After being regarded as a last resort for over two decades, the role of combination therapy as a treatment strategy for epilepsy is undergoing re-evaluation. This is a result of the growing appreciation that all seizures cannot be controlled by monotherapy in a substantial proportion of patients, and of the development of a range of modern antiepileptic drugs (AEDs), some of which are better tolerated and less prone to complex pharmacokinetic drug interactions than their older counterparts.
Robust evidence to guide clinicians on when and how to combine AEDs is lacking, and current practice recommendations are largely empirical. Monotherapy should remain the treatment of choice for newly diagnosed epilepsy. A combination of two AEDs can be considered after failure, resulting from lack of efficacy, of one or two different monotherapy regimens. A few patients will become seizure-free with a combination of three AEDs, but treatment with a combination of four or more is unlikely to be successful. There is some evidence to support a pharmacomechanistic approach to AED combination. Care should be taken to avoid excessive drug load, which is associated with increased toxicity.
Bigger and better randomised, controlled studies are needed to determine the optimal time and way to combine AEDs.
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.
Professor Brodie has received research grants and/or honoraria from and/or acted as a consultant at some time for the following pharmaceutical companies: Sanofi-Aventis, Glaxo SmithKline, Pfizer, Janssen-Cilag, Eisai, UCB, Novartis and Cephalon. Dr Kwan has received research grants and/or honoraria at some time from the following pharmaceutical companies: Pfizer, Janssen-Cilag and UCB.
Deckers CLP, Hekster YA, Keyser A, et al. Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects. Epilepsia 1997; 38: 570–5PubMedCrossRefGoogle Scholar
Deckers CLP, Hekster YA, Keyser A, et al. Drug load in clinical trials: a neglected factor. Clin Pharmacol Ther 1997; 62: 592–5PubMedCrossRefGoogle Scholar
WHO Collaborating Centre for Drug Statistics Methodology. ATC / DDD Index 2006 [online]. Available from URL: http://www.whocc.no/atcddd [Accessed 2005 Dec 28]
Lammers MW, Hekster YA, Keyser A, et al. Monotherapy or polytherapy for epilepsy revisited: a quantitative assessment. Epilepsia 1995; 36: 440–6PubMedCrossRefGoogle Scholar
Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia 1999; 40: 985–91PubMedCrossRefGoogle Scholar
Cunnington M, Tennis P, for the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005; 64: 955–60PubMedCrossRefGoogle Scholar
Morrow JI, Russell A, Gutherie E, et al. Malformation risks of anti-epileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77: 193–8PubMedCrossRefGoogle Scholar
Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003; 2: 347–56PubMedCrossRefGoogle Scholar
Radulov LL, Wilder BJ, Leppik IE, et al. Lack of interaction of gabapentin with carbamazepine or valproate. Epilepsia 1995; 35: 155–61CrossRefGoogle Scholar
Brodie MJ, Wilson EA, Wesche DL, et al. Pregabalin drug interaction studies: lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine and valproate in patients with partial epilepsy. Epilepsia 2005; 46: 1407–13PubMedCrossRefGoogle Scholar
Temkin MR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: metanalysis of controlled trials. Epilepsia 2001; 42: 515–24PubMedCrossRefGoogle Scholar
Kwan P, Brodie MJ. Drug treatment of epilepsy: when does it fail and how to optimize its use? CNS Spectr 2004; 9: 110–9PubMedGoogle Scholar
Perucca E, Kwan P. Overtreatment in epilepsy: how it occurs and how it can be avoided. CNS Drugs 2005; 19: 897–908PubMedCrossRefGoogle Scholar
Deckers CL, Hekster YA, Keyser A, et al. Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study. Epilepsia 2001; 42: 1387–94PubMedCrossRefGoogle Scholar
Baldy-Moulinier M, Covanis A, et al. Therapeutic strategies against epilepsy in Mediterranean countries: a report from an international collaborative survey. Seizure 1998; 7: 513–20PubMedCrossRefGoogle Scholar
Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav 2005; 7 Suppl. 1: S1–64PubMedCrossRefGoogle Scholar
Beghi E, Gatti G, Tonini C, et al. Adjuctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial. Epilepsy Res 2003; 57: 1–13PubMedCrossRefGoogle Scholar
Lindberger M, Alenius M, Frisen L, et al. Gabapentin versus vigabatrin as first add-on for patients with partial seizures that failed to respond to monotherapy: a randomized, double-blind, dose titration study. Epilepsia 2000; 41: 1289–95PubMedCrossRefGoogle Scholar
Marson AG, Kadir ZA, Hutton JL, et al. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997; 38: 859–80PubMedCrossRefGoogle Scholar
Marson AG, Hutton JL, Leach JP, et al. Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res 2001; 46: 259–70PubMedCrossRefGoogle Scholar
Cramer JA, Fisher R, Ben-Menachem E, et al. New antiepileptic drugs: comparison of key clinical trials. Epilepsia 1999; 40: 590–600PubMedCrossRefGoogle Scholar
Brodie MJ, Yuen AWC. Lamotrigine substitution study: synergism with sodium valproate? 105 Study Group. Epilepsy Res 1997; 26: 423–32PubMedCrossRefGoogle Scholar
Pisani F, Otero G, Russo MF, et al. The efficacy of valproate-lamotrigine comedicatoin in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia 1999; 40: 1141–6PubMedCrossRefGoogle Scholar
Rowan AJ, Meijer JWA, de Beer-Pawlikowski N, et al. Valproate ethosuximide combination therapy for refractory absence seizures. Arch Neurol 1983; 40: 797–802PubMedCrossRefGoogle Scholar
Cereghino JJ, Brock JT, Van-Meter JC, et al. The efficacy of carbamazepine combination in epilepsy. Clin Pharmacol Ther 1975; 18: 733–41PubMedGoogle Scholar
Brodie MJ, Mumford JP. Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy. 012 Study Group. Epilepsy Res 1999; 34: 199–205CrossRefGoogle Scholar
Brandt C, Bethmann K, Gastens A, et al. Resistance to antiepileptic drug treatment can be counteracted by inhibition of P-glycoprotein in a rat model of temporal lobe epilepsy [abstract]. Epilepsia 2005; 46 Suppl. 6: 60Google Scholar