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Seizure 20 (2011) 369–375

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Review Combining antiepileptic —Rational polytherapy?

Martin J. Brodie a,*, Graeme J. Sills b a Unit, Western Infirmary, Glasgow, Scotland, United Kingdom b Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, England, United Kingdom

ARTICLE INFO ABSTRACT

Article history: The global introduction of 14 new antiepileptic drugs (AEDs) over the past 20 years as adjunctive Received 7 January 2011 treatment in refractory epilepsy has triggered an increased interest in optimising combination therapy. Accepted 10 January 2011 With a widening range of available mechanisms of AED action, much activity has been focused on the defining and refining ‘‘rational polytherapy’’ with AEDs that have differing pharmacological properties. Keywords: This paper reviews the available animal and human data exploring this issue. The experimental and Antiepileptic drugs clinical evidence in support of ‘‘rational polytherapy’’ is sparse, with only the combination of sodium Mechanism of action with demonstrating synergism. Robust evidence to guide clinicians on how and interactions when to combine AEDs is lacking and current practice recommendations are largely empirical. Practical Combinations Refractory epilepsy guidance for the clinician is summarised and discussed in this review. In particular, care should be taken to avoid excessive drug load, which can be associated with decreased tolerability and, therefore, reduced likelihood of seizure freedom. A palliative strategy should be defined early for the more than 30% of patients with refractory epilepsy. Nevertheless, the availability of an increasing number of pharmacologically distinct AEDs has produced a modest improvement in prognosis with combination therapy, which will encourage the clinician to persevere with continued pharmacological manipulation when other therapeutic options have been tried or are not appropriate. ß 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction choices does the modern neurologist have in his therapeutic arsenal for treating drug-resistant epilepsy? Over the past 20 years, no fewer than 14 antiepileptic drugs ‘‘The combinations of with other drugs are of much (AEDs) have been licensed for use in the common and a value in the treatment of epilepsy. In many cases a greater effect range of more unusual syndromes (Fig. 1). Of these is produced by the combination than by other drugs given (blood dyscrasias and hepatotoxicity) and (concentric alone’’ (William Gowers, 1881) visual field defects) are rarely prescribed because of their 2 The modern treatment of epilepsy began with potassium association with serious adverse effects. Eslicarbazepine is bromide and this drug is still in use to this day.1 The next effective available in Europe, but not in the United States. has agent, , was not synthesised until 1911. So what else been licensed for Dravet’s syndrome via the European orphan drug 3 was Gowers giving his epilepsy patients together with potassium system and rufinamide’s usage is confined to seizures associated 4 bromide? The list included digitalis, belladonna, , opium, with Lennox–Gastaut syndrome. Nevertheless, the potential borax and many other noxious substances. It is well known that choices of AEDs as monotherapy or in combination are so Vincent van Gogh benefited from treatment with potassium numerous that it is not possible for a doctor and his or her patient bromide. He also took digitalis for a period of time. Indeed, he may to try every permutation in a single lifetime. Adding the newer have been digitoxic when he painted some of the canvases with AEDS to the established drugs brings their total number up to bright yellow overtones, since digitalis toxicity traditionally around 20 for use in the common epilepsies. This allows the distorts colour vision in this way. It is unlikely, but not impossible, possibility of nearly 200 duotherapies or more than 1000 that he was taking both drugs together at some point! So if Gowers combinations of 3 AEDs! had many polytherapy options more than 100 years ago, what Most patients with refractory epilepsy take 2, 3 or even 4 AEDs. How then are we to rationalise their usage to provide the best possibility of an optimal outcome? What evidence is there in support of ‘‘rational polytherapy’’? Conventional wisdom suggests * Corresponding author. Tel.: +44 141 211 2534; fax: +44 141 211 2072. E-mail addresses: [email protected], [email protected] that combining AEDs with different mechanisms of action is more (M.J. Brodie). likely to produce seizure freedom than prescribing those with

1059-1311/$ – see front matter ß 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2011.01.004 370[()TD$FIG] M.J. Brodie, G.J. Sills / Seizure 20 (2011) 369–375

Fig. 1. Chronology of antiepileptic drug introduction over the past 150 years.

