Elsevier

Epilepsy & Behavior

Volume 27, Issue 3, June 2013, Pages 439-442
Epilepsy & Behavior

Review
When one plus one makes three: The quest for rational antiepileptic polytherapy with supraadditive anticonvulsant efficacy

https://doi.org/10.1016/j.yebeh.2013.03.010Get rights and content

Highlights

  • The evidence in support of “rational polytherapy” is sparse.

  • Ideally, a drug combination should have supraadditive efficacy and infraadditive toxicity.

  • The combination valproate–lamotrigine seems to be synergic against focal seizures.

  • Further studies are required on this topic.

Abstract

The experimental and clinical evidence in support of “rational polytherapy” is sparse, and to date, no clear evidence-based indications can be made to help physicians in their choice of a specific drug combination against specific forms of epilepsy. This article briefly reviews the data available in the literature and obtained from studies conducted in humans to evaluate which main AED combinations might possess supraadditive, synergistic effects in terms of efficacy, with infraadditive toxicity. By far, the most documented association resulting in supraadditive anticonvulsant effects against focal seizures is that of VPA and LTG. There are some indications that combinations of drugs with different primary mechanisms of action may be more effective than combining drugs with the same mechanisms of action. However, further animal and human research studies that focus both on toxicity and anticonvulsant effects of various combinations of AEDs are required.

Introduction

It is observed from daily experience that a minority of patients with difficult-to-treat epilepsy may significantly benefit from a combination therapy with two or more AEDs [1]. Indeed, the introduction of several new antiepileptic drugs (AEDs) over the last years as add-on treatment for drug-resistant epilepsy has led to an increased interest in optimizing combination therapy. Much attention has been focused on “rational polytherapy” using AEDs with different mechanisms of action [1], [2], [3]. However, the experimental and clinical evidence in support of “rational polytherapy” is sparse, and to date, no clear evidence-based indications can be made to help physicians in their choice of a specific drug combination against specific forms of epilepsy. This article briefly reviews the data available in the literature and obtained from studies conducted in humans to evaluate which main AED combinations might possess supraadditive, synergistic effects in terms of efficacy, with infraadditive toxicity.

Section snippets

The ideal AED polytherapy: supraadditive efficacy with infraadditive toxicity

Patients with newly diagnosed epilepsy usually start their treatment with monotherapy. Approximately 60–70% of them may reach benefit and control of seizures [4]. Conversely, around 30% of patients with epilepsy require polytherapy, as epilepsy persists despite receiving the highest dose of monotherapeutic AED. Polytherapy often represents, therefore, an unavoidable choice which should be carefully considered before initiating a treatment, as this carries a high risk of pharmacological

Mechanisms of action: how much do they matter?

Hypothetically, it is reasonable that supraadditive effects are more likely in polytherapy as many AEDs have multiple and potentially overlapping mechanisms of action.

Some studies conducted in patients with epilepsy have yielded results suggesting that supraadditive adverse effects due to pharmacodynamic interactions in polytherapy are more likely to occur when AEDs share similar mechanisms of action.

For example, a study conducted in 47 patients with epilepsy and cognitive impairment revealed

Irrational polytherapy

Polytherapy is often unavoidable in order to reach better seizure control; however, irrational polytherapy may also occur. The use of several AEDs may, in fact, cause adverse events, pharmacological interactions, reduced patient's compliance, and increased risk of mortality.

An irrational combination between two or more AEDs may be explained by several reasons. A poor initial diagnosis with choice of an inappropriate AED as first therapy may lead to unfavorable events (such as paradoxical

Ethosuximide–valproate

A case series has indicated that, when associated with ethosuximide (ESM), valproate (VPA) may prove useful against atypical absences not responding to monotherapy [17]. In this report, five patients with absence seizures refractory to treatment with either ESM or VPA became seizure-free with combination therapy. To our best knowledge, no further studies assessing the potential synergic anticonvulsant effect of this drug combination therapy have been conducted.

Lamotrigine–valproate

Combination therapy with lamotrigine–valproate has the best human evidence for synergy.

The first report of a possible synergic antiepileptic effect of the association between these two drugs dates back to 1992 when a drastic response to VPA–LTG combination therapy was observed in some patients with focal seizures refractory to other therapies.

Subsequently, Brodie and Yuen [9] conducted a study on a large sample (347 patients recruited in 54 centers across Europe) in order to assess the efficacy

Lacosamide–levetiracetam

A post hoc analysis derived from three randomized, double-blind, placebo-controlled trials evaluating adjunctive lacosamide (LCM) in patients with partial-onset seizures with or without secondary generalization showed a high 50% responder rate (43% of the patients) in the subgroup treated with LCM and concomitant levetiracetam (LEV) use [25]. Other subgroups treated with LCM and other AEDs showed responder rates below 50% (valproate: 48%, lamotrigine: 34%, topiramate: 42%, oxcarbazepine: 30%,

Stiripentol–clobazam

Stiripentol is a new AED acting through the increase of the GABAergic transmission in vitro in an experimental immature rat model. Pharmacological studies showed that STP also acts as an inhibitor of CYP3A4, CYP1A2, and CYP2C19 in patients with epilepsy. Whereas the studies in adult patients were disappointing, the trials conducted in pediatric populations demonstrated the specific efficacy of stiripentol in severe myoclonic epilepsy in infancy, especially when combined with valproate and

Conclusion

Rational choice of drug combinations is currently based more on avoidance of pharmacodynamic or pharmacokinetic side effects than on evidence for synergic anticonvulsant effects [1]. Considering the heterogeneity of patients suffering from epilepsy, until further, conclusive data on rational polytherapy are reached, therapeutical strategy and combination therapy should be tailored to each patient.

Although various investigative approaches have been made, including polytherapy studies both in

Conflict of interest

None.

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