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Calcium antagonists as an add-on therapy for drug-resistant epilepsy

  1. Mohammad Hasan*,
  2. Jennifer Pulman,
  3. Anthony G Marson

Editorial Group: Cochrane Epilepsy Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 27 FEB 2013

DOI: 10.1002/14651858.CD002750.pub2


How to Cite

Hasan M, Pulman J, Marson AG. Calcium antagonists as an add-on therapy for drug-resistant epilepsy. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD002750. DOI: 10.1002/14651858.CD002750.pub2.

Author Information

  1. Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, UK

*Mohammad Hasan, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre, University Hospital Aintree, Lower Lane, Fazakerley, Liverpool, L9 7AL, UK. dr.mohammadhasan@gmail.com. M.Hasan@liverpool.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 MAR 2013

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Characteristics of included studies [ordered by study ID]
Alving 1989

MethodsRandomised double-blind placebo-controlled cross-over trial.
2 treatment sequences: placebo-flunarizine and flunarizine-placebo sequences.
Baseline = 4 weeks.
No titration period.
Treatment phase 1 and 2 = 16 weeks each.


ParticipantsSingle Danish centre.
Total randomised 29; all with drug-resistant partial epilepsy; numbers of randomised patients into individual treatment sequence groups = data not available.
41% male.
Age range 14 to 58 years.
Other AEDs = 1 to 3.
Baseline seizure frequency: data not available.


InterventionsFlunarizine 15 mg per day.

Placebo.


OutcomesThe following outcomes were measured:

1) Seizure incidence during flunarizine and placebo periods were measured.

2) 50% or greater reduction in seizure frequency.

3) Treatment withdrawal.

4) Side effects.

5) Neuropsychological changes.

6) Treatment preference.


NotesWe were not able to acquire the data from the first treatment phase for meta-analysis for any outcomes.

Study was funded by Janssenpharma A/S.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of randomisation therefore uncertain risk of bias.

Allocation concealment (selection bias)Unclear riskComment - No details of allocation concealment therefore uncertain risk of bias.

Blinding (performance bias and detection bias)
Seizure Reduction
Unclear riskQuote - "Double Blinded"

Comment - No details given to how blinding was achieved

Blinding of participants and personnel (performance bias)
Seizure Reduction
Low riskQuote - "Flunarazine pills and placebo were identical"

Comment - Participants were adequately blinded

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskQuote - "Double Blinded"

Comment - No details given to how blinding was achieved

Incomplete outcome data (attrition bias)
Seizure Reduction
Unclear riskComment - Missing data and study attrition reported but no intention-to-treat analysis

Selective reporting (reporting bias)Low riskComment - Outcomes were reported clearly

Other biasLow riskNone identified

Battaglia 1991

MethodsRandomised double-blind placebo-controlled cross-over trial.
2 treatment sequences: placebo-flunarizine and flunarizine-placebo sequences.
Baseline = 16 weeks.
No titration period.
Treatment phase 1 and 2 = 16 weeks each.


ParticipantsSingle Italian centre.
Total fed 20; all with drug-resistant partial or generalized epilepsy; numbers of randomised patients into individual treatment sequence groups = data not available.
50% male.
Age range = 6 to 18 years (mean 12 years 7 months).
Other AEDs: most patients on 2 to 3.
Baseline seizure frequency: data not available.


Interventions1) Flunarizine 5 mg/d for age < 10 years or 10 mg/d for age > 10 years.

2) Placebo.


OutcomesThe following outcomes were measured:

1) Seizure incidence during flunarizine and placebo periods.

2) 30%, 40% and 60% greater reduction in seizure frequency.

3) Treatment withdrawal.

4) Adverse effects.


NotesWe were not able to acquire the data from the first treatment phase for meta-analysis for any outcomes.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of randomisation therefore uncertain risk of bias

Allocation concealment (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of allocation concealment therefore uncertain risk of bias

Blinding (performance bias and detection bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Blinding of participants and personnel (performance bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Incomplete outcome data (attrition bias)
Seizure Reduction
Unclear riskComment - Missing data reported but no intention to treat analysis performed

Selective reporting (reporting bias)Low riskComment- Outcomes were reported clearly

Other biasLow riskNone identified

Fröscher 1988

MethodsRandomised double-blind placebo-controlled cross-over trial.
2 treatment sequences: placebo-flunarizine and flunarizine-placebo sequences.
Baseline = 8 weeks.
Titration period = 3 weeks.
Treatment phase 1 and 2 = 16 weeks each.


