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.

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.

Read the full 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 strategy: 

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.

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