CNS Drugs

, Volume 31, Issue 10, pp 835–844 | Cite as

Selecting Rational Drug Combinations in Epilepsy

Therapy in Practice


Monotherapy remains the standard initial therapy of epilepsy, but when the first antiepileptic drug (AED) fails, combination therapy may be considered. The choice of combination therapy should take into consideration pharmacokinetic interactions, as well as pharmacodynamic interactions related to mechanism of action. There is evidence that an AED combination with different mechanisms of action is more likely to be successful than a combination with the same mechanisms. The combination of lamotrigine and valproate has been demonstrated to be synergistic in its efficacy. However, there are limited data to support other synergistic AED combinations.


Compliance with Ethical Standards



Conflict of interest

Bassel Abou-Khalil declares no conflict of interest.


  1. 1.
    Shorvon SD, Reynolds EH. Reduction in polypharmacy for epilepsy. Br Med J. 1979;2(6197):1023–5.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schmidt D. Reduction of two-drug therapy in intractable epilepsy. Epilepsia. 1983;24(3):368–76.CrossRefPubMedGoogle Scholar
  3. 3.
    Lesser RP, Pippenger CE, Luders H, Dinner DS. High-dose monotherapy in treatment of intractable seizures. Neurology. 1984;34(6):707–11.CrossRefPubMedGoogle Scholar
  4. 4.
    Deckers CL, Hekster YA, Keyser A, Meinardi H, Renier WO. Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects. Epilepsia. 1997;38(5):570–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Lammers MW, Hekster YA, Keyser A, Meinardi H, Renier WO, van Lier H. Monotherapy or polytherapy for epilepsy revisited: a quantitative assessment. Epilepsia. 1995;36(5):440–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Deckers CL, Hekster YA, Keyser A, Meinardi H, Renier WO. Drug load in clinical trials: a neglected factor. Clin Pharmacol Ther. 1997;62(6):592–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Deckers CL, Hekster YA, Keyser A, van Lier HJ, Meinardi H, Renier WO. Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study. Epilepsia. 2001;42(11):1387–94.CrossRefPubMedGoogle Scholar
  8. 8.
    Canevini MP, De Sarro G, Galimberti CA, Gatti G, Licchetta L, Malerba A, et al. Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug-refractory epilepsy. Epilepsia. 2010;51(5):797–804.CrossRefPubMedGoogle Scholar
  9. 9.
    Azar NJ, Abou-Khalil BW. Considerations in the choice of an antiepileptic drug in the treatment of epilepsy. Semin Neurol. 2008;28(3):305–16.CrossRefPubMedGoogle Scholar
  10. 10.
    Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med. 1992;327(11):765–71.CrossRefPubMedGoogle Scholar
  11. 11.
    Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic–clonic seizures. N Engl J Med. 1985;313(3):145–51.CrossRefPubMedGoogle Scholar
  12. 12.
    Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group. Epilepsy Res. 1999;37(1):81–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet. 1995;345(8948):476–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Dam M, Ekberg R, Loyning Y, Waltimo O, Jakobsen K. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res. 1989;3(1):70–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Reinikainen KJ, Keranen T, Halonen T, Komulainen H, Riekkinen PJ. Comparison of oxcarbazepine and carbamazepine: a double-blind study. Epilepsy Res. 1987;1(5):284–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369(9566):1000–15.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Saetre E, Perucca E, Isojarvi J, Gjerstad L, Group LAMS. An international multicenter randomized double-blind controlled trial of lamotrigine and sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly. Epilepsia. 2007;48(7):1292–302.CrossRefGoogle Scholar
  18. 18.
    Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ, Levetiracetam Monotherapy Study G. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology. 2007;68(6):402–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Baulac M, Brodie MJ, Patten A, Segieth J, Giorgi L. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol. 2012;11(7):579–88.CrossRefPubMedGoogle Scholar