ParticipantsSingle Belgian centre.
Total randomised 30; all with drug-resistant partial epilepsy. 14 to placebo-flunarizine sequence; 16 to flunarizine-placebo sequence.
57% male.
Age range 14 to 51 years.
Other AEDs: most patients on 1 to 3.
Baseline seizure frequency: data not available.


Interventions1) Flunarizine 15 mg/day

2) Placebo pill.


OutcomesFollowing outcomes were reported:

1) Seizure incidence during flunarizine and placebo periods.

2) Change (%) of seizure frequency compared between the last month of each treatment phase.

3) Effect on severity and duration of seizures.

4) Treatment withdrawal.

5) Adverse effects.

6) Flunarizine plasma concentration.

7) Interaction with existing AEDs (total and free blood levels).


NotesThe first author was not able to provide data for the treatment allocation method and its concealment as well as data for the following outcomes from the first treatment phase due to those data no longer being available: (a) 50% or greater reduction in seizure frequency; (b) side effects.

We used the data of treatment withdrawal from the first treatment phase for meta-analysis.

We presented the data of 50% responders and side effects from both treatment phases in  Table 1 and  Table 2 respectively.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of randomisation therefore uncertain risk of bias

Allocation concealment (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of allocation concealment therefore uncertain risk of bias

Blinding (performance bias and detection bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Blinding of participants and personnel (performance bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Incomplete outcome data (attrition bias)
Seizure Reduction
High riskComment - The study has two phases and seizure reduction was not provided for the first phase and the authors commented that the data was lost as such it is not possible to discern attrition rates or ITT analysis

Selective reporting (reporting bias)High riskComment - Selective outcome reporting as the authors did not report seizure reduction or side effects of AED for first phase of the study

Other biasLow riskNone identified

Keene 1989

MethodsRandomised double-blind placebo-controlled cross-over trial.
2 treatment sequences: placebo-flunarizine and flunarizine-placebo sequences.
Baseline = 4 weeks.
No titration period.
Treatment phase 1 and 2 = 12 weeks each.


ParticipantsSingle Canadian centre.
Total randomised 34; all with drug-resistant partial and generalized epilepsy; 16 to placebo-flunarizine sequence; 18 to flunarizine-placebo sequence.
56% male.
Age range 2 to 18 years (mean 15.5 years).
Other AEDs: data not available.
Baseline seizure frequency: data not available.


Interventions1) Flunarizine:
(a) 5 mg/d for BW less than 20 kg;
(b) 10 mg/d for BW 20 to 40 kg;
(c) 15 mg/d for BW more than 40 kg.

2) Placebo pill


OutcomesFollowing outcomes were measured:

1) 50% or greater reduction in seizure frequency.

2) Treatment withdrawal.

3) Adverse effects.

4) Serum flunarizine level.


NotesThe first author was not able to provide data for the treatment allocation method and data for the following outcomes from the first treatment phase:
(a) 50% or greater reduction in seizure frequency;
(b) adverse effects.

We used the data of treatment withdrawal from the first treatment phase for meta-analysis.

We presented the data of 50% responders and adverse effects from both treatment phases in  Table 1 and  Table 2 respectively.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of randomisation therefore uncertain risk of bias

Allocation concealment (selection bias)Low riskQuote - "randomised"

Comment - No explicit details provided in the study but authors contacted and said sealed envelopes were given to subjects

Blinding (performance bias and detection bias)
Seizure Reduction
Low riskQuote - "Identical appearance for flunarazine and placebo pills"

Comment - Key study personnel were not aware which pills were active and which were placebo

Blinding of participants and personnel (performance bias)
Seizure Reduction
Low riskQuote - "Identical appearance for flunarazine and placebo pills"

Comment - Participants were not aware which pills were active and which were placebo

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskComment - No details on outcome assessors provided and how they were blinded

Incomplete outcome data (attrition bias)
Seizure Reduction
Low riskComment - All patients completed the study and no intention to treat analysis was needed

Selective reporting (reporting bias)High riskComment - Required primary outcomes not reported for first phase of study

Other biasLow riskNone identified

Larkin 1991

MethodsRandomised double-blind placebo-controlled cross-over trial.
2 treatment sequences: placebo-nimodipine and nimodipine-placebo sequences.
Baseline = 4 weeks.
No titration period.
Treatment phase 1 and 2 = 12 weeks each.