similar or overlapping pharmacological properties. It should be Sodium valproate may have a similar action.20 Lamotrigine limits remembered too that the spectrum of efficacy for every drug does release by blocking both N- and P/Q-types of the not always correspond to the license. high-voltage-activated (HVA) calcium channel21 and levetirace- tam exerts a partial blockade of N-type calcium currents.22 2. Pharmacological targets Phenobarbital, felbamate, and are also believed to influence HVA calcium channel conductance, although their effects To best use the range of available AEDs, the prescriber must are less well characterised in terms of channel subtypes or possess some understanding of what we know about how these interaction with specific protein subunits.8,9 Finally, agents act in the brain. The knowledge base regarding their and also exert their effects via HVA calcium channels. pharmacology is limited but slowly increasing. We can now Uniquely, they bind to an accessory subunit, termed a2d-1, which identify a range of mechanisms that differ sufficiently from each can modulate the function of various native channels.23 other to provide some discrimination in their usage. Activation of the ionotropic GABAA receptor resulting in an Blockade of voltage-gated sodium channels is the most enhanced response to synaptically released GABA is a major AED common mechanism of action among currently available AEDs.5 mechanism.24 Phenobarbital and the share this The established agents and are arche- effect. They bind to distinct sites on the receptor complex and typal blockers,6,7 a mechanism they share with the differentially influence the opening of the chloride ion pore. newer drugs lamotrigine, , topiramate, felbamate, Typical -sensitive GABAA receptors are composed , rufinamide and lacosamide.8–10 Sodium valproate and of two a-subunits (a1, a2, a3ora5), two b-subunits (b2orb3), gabapentin may also have inhibitory effects on neuronal sodium and a g2 subunit, whereas are less selective in terms channels.11,12 Voltage-gated sodium channels exist in one of three of subunit preference.25 Barbiturates prolong the duration of basic conformational states; resting, open, and inactivated. During chloride channel opening, while benzodiazepines increase the a single round of depolarisation, channels cycle through these frequency of opening.26 In addition, phenobarbital is capable of states in turn and the neurone is unable to respond to further direct activation of the GABAA receptor in the absence of GABA, an depolarisations until a sufficient numbers of voltage-gated sodium effect which is believed to underlie its sedative properties.27 13 channels have returned to the resting state. AEDs with sodium Stiripentol has been identified as a subunit selective GABAA channel blocking properties have highest affinity for the channel enhancer with a preference for a3-B3-g2 containing receptors.28 protein in the inactivated state and binding slows the otherwise Felbamate and topiramate also modulate GABA responses at the rapid recycling process. As a result, these drugs produce a GABAA receptor. While their subunit specificity remains to be characteristic voltage- and frequency-dependent reduction in established, their binding sites and effects on channel kinetics are channel conductance, resulting in a limitation of repetitive reported to be distinct from one another and from those observed neuronal firing with little effect on the generation of single action with barbiturates and benzodiazepines.29,30 Finally, 14 potentials. While most sodium channel blocking AEDs interfere can indirectly influence GABAA receptor function by reducing the with the fast inactivation pathway, lacosamide selectively negative allosteric modulation of the receptor complex by b- influences slow inactivation.15 Recent evidence suggests that this carbolines and zinc.31 drug can be usefully combined with sodium channel blockers that Vigabatrin and exert their actions by selective act on fast inactivation.16 neurochemical effects at the inhibitory synapse, resulting in Voltage-gated calcium channels represent another important altered GABA turnover.32 Vigabatrin is an irreversible inhibitor of target for several AEDs.17 The efficacy of and the mitochondrial enzyme GABA-transaminase, which is respon- zonisamide in generalised absence epilepsy is believed to be sible for the catabolism of GABA, whereas tiagabine prevents the mediated by blockade of the low voltage-activated T-type calcium removal of GABA