants were randomised 1:1 to pregabalin 450 mg/d (n = 241) or gabapentin 1500 mg/d (n = 241). The trial included a six‐week baseline phase (screening), a nine‐week double‐blind dose escalation (titration) phase, and a 12‐week double‐blind maintenance phase (21‐week treatment phase overall). The primary endpoint was the percentage change from baseline in 28‐day seizure rate to the treatment phase. Around 74% of participants completed the study.

Lee and colleagues conducted a multicentre (nine sites in Korea) trial consisting of two treatment arms (Lee 2009). A total of 178 participants, aged 18 years and above, were randomised to either 75 mg to 300 mg pregabalin twice daily (n = 119) or placebo (n = 59) using a 2:1 ratio. Following a six‐week baseline period, treatment was conducted over 12 weeks with a one‐week taper period at the end. Participants were assessed at weeks two, four, six, eight, and 12 with a follow‐up visit at week 13. Eighty‐eight per cent of randomised participants completed the study.

Zaccara and colleagues randomised 509 participants aged ≥ 18 from 71 centres in Europe, the USA, and Asia to one of two groups: pregabalin (n= 254; median dose 450 mg) or levetiracetam (n = 255; median dose 2000 mg) (Zaccara 2014). The trial included a six‐week baseline phase, a four‐week dose escalation phase, and a 12‐week maintenance phase. During the trial an interim analysis was carried out after approximately 50% of participants had completed the maintenance phase. The trial continued as planned.

Excluded studies

From the searches conducted since the previous review update, it was clear that one previously ongoing trial (Bali 2012), has since been published (Taghdiri 2015). This study was, however, excluded due to the ineligibility regarding the study population. Further details are provided in the Characteristics of excluded studies table.

Studies awaiting classification

We assessed two studies as awaiting classification (see Characteristics of studies awaiting classification table), as we have obtained no additional information regarding either study since the publication of the previous review (Russi 2006; Tata 2007).

Risk of bias in included studies

We assessed all nine included studies for risk of bias based on the six domains of the Cochrane 'Risk of bias' tool. See Characteristics of included studies tables for each study for further details and Figure 2 for 'Risk of bias' graph and Figure 3 for 'Risk of bias' summary.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Seven of the nine included studies employed an adequate method of sequence generation by using computer‐generated identification numbers and block sizes of five or six (Arroyo 2004; Beydoun 2005; Elger 2005; French 2003; French 2014; French 2016; Zaccara 2014), therefore we assessed them as being at low risk of selection bias with regard to random sequence generation. Two of the studies did not provide details regarding method of randomisation and were judged as at unclear risk of bias (Baulac 2010; Lee 2009). None of the studies reported methods employed to prevent foreknowledge of group assignment (allocation concealment), and were therefore assessed as at unclear risk of bias for selection bias with regard to allocation concealment.

Blinding

Six studies were reported as double‐blinded with the use of identical tablets with identical packaging for all treatment groups (Arroyo 2004; Beydoun 2005; Elger 2005; French 2003; French 2016; Zaccara 2014); we assessed these studies as at low risk of performance and detection bias. Two studies were reported as double‐blinded, but no further details were provided (French 2014; Lee 2009). Another study stated that the same number of capsules per day were administered to each study group, however the study did not specify whether the tablets were identical in appearance (Baulac 2010). As a result, it was not clear whether blinding was effectively maintained. We therefore assessed these three studies as at unclear risk of performance and detection bias (Baulac 2010; French 2014; Lee 2009).

Incomplete outcome data

All studies reported study attrition rates, and all studies used an ITT analysis on randomised participants who took at least one dose of medication, using the 'last observation carried forward' approach (Arroyo 2004; Baulac 2010; Beydoun 2005; Elger 2005; French 2003; French 2014; French 2016; Lee 2009), that is for participants failing to complete follow‐up, seizure‐frequency data were extrapolated from the last participant observation point for the whole treatment period, whilst for participants with no seizure data during the treatment period, baseline data were extrapolated. In the trial reports a total of six participants were excluded from analyses; these participants have been included in the denominator as non‐responders for the primary analysis.

Selective reporting

Most of the included studies distinguished between the primary and secondary outcome variables. No trial protocols were available for examination to compare reported outcomes, however all studies reported the primary/secondary outcomes stated in the methods section in the results section of the articles. Notably, all expected outcomes with respect to this review were reported, therefore we had no suspicions or concerns about any purposefully withheld data.