  20. 20.
    Baulac M, Rosenow F, Toledo M, Terada K, Li T, De Backer M, et al. Efficacy, safety, and tolerability of lacosamide monotherapy versus controlled-release carbamazepine in patients with newly diagnosed epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol. 2017;16(1):43–54.CrossRefPubMedGoogle Scholar
  21. 21.
    Sperling MR, Harvey J, Grinnell T, Cheng H, Blum D, Study T. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America. Epilepsia. 2015;56(4):546–55.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med. 2010;362(9):790–9.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369(9566):1016–26.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Gesche J, Khanevski M, Solberg C, Beier CP. Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies. Epilepsia. 2017;58(4):e64–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Biton V, Montouris GD, Ritter F, Riviello JJ, Reife R, Lim P, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group. Neurology. 1999;52(7):1330–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Biton V, Sackellares JC, Vuong A, Hammer AE, Barrett PS, Messenheimer JA. Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. Neurology. 2005;65(11):1737–43.CrossRefPubMedGoogle Scholar
  27. 27.
    Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U, Levetiracetam NSG. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology. 2007;69(18):1751–60.CrossRefPubMedGoogle Scholar
  28. 28.
    Noachtar S, Andermann E, Meyvisch P, Andermann F, Gough WB, Schiemann-Delgado J, et al. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology. 2008;70(8):607–16.CrossRefPubMedGoogle Scholar
  29. 29.
    Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78(20):1548–54.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Deckers CL. Place of polytherapy in the early treatment of epilepsy. CNS Drugs. 2002;16(3):155–63.CrossRefPubMedGoogle Scholar
  32. 32.
    Kwan P, Brodie MJ. Epilepsy after the first drug fails: substitution or add-on? Seizure. 2000;9(7):464–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Beghi E, Gatti G, Tonini C, Ben-Menachem E, Chadwick DW, Nikanorova M, et al. Adjunctive 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):1–13.CrossRefPubMedGoogle Scholar
  34. 34.
    Millul A, Iudice A, Adami M, Porzio R, Mattana F, Beghi E. Alternative monotherapy or add-on therapy in patients with epilepsy whose seizures do not respond to the first monotherapy: an Italian multicenter prospective observational study. Epilepsy Behav E&B. 2013;28(3):494–500.CrossRefGoogle Scholar
  35. 35.
    Semah F, Thomas P, Coulbaut S, Derambure P. Early add-on treatment vs alternative monotherapy in patients with partial epilepsy. Epileptic Disord Int Epilepsy J Videotape. 2014;16(2):165–74.Google Scholar
  36. 36.
    French JA, Gidal BE. Antiepileptic drug interactions. Epilepsia. 2000;41(Suppl 8):S30–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Zaccara G, Perucca E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord Int Epilepsy J Videotape. 2014;16(4):409–31.Google Scholar
  38. 38.
    Bernus I, Dickinson RG, Hooper WD, Eadie MJ. The mechanism of the carbamazepine-valproate interaction in humans. Br J Clin Pharmacol. 1997;44(1):21–7.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Wagner ML, Remmel RP, Graves NM, Leppik IE. Effect of felbamate on carbamazepine and its major metabolites. Clin Pharmacol Ther. 1993;53(5):536–43.CrossRefPubMedGoogle Scholar
  40. 40.
    Yamamoto Y, Takahashi Y, Suzuki E, Mishima N, Inoue K, Itoh K, et al. Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients. Epilepsy Res. 2012;101(3):202–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Kondo T, Otani K, Hirano T, Kaneko S, Fukushima Y. The effects of phenytoin and carbamazepine on serum concentrations of mono-unsaturated metabolites of valproic acid. Br J Clin Pharmacol. 1990;29(1):116–9.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Longin E, Teich M, Koelfen W, Konig S. Topiramate enhances the risk of valproate-associated side effects in three children. Epilepsia. 2002;43(4):451–4.CrossRefPubMedGoogle Scholar
  43. 43.
    Deutsch SI, Burket JA, Rosse RB. Valproate-induced hyperammonemic encephalopathy and normal liver functions: possible synergism with topiramate. Clin Neuropharmacol. 2009;32(6):350–2.CrossRefPubMedGoogle Scholar
  44. 44.
    Stephen LJ, Kelly K, Parker P, Brodie MJ. Adjunctive lacosamide—5 years’ clinical experience. Epilepsy Res. 2014;108(8):1385–91.CrossRefPubMedGoogle Scholar
  45. 45.
    White HS, Smith MD, Wilcox KS. Mechanisms of action of antiepileptic drugs. Int Rev Neurobiol. 2007;81:85–110.CrossRefPubMedGoogle Scholar
  46. 46.
    Beydoun A, D’Souza J, Hebert D, Doty P. Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures. Expert Rev Neurother. 2009;9(1):33–42.CrossRefPubMedGoogle Scholar
  47. 47.
    Errington AC, Stohr T, Heers C, Lees G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol. 2008;73(1):157–69.CrossRefPubMedGoogle Scholar
  48. 48.
    Cai K, Nanga RP, Lamprou L, Schinstine C, Elliott M, Hariharan H, et al. The impact of gabapentin administration on brain GABA and glutamate concentrations: a 7T (1)H-MRS study. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2012;37(13):2764–71.CrossRefGoogle Scholar
  49. 49.
    Petroff OA, Rothman DL, Behar KL, Lamoureux D, Mattson RH. The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol. 1996;39(1):95–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Carunchio I, Pieri M, Ciotti MT, Albo F, Zona C. Modulation of AMPA receptors in cultured cortical neurons induced by the antiepileptic drug levetiracetam. Epilepsia. 2007;48(4):654–62.CrossRefPubMedGoogle Scholar
  51. 51.
    Loscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H. Synaptic vesicle glycoprotein 2A ligands in the treatment of epilepsy and beyond. CNS Drugs. 2016;30(11):1055–77.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Cereghino JJ, Brock JT, Van Meter JC, Penry JK, Smith LD, White BG. The efficacy of carbamazepine combinations in epilepsy. Clin Pharmacol Ther. 1975;18(6):733–41.CrossRefPubMedGoogle Scholar
  53. 53.
    Besag FM, Berry DJ, Pool F, Newbery JE, Subel B. Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia. 1998;39(2):183–7.CrossRefPubMedGoogle Scholar
  54. 54.
    Barcs G, Walker EB, Elger CE, Scaramelli A, Stefan H, Sturm Y, et al. Oxcarbazepine placebo-controlled, dose-ranging trial in refractory partial epilepsy. Epilepsia. 2000;41(12):1597–607.CrossRefPubMedGoogle Scholar
  55. 55.
    Shorvon SD, Trinka E, Steinhoff BJ, Holtkamp M, Villanueva V, Peltola J, et al. Eslicarbazepine acetate: its effectiveness as adjunctive therapy in clinical trials and open studies. J Neurol. 2017;264(3):421–31.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Sake JK, Hebert D, Isojarvi J, Doty P, De Backer M, Davies K, et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs. CNS Drugs. 2010;24(12):1055–68.CrossRefPubMedGoogle Scholar
  57. 57.
    Kwan P, Brodie MJ. Combination therapy in epilepsy: when and what to use. Drugs. 2006;66(14):1817–29.CrossRefPubMedGoogle Scholar
  58. 58.
    Ferrendelli JA. Rational polypharmacy. Epilepsia. 1995;36(Suppl 2):S115–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Deckers CL, Czuczwar SJ, Hekster YA, Keyser A, Kubova H, Meinardi H, et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia. 2000;41(11):1364–74.CrossRefPubMedGoogle Scholar
  60. 60.
    Margolis JM, Chu BC, Wang ZJ, Copher R, Cavazos JE. Effectiveness of antiepileptic drug combination therapy for partial-onset seizures based on mechanisms of action. JAMA Neurol. 2014;71(8):985–93.CrossRefPubMedGoogle Scholar
  61. 61.
    Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam add-on for refractory focal epilepsy: a systematic review and meta-analysis. Neurology. 2016;86(14):1344–52.CrossRefPubMedGoogle Scholar
  62. 62.
    Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia. 2014;55(1):47–56.CrossRefPubMedGoogle Scholar
  63. 63.
    Biton V, Berkovic SF, Abou-Khalil B, Sperling MR, Johnson ME, Lu S. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia. 2014;55(1):57–66.CrossRefPubMedGoogle Scholar
  64. 64.
    Brigo F, Ausserer H, Tezzon F, Nardone R. When one plus one makes three: the quest for rational antiepileptic polytherapy with supraadditive anticonvulsant efficacy. Epilepsy Behav E&B. 2013;27(3):439–42.CrossRefGoogle Scholar
  65. 65.
    St Louis EK. Truly “rational” polytherapy: maximizing efficacy and minimizing drug interactions, drug load, and adverse effects. Curr Neuropharmacol. 2009;7(2):96–105.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    French JA, Faught E. Ration Polyther. Epilepsia. 2009;50(Suppl 8):63–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Czuczwar SJ, Kaplanski J, Swiderska-Dziewit G, Gergont A, Kroczka S, Kacinski M. Pharmacodynamic interactions between antiepileptic drugs: preclinical data based on isobolography. Expert Opin Drug Metab Toxicol. 2009;5(2):131–6.CrossRefPubMedGoogle Scholar
  68. 68.
    Stafstrom CE. Mechanisms of action of antiepileptic drugs: the search for synergy. Curr Opin Neurol. 2010;23(2):157–63.CrossRefPubMedGoogle Scholar
  69. 69.
    Brodie MJ, Yuen AW. Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group. Epilepsy Res. 1997;26(3):423–32.CrossRefPubMedGoogle Scholar
  70. 70.
    Pisani F, Oteri G, Russo MF, Di Perri R, Perucca E, Richens A. The efficacy of valproate-lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia. 1999;40(8):1141–6.CrossRefPubMedGoogle Scholar
  71. 71.
    Poolos NP, Warner LN, Humphreys SZ, Williams S. Comparative efficacy of combination drug therapy in refractory epilepsy. Neurology. 2012;78(1):62–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Poolos NP, Castagna CE, Williams S, Miller AB, Story TJ. Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy. Epilepsy Behav E&B. 2017;69:59–68.CrossRefGoogle Scholar
  73. 73.
    Rowan AJ, Meijer JW, de Beer-Pawlikowski N, van der Geest P, Meinardi H. Valproate-ethosuximide combination therapy for refractory absence seizures. Arch Neurol. 1983;40(13):797–802.CrossRefPubMedGoogle Scholar
  74. 74.
    Kinirons P, McCarthy M, Doherty CP, Delanty N. Predicting drug-resistant patients who respond to add-on therapy with levetiracetam. Seizure. 2006;15(6):387–92.CrossRefPubMedGoogle Scholar
  75. 75.
    Villanueva V, Lopez-Gomariz E, Lopez-Trigo J, Palau J, Garcia M, Villarroya T, et al. Rational polytherapy with lacosamide in clinical practice: results of a Spanish cohort analysis RELACOVA. Epilepsy Behav E&B. 2012;23(3):298–304.CrossRefGoogle Scholar
  76. 76.
    Biton V, Rogin JB, Krauss G, Abou-Khalil B, Rocha JF, Moreira J, et al. Adjunctive eslicarbazepine acetate: a pooled analysis of three phase III trials. Epilepsy Behav E&B. 2017;72:127–34.CrossRefGoogle Scholar
  77. 77.
    Brodie MJ, French JA, McDonald SA, Lee WJ, Adams B, Scott A, et al. Adjunctive use of ezogabine/retigabine with either traditional sodium channel blocking antiepileptic drugs (AEDs) or AEDs with other mechanisms of action: evaluation of efficacy and tolerability. Epilepsy research. 2014;108(5):989–94.CrossRefPubMedGoogle Scholar
  78. 78.
    Kwan P, Brodie MJ, Laurenza A, FitzGibbon H, Gidal BE. Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: impact of mechanism of action and pharmacokinetics on clinical outcomes. Epilepsy research. 2015;117:117–24.CrossRefPubMedGoogle Scholar
  79. 79.
    Morrison PF, Pyzik PL, Hamdy R, Hartman AL, Kossoff EH. The influence of concurrent anticonvulsants on the efficacy of the ketogenic diet. Epilepsia. 2009;50(8):1999–2001.CrossRefPubMedGoogle Scholar
  80. 80.
    Kossoff EH, Pyzik PL, Rubenstein JE, Bergqvist AG, Buchhalter JR, Donner EJ, et al. Combined ketogenic diet and vagus nerve stimulation: rational polytherapy? Epilepsia. 2007;48(1):77–81.CrossRefPubMedGoogle Scholar
  81. 81.
    Jehi LE, Irwin AI, Kayyali H, Vadera S, Bingaman W, Najm I. Levetiracetam may favorably affect seizure outcome after temporal lobectomy. Epilepsia. 2012;53(6):979–86.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Vanderbilt University Medical CenterNashvilleUSA

Personalised recommendations