from the synaptic cleft by blockade of GABA channel in the dendrites of thalamocortical relay neurones.18,19 transport.33,34 These distinct mechanisms result in the global M.J. Brodie, G.J. Sills / Seizure 20 (2011) 369–375 371 elevation of brain GABA concentrations and the temporarily Together, these models offer an opportunity to characterise the prolonged presence of neuronally released GABA in the synapse, efficacy and toxicity of individual drugs and drug combinations in respectively. Although these drugs target neurones and glial cells, large groups of genetically homogeneous animals. Despite vigabatrin has marginally higher affinity for neuronal GABA- question marks over their relevance to human epilepsy, and of transaminase, whereas tiagabine is slightly more effective in the doses and acute treatment regimens employed in preclinical reducing glial GABA uptake.32 Furthermore, tiagabine is selective studies, these models have been instrumental in the identification for the GAT-1 GABA transporter and its pharmacological effects of almost all current AEDs and, as such, are a valuable surrogate in mirror the regional distribution of this protein with a more the search for optimal combination therapy.51 Those most pronounced action in hippocampus and neocortex.35 Other AEDs, commonly used in drug screening in rodents are including sodium valproate, gabapentin and topiramate have also maximal electroshock (MES), pentylenetetrazol (PTZ) and spike- been reported to influence GABA turnover by increasing neuro- wave and kindling models for efficacy purposes and the rotarod, transmitter synthesis and/or release.36–38 horizontal screen, and chimney tests for neurotoxicity.52 None of the currently available AEDs exerts its effects solely by Experimental combination studies should incorporate efficacy an action on the glutamate system. Blockade of the NMDA subtype and toxicity models in which both drugs are at least minimally of glutamate receptor is, however, believed to contribute to the effective, use drug ratios that reflect those employed clinically, pharmacological profile of felbamate.39 Topiramate is similarly include drug concentration analysis in both plasma and brain to distinguished by an inhibitory action on AMPA and kainate rule out confounding pharmacokinetic interactions, and employ an receptors with a higher affinity for the latter.40 It has also been appropriate method of analysis such as isobolography or suggested that zonisamide may inhibit glutamate-mediated comparison of protective indices.53 Isobolography is preferable excitatory synaptic transmission, although this is likely to reflect as it provides a robust measure of effectiveness and affords a an indirect action on glutamate release mediated by pre-synpatic definitive determination of infra-additive (antagonistic), additive, blockade of sodium and calcium channels.41 or supra-additive (synergistic) interactions.54 The ideal AED Levetiracetam was developed for the treatment of epilepsy with combination displays pharmacological synergism, whether it is no clear indication of how it worked at the cellular level. The defined as improved efficacy with similar toxicity, similar efficacy identification of a specific binding site for the drug in mammalian with improved toxicity or, ideally, improved efficacy with brain with its later classification as synaptic vesicle protein 2A improved toxicity. (SV2A) has resulted in claims that levetiracetam represents the Experimental investigation of AED combinations has a long first in a new class of AEDs.42,43 However, the precise physiological pedigree.55 Early studies exploring combinations of established role of SV2A is still unclear and important details of the interaction drugs, such as phenobarbital, phenytoin, and carbamazepine, were between drug and protein remain to be defined. Indeed, there is performed without any knowledge of their mechanisms of action. still no convincing evidence to suggest whether the interaction is Interestingly, combinations were commonly reported to be facilitatory or inhibitory or if it results in altered packaging, superior, in terms of efficacy, toxicity or both, than either trafficking, membrane fusion or recycling of synaptic vesicles constituent drug alone irrespective of the drugs under investiga- within the nerve terminal.44 There is, however, credible evidence tion.56 However, this was most evident when two drugs with to support selective binding of levetiracetam to SV2A with little or differing mechanisms