Skip to main content
SpringerLink
Log in

Lacosamide

A New Approach to Target Voltage-Gated Sodium Currents in Epileptic Disorders

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

The mechanism of action of several antiepileptic drugs (AEDs) rests on their ability to modulate the activity of voltage-gated sodium currents that are responsible for fast action potential generation. Recent data indicate that lacosamide (a compound with analgesic and anticonvulsant effects in animal models) shares a similar mechanism. When compared with other AEDs, lacosamide has the unique ability to interact with sodium channel slow inactivation without affecting fast inactivation. This article reviews these findings and discusses their relevance within the context of neuronal activity seen during epileptiform discharges generated by limbic neuronal networks in the presence of chemical convulsants. These seizure-like events are characterized by sustained discharges of sodium-dependent action potentials supported by robust depolarizations, thus providing synchronization within neuronal networks. Generally, AEDs such as phenytoin, carbamazepine and lamotrigine block sodium channels when activated. In contrast, lacosamide facilitates slow inactivation of sodium channels both in terms of kinetics and voltage dependency. This effect may be relatively selective for repeatedly depolarized neurons, such as those participating in seizure activity in which the persistence of sodium currents is more pronounced and promotes neuronal excitation.

The clinical effectiveness of lacosamide has been demonstrated in randomized, double-blind, parallel-group, placebo-controlled, adjunctive-therapy trials in patients with refractory partial seizures. Further studies should determine whether the effects of lacosamide in animal models and in clinical settings are fully explained by its selective action on sodium current slow inactivation or whether other effects (e.g. interactions with the collapsinresponse mediator protein-2) play a contributory role.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Fig. 2
Fig. 3
Table II

Similar content being viewed by others

References

  1. Avoli M, D’Antuono M, Louvel J, et al. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system. Prog Neurobiol 2002; 68: 167–207

    Article  PubMed  CAS  Google Scholar 

  2. Inaba Y, Biagini G, Avoli M. The H current blocker ZD7288 decreases epileptiform hyperexcitability in the rat neocortex by depressing synaptic transmission. Neuropharmacology 2006; 51: 681–91

    Article  PubMed  CAS  Google Scholar 

  3. Panuccio G, Curia G, Colosimo A, et al. Epileptiform synchronization in the cingulate cortex. Epilepsia 2009; 50: 521–36

    Article  PubMed  CAS  Google Scholar 

  4. Lopantsev V, Avoli M. Participation of GABAA-mediated inhibition in ictal-like discharges in the rat entorhinal cortex. J Neurophysiol 1998; 79: 352–60

    PubMed  CAS  Google Scholar 

  5. Detlev B. Cell and gene therapies for refractory epilepsy. Curr Neuropharmacol 2007; 5: 115–25

    Article  Google Scholar 

  6. Kwan P, Brodie MJ. Emerging drugs for epilepsy. Expert Opin Emerg Drugs 2007; 12: 407–22

    Article  PubMed  CAS  Google Scholar 

  7. Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics 2007; 4: 18–61

    Article  PubMed  CAS  Google Scholar 

  8. Perucca E, French J, Bialer M. Development of new anti-epileptic drugs: challenges, incentives, and recent advances. Lancet Neurol 2007; 6: 793–804

    Article  PubMed  CAS  Google Scholar 

  9. Bialer M, Johannessen SI, Levy RH, et al. Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX). Epilepsy Res 2009; 83: 1–43

    Article  PubMed  Google Scholar 

  10. Spencer SS. When should temporal-lobe epilepsy be treated surgically? Lancet Neurol 2002; 1: 375–82

    Article  PubMed  Google Scholar 

  11. Schuele SU, Lüders HO. Intractable epilepsy: management and therapeutic alternatives. Lancet Neurol 2008; 7: 514–24

    Article  PubMed  Google Scholar 

  12. Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia 2007; 48: 1223–44

    Article  PubMed  CAS  Google Scholar 

  13. White HS, Johnson M, Wolf HH, et al. The early identification of anticonvulsant activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models. Ital J Neurol Sci 1995; 16: 73–7

    Article  PubMed  CAS  Google Scholar 

  14. Schmidt D, Rogawski MA. New strategies for the identification of drugs to prevent the development or progression of epilepsy. Epilepsy Res 2002; 50: 71–8

    Article  PubMed  CAS  Google Scholar 

  15. Bayer K, Ahmadi S, Zeilhofer HU. Gabapentin may inhibit synaptic transmission in the mouse spinal cord dorsal horn through a preferential block of P/Q-type Ca2+ channels. Neuropharmacology 2004; 46: 743–9

