title: Calcium antagonists as an add-on therapy for drug-resistant epilepsy.
abstract: BACKGROUND
  This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4.Nearly a third of people with epilepsy do not have their seizures controlled with current treatments. Continuous attempts have been made to find new antiepileptic drugs based on increasing knowledge of the cellular and molecular biology involved in the genesis of epilepsy and seizures. Therefore, calcium antagonists that can alter the effects of calcium on brain cells have been investigated for their effect on epileptic seizures.
  
  
  OBJECTIVE
  To evaluate the effects of calcium antagonists when used as an add-on therapy for people with drug-resistant epilepsy.
  
  
  METHODS
  We searched the Cochrane Epilepsy Group Specialized Register (29 January 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12), MEDLINE (1948 to 29 January 2013) and SCOPUS (all years to 29 January 2013).
  
  
  METHODS
  Randomised placebo-controlled or active-controlled add-on trials of any calcium antagonist in people with drug-resistant epilepsy.
  
  
  METHODS
  Two review authors (MH and JP) independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, cognition and quality of life. Analyses were by intention to treat.
  
  
  RESULTS
  Eleven trials were included with a total of 424 participants, one parallel-group and seven cross-over trials of flunarizine, two cross-over trials of nimodipine and one cross-over trial of nifedipine.For flunarizine, the risk ratio (RR) with 95% confidence interval (CI) for a 50% or greater reduction in seizure frequency in a single parallel trial was 1.53 (95% CI 0.59 to 3.96) indicating a non-significant advantage of flunarizine. We were unable to acquire data for this outcome from the other seven cross-over trials. The overall RR for treatment withdrawal of flunarizine was 7.11 (95% CI 1.73 to 29.30) indicating individuals were significantly more likely to have flunarizine withdrawn than placebo. No adverse effects were associated statistically with flunarizine.For nifedipine, we were unable to acquire the data we required for our specified outcomes.For nimodipine, we had data only from the first treatment period from one of the two cross-over trials (17 participants). The RR for a 50% or greater reduction in seizure frequency was 7.78 (99% CI 0.46 to 130.88) and for treatment withdrawal the RR was 2.25 (99% CI 0.25 to 20.38).
  
  
  CONCLUSIONS
  Flunarizine may have a weak effect on seizure frequency but had a significant withdrawal rate, probably due to adverse effects, and should not be recommended for use as an add-on treatment. Similarly, there is no convincing evidence to support the use of nifedipine or nimodipine as add-on treatments for epilepsy.
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. dr.mohammadhasan@gmail.com
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hasan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pulman
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Marson
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D004351:Drug Resistance; D004359:Drug Therapy, Combination / Q000379:methods; D004827:Epilepsy / Q000188:drug therapy*; D005444:Flunarizine / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D009543:Nifedipine / Q000627:therapeutic use; D009553:Nimodipine / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic
chemical_list: D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D009553:Nimodipine; D009543:Nifedipine; D005444:Flunarizine
references.citation: Can J Neurol Sci. 1989 May;16(2):191-3
references.pmid: 2731087
references.citation: Lancet. 2001 Sep 8;358(9284):801-7
references.pmid: 11564488
references.citation: Funct Neurol. 1986 Oct-Dec;1(4):551-4
references.pmid: 3609882
references.citation: BMJ. 2012 Jan 26;344:e281
references.pmid: 22282528
references.citation: Brain Dev. 1991 Jul;13(4):217-22
references.pmid: 1957968
references.citation: J Child Neurol. 1996 Nov;11(6):500-1
references.pmid: 9120234
references.citation: Cochrane Database Syst Rev. 2001;(4):CD002750
references.pmid: 11687158
references.citation: Can J Neurol Sci. 1989 May;16(2):187-90
references.pmid: 2731086
references.citation: Clin Neuropharmacol. 1988 Jun;11(3):232-40
references.pmid: 3042126
references.citation: Lancet Neurol. 2012 Apr;11(4):331-40
references.pmid: 22377180
references.citation: Epilepsia. 1985 Sep-Oct;26(5):424-8
references.pmid: 3899624
references.citation: Eur J Clin Pharmacol. 1995;49(1-2):91-4
references.pmid: 8751028
references.citation: Epilepsy Res. 1991 May-Jun;9(1):71-7
references.pmid: 1909241
references.citation: Mayo Clin Proc. 1995 Jul;70(7):623-7
references.pmid: 7791383
references.citation: Biochem Pharmacol. 2007 Jun 30;74(1):1-9
references.pmid: 17276408
references.citation: Neurology. 1994 Oct;44(10):1830-6
references.pmid: 7936231
references.citation: Acta Neurol Scand. 1989 Feb;79(2):128-32
references.pmid: 2496577
references.citation: Epilepsia. 1984 Apr;25(2):217-22
references.pmid: 6705752
references.citation: Ann Pharmacother. 2004 Oct;38(10):1631-4
references.pmid: 15328394
references.citation: Funct Neurol. 1986 Oct-Dec;1(4):547-50
references.pmid: 3301560
references.citation: Epilepsia. 1992 Mar-Apr;33(2):346-52
references.pmid: 1547765
references.citation: J Neurol Neurosurg Psychiatry. 2005 Jun;76 Suppl 2:ii2-7
references.pmid: 15961864
references.citation: Epilepsia. 1993 Sep-Oct;34(5):944-53
references.pmid: 8404751