Clinical evidence of synergistic combinations

The most scientifically valid approach to study such potential interactions is the isobolographic method (Figure 8.2), in which two AEDs are given in various dose proportions to identify the most effective regimen in terms of seizure control [34]. This approach has been successfully applied in animal studies [35], but presents logistic difficulties in the clinical trial setting because of the wide inter-individual variation in the pharmacokinetics and pharmacodynamics of different AEDs. The ideal way to test for synergism in the clinical setting has not been agreed upon [29].

There is a paucity of data on the comparative efficacy of different AED combinations in clinical practice. The only published head-to-head, double-blind, randomized trial conducted for such a purpose compared gabapentin and vigabatrin as the first add-on drug for partial seizures that had not been controlled by monotherapy [36]. Unfortunately, this study was terminated prematurely due to emerging concerns regarding vigabatrin-associated visual field defects. There was no significant difference in the improvement rate, proportion of seizure-free patients, or quality of life scores between the drug groups during the 8-week treatment period.

The best non-randomized controlled data in favour of true synergism exist with valproate and lamotrigine for partial-onset and generalized seizures [37, 38]. Brodie et al. [37] added lamotrigine in 345 patients with uncontrolled epilepsy receiving a single AED (valproate, carbamazepine or phenytoin). The addition of lamotrigine to valproate produced a significantly better response than adding it to carbamazepine or phenytoin despite similar lamotrigine concentrations (Figure 8.3). Pisani et al. [38] performed a well-designed, crossover study in 20 patients. Among the 13 patients who did not respond to the consecutive monotherapy with valproate and lamotrigine, four became seizure free and an additional four experienced > 60% seizure reduction when both drugs were given in combination, despite lower doses and serum concentrations than during separate administration.

Other 'recommended' combinations are largely based on anecdotal reports or studies with small sample sizes. They include valproate with ethosuximide for absence seizures [39], phenobarbital and phenytoin for generalized tonic-clonic and partial seizures [40], carbamazepine and vigabatrin or valproate for partial seizures [41], vigabatrin and tiagabine for partial seizures [42] and lamotrigine with topiramate for a range of seizure types [43].

Dl U

Dose of drug B

Figure 8.2 Hypothetical isobologram showing the doses of two drugs required to produce a specified effect (either efficacy or toxicity) where the drugs have additive, supra-additive (synergistic) or infra-additive (antagonistic) effects [29].

Dose of drug B

Figure 8.2 Hypothetical isobologram showing the doses of two drugs required to produce a specified effect (either efficacy or toxicity) where the drugs have additive, supra-additive (synergistic) or infra-additive (antagonistic) effects [29].

Baseline

Add-on Withdrawal Monotherapy

Study phase

Baseline

Add-on Withdrawal Monotherapy

Study phase

Figure 8.3 Median monthly seizure counts for patients receiving add-on lamotrigine to baseline treatment with phenytoin, carbamazepine or valproate. The study consisted of a 12-week 'baseline phase', followed by the 'add-on phase', when lamotrigine was introduced with baseline medication unchanged. Patients showing at least 50% reduction in seizure frequency compared with baseline entered the 12-week 'withdrawal phase' when the baseline anti-epileptic drug was tapered off. Patients who successfully completed the withdrawal phase entered the lamotrigine 'monotherapy phase' of 12 weeks' duration [37].

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