    Article  PubMed  CAS  Google Scholar 

  16. Fink K, Dooley DJ, Meder WP, et al. Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 2002; 42: 229–36

    Article  PubMed  CAS  Google Scholar 

  17. Gillard M, Chatelain P, Fuks B. Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein. Eur J Pharmacol 2006; 536: 102–8

    Article  PubMed  CAS  Google Scholar 

  18. Meisler MH, Kearney JA. Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest 2005; 115:2010–7

    Article  PubMed  CAS  Google Scholar 

  19. Berkovic SF, Mulley JC, Scheffer IE, et al. Human epilepsies: interaction of genetic and acquired factors. Trends Neurosci 2006; 29: 391–7

    Article  PubMed  CAS  Google Scholar 

  20. Köhling R. Voltage-gated sodium channels in epilepsy. Epilepsia 2002; 43: 1278–95

    Article  PubMed  Google Scholar 

  21. Agrawal N, Alonso A, Ragsdale DS. Increased persistent sodium currents in rat entorhinal cortex layer V neurons in a post-status epilepticus model of temporal lobe epilepsy. Epilepsia 2003; 44: 1601–4

    Article  PubMed  Google Scholar 

  22. Vreugdenhil M, Hoogland G, van Veelen CW, et al. Persistent sodium current in subicular neurons isolated from patients with temporal lobe epilepsy. Eur J Neurosci 2004; 19: 2769–78

    Article  PubMed  Google Scholar 

  23. Ragsdale DS, Avoli M. Sodium channels as molecular targets for antiepileptic drugs. Brain Res Rev 1998; 26: 16–28

    Article  PubMed  CAS  Google Scholar 

  24. Stafstrom CE. Persistent sodium current and its role in epilepsy. Epilepsy Curr 2007; 7: 15–22

    Article  PubMed  Google Scholar 

  25. Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med 2004; 10: 685–92

    Article  PubMed  CAS  Google Scholar 

  26. Spina E, Perugi GG. Antiepileptic drugs: indications other than epilepsy. Epileptic Disord 2004; 6: 57–75

    PubMed  Google Scholar 

  27. Lang DG, Wang CM, Barrett RC. Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells. J Pharmacol Exp Ther 1993; 266: 829–34

    PubMed  CAS  Google Scholar 

  28. Zona C, Avoli M. Lamotrigine reduces voltage-gated sodium currents in rat central neurons in culture. Epilepsia 1997; 38: 522–5

    Article  PubMed  CAS  Google Scholar 

  29. Errington AC, Coyne L, Stohr T, et al. Seeking a mechanism of action for the novel anticonvulsant lacosamide. Neuropharmacology 2006; 50: 1016–29

    Article  PubMed  CAS  Google Scholar 

  30. Willow M, Gonoi T, Catterall WA, et al. Voltage-clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Mol Pharmacol 1985; 27: 549–58

    PubMed  CAS  Google Scholar 

  31. Xie X, Lancaster B, Peakman T, et al. Interactions of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na channels and native Na channels in rat hippocampal neurons. Pflugers Arch 1995; 430: 437–46

    Article  PubMed  CAS  Google Scholar 

  32. Vreugdenhil M, Wadman WJ. Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis. Epilepsia 1999; 40: 1512–22

    Article  PubMed  CAS  Google Scholar 

  33. Errington AC, Stohr T, Heers C, et al. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 2008; 73: 157–69

    Article  PubMed  CAS  Google Scholar 

  34. Fozzard HA, Hank DA. Structure and function of voltage-dependent sodium channels: comparison of brain II and cardiac isoforms. Physiol Rev 1996; 76: 887–926

    PubMed  CAS  Google Scholar 

  35. Vassilev PM, Scheuer T, Catterall WA. Identification of an intracellular peptide segment involved in sodium channel inactivation. Science 1988; 241: 1658–61

    Article  PubMed  CAS  Google Scholar 

  36. Stühmer W, Conti F, Suzuki H, et al. Structural parts involved in activation and inactivation of the sodium channel. Nature 1989; 339: 597–603

    Article  PubMed  Google Scholar 

  37. Lees G, Stohr T, Errington AC. Stereoselective effects of the novel anticonvulsant lacosamide against 4-AP induced epileptiform activity in rat visual cortex in vitro. Neuropharmacology 2006; 50: 98–110

    Article  PubMed  CAS  Google Scholar 

  38. Beyreuther BK, Freitag J, Heers C, et al. Lacosamide: a review of preclinical properties. CNS Drug Rev 2007; 13: 21–42

    Article  PubMed  CAS  Google Scholar 

  39. Doty P, Rudd GD, Stöhr T, et al. Lacosamide. Neurotherapeutics 2007; 4: 145–8

    Article  PubMed  CAS  Google Scholar 

  40. Choi D, Stables JP, Kohn H. Synthesis and anticonvulsant activities of N-benzyl-2-acetamidopropionamide derivatives. J Med Chem 1996; 39: 1907–16

    Article  PubMed  CAS  Google Scholar 

  41. Choi D, Stables JP, Kohn H. The anticonvulsant activities of functionalized N-benzyl-2-acetamidoacetamides: the importance of the 2-acetamido substituent. Bioorg Med Chem 1996; 4: 2105–14

    Article  PubMed  CAS  Google Scholar 

  42. Stöhr T, Kupferberg HJ, Stables JP, et al. Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodents models for epilepsy. Epilepsy Res 2007; 74: 147–54

    Article  PubMed  Google Scholar 

  43. Duncan GE, Kohn H. The novel antiepileptic drug lacosamide blocks behavioral and brain metabolic manifestations of seizure activity in the 6 Hz psychomotor seizure model. Epilepsy Res 2005; 67: 81–7

    Article  PubMed  CAS  Google Scholar 

  44. Brandt C, Heile A, Potschka H, et al. Effects of the novel antiepileptic drug lacosamide on the development of amygdala kindling in rats. Epilepsia 2006; 47: 1803–9

    Article  PubMed  CAS  Google Scholar 

  45. White S, Perucca E, Privitera M. Investigational drugs. In: Engel Jr J, Pedley TA, Aicardi J, et al., editors. Epilepsy, a comprehensive textbook. Philadelphia (PA): Lippincott, Williams & Wilkins, 2007: 1721–40

    Google Scholar 

  46. Hao JX, Stöhr T, Selve N, et al. Lacosamide, a new antiepileptic, alleviates neuropathic pain-like behaviors in rat models of spinal cord or trigeminal nerve injury. Eur J Pharmacol 2006; 553: 135–40

    Article  PubMed  CAS  Google Scholar 

  47. Beyreuther BK, Callizot N, Brot MD, et al. Antinociceptive efficacy of lacosamide in rat models for tumor- and chemotherapy-induced cancer pain. Eur J Pharmacol 2007; 565: 98–104

    Article  PubMed  CAS  Google Scholar 

  48. Beyreuther BK, Geis C, Stöhr T, et al. Antihyperalgesic efficacy of lacosamide in a rat model for muscle pain induced by TNF. Neuropharmacology 2007; 52: 1312–7

    Article  PubMed  CAS  Google Scholar 

  49. Beyreuther B, Callizot N, Stöhr T. Antinociceptive efficacy of lacosamide in the monosodium iodoacetate rat model for osteoarthritis pain [abstract]. Arthritis Res Ther 2007; 9: R14

    Article  PubMed  Google Scholar 

  50. Beyreuther B, Callizot N, Stöhr T. Antinociceptive efficacy of lacosamide in a rat model for painful diabetic neuropathy. Eur J Pharmacol 2006; 539: 64–70

    Article  PubMed  CAS  Google Scholar 

  51. Sheets PL, Heers C, Stoher T, et al. Differential block of sensory neuronal voltage-gated sodium channels by lacosamide, lidocaine and carbamazepine. J Pharm Exp Ther 2008; 26: 89–99

    Article  Google Scholar 

  52. Kropeit D, Schiltmeyer B, Cawello W, et al. Bioequivalence of short-time infusions compared to oral administration of SPM 927. Epilepsia 2004; 45Suppl. 7: 123–4

    Google Scholar 

  53. Biton V, Rosenfeld WE, Whitesides J, et al. Intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. Epilepsia 2008; 49: 418–24

    Article  PubMed  CAS  Google Scholar 

  54. Cawello W, Kropeit D, Schiltmeyer B, et al. Food does not affect the pharmacokinetics of SPM 927 [abstract]. Epilepsia 2004; 45Suppl. 7: 307

    Google Scholar 

  55. Schiltmeyer B, Cawello W, Kropeit D, et al. Pharmacokinetics of the new antiepileptic drug SPM 927 in human subjects with different age and gender [abstract]. Epilepsia 2004; 45Suppl. 7: 313

    Google Scholar 

  56. UCB Pharma. Vimpat (Lacosamide): summary of product characteristics. Brussels: UCB Pharma, 2008 Sep

    Google Scholar 

  57. Sachdeo R. Lacosamide. In: Shorvon SD, Perucca E, Engel Jr J, editors. The treatment of epilepsy. 3rd ed. Oxford: J Wiley and Sons, 2009: 527–34

    Chapter  Google Scholar 

  58. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007; 48: 1308–17

    Article  PubMed  CAS  Google Scholar 

  59. Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Eighth Eilat Conference (EILAT VIII). Epilepsy Res 2007; 73: 1–52

    Article  PubMed  Google Scholar 

  60. Halász P, Kälviäinen R, Mazurkiewicz-Beldziñska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009; 50: 443–53

    Article  PubMed  Google Scholar 

  61. Chung SM, Sperling M, Biton V, et al. Lacosamide: efficacy and safety as oral adjunctive therapy in adults with partial-onset seizures [abstract]. Epilepsia 2007; 48Suppl. 7: 57

    Google Scholar 

  62. Rosenfeld W, Fountain NB, Kaubrys G, et al. Lacosamide: an interim evaluation of long-term safety and efficacy as oral adjunctive therapy in subjects with partial-onset seizures. Epilepsia 2007; 48Suppl. 6: 318–9

    Google Scholar 

  63. Biton V, Fountain N, Rosenow F, et al. Safety and tolerability of lacosamide: a summary of adverse events in epilepsy clinical trials [abstract]. Ann Neurol 2008; 64Suppl. 12: S21

    Google Scholar 

  64. Cawello W, Horstmann R, Doty P, et al. No influence of lacosamide on the ECG time intervals QTC and PR. 58th Annual American Epilepsy Society Meeting, Scientific Exhibit; 2004 Dec 3–7; New Orleans (LA)

  65. European Medicines Agency (EMEA). European Public Assessment Report-Vimpat [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/vimpat/H-863-PI-en.pdf [Accessed 2009 Mar 23]

  66. Wymer JP, Simpson J, Sen D, et al. Lacosamide SP742 Study Group. Efficacy and safety of lacosamide in diabetic neuropathic pain: an 18-week double-blind placebocontrolled trial of fixed-dose regimens. Clin J Pain 2009; 25: 376–85

    Article  PubMed  Google Scholar 

  67. Shaibani A, Fares S, Selam JL, et al. Lacosamide in painful diabetic neuropathy: an 18-week double-blind placebo-controlled trial. Pain. Epub 2009 Apr 29

  68. Freitag J, Beyreuther B, Heers C, et al. Lacosamide modulates collapsin response mediated protein 2 (CRMP-2) [abstract]. Epilepsia 2007; 48Suppl. 6: 320

    Google Scholar 

Download references

Acknowledgements

This review was supported by grants from the Italian Ministry of Education, University & Research (FIRB2001 RBNE01NR34_011, PRIN 2003060538), the Canadian Institutes of Health Research (CIHR; Grant MT-8109), the Savoy Foundation and the Pierfranco and Luisa Mariani Foundation (R-06-50). Dr Giulia Curia was supported by a postdoctoral fellowship from Fragile X Research Foundation of Canada (FXRFC) in partnership with the CIHR.

Dr Emilio Perucca has received speaker’s or consultancy fees and/or research grants from Novartis, Bial, Pfizer, GlaxoSmithKline, UCB Pharma, Sanofi-aventis, Eisai, Johnson & Johnson and Valeant Pharmaceuticals. Dr Massimo Avoli has received grants from Pfizer and UCB Pharma. Drs Curia and Biagini have no conflicts of interest that are directly relevant to the current review.

Author information

Authors and Affiliations

  1. Montreal Neurological Institute and Departments of Neurology & Neurosurgery, and of Physiology, McGill University, Montréal, Québec, Canada

    Giulia Curia &  Massimo Avoli

  2. Department of Biomedical Science, University of Modena and Reggio Emilia, Modena, Italy

    Giuseppe Biagini

  3. Department of Internal Medicine and Medical Therapy, University of Pavia and Clinical Trial Center, Neurological Institute IRCCS “Fondazione C. Mondino”, Pavia, Italy

    Emilio Perucca

  4. Department of Experimental Medicine, “La Sapienza” University of Rome, Rome, Italy

    Massimo Avoli

Authors
  1. Giulia Curia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuseppe Biagini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emilio Perucca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Massimo Avoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo Avoli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Curia, G., Biagini, G., Perucca, E. et al. Lacosamide. CNS Drugs 23, 555–568 (2009). https://doi.org/10.2165/00023210-200923070-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-200923070-00002

Keywords

Search

Navigation