of action were combined, e.g. phenobarbital no affinity for other members of the same protein family, and an with phenytoin.57 Less successful were combinations of AEDs with impressive correlation between SV2A binding affinity and the similar mechanisms, e.g. phenytoin with carbamazepine.58 These anticonvulsant efficacy of a series of levetiracetam analogues in studies set the benchmark for the concept of rational polyphar- audiogenic seizure sensitive mice.42 macy as it evolved in the 1990s with the advent of modern AEDs, The acid–base balance and maintenance of local pH is critical to which are invariably introduced as adjunctive therapy for normal functioning of the nervous system. Various isoenzymes of refractory partial epilepsy, and new knowledge surrounding carbonic anhydrase play an important role in this regard. They are AED pharmacology.59 responsible for catalysing the bi-directional conversion of carbon Identifying preferred combinations of AEDs, particularly when dioxide and water to bicarbonate and hydrogen ions starting a new drug, might be regarded as advantageous in terms of + (CO2 +H2O $ HCO3 +H ). The forward reaction is rapid, whereas maximising efficacy and minimising adverse effects. Considerable the rate of the reverse reaction is more modest. As a result, experimental effort has been expended on studying combinations inhibition of carbonic anhydrase influences the latter more of modern AEDs with their older counterparts and, more latterly, significantly, producing a localised acidosis and increased bicar- with each other.60,61 Some common themes have emerged from bonate ion concentration.45 This, in turn, attenuates excitatory the vast literature, most notably that combining drugs with neurotransmission by reducing NMDA receptor activity and differing mechanisms of action appears superior to combining enhances inhibitory neurotransmission by facilitating the respon- those possessing the same or similar cellular effects.56 This 46 siveness of GABAA receptors. is a classical observation is exemplified by the consistent demonstration of carbonic anhydrase inhibitor which has been employed as an synergism between lamotrigine and sodium valproate in multiple AED for more than 50 years.47 Topiramate and zonisamide share efficacy models62,63 and the repeated failure to demonstrate this mechanism, but are significantly less potent and have greater synergism between lamotrigine and either carbamazepine or selectivity for individual isoenzymes. For instance, topiramate phenytoin.62,64 Other combinations appear to produce less selectively inhibits CA-II and CA-IV.48 Lacosamide may also inhibit consistent results; for example, gabapentin with carbamazepine this enzyme.49 Thus, it is possible that inhibition of carbonic is synergistic in the MES model but not in the DBA/2 audiogenic- anhydrase might make a modest contribution to the overall seizure susceptible mouse.65,66 Overall, the message is relatively efficacy of a range of AEDs. clear; reinforcement on a single pharmacological pathway is less effective than a combined effect on two distinct pathways. 2.1. Experimental data The most successful two drug combination in laboratory studies appears to be a single mechanism drug combined with an AED Animal models of seizures, epilepsy and drug-related neuro- known to possess multiple mechanisms of action.56 Combinations toxicity are widely used in the identification of novel AEDs and of drugs that selectively target neuronal voltage-gated sodium many of them have been in routine laboratory use for decades.50 channels appear to offer only additive improvements in efficacy 372 M.J. Brodie, G.J. Sills / Seizure[()TD$FIG] 20 (2011) 369–375 and often supra-additive enhancement of neurotoxicity.61 Unfor- tunately, there are no meta-analyses or systematic reviews of experimental combination studies which would permit an objective assessment of the available data. This is most likely due to variability in experimental methodology and the difficulty in comparing results across multiple studies. Many investigations are also incomplete; neurotoxicity testing is often not reported, which undermines any suggestion of synergism in terms of efficacy. Pharmacokinetic analysis is rarely performed, which is necessary to rule out the potential for altered drug absorption or brain penetration. Fig. 2. Median monthly seizure counts for patients receiving add-on lamotrigine to 2.2. Clinical evidence baseline treatment with phenytoin, carbamazepine or sodium