ParticipantsSingle British centre.
Total randomised 22; all with drug-resistant partial and generalized epilepsy; numbers of randomised participants into individual treatment sequence groups = data not available.
36% male.
Age range 18 to 53 years.
Other AEDs = 1 to 2.
Baseline seizure frequency: data not available.


Interventions1) Nimodipine:
(a) 90 mg/d for the initial 4 weeks;
(b) 180 mg/d for the middle 4 weeks;
(c) 270 mg/d for the final 4 weeks.

2) Placebo.


OutcomesOutcomes reported:

1) 25% and 50% or greater reduction in generalized tonic-clonic or partial seizures or seizure days.

2) Treatment withdrawal.

3) Adverse effects.

4) Heart rate and systolic blood pressure.

5) Drug preference.

6) Serum concentration of nimodipine and concomitant AEDs.

7) Correlations between nimodipine concentrations and changes in seizure control.


NotesThe last author was not able to provide data for the randomisation method, allocation concealment and blinding method as well as data for any outcomes from the first treatment phase because those data are no longer available.

Study was funded by Bayer U.K.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of randomisation therefore uncertain risk of bias

Allocation concealment (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of allocation concealment therefore uncertain risk of bias

Blinding (performance bias and detection bias)
Seizure Reduction
Low riskQuote - "Identical appearance for Nimodipine and placebo pills"

Comment - Key study personnel were not aware which pills were active and which were placebo

Blinding of participants and personnel (performance bias)
Seizure Reduction
Low riskQuote "Identical appearance for Nimodipine and placebo pills"

Comment - Participants were not aware which pills were active and which were placebo

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskComment - No details on outcome assessors provided and how they were blinded

Incomplete outcome data (attrition bias)
Seizure Reduction
High riskQuote - "17 patients out of 22 completed the study"

Comment - The authors reported attrition but did not perform an intention to treat analysis

Selective reporting (reporting bias)Low riskComment - Primary and secondary outcomes reported

Other biasLow riskNone identified

Larkin 1992

MethodsBalanced double-blind placebo-controlled cross-over trial.
2 treatment sequences: placebo-nifedipine and nifedipine-placebo sequences.
Baseline = 8 weeks.
No titration period.
Treatment phase 1 and 2 = 8 weeks each.


ParticipantsSingle British centre.
Total randomised 22; all with drug-resistant partial and generalized epilepsy; 12 to placebo-nifedipine sequence; 10 to nifedipine-placebo sequence.
55% male.
Age range 17 to 22 years.
Other AEDs = 1 to 4.
Baseline seizure frequency: data not available.


Interventions1) Nifedipine 40 mg/d during the initial half period then 80 mg/d during the final half period.

2) Placebo.


OutcomesFollowing outcomes reported:

1) Total number of any seizures in each treatment phase.

2) Total number of partial seizures in each treatment phase.

3) 50% or greater reduction in seizure frequency.

4) Treatment withdrawal.

5) Adverse events.

6) Heart rate and blood pressure.

7) Serum nifedipine concentrations 1 hour post dosing at 4 weeks on 20 mg twice daily and at 4 weeks on 40 mg twice daily.

8) Correlation between improvement in total seizure numbers, in partial seizure numbers, and nifedipine concentration following 8 weeks of treatment.

9) Comparison of total electroencephalography scores with nifedipine and placebo.


NotesThe last author was not able to provide data for the treatment allocation method and its concealment as well as data for the following outcomes from the first treatment phase because those data are no longer available:
(a) 50% or greater reduction in seizure frequency;
(b) adverse effects.

