Skip to main content
Log in

The Role of Benzodiazepines in the Treatment of Epilepsy

  • Epilepsy (E Waterhouse, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Opinion statement

Benzodiazepines are commonly prescribed as anxiolytics, sedatives, and anticonvulsants. They act on the GABAA receptor by increasing the conductance chloride through ionic channels, promoting a state of central nervous system depression. The clinical properties of benzodiazepines are dependent upon the composition of the different subunits of the GABAA receptor. Each subunit, in turn, has multiple subtypes that are present throughout the central nervous system, all of which impart different clinical responses. Benzodiazepines are the first-line treatment of status epilepticus. Time to treatment is crucial, and clinical response to benzodiazepines is lost with prolonged status epilepticus. Non-intravenous routes of midazolam should be considered as an equally efficacious alternative to intravenous lorazepam, which is the most commonly administered benzodiazepine for status epilepticus when intravenous access is available. Outpatient therapy with benzodiazepines for the acute treatment of seizures is currently limited to rectal diazepam, but alternative routes of administration are under development. Clobazam and clonazepam are good options for seizure prophylaxis in patients with epilepsy refractory to multiple antiepileptic drugs. Clobazam is preferred due to its affinity for the α2 subunit of the GABAA receptor, which leads to less potential for sedation. Adverse effects of chronic benzodiazepine use are sedation, tolerance, and potential for addiction and misuse in some patients.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance ••Of major importance

  1. Olsen RW, Sieghart W. GABAA receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology. 2009;56:141–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hevers W, Lüddens H. The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes. Mol. Neurobiol. 1998;18:35–86.

    Article  CAS  Google Scholar 

  3. Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, Fritschy JM, et al. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature. 1999;401:796–800.

    Article  CAS  PubMed  Google Scholar 

  4. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci. 2000;3:587–92.

    Article  CAS  PubMed  Google Scholar 

  5. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci Off J Soc Neurosci. 2002;22:5572–80.

    CAS  Google Scholar 

  6. Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Epilepsia. 1993.34: 592–6.

  7. Kapur J, Macdonald RL. Rapid Seizure-Induced Reduction of Benzodiazepine and Zn2+ Sensitivity of Hippocampal Dentate Granule Cell GABAA Receptors. J Neurosci. 1997;17:7532–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Naylor DE, Liu H, Wasterlain CG. Trafficking of GABAA Receptors, Loss of Inhibition, and a Mechanism for Pharmacoresistance in Status Epilepticus. J Neurosci. 2005;25:7724–33.

    Article  CAS  PubMed  Google Scholar 

  9. Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol. 2011;10:922–30.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain. 2011;134:2802–18. Review of available therapies in the treatment of status epilepticus beyond first and second line treatments.

    Article  PubMed  Google Scholar 

  11. Shorvon S, Ferlisi M. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain. 2012;135:2314–28. Outcomes of the different therapies for super-refractory status epilepticus.

    Article  PubMed  Google Scholar 

  12. Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med. 2001;345:631–7.

    Article  CAS  PubMed  Google Scholar 

  13. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012;366:591–600. Silbergleit: large-scale trial that showed equivalence between IM midazolam and IV lorazepam in the treatment of prehospital status epilepticus. IM midazolam should be considered as the first-line treatment in ambulatory settings due to the difficulties of gaining IV access, which may compromise the time to treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Knudsen FU. Rectal administration of diazepam in solution in the acute treatment of convulsions in infants and children. Arch Dis Child. 1979;54:855–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dreifuss FE, Rosman NP, Cloyd JC, Pellock JM, Kuzniecky RI, Lo WD, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med. 1998;338:1869–75.

    Article  CAS  PubMed  Google Scholar 

  16. Scott RC, Besag FM, Neville BG. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet. 1999;353:623–6.

    Article  CAS  PubMed  Google Scholar 

  17. Mpimbaza A, Ndeezi G, Staedke S, Rosenthal PJ, Byarugaba J. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in ugandan children: a randomized clinical trial. Pediatrics. 2008;121:e58–64.

    Article  PubMed  Google Scholar 

  18. Nakken KO, Lossius MI. Buccal midazolam or rectal diazepam for treatment of residential adult patients with serial seizures or status epilepticus. Acta Neurol Scand. 2011;124:99–103. A comparison of buccal midazolam to rectal diazepam among adult residential patients with intractable seizures. Buccal midazolam was preferred by both patients and caregivers and had similar efficacy.

    Article  CAS  PubMed  Google Scholar 

  19. Scheepers M, Scheepers B, Clarke M, Comish S, Ibitoye M. Is intranasal midazolam an effective rescue medication in adolescents and adults with severe epilepsy? Seizure. 2000;9:417–22.

    Article  CAS  PubMed  Google Scholar 

  20. Bancke LL, Dworak HA, Rodvold KA, Halvorsen MB, Gidal BE. Pharmacokinetics, pharmacodynamics, and safety of USL261, a midazolam formulation optimized for intranasal delivery, in a randomized study with healthy volunteers. Epilepsia. 2015. n/a – n/a.

  21. Henney III HR, Sperling MR, Rabinowicz AL, Bream G, Carrazana EJ. Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults. Epilepsy Res. 2014;108:1204–11. A comparison of an intranasal diazepam formulation to rectal diazepam for tolerability and safety in healthy adults. Similar results were achieved.

    Article  CAS  PubMed  Google Scholar 

  22. Agarwal SK, Kriel RL, Brundage RC, Ivaturi VD, Cloyd JC. A pilot study assessing the bioavailability and pharmacokinetics of diazepam after intranasal and intravenous administration in healthy volunteers. Epilepsy Res. 2013;105:362–7.

    Article  CAS  PubMed  Google Scholar 

  23. Leppik IE, Patel SI. Intramuscular and rectal therapies of acute seizures. Epilepsy Behav. 2015;49. A review of the intramuscular and rectal therapies for acute seizures. IM midazolam and rectal diazepam remain as the two best alternatives to IV lorazepam at this time.

  24. Jensen HS, Nichol K, Lee D, Ebert B. Clobazam and its active metabolite N-desmethylclobazam display significantly greater affinities for α2- versus α1-GABA(A)-receptor complexes. PLoS One. 2014;9:e88456.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Shimizu H, Kawasaki J, Yuasa S, Tarao Y, Kumagai S, Kanemoto K. Use of clobazam for the treatment of refractory complex partial seizures. Seizure. 2003;12:282–6.

    Article  PubMed  Google Scholar 

  26. Ng Y-T, Conry J, Paolicchi J, Kernitsky L, Mitchell W, Drummond R, et al. Long-term safety and efficacy of clobazam for Lennox–Gastaut syndrome: interim results of an open-label extension study. Epilepsy Behav. 2012;25:687–94.

    Article  PubMed  Google Scholar 

  27. Conry JA, Ng Y-T, Kernitsky L, Mitchell WG, Veidemanis R, Drummond R, et al. Stable dosages of clobazam for Lennox-Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years. Epilepsia. 2014;55:558–67. Long term open label extension trial for clobazam. A large amount of patients had sustained response at stable dose for three years. Several patients remained on the drug up to five years at relatively stable doses and sustained seizure reduction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pinder RM, Brogden RN, Speight TM, Avery GS. Clonazepam: a review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs. 1976;12:321–61.

    Article  CAS  PubMed  Google Scholar 

  29. Troupin AS, Friel P, Wilensky AJ, Moretti-Ojemann L, Levy RH, Feigl P. Evaluation of clorazepate (Tranxene®) as an anticonvulsant—a pilot study. Neurology. 1979;29:458.

    Article  CAS  PubMed  Google Scholar 

  30. Trimble MR. On the Use of Tranquillisers in Epilepsy. Epilepsia. 2002;43:25–7.

    Article  PubMed  Google Scholar 

  31. Tan KR, Rudolph U, Lüscher C. Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 2011;34:188–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Barker MJ, Greenwood KM, Jackson M, Crowe SF. Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Arch Clin Neuropsychol. 2004;19:437–54.

    Article  PubMed  Google Scholar 

  33. Bateson A. Basic Pharmacologic Mechanisms Involved in Benzodiazepine Tolerance and Withdrawal. Curr Pharm Des. 2002;8:5–21.

    Article  CAS  PubMed  Google Scholar 

  34. Vinkers CH, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABA(A) receptor modulators? Adv Pharmacol Sci. 2012;2012:416864.

    PubMed  PubMed Central  Google Scholar 

  35. Clobazam in Treatment of Refractory Epilepsy: The Canadian Experience. A Retrospecti. Epilepsia. 1991. 32: 407–16.

  36. Mitchell WG, Conry JA, Crumrine PK, Kriel RL, Cereghino JJ, Groves L, et al. An open-label study of repeated use of diazepam rectal gel (Diastat) for episodes of acute breakthrough seizures and clusters: safety, efficacy, and tolerance. Epilepsia. 1999;40:1610–7.

    Article  CAS  PubMed  Google Scholar 

  37. Tan KR, Brown M, Labouèbe G, Yvon C, Creton C, Fritschy J-M, et al. Neural bases for addictive properties of benzodiazepines. Nature. 2010;463:769–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Engin E, Bakhurin KI, Smith KS, Hines RM, Reynolds LM, Tang W, et al. Neural basis of benzodiazepine reward: requirement for α2 containing GABAA receptors in the nucleus accumbens. Neuropsychopharmacology. 2014;39:1805–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Reynolds LM, Engin E, Tantillo G, Lau HM, Muschamp JW, Carlezon WA, et al. Differential roles of GABAA receptor subtypes in benzodiazepine-induced enhancement of brain-stimulation reward. Neuropsychopharmacology. 2012;37:2531–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Juan G. Ochoa MD.

Ethics declarations

Conflict of Interest

William A. Kilgo declares that he has no conflict of interest.

Juan G. Ochoa has received speaker fees from Sunovion Pharmaceuticals.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Epilepsy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ochoa, J.G., Kilgo, W.A. The Role of Benzodiazepines in the Treatment of Epilepsy. Curr Treat Options Neurol 18, 18 (2016). https://doi.org/10.1007/s11940-016-0401-x

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11940-016-0401-x

Keywords

Navigation