Abstract
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.
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References
Reynolds EH, Shorvon SD. Monotherapy or polytherapy for epilepsy? Epilepsia 1981; 22: 1–10
Reynolds EH, Chadwick D, Galbraith AW. One drug (phenytoin) in the treatment of epilepsy. Lancet 1976; 307: 923–6
Shorvon SD, Reynolds EH. Reduction in polypharmacy for epilepsy. BMJ 1979; 2: 1023–5
Schmidt D. Reduction of two-drug therapy in intractable epilepsy. Epilepsia 1983; 24: 368–76
Albright P, Bruni J. Reduction of polypharmacy in epileptic patients. Arch Neurol 1985; 42: 797–9
Deckers C. Overtreatment in adults with epilepsy. Epilepsy Res 2002; 52: 43–52
Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342: 314–9
Mohanraj R, Brodie MJ. Outcomes in newly diagnosed localisation-related epilepsies. Seizure 2005; 14: 318–23
Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 2006; 13: 277–82
Kwan P, Brodie MJ. Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy. Neurology 2003; 60 Suppl. 4: 2–12
Kwan P, Sills GJ, Brodie MJ. The mechanisms of action of commonly used antiepileptic drugs. Pharmacol Ther 2001; 90: 21–34
Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004; 5: 553–64
Mawer CE, Pleuvry BJ. Interactions involving new antiepileptic drugs. Pharmacol Ther 1995; 68: 209–31
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: 570–5
Deckers CLP, Hekster YA, Keyser A, et al. Drug load in clinical trials: a neglected factor. Clin Pharmacol Ther 1997; 62: 592–5
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: 440–6
Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia 1999; 40: 985–91
Cunnington M, Tennis P, for the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005; 64: 955–60
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: 193–8
Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003; 2: 347–56
Radulov LL, Wilder BJ, Leppik IE, et al. Lack of interaction of gabapentin with carbamazepine or valproate. Epilepsia 1995; 35: 155–61
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: 1407–13
Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet 2004; 43: 707–24
May TW, Korn-Merker E, Rambeck B. Clinical pharmacokinetics of oxcarbazepine. Clin Pharmacokinet 2003; 42: 1023–42
Bialer M, Doose DR, Murthy B, et al. Pharmacokinetic interactions of topiramate. Clin Pharmacokinet 2004; 43: 763–80
PROGRESS Collaborative Group. Randomised trial of perinopril-based blood pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033–41
Czuczwar SJ, Borowicz KK. Polytherapy in epilepsy: the experimental evidence. Epilepsy Res 2002; 52: 15–23
Temkin MR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: metanalysis of controlled trials. Epilepsia 2001; 42: 515–24
Kwan P, Brodie MJ. Drug treatment of epilepsy: when does it fail and how to optimize its use? CNS Spectr 2004; 9: 110–9
Perucca E, Kwan P. Overtreatment in epilepsy: how it occurs and how it can be avoided. CNS Drugs 2005; 19: 897–908
Deckers CL, Hekster YA, Keyser A, et al. Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study. Epilepsia 2001; 42: 1387–94
Baldy-Moulinier M, Covanis A, et al. Therapeutic strategies against epilepsy in Mediterranean countries: a report from an international collaborative survey. Seizure 1998; 7: 513–20
Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav 2005; 7 Suppl. 1: S1–64
Deckers CLP. Place of polytherapy in the early treatment of epilepsy. CNS Drugs 2002; 16: 155–63
Kwan P, Brodie MJ. Epilepsy after the first drug fails: substitution or add-on? Seizure 2000; 9: 464–8
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: 1–13
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: 1289–95
Marson AG, Kadir ZA, Hutton JL, et al. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997; 38: 859–80
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: 259–70
Cramer JA, Fisher R, Ben-Menachem E, et al. New antiepileptic drugs: comparison of key clinical trials. Epilepsia 1999; 40: 590–600
Brodie MJ, Yuen AWC. Lamotrigine substitution study: synergism with sodium valproate? 105 Study Group. Epilepsy Res 1997; 26: 423–32
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: 1141–6
Rowan AJ, Meijer JWA, de Beer-Pawlikowski N, et al. Valproate ethosuximide combination therapy for refractory absence seizures. Arch Neurol 1983; 40: 797–802
Cereghino JJ, Brock JT, Van-Meter JC, et al. The efficacy of carbamazepine combination in epilepsy. Clin Pharmacol Ther 1975; 18: 733–41
Brodie MJ, Mumford JP. Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy. 012 Study Group. Epilepsy Res 1999; 34: 199–205
Leach JP, Brodie MJ. Synergism with GABA-ergic drugs in refractory epilepsy. Lancet 1994; 343: 1650
Stephen LJ, Sills GJ, Brodie MJ. Lamotrigine and topiramate may be a useful combination. Lancet 1998; 351: 958–9
Deckers CLP, Czuczwar SJ, Hekster YA, et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia 2000; 41: 1364–74
Kwan P, Brodie MJ. Pharmacological treatment of epilepsy in adolescents and adults. In: Gilman S, editor. MedLink Neurology [online]. Available from URL: http://medlink.com [Accessed 2006 Sep 5]
Stephen LJ, Brodie MJ. Seizure freedom with more than one antiepileptic drug. Seizure 2002; 11: 349–51
Besag FMC, Berry DJ, Pool F, et al. Carbamazepine toxicity with lamotrigine: Pharmacokinetic or pharmacodynamic interaction? Epilepsia 1998; 39: 183–7
Barcs G, Walker EB, Elger CE, et al. Oxcarbazepine placebo-controlled, dose ranging trial in refractory partial epilepsy. Epilepsia 2000; 41: 1597–607
Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001; 42: 1255–60
Mohanraj R, Brodie MJ. Pharmacological outcomes in newly diagnosed epilepsy. Epilepsy Behav 2005; 6: 382–7
Brodie MJ, Kwan P. The star systems: overview and use in determining antiepileptic drug choice. CNS Drugs 2001; 18: 1–12
Trevathan E, Gilliam F. Lost years: delayed referral for surgically treatable epilepsy. Neurology 2003; 61: 432–3
Perucca E. Pharmacoresistance in epilepsy: how should it be defined? CNS Drugs 1998; 10: 171–9
Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003; 2: 347–56
Pellock JM, Brodie MJ. Felbamate: an update. Epilepsia 1997; 38: 1261–4
McDonagh J. Stephen LJ, Dolan F, et al. Peripheral retinal dysfunction in patients taking vigabatrin. Neurology 2003; 61: 1690–4
Arts WFM, Geerts AT, Brouwer OF, et al. The early prognosis of epilepsy in childhood: the prediction of a poor outcome. Epilepsia 1999; 40: 726–34
MacDonald BK, Johnson AL, Goodridge DM, et al. Factors predicting prognosis of epilepsy after presentation with seizures. Ann Neurol 2000; 48: 833–41
Berg AT, Shinnar S, Levy SR, et al. Early development of intractable epilepsy in children: a prospective study. Neurology 2001; 56: 1445–52
Brodie MJ. Glasgow outcome studies. Epilepsy Res 2004; 60: 96–7
Kwan P, Brodie MJ. Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia 2005; 46: 225–35
Loscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 2005; 6: 591–602
Kwan P, Brodie MJ. Refractory epilepsy: mechanisms and solutions. Expert Rev Neurother 2006; 6: 397–406
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: 60
Acknowledgments
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.
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Kwan, P., Brodie, M.J. Combination Therapy in Epilepsy. Drugs 66, 1817–1829 (2006). https://doi.org/10.2165/00003495-200666140-00004
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DOI: https://doi.org/10.2165/00003495-200666140-00004