valproate. The study consisted of a 12-week ‘‘baseline phase’’ of the original baseline monotherapy, followed by the ‘‘add on phase’’ when lamotrigine was introduced with baseline The situation regarding clinical evidence in support of ‘‘rational 67–69 unchanged. Patients showing at least 50% reduction in seizure polytherapy’’ is similarly sparse. There are claims in the frequency compared with baseline entered the 12-week ‘‘withdrawal phase’’ literature supporting particular efficacy for combinations including when the baseline antiepileptic drug was tapered off. Patients who successfully a sodium with a GABA-ergic drug56 or one with completed the withdrawal phase entered the lamotrigine ‘‘monotherapy phase’’ of multiple mechanisms of action.70 However, once again the only 12 weeks duration.(reproduced from Ref. [71], with permission). supportive evidence for synergism is with sodium valproate and lamotrigine. Brodie and colleagues undertook a pragmatic trial compared with those taking other AEDs in a pooled analysis of during which an attempt was made to substitute lamotrigine as data with adjunctive lacosamide.16 Introducing monotherapy in patients suboptimally treated with carbamazepine, lamotrigine in patients established on sodium valproate produces phenytoin or sodium valproate.71 Adjustment was made in the a substantially greater risk of allergic rash than occurs in patients lamotrigine dosing schedules for the pharmacokinetic interactions starting on the drug as monotherapy.82 This is presumed to be a among these drugs resulting in similar circulating lamotrigine consequence of the inhibitory effect of valproate on lamotrigine concentrations for all 3 combinations. When patients were metabolism resulting in higher concentrations. established on both drugs, it was noted that the efficacy was substantially higher in the valproate group than in the patients 2.3. Improved outcomes taking lamotrigine with carbamazepine or phenytoin (Fig. 2). Following up on this observation, Pisani et al. performed a well- There is increasing evidence that the prognosis of treated designed crossover study in 20 patients with partial seizures epilepsy has improved over the past decade, although this has not stabilised on combination therapy.72 Among the 13 who did not had a major impact in substantially reducing the size of the respond to the consecutive addition of sodium valproate and refractory epilepsy population.83–85 This is perhaps not too lamotrigine, four patients became seizure free and an additional four surprising since the -corrected efficacy of adjunctive experienced >50% seizure reduction when both drugs were given in treatment with modern AEDs in double-blind randomized trials combination despite lower doses and circulating concentrations has been disappointingly small86 with very few patients becoming than occurred during their separate administration. seizure-free even for the limited duration of the study.87 Other useful combinations suggested in the literature are Data from the expanding cohort of adolescents and adults with largely based on anecdotal reports in small groups of patients or newly diagnosed epilepsy in Glasgow, Scotland also support the studies with modest sample sizes. These include valproate with suggestion that the prognosis has marginally improved since the ethosuximide for absence seizures,73 phenobarbital with phenyt- first analysis a decade ago reported a likely bleak outcome oin for generalised tonic–clonic seizures,74 carbamazepine with following failure of the first drug due to lack of efficacy.88 With the valproate or vigabatrin for partial seizures,75 vigabatrin with advent of a range of mechanistically different AEDs, some patients tiagabine for partial seizures76 and lamotrigine with topiramate for will now respond to their 3rd, 4th or 5th treatment schedules.89 a range of seizure types.77 Overall a higher percentage of this expanding population had Interestingly, in a multicentre double-blind, placebo-con- attained seizure-freedom by 2008 (n = 1098; 68.4%) than in the trolled, randomized, parallel group trial of rufinamide 1600 mg initial analysis conducted in 1998 (n = 470; 64%). Of the 70 in this twice daily in adults and adolescents with refractory partial cohort controlled on polypharmacy, 67 (96%) were taking just two seizures, there was a 12% reduction in monthly seizure frequency AEDs. These data support those of Schiller and Najjar in suggesting in the 96 patients established on carbamazepine compared with a that patients need to fail five, six or even seven drug schedules 29% seizure reduction (p = 0.05) in the 60 patients taking a regimen before they can be recognised as having truly refractory epilepsy.85 that did not contain carbamazepine.78 Arguably, this observation This picture appears similar for the common childhood epilep- could suggest that carbamazepine and rufinamide have similar sies.90,91 effects on voltage-dependent sodium channels. More recently it has been demonstrated in placebo-controlled dose ranging 2.4. Drug usage adjunctive trials with lacosamide that response to this drug was less impressive in patients established on traditional sodium The mechanisms of action of the currently marketed drugs are blockers than those taking AEDs with different mechanisms of relatively limited since their anti-seizure properties were identi- action, although a dose-dependent statistically significant im- fied using a similar array of rodent seizure models.92 They all provement over placebo was demonstrated in both groups.16 inhibit the onset and/or spread of abnormal neuronal synchrony Combining drugs that block voltage-dependent sodium chan- either by decreasing excitation and/or increasing inhibition.8 nels is more likely to produce neurotoxic side-effects, such as Given that we know little about the processes in the brain of , diplopia and .71,79–81 A similar scenario, particu- individual patients that trigger the initiation of a seizure or switch larly related to a greater likelihood of dizziness, has been reported off the abnormal electrical activity, it seems reasonable to combine in patients established on traditional sodium channel blockers AEDs that are pharmacologically distinct.93. Even though we do not M.J. Brodie, G.J. Sills / Seizure 20 (2011) 369–375 373 fully understand the mechanistic minutiae of many available Table 2 drugs, we can make a good start at separating those that work in Guidance for combining antiepileptic drugs. similar ways from those that act differently. These are simplified Establish optimal dose of baseline agent and summarised in Table 1. This forms the template for those AEDs Add drug with multiple mechanisms Avoid combining similar modes of action that can reasonably be combined in patients with drug-resistant Titrate new agent slowly and carefully epilepsy. Be prepared to reduce dose of original drug AEDs have different spectra of activity with most sodium Replace less effective drug if response still poor blockers, except rufinamide and possibly also lamotrigine, having Try range of different duotherapies Add third drug if still sub-optimal control efficacy for partial and tonic–clonic seizures only. It has been Devise palliative strategy for refractory epilepsy suggested for some time that better outcomes can be obtained in patients established on a in combination with a drug that possess a different mechanism of action.94 classification.98 This has recently been defined by an International Regulatory trial data have demonstrated that lacosamide can be League Against Epilepsy task force as ‘‘failure of an adequate trial of usefully combined with traditional sodium blocking agents.16 two tolerated, appropriately chosen and used AED schedules Ethosuximide use is largely confined to absence seizures, whereas (whether as monotherapies or in combination) to achieve gabapentin and pregabalin are used for partial seizures with or sustained seizure freedom’’.99 The development of this definition without secondary generalisation.95 As we do not understand how encourages a more aggressive approach toward earlier combina- seizures are generated and propagated in the brains of individual tion therapy and more rapid access to non-pharmacological patients, adding molecules that possess multiple mechanisms of treatment options, such as vagal nerve stimulation or epilepsy action, such as valproic acid, levetiracetam, topiramate and surgery.100 Special attention should be paid to drug load to avoid zonisamide, may be more likely to provide a beneficial pharmaco- side-effects and optimise the potential for complete seizure logical effect in the setting of refractory epilepsy.56,70 These agents control.101 It would also be worthwhile raising the possibility at also tend to be broad spectrum across a range of seizure types. this early stage that seizure freedom may not be attainable, paving Interestingly, the barbiturates and benzodiazepines, which act on the way for a later palliative strategy if this proves to be necessary. the GABAA receptor, also have a broader range of efficacy than All patients with refractory epilepsy should be informed of the risk other GABA-ergic drugs, such as vigabatrin and tiagabine, that have of sudden unexpected death in epilepsy and appropriate precau- a selective effect on GABA turnover. In addition there are a handful tions taken.102 of AEDs in the pipeline with novel mechanisms of action that Even with the contribution from experimental combination should offer opportunities for new and pharmacologically distinct studies, the issue of rational polypharmacy for epilepsy remains combinations.96 In particular ezogabine/ (potassium largely unresolved. This is, to some extent, due to uncertainty ) and (selective (AMPA/kainate antag- about the definition. If it is the application of common sense, then onist) may be useful additions to the therapeutic armamentarium we should combine drugs with different, perhaps multiple, for drug-resistant epilepsy. mechanisms of action in order to cover more pharmacological If a patient tolerates the first, second or third monotherapy well bases. If it is to be evidence-based, then robust evidence does not with a useful but suboptimal response, combination therapy exist in support of the above strategy with the exception of should be considered, particularly if there is a high seizure density combining sodium valproate with lamotrigine. Whatever strategy and demonstrable underlying pathology, such as mesial temporal we use is confounded by our incomplete understanding of how sclerosis or cortical dysplasia (Table 2). Several duotherapy AEDs work, not to mention our lack of knowledge about the combinations should be tested sequentially before adding a third neurobiologies underpinning most epilepsies. These deficiencies drug. Higher numbers of AEDs should be avoided if possible as it is arguably limit our ability to use single drugs in a rational manner, highly unlikely that this strategy will produce useful seizure far less in combinations. However, on the basis of current reduction without side effects.97 experimental and clinical evidence, it would appear that combin- A personalized treatment plan should be formulated once a ing AEDs with similar mechanisms of action is counter-intuitive patient fulfils the criterion for drug-resistant epilepsy to limit as far and counter-productive. At present, however, this principle can as possible cognitive deterioration and psychosocial dysfunction, only be reasonably applied to selective sodium channel blockers while taking into consideration seizure type(s) and syndrome and not other mechanistic classes of AEDs.

3. Conclusion Table 1 Different mechanistic groups suitable for combination therapy. After being viewed as a last resort for many years, the role of 1Sodium channel blockers combination therapy as an acceptable treatment strategy for (a) Fast-inactivated state—phenytoin, carbamazepine, lamotrigine, oxcarbaze- epilepsy is undergoing re-evaluation. This is a result of the growing pine, eslicarbazepine (b) Slow-inactivated state—lacosamide appreciation that a substantial proportion of patients will not respond optimally to monotherapy, coupled with the availability 2Calcium channel blockers of a wide range of modern AEDs, some of which are better tolerated (a) Low voltage activated channel—ethosuximide (b) High voltage activated channel—gabapentin, pregabalin and less prone to complex pharmacokinetic drug interactions than their older counterparts. Convincing evidence to guide clinicians 3GABA-ergic drugs on when and how to combine AEDs is still lacking, and current (a) Prolongs chloride channel opening—barbiturates (b) Increased frequency of chloride channel opening—benzodiazepines practice recommendations remain empirical. Well designed (c) Inhibits GABA-transaminase—vigabatrin studies exploring the ever expanding possibilities of AED (d) Blocks synaptic GABA —tiagabine combinations would address these practical questions so that 4Synaptic vesicle protein 2A modulation—levetiracetam effective therapy could be offered to many more patients in a pharmacologically targeted fashion. A mechanistic approach to the 5Carbonic anhydrase inhibition—acetazolamide pharmacological management of each epilepsy syndrome has the 6Multiple pharmacological targets—sodium valproate, felbamate, topiramate, potential to optimise the chance of perfect seizure control and help zonisamide, rufinamide more people achieve safer and more fulfilled lives. 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