Further to this, we also completed an outcome matrix (Figure 4) according to the ORBIT I and ORBIT II matrix system to investigate the potential for outcome reporting bias (Kirkham 2010; Saini 2014). Four included studies did not report seizure freedom (Arroyo 2004; French 2003; French 2014; French 2016), however we did not find this to be concerning. All of the participants in the included studies had drug‐resistant epilepsy, meaning that their epilepsy is refractory despite treatment with currently available antiepileptic medication. As a result, it is unlikely that many patients will achieve seizure freedom. Instead, 50% or greater reduction in seizure frequency is a more clinically relevant efficacy outcome for these patients. Consequently, it would be much more concerning and suspicious if any of the included studies failed to report the primary outcome, 50% or greater reduction in seizure frequency.

In addition, we noted that several of the included studies did not report all of the adverse effects investigated as part of this review. However, because the majority of other harms were fully reported, we did not find this to be suspicious. The studies specified that they only reported the most common adverse events, for example only those reported by more than 5% of the study population, thus further justifying the absence of some data.

We consequently rated all nine included studies as at low risk of reporting bias.

Other potential sources of bias

In two included studies (Arroyo 2004; French 2003), individuals with primary generalised epilepsy may have been included in the trials, possibly leading to bias within the results, thus we assessed these studies as at unclear risk of other bias. We detected no other potential sources of bias for the remaining seven studies (Baulac 2010; Beydoun 2005; Elger 2005; French 2014; French 2016; Lee 2009; Zaccara 2014), resulting in a judgement of low risk of other bias for these studies.

Effects of interventions

See: Table 1; Table 2

Summary of findings for the main comparison. Pregabalin compared to placebo for drug‐resistant focal epilepsy.

Pregabalin compared to placebo for drug‐resistant focal epilepsy
Patient or population: drug‐resistant focal epilepsy  Setting: outpatient setting  Intervention: pregabalin  Comparison: placebo
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with placebo	Risk with pregabalin
50% or greater reduction in seizure frequency ‐ ITT analysis Follow‐up: range 12 to 17 weeks	Study population		RR 2.28  (1.52 to 3.42)	2193  (7 RCTs)	⊕⊕⊝⊝  LOW^{1 2 3 5 6}	Pregabalin may increase the proportion of people achieving 50% or greater reduction in seizure frequency according to ITT analysis, but we are uncertain.
	184 per 1000	420 per 1000  (280 to 631)
50% or greater reduction in seizure frequency ‐ best‐case analysis Follow‐up: range 12 to 17 weeks	Study population		RR 3.57  (2.17 to 5.86)	2193  (7 RCTs)	⊕⊝⊝⊝  VERY LOW^{1 2 3 5}	Pregabalin may increase the proportion of people achieving 50% or greater reduction in seizure frequency according to best‐case analysis, but we are very uncertain.
	184 per 1000	658 per 1000  (400 to 1000)
50% or greater reduction in seizure frequency ‐ worst‐case analysis Follow‐up: range 12 to 17 weeks	Study population		RR 1.15  (0.92 to 1.43)	2193  (7 RCTs)	⊕⊝⊝⊝  VERY LOW^{1 2}	Pregabalin might have no effect on the proportion of people achieving 50% or greater reduction in seizure frequency according to worst‐case analysis, however, we are very uncertain.
	345 per 1000	397 per 1000  (318 to 494)
Seizure freedom Follow‐up: 12 weeks	Study population		RR 3.94  (1.50 to 10.37)	1125  (4 RCTs)	⊕⊕⊕⊝  MODERATE^{1 4 5}	Pregabalin likely increases the number of people achieving seizure freedom.
	11 per 1000	42 per 1000  (16 to 112)
Treatment withdrawal for any reason Follow‐up: range 12 to 17 weeks	Study population		RR 1.35  (1.11 to 1.65)	2193  (7 RCTs)	⊕⊕⊕⊝  MODERATE¹	Pregabalin likely slightly increases the number of people who withdraw from treatment for any reason, however this effect may or may not be important.
	161 per 1000	217 per 1000  (178 to 265)
Treatment withdrawal due to adverse effects Follow‐up: range 12 to 17 weeks	Study population		RR 2.65  (1.88 to 3.74)	2193  (7 RCTs)	⊕⊕⊕⊝  MODERATE^{1 4 5}	Pregabalin likely increases the number of people withdrawing from treatment due to adverse effects.
	53 per 1000	141 per 1000  (100 to 199)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; ITT: intention‐to‐treat; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Pregabalin compared to active comparator for drug‐resistant focal epilepsy
Patient or population: drug‐resistant focal epilepsy  Setting: outpaitent setting  Intervention: pregabalin  Comparison: active comparator (gabapentin, lamotrigine and levetiracetam)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with active comparator	Risk with Pregabalin
50% or greater reduction in seizure frequency Follow‐up: range 16 to 21 weeks	Study population		RR 1.03  (0.85 to 1.25)	1286  (3 RCTs)	⊕⊕⊝⊝  LOW^{1 2}	According to ITT analysis, pregabalin does not appear to affect the proportion of people achieving a 50% or greater reduction in seizure frequency compared to other active comparators. We are, however, uncertain about this finding.
	491 per 1,000	505 per 1,000  (417 to 613)
50% or greater reduction in seizure frequency ‐ best‐case analysis Follow‐up: range 16 to 21 weeks	Study population		RR 1.60  (1.17 to 2.19)	1286  (3 RCTs)	⊕⊝⊝⊝  VERY LOW^{1 3}	According to best‐case analysis, pregabalin may increase the proportion of participants achieving a 50% or greater reduction in seizure frequency, however, we are very uncertain about this finding.
	491 per 1,000	785 per 1,000  (574 to 1,000)
50% or greater reduction in seizure frequency ‐ worst‐case analysis Follow‐up: range 16 to 21 weeks	Study population		RR 0.67  (0.62 to 0.74)	1286  (3 RCTs)	⊕⊕⊕⊝  MODERATE¹	According to worst‐case analysis, pregabalin may decrease the proportion of participants achieving a 50% or greater reduction in seizure frequency. We are moderately certain about this finding.
	732 per 1,000	490 per 1,000  (454 to 542)
Seizure freedom Follow‐up: range 16 to 17 weeks	Study population		RR 0.59  (0.37 to 0.95)	802  (2 RCTs)	⊕⊝⊝⊝  VERY LOW^{1 4}	Pregabalin may reduce the number of people achieving seizure freedom, but we are very uncertain.
	106 per 1,000	63 per 1,000  (39 to 101)
Treatment withdrawal for any reason Follow‐up: range 16 to 21 weeks	Study population		RR 0.93  (0.76 to 1.13)	1286  (3 RCTs)	⊕⊕⊝⊝  LOW^{1 5}	Pregabalin does not appear to affect the number of participants withdrawing from treatment for any reason, however, we are uncertain.
	241 per 1,000	224 per 1,000  (183 to 273)
Treatment withdrawal for adverse events Follow‐up: range 16 to 21 weeks	Study population		RR 1.04  (0.73 to 1.48)	1286  (3 RCTs)	⊕⊕⊝⊝  LOW^{1 5}	Pregabalin does not appear to affect the number of participants withdrawing from treatment for adverse effects, but we are uncertain.
	85 per 1,000	88 per 1,000  (62 to 125)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; ITT: intention‐to‐treat; RCT: randomised controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Date	Event	Description
5 July 2018	New citation required but conclusions have not changed	Conclusions remain the same.
5 July 2018	New search has been performed	Searches updated 5 July 2018; three new studies (French 2014, French 2016 and Zaccara 2014) have been added to the review. The term 'partial' has been replaced by 'focal', in accordance with the most recent classification of epilepsies of the International League Against Epilepsy (Scheffer 2017).

Date	Event	Description
9 January 2014	New search has been performed	Searches updated 9 January 2014; one previously ongoing study, Bali 2012, has been added to excluded studies (Taghdiri 2015).
9 January 2014	New citation required but conclusions have not changed	Conclusions remain the same.
12 June 2012	New search has been performed	Two new studies were included in this update of the original review.
7 August 2009	Amended	Copy edits made at editorial base.
16 September 2008	Amended	Converted to new review format.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 50% or greater reduction in seizure frequency ‐ ITT	7	2193	Risk Ratio (IV, Random, 95% CI)	2.28 [1.52, 3.42]
2 50% or greater reduction in seizure frequency ‐ best‐case analysis	7	2193	Risk Ratio (IV, Random, 95% CI)	3.57 [2.17, 5.86]
3 50% or greater reduction in seizure frequency ‐ worst‐case analysis	7	2193	Risk Ratio (IV, Random, 95% CI)	1.15 [0.92, 1.43]
4 Seizure freedom	4	1125	Risk Ratio (M‐H, Fixed, 95% CI)	3.94 [1.50, 10.37]
5 Treatment withdrawal for any reason	7	2193	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [1.11, 1.65]
6 Treatment withdrawal due to adverse effects	7	2193	Risk Ratio (M‐H, Fixed, 95% CI)	2.65 [1.88, 3.74]
7 Ataxia	6	1868	Risk Ratio (M‐H, Fixed, 99% CI)	3.90 [2.05, 7.42]
8 Dizziness	7	2193	Risk Ratio (M‐H, Fixed, 99% CI)	3.15 [2.23, 4.44]
9 Fatigue	7	2193	Risk Ratio (M‐H, Fixed, 99% CI)	1.34 [0.93, 1.94]
10 Headache	5	1555	Risk Ratio (M‐H, Fixed, 99% CI)	0.63 [0.42, 0.93]
11 Nausea	4	1267	Risk Ratio (M‐H, Fixed, 99% CI)	1.20 [0.56, 2.58]
12 Somnolence	7	2193	Risk Ratio (M‐H, Fixed, 99% CI)	2.15 [1.50, 3.09]
13 Weight gain	7	2193	Risk Ratio (M‐H, Fixed, 99% CI)	5.02 [2.49, 10.10]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 50% or greater reduction in seizure frequency ‐ ITT	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.52, 2.12]
1.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 95% CI)	2.22 [1.36, 3.63]
1.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 95% CI)	2.86 [1.65, 4.94]
1.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 95% CI)	4.62 [3.34, 6.39]
1.5 Titrated dose of pregabalin (150 to 600 mg/d)	3	675	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [1.35, 2.30]
1.6 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.72, 1.48]
1.7 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.91, 1.75]
2 50% or greater reduction in seizure frequency ‐ best‐case analysis	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [1.03, 3.40]
2.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 95% CI)	3.18 [2.00, 5.06]
2.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 95% CI)	4.37 [2.61, 7.29]
2.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 95% CI)	7.72 [5.64, 10.57]
2.5 Titrated dose of pregabalin (150 to 600 mg/d)	3	675	Risk Ratio (M‐H, Fixed, 95% CI)	2.86 [2.24, 3.65]
2.6 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.92, 1.79]
2.7 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [1.21, 2.20]
3 50% or greater reduction in seizure frequency ‐ worst‐case analysis	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.30, 0.99]
3.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.66, 1.38]
3.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.98, 2.23]
3.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 95% CI)	1.72 [1.42, 2.09]
3.5 Titrated dose of pregabalin (150 to 600 mg/d)	3	675	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.76, 1.12]
3.6 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.57, 1.09]
3.7 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.72, 1.28]
4 Seizure freedom	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1 600 mg/d	2	523	Risk Ratio (M‐H, Fixed, 95% CI)	6.92 [1.31, 36.70]
4.2 Titrated dose of pregabalin (150 to 600 mg/d)	3	675	Risk Ratio (M‐H, Fixed, 95% CI)	2.39 [0.83, 6.89]
5 Treatment withdrawal for any reason	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.40, 1.89]
5.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.41, 1.28]
5.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 95% CI)	1.62 [0.85, 3.10]
5.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 95% CI)	1.84 [1.42, 2.40]
5.5 Titrated dose of pregabalin (150 to 600 mg/d)	3	675	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.89, 1.62]
5.6 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.36, 1.86]
5.7 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.59, 2.46]
6 Treatment withdrawal due to adverse effects	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [0.43, 4.31]
6.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.45, 2.32]
6.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 95% CI)	2.89 [1.07, 7.78]
6.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 95% CI)	3.78 [2.47, 5.81]
6.5 Titrated dose of pregabalin (150 to 600 mg/d)	3	675	Risk Ratio (M‐H, Fixed, 95% CI)	2.26 [1.30, 3.95]
6.6 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.22, 5.27]
6.7 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 95% CI)	2.57 [0.70, 9.45]
7 Ataxia	6		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
7.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 99% CI)	1.14 [0.14, 9.00]
7.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 99% CI)	1.98 [0.56, 7.01]
7.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 99% CI)	3.33 [0.62, 17.81]
7.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 99% CI)	4.49 [2.25, 8.95]
7.5 Titrated dose pregabalin (150 to 600 mg/d)	3	675	Risk Ratio (M‐H, Fixed, 99% CI)	4.46 [1.28, 15.48]
8 Dizziness	7		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
8.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 99% CI)	1.01 [0.31, 3.33]
8.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 99% CI)	2.04 [0.99, 4.22]
8.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 99% CI)	3.46 [1.39, 8.62]
8.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 99% CI)	3.72 [2.42, 5.69]
8.5 Titrated dose of pregabalin (150 to 600 mg/d pregabalin)	3	675	Risk Ratio (M‐H, Fixed, 99% CI)	3.08 [1.80, 5.28]
8.6 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 99% CI)	5.99 [0.85, 42.02]
8.7 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 99% CI)	5.31 [0.76, 37.30]
9 Fatigue	7		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
9.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 99% CI)	0.71 [0.17, 2.94]
9.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 99% CI)	1.09 [0.50, 2.39]
9.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 99% CI)	1.53 [0.49, 4.76]
9.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 99% CI)	1.50 [0.89, 2.52]
9.5 Titrated dose of pregabalin (150 to 600 mg/d)	3	675	Risk Ratio (M‐H, Fixed, 99% CI)	1.15 [0.69, 1.91]
9.6 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 99% CI)	3.27 [0.17, 62.62]
9.7 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 99% CI)	5.79 [0.37, 91.55]
10 Headache	5		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
10.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 99% CI)	0.52 [0.16, 1.77]
10.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 99% CI)	0.53 [0.24, 1.17]
10.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 99% CI)	0.43 [0.12, 1.57]
10.4 600 mg/d pregabalin	3	588	Risk Ratio (M‐H, Fixed, 99% CI)	0.63 [0.33, 1.19]
10.5 Titrated dose of pregabalin (150 to 600 mg/d)	3	675	Risk Ratio (M‐H, Fixed, 99% CI)	0.74 [0.44, 1.25]
11 Nausea	4		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
11.1 150 mg/d pregabalin	1	196	Risk Ratio (M‐H, Fixed, 99% CI)	1.31 [0.34, 5.00]
11.2 600 mg/d pregabalin	3	712	Risk Ratio (M‐H, Fixed, 99% CI)	1.18 [0.51, 2.75]
11.3 Titrated dose of pregabalin (150 to 600 mg/d)	1	204	Risk Ratio (M‐H, Fixed, 99% CI)	1.11 [0.12, 10.05]
11.4 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 99% CI)	3.27 [0.17, 62.62]
11.5 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 99% CI)	0.96 [0.03, 36.26]
12 Somnolence	7		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
12.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 99% CI)	0.93 [0.31, 2.78]
12.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 99% CI)	1.26 [0.58, 2.74]
12.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 99% CI)	1.62 [0.63, 4.12]
12.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 99% CI)	2.57 [1.64, 4.03]
12.5 Titrated dose of pregabalin	3	675	Risk Ratio (M‐H, Fixed, 99% CI)	2.35 [1.31, 4.19]
12.6 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 99% CI)	2.18 [0.24, 19.70]
12.7 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 99% CI)	2.89 [0.36, 23.05]
13 Weight gain	7		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
13.1 50 mg/d pregabalin	1	188	Risk Ratio (M‐H, Fixed, 99% CI)	3.40 [0.05, 224.69]
13.2 150 mg/d pregabalin	2	384	Risk Ratio (M‐H, Fixed, 99% CI)	3.85 [0.64, 23.35]
13.3 300 mg/d pregabalin	1	190	Risk Ratio (M‐H, Fixed, 99% CI)	14.43 [0.34, 620.87]
13.4 600 mg/d pregabalin	4	901	Risk Ratio (M‐H, Fixed, 99% CI)	5.88 [2.52, 13.73]
13.5 Titrated dose of pregabalin (150 to 600 mg/d pregabalin)	3	675	Risk Ratio (M‐H, Fixed, 99% CI)	3.64 [1.49, 8.87]
13.6 165 mg/d pregabalin (controlled release)	1	211	Risk Ratio (M‐H, Fixed, 99% CI)	3.26 [0.05, 215.86]
13.7 330 mg/d pregabalin (controlled release)	1	224	Risk Ratio (M‐H, Fixed, 99% CI)	14.48 [0.34, 613.54]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 50% or greater reduction in seizure frequency	3	1286	Risk Ratio (IV, Random, 95% CI)	1.03 [0.85, 1.25]
2 50% or greater reduction in seizure frequency ‐ best‐case analysis	3	1286	Risk Ratio (IV, Random, 95% CI)	1.60 [1.17, 2.19]
3 50% or greater reduction in seizure frequency ‐ worst‐case analysis	3	1286	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.62, 0.74]
4 Seizure freedom	2	802	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.37, 0.95]
5 Treatment withdrawal for any reason	3	1286	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.76, 1.13]
6 Treatment withdrawal due to adverse effects	3	1286	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.73, 1.48]
7 Ataxia	1	293	Risk Ratio (M‐H, Fixed, 99% CI)	1.72 [0.54, 5.55]
8 Dizziness	3	1286	Risk Ratio (IV, Random, 99% CI)	1.64 [0.85, 3.16]
9 Fatigue	1	293	Risk Ratio (M‐H, Fixed, 99% CI)	1.72 [0.77, 3.83]
10 Headache	3	1286	Risk Ratio (IV, Random, 99% CI)	0.83 [0.41, 1.65]
11 Nausea	1	509	Risk Ratio (M‐H, Fixed, 99% CI)	0.20 [0.04, 1.01]
12 Somnolence	3	1286	Risk Ratio (M‐H, Fixed, 99% CI)	1.16 [0.88, 1.53]
13 Weight gain	3	1286	Risk Ratio (IV, Random, 99% CI)	2.87 [0.94, 8.75]

Methods	Randomised, double‐blind, PBO‐controlled, parallel, multicentre (45 in Europe, Australia, and South Africa) trial. 3 treatment arms: 1 PBO, 2 PGB. Participants randomised in blocks of 6, each allocated unique ID number. All participants received 2 capsules 3 times a day, but 2 capsule sizes were used (no further information available). Duration of baseline period: 8 weeks. 12‐week treatment period included 4‐ to 8‐day titration period.
Participants	Adults aged 17 to 73 years (mean 37 years), 50.5% male, all with drug‐resistant focal epilepsy. Participants were on 1 to 4 baseline AEDs. 344 patients screened, 288 participants randomised: 97 participants to PBO (mean baseline 28‐day seizure frequency: 23.5); 99 participants to 50 mg/d PGB 3 times a day (mean baseline 28‐day seizure frequency: 26.2); and 92 participants to 200 mg/d PGB 3 times a day (mean baseline 28‐day seizure frequency: 19.3).
Interventions	Group 1: Placebo  Group 2: PGB 50 mg 3 times a day (150 mg/d; 4‐day titration phase)  Group 3: PGB 200 mg 3 times a day (600 mg/d; 8‐day titration phase)
Outcomes	Primary outcome: reduction in seizure frequency compared to baseline (response ratio) Secondary outcomes: responder rate, seizure freedom, change in seizure frequency, adverse effects
Notes	Study used capsules of 2 sizes, containing 25 mg PGB or PBO (size 1# = small capsules) and 100 mg PGB or PBO (size 4# = large capsules). It is stated that participants received 2 capsules 3 times a day. 1 patient excluded from ITT in PBO arm, as failed to take study drugs. Study was sponsored by Pfizer Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random computer‐generated code used stratified by centre using block size of 6.
Allocation concealment (selection bias)	Unclear risk	No information provided.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Medication presented in identical capsules.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition rates reported. ITT analysis performed.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results, however there was no protocol available to check a priori outcomes.
Other bias	Unclear risk	As an EEG was not required to confirm the above, some of the 18 patients included who were stated as having "generalised seizures", rather than secondary generalised, may have had primary generalised epilepsy.

Methods	Randomised, double‐blind, PBO‐ and active‐drug‐controlled, parallel, multicentre (97 in Europe, Canada, and Australia) trial. 3 treatment arms: 1 PBO, 1 PGB, and 1 LTG. Participants randomised to 1 of 3 treatment arms (no further information available). Duration of baseline period: 6 weeks. 17‐week treatment period with 2 phases in addition to a titration phase (1 week of titration for PGB and 5 weeks of titration for LTG). (Phase I: 11 weeks treatment including 1 week titration for PGB and 5 weeks titration for LTG; Phase II: 6 weeks treatment)
Participants	Adults aged 16 to 82 years (mean 39.4 years), 48.5% male, all with treatment‐resistant focal epilepsy confirmed by history and recent EEG. Participants were on 1 to 3 baseline AEDs. 546 patients screened, 434 participants randomised: 141 participants to PBO (mean baseline 28‐day seizure frequency: 16.38); 152 participants to 150 mg to 300 mg PGB twice daily (mean baseline 28‐day seizure frequency: 21.32); and 141 participants to 150 mg to 300 mg LTG twice daily (mean baseline 28‐day seizure frequency: 21.80).
Interventions	Group 1: Placebo Group 2: PGB 150 mg to 300 mg twice daily (300 to 600 mg/d; 1‐week titration phase) Group 3: LTG 150 mg to 300 mg twice daily (300 to 600 mg/d; 5‐week titration phase)
Outcomes	Primary outcome: change in seizure frequency compared to baseline (response ratio) Secondary outcomes: responder rate, seizure freedom, adverse effects
Notes	One participant randomised to the PBO group failed to take > 1 dose of medication and was therefore excluded from ITT analysis. No information provided on methods of randomisation, concealment, or blinding. Study was sponsored by Pfizer Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details of method of randomisation.
Allocation concealment (selection bias)	Unclear risk	No details of allocation concealment.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Same number of capsules administered per study day per group. No further details provided.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition rates reported. ITT analysis employed.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results, however there was no protocol available to check a priori outcomes.
Other bias	Low risk	None detected.

Methods	Randomised, double‐blind, placebo‐controlled, parallel, multicentre (18 countries) trial assessing the efficacy and tolerability of controlled‐release PGB. 3 treatment arms: 1 PBO, 2 PGB Randomised 1:1:1 to PGB 165 mg/d or PGB 330 mg/d or placebo using a computer‐generated randomisation system. Duration of baseline period: 8 weeks. 14‐week double‐blind treatment period with 2‐week double‐blind dose escalation (titration phase); 1‐week taper.
Participants	Adults aged 18 to 75 years, 47.7% male, all with focal epilepsy. Participants were on 1 to 3 baseline AEDs. 400 patients screened, 325 participants randomised: 110 participants to placebo (mean baseline 28‐day seizure frequency: 17.8); 101 participants to PGB 165 mg (mean baseline 28‐day seizure frequency: 13.0); 114 participants to PGB 330 mg (mean baseline 28‐day seizure frequency: 17.0).
Interventions	Group 1: Placebo Group 2: PGB 165 mg/d controlled release  Group 3: PGB 330 mg/d controlled release
Outcomes	Primary outcomes: reduction in seizure frequency compared to baseline (response ratio) Secondary outcomes: responder rate, adverse effects
Notes	Clinical trials: NCT01262677 Study sponsored by Pfizer Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation system.
Allocation concealment (selection bias)	Unclear risk	Allocate participants to each of the 3 treatment groups in a 1:1:1 manner. No further details provided.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No details regarding blinding of participants and personnel provided.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition rates reported. ITT efficacy analysis performed.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. There was no protocol available to check a priori outcomes.
Other bias	Low risk	None detected.

Methods	Randomised, double‐blind, parallel, multicentre (56 centres in Eastern and Western Europe, Asia, South and Central America) trial assessing the efficacy and safety of PGB and GPN. 2 treatment arms: PGB and GPN Randomised 1:1 to PGB 242 or GPN 242 using a computer‐generated randomisation system. Duration of baseline period: 6 weeks. 21‐week double‐blind phase (9 weeks of double‐blind dose escalation and 12 weeks of double‐blind maintenance phase).
Participants	Adults aged 18 to 80 years, 53.3% male, all with drug‐resistant focal epilepsy (inadequately controlled with ≥ 2 to < 5 prior AEDs). All participants were on 1 to 2 baseline AEDs. 561 patients screened, 484 participants randomised: 242 participants to PGB 450 mg median dose (mean baseline 28‐day seizure frequency: 14.1); 242 participants to GPN 1500 mg median dose (mean baseline 28‐day seizure frequency: 13.1).
Interventions	Group 1: PGB (150, 300, 450, and 600 mg/d during the 9‐week dose escalation phase)  Group 2: GPN (300, 600, 1200, 1500, and 1800 mg/d during the 9‐week dose escalation phase)
Outcomes	Primary outcome: reduction in seizure frequency (50% or more reduction of seizures and 75% or more reduction of seizures) Secondary outcomes: seizure freedom for maintenance phase (last 28‐day seizure‐free rates), adverse effects
Notes	Clinical trials: NCT00537940 Study was sponsored by Pfizer Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation system.
Allocation concealment (selection bias)	Unclear risk	Allocate participants to each of the 2 treatment groups in a 1:1 manner. No further details provided.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Medication presented in identical tablets. Identical analysis of results.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition rates reported. ITT efficacy analysis performed.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. There was no protocol available to check a priori outcomes.
Other bias	Low risk	None detected.

Methods	Randomised, double‐blind, flexible‐dose, parallel, multicentre (71 centres in Western and Eastern Europe, South and Central America, Asia) trial. 2 treatment arms: PGB and LEV Randomised 1:1 to either PGB or LEV using a computer‐generated randomisation system. Duration of baseline phase: 6 weeks; 4‐week double‐blind dose escalation (titration phase); 12‐week double‐blind maintenance phase.
Participants	Adults aged 18 to 65 years (mean 37 years), all with drug‐resistant focal epilepsy (inadequately controlled with at least 2, but no more than 5 AEDs). Participants were on 1 to 2 baseline AEDs. 633 patients were screened, 509 participants were randomised: 254 participants to PGB (mean baseline 28‐day seizure frequency: 16.2) and 255 participants to LEV (mean baseline 28‐day seizure frequency: 13.9).
Interventions	Group 1: PGB twice daily (150, 300, 450, and 600 mg/d)  Group 2: LEV twice daily (1000, 2000, and 3000 mg/d)
Outcomes	Primary outcome: reduction in seizure frequency (50% or more reduction of seizures) Secondary outcomes: seizure freedom for maintenance phase, adverse effects
Notes	Clinical trials: NCT00537238 Study was sponsored by Pfizer Inc.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation system.
Allocation concealment (selection bias)	Unclear risk	Allocate participants to each of the 2 treatment group in a 1:1 ratio. No further details provided.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Details are not provided, however it is likely that blinding of participants and personnel was maintained due to the methods used. Medication presented in identical tablets. Identical analysis of results.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition rates reported. ITT efficacy analysis performed.
Selective reporting (reporting bias)	Low risk	All outcomes stated in methods section of paper were reported in the results. No protocol available to check a priori outcomes.
Other bias	Low risk	None detected.

Methods	Randomised observational controlled study. 4 treatment arms: 1 LEV fast‐rate, 2 LEV slow‐rate, 3 PGB fast‐rate, 4 PGB slow‐rate dosage
Participants	128 patients with refractory focal epilepsy (32 in each treatment arm)
Interventions	Group 1: starting dose of 1000 mg twice daily LEV fast rate with weekly increments of 500 mg Group 2: starting dose of 500 mg twice daily LEV slow rate with weekly increments of 250 mg Group 3: starting dose of 300 mg twice daily PGB fast rate with weekly increments of 150 mg Group 4: starting dose of 150 mg twice daily PGB slow rate with weekly increments of 75 mg
Outcomes	Rate of withdrawals and continuation to maximum dose Incidence of adverse effects
Notes	Study reported in abstract form only. Further details of study are unavailable.

Methods	Randomised cross‐over trial consisting of 2 treatment arms: 1 PGB, 2 LEV. Participants randomised to groups using 1:1 ratio. Study was open‐label. Long‐term study duration of minimum 6 months.
Participants	28 adults aged 19 to 62 years, 54% male. Participants currently taking different AED without maintaining good seizure control, stabilised to therapeutic association of valproate and lamotrigine.
Interventions	Group 1: starting dose of 150 mg to target dose of 600 mg PGB Group 2: starting dose of 1000 mg to target dose of 3000 mg LEV
Outcomes	Seizure freedom Seizure reduction Withdrawals Adverse effects
Notes	Study reported in abstract only. Further details of study are unavailable.

PERMALINK

Pregabalin add‐on for drug‐resistant focal epilepsy

Mariangela Panebianco

Rebecca Bresnahan

Karla Hemming

Anthony G Marson

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

50% or greater reduction in seizure frequency

Secondary outcomes

Seizure freedom

Treatment withdrawal

Adverse effects

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Methodological/trial design

Participant/demographic information

For all trials sponsored by Pfizer Ltd, confirmation of the following information

Outcomes

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Dose regression analysis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summarising and interpreting results

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Studies awaiting classification

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

4.

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Pregabalin compared to placebo for drug‐resistant focal epilepsy.

Summary of findings 2. Pregabalin compared to active comparators for drug‐resistant focal epilepsy.

Pregabalin versus placebo control

50% or greater reduction in seizure frequency

1.1. Analysis.

2.1. Analysis.

Best‐case and worst‐case analyses

1.2. Analysis.