We used the data of treatment withdrawal from the first treatment phase for analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of randomisation therefore uncertain risk of bias

Allocation concealment (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of allocation concealment therefore uncertain risk of bias

Blinding (performance bias and detection bias)
Seizure Reduction
Unclear riskQuote - "Identical appearance for Nifdepine and placebo pills"

Comment- Did not mention if Key study personnel were aware which pills were active and which were placebo

Blinding of participants and personnel (performance bias)
Seizure Reduction
Low riskQuote - "Identical appearance for Nifdepine and placebo pills"

Comment - Patients were not aware which pills were active and which were placebo

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskComment - No details given on how assessors were blinded

Incomplete outcome data (attrition bias)
Seizure Reduction
Unclear riskQuote - "20 patients completed the study" This was out of total of 22 patients

Comment - Authors did not perform intention to treat analysis

Selective reporting (reporting bias)Low riskComment - No selective reporting of outcomes

Other biasLow riskNone identified

Moglia 1986

MethodsRandomised double-blind placebo-controlled cross-over trial.
2 treatment sequences: placebo-flunarizine and flunarizine-placebo sequences.
Baseline = 12 weeks.
No titration period.
Treatment phase 1 and 2 = 12 weeks each.


ParticipantsSingle Italian centre.
Total randomised 90; all with drug-resistant partial and generalized epilepsy; 42 to placebo-flunarizine sequence; 48 to flunarizine-placebo sequence.
57% male.
Age range 15 to 73 years.
Other AEDs: data not available.
Baseline seizure frequency: data not available.


Interventions1) Flunarizine:
(a) 10 mg/d for BW less than 70 kg;
(b) 15 mg/d for BW more than70 kg.

2) Placebo pill.


OutcomesOutcomes Reported:

1) Incidence of seizure per month before and at the end of each treatment.

2) 50% or greater reduction in seizure frequency.

3) Treatment withdrawal.

4) Adverse effects.


NotesThe first author was not able to provide data for the treatment allocation method and its concealment as well as data for the following outcomes from the first treatment phase because those data are no longer available:
(a) 50% or greater reduction in seizure frequency;
(b) adverse effects.

We used the data of treatment withdrawal from the first treatment phase for meta-analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote - "Patients divided into two equal groups"

Comment - The study is listed as a randomised trial but there is no evidence in the paragraphs of the study, only this vague sentence

Allocation concealment (selection bias)Unclear riskComment - Unclear, no data available on concealment

Blinding (performance bias and detection bias)
Seizure Reduction
Unclear riskComment - No data regarding blinding was provided. The word itself is not mentioned in the study

Blinding of participants and personnel (performance bias)
Seizure Reduction
Unclear riskComment - No data regarding blinding was provided. The word itself is not mentioned in the study

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskComment - No data regarding blinding was provided. The word itself is not mentioned in the study

Incomplete outcome data (attrition bias)
Seizure Reduction
High riskComment - Attrition rate was repoted but no intention to treat analysis performed. 28 patients dropped out from the 90 patient sample, this constitutes a high risk of attrition bias

Selective reporting (reporting bias)High riskComment - Authors did not report the required primary and secondary outcomes

Other biasLow riskNone identified

Overweg 1984

MethodsRandomised double-blind placebo-controlled cross-over trial.
2 treatment sequences: placebo-flunarizine and flunarizine-placebo sequences.
Baseline = 12 weeks.
No titration period.
Treatment phase 1 and 2 = 12 weeks each.


ParticipantsSingle Dutch centre.
Total randomised 33; all with drug-resistant partial and generalized epilepsy; numbers of randomised participants to individual treatment sequence groups not available.
55% male.
All adults.
Other AEDs: most patients on 1 to 3.
Baseline seizure frequency: data not available.


Interventions1) Flunarizine 10 mg per day.

2) Placebo pill.


OutcomesFollowing outcomes reported:

1) Total seizure incidence during on each treatment.

2) 25% or more and 50% or greater reduction in seizure frequency.

3) Treatment withdrawal.

4) Adverse effects.

5) Blood level of concomitant AEDs.


NotesWe were not able to acquire the data from the first treatment phase for meta-analysis for any outcomes.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of randomisation therefore uncertain risk of bias

Allocation concealment (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of allocation concealment therefore uncertain risk of bias

Blinding (performance bias and detection bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Blinding of participants and personnel (performance bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Incomplete outcome data (attrition bias)
Seizure Reduction
Unclear riskComment - Study attrition was reported but no intention to treat analysis was performed

Selective reporting (reporting bias)High riskComment - Required primary and secondary outcomes were not reported for Phase 1 of the study

Other biasLow riskNone identified

Pelliccia 1993

MethodsQuasi-randomised, double-blind, placebo-controlled, cross-over trial.
2 treatment sequences: placebo-nimodipine and nimodipine-placebo sequences.
Baseline = 30 days.
No titration period.
Treatment phase 1 and 2 = 12 weeks each.


ParticipantsSingle Italian centre.
Total randomised 17; 8 randomised into nimodipine-placebo sequence and 9 randomised into placebo-nimodipine sequence.
All with drug-resistant partial and generalized epilepsy.
53% male.
Age range 5 to 22 years.
Other AEDs: 1 to 3.
Baseline seizure frequency: range 3 to 603 per month, mean 166.7 per month.


Interventions1) Nimodipine 1.5 to 2 mg/kg/d.

2) Placebo.


OutcomesFollowing outcomes reported:

1) Incidence of total, partial, generalized, absence seizures or seizure days.

2) 25% or more and 50% or greater reduction in seizure frequency.

3) Treatment withdrawal.

4) Adverse effects.

5) Blood level of concomitant AEDs.


NotesWe used the data from the first treatment phase for analysis for the outcomes of 50% or greater reduction in seizure frequency, treatment withdrawal and adverse effects.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskComment - Random list generation: order of entry into trial, allocation by odd or even numbers

No true “Randomisation”. There is a pattern to the selection

Allocation concealment (selection bias)Low riskQuote - "sequential sealed packages."

Comment - adequate method of concealment chosen

Blinding (performance bias and detection bias)
Seizure Reduction
High riskQuote - "allocation by odd or even numbers."

Comment - Key study personnel would be able to memorize if the patient is on an active or placebo pill if they knew what their order was (odd or even)

Blinding of participants and personnel (performance bias)
Seizure Reduction
Low riskQuote - "Identical appearance for nimodipine and placebo"

Comment - Subjects unaware of the medication they were taking

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskComment - No information given on how outcome assessors were blinded

Incomplete outcome data (attrition bias)
Seizure Reduction
Unclear riskComment - Attrition was reported, but no intention to treat analysis preformed.Three out of 17 patients missing from analysis

Selective reporting (reporting bias)Low riskComment - no selective outcome reporting

Other biasLow riskNone identified

Pledger 1994

MethodsRandomised double-blind placebo-controlled parallel trial.
2 treatment arms: 1 placebo and 1 flunarizine.
Baseline = 12 weeks.
Titration period = 1 week.
Treatment phase = 24 weeks.


ParticipantsAll adults. Multicentre across USA.
Total randomised 93; all with drug-resistant partial epilepsy; 47 to placebo; 46 to flunarizine.
47% male.
Age range 16 to 64 years.
Other AEDs: 1 to 2.
Baseline seizure frequency per week: mean = 6, median = 3.5, range = 1 to 31.8.


Interventions1) Adjusted dose of flunarizine to keep plasma concentration at 60 ng/ml.

2) Placebo pills.


OutcomesFollowing outcomes reported:

1) Seizures, seizure duration and seizure severity per cent reduction.

2) 50% or greater reduction in seizure frequency.

3) Treatment withdrawal.

4) Adverse effects.

5) Plasma concentrations of flunarizine and concomitant AEDs.


NotesWe used the data of 50% or greater reduction in seizure frequency and adverse effects for analyses.
We also used the data of treatment withdrawal for meta-analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment - Authors noted that the random sequence was stratified by a computer

Allocation concealment (selection bias)Low riskQuote "treatment allocated by the centre and kept at pharmacy separated from study site."

Comment - Appropriate treatment allocation sequence by authors

Blinding (performance bias and detection bias)
Seizure Reduction
Low riskComment - All personnel involved in the study were blinded

Blinding of participants and personnel (performance bias)
Seizure Reduction
Low riskComment - All personnel involved in the study were blinded

Blinding of outcome assessment (detection bias)
Seizure Reduction
Low riskComment - All personnel involved in the study were blinded

Incomplete outcome data (attrition bias)
Seizure Reduction
Low riskComment - No study attