Tiagabine add-on therapy for drug-resistant focal epilepsy

Background

Epilepsy is a disorder in which recurrent seizures are caused by abnormal electrical discharges from the brain. Most seizures can be controlled by a single antiepileptic drug. Unfortunately, some people require more than one antiepileptic drug to control their seizures (drug-resistant epilepsy), especially if the seizures originate from one area of the brain (focal epilepsy), rather than affecting the entire brain (generalised epilepsy).

Tiagabine is a newer antiepileptic drug that can be used in conjunction with a person's normal antiepileptic drug regimen. This review assessed the evidence available for how effective tiagabine is in reducing seizures, as well as looking at the side effects that may be associated with its use when it is used alongside other antiepileptic medication(s) for people with drug-resistant focal epilepsy.

Results

We found six trials that included 948 people with focal epilepsy. These trials were all randomised controlled trials (RCTs) that compared the antiepileptic drug tiagabine with a placebo (an inactive, dummy treatment which should not affect epilepsy) or with a different antiepileptic drug for a period of up to 24 weeks. We found that tiagabine, when used with another antiepileptic drug, was three times more effective than placebo at reducing the number of seizures in people with drug-resistant focal epilepsy. Adding tiagabine to people's usual treatment was, however, associated with an increase in side effects, such as dizziness and tremor. People using tiagabine were over four times more likely to experience tremor than those using placebo; however, only one trial reported this adverse event so the evidence for this is limited. People taking tiagabine in addition to other drugs were nearly twice as likely to withdraw from treatment than those taking placebo. We found no significant differences between tiagabine and topiramate, another antiepileptic drug, as add-on drugs.

Conclusions

Overall, there was high-certainty evidence for the outcome of seizure reduction, which means that we are confident that the effect we have reported is accurate. The trials included in this review did not examine the long-term effects of tiagabine as an add-on treatment or the effects of tiagabine in children aged below the age of 12 years. Future research is needed to determine how tiagabine performs in comparison with other newer antiepileptic drugs.

The evidence is current to January 2019.

Authors' conclusions: 

Tiagabine reduced seizure frequency but was associated with some adverse effects when used as an add-on treatment in people with drug-resistant focal epilepsy. The findings of the current review are mainly applicable to adults and adolescents, and may not necessarily be applicable to children as none of the trials included participants aged under 12 years. We found no significant differences between tiagabine and topiramate as add-on drugs; however, evidence was provided by a single trial and was therefore limited.

Read the full abstract...
Background: 

Epilepsy is a common neurological condition that affects up to 1% of the population. Nearly 30% of people with epilepsy are resistant to currently available antiepileptic drugs (AEDs) and require treatment with multiple antiepileptic drugs in combination. Tiagabine is one of the newer AEDs that can be used as an adjunct (add-on) to standard AEDs.

Objectives: 

To evaluate the efficacy and tolerability of tiagabine when used as an add-on treatment for people with drug-resistant focal seizures.

Search strategy: 

This is an updated Cochrane review, last published in 2014. For the latest update, we searched the following databases on 22 January 2019: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials, MEDLINE (Ovid, 1946 to January 21, 2019), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. We imposed no language restrictions. We also contacted the manufacturers of tiagabine and experts in the field to identify any ongoing or unpublished studies.

Selection criteria: 

We included randomised placebo-controlled add-on trials conducted in people of any age with focal epilepsy. The studies could be double-, single-, or unblinded and of parallel or cross-over design. They had to have a minimum treatment period of eight weeks. We also included trials using an active drug control group.

Data collection and analysis: 

Two review authors independently assessed trials for inclusion and extracted data according to the standard methodological procedures expected by the Cochrane Collaboration for this review update. We resolved disagreements by discussion. Outcomes investigated included 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, effects on cognition and quality of life. The primary analyses were performed by intention-to-treat. We calculated worst-case and best-case analyses for seizure outcomes. We evaluated dose response using regression models. Two review authors assessed risk of bias in each study using the Cochrane 'Risk of bias' tool.

Main results: 

No further studies were added since the previous update in 2014. The review included six trials (four parallel-group and two cross-over group trials) consisting of 948 participants. For the main comparison, tiagabine versus placebo, all participants were aged between 12 and 77 years and the study treatment periods ranged from 12 to 22 weeks. The overall risk ratio (RR) with 95% confidence intervals (CIs) for a 50% or greater reduction in seizure frequency (tiagabine versus placebo) was 3.16 (95% CI 1.97 to 5.07; 3 trials; 769 participants; high-certainty evidence). Because of differences in response rates among trials, regression models were unable to provide reliable estimates of response to individual doses. The RR for treatment withdrawal (tiagabine versus placebo) was 1.81 (95% CI 1.25 to 2.62; 3 trials, 769 participants; moderate-certainty evidence). Dizziness and tremor were significantly associated with tiagabine therapy. For cognitive and quality-of-life outcomes, the limited available data suggested no significant effects on cognition, mood, or adjustment. One trial comparing tiagabine with an active drug control group (tiagabine versus topiramate) found no significant differences between the two add-on drugs for a 50% or greater reduction in seizure frequency (RR 0.54, 95% CI 0.19 to 1.58; 1 trial; 41 participants) or for treatment withdrawal (RR 1.43, 95% CI 0.74 to 2.74; one trial; 41 participants). We judged two of the six included studies to have low risk of bias, three studies to have an unclear risk of bias, and one study to have a high risk of bias. Methods for randomisation sequence generation were the least reported trial design factor and generated the most concerns regarding risk of bias. We rated the overall certainty of the evidence as largely moderate to high using the GRADE approach. We rated the evidence for two of the adverse effect outcomes, nausea and tremor, as low certainty.

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