ReviewWhen one plus one makes three: The quest for rational antiepileptic polytherapy with supraadditive anticonvulsant efficacy
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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Cited by (53)
Adult epilepsy
2023, The LancetPharmacodynamic interactions of antiepileptic drugs: From bench to clinical practice
2020, Epilepsy and BehaviorClinical opinion: Earlier employment of polytherapy in sequential pharmacotherapy of epilepsy
2019, Epilepsy ResearchCitation Excerpt :It is focused at producing desirable pharmacodynamic drug interactions of AEDs by combining drugs having different MOAs but avoiding drugs having adverse pharmacological (pharmacokinetic and/or pharmacodynamic) interactions, similar side effects profiles, and narrow therapeutic index. In clinical practice, several combination regimens have been reported to carry synergistic interactions (Rowan et al., 1983; Deckers et al., 2000; Kinirons et al., 2006; Stephen et al., 1998; Chung et al., 2010; Brigo et al., 2013; Brodie, 2016; Legge et al., 2018) (Table 1). Synergistic interaction of lamotrigine (LTG) and VPA combination therapy was first reported by Brodie and Yuen (1997), who found a much higher responder rate in add-on therapy of LTG in patients under VPA monotherapy than patients taking either CBZ or PHT monotherapy.
Effect of newer anti-epileptic drugs (AEDs) on the cognitive status in pentylenetetrazol induced seizures in a zebrafish model
2019, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :The treatments for each group are described as X + Y, whereby X is the substance used to pre-treat the zebrafish and Y is the substance used to challenge the zebrafish 10 min after the pre-treatment. The two AED combinations were chosen to reflect clinical practice as per studies by Brigo et al. (2013); Luszczki et al. (2006). PTZ and the AEDs were intraperitoneally injected into the zebrafish according to the protocol given by Kundap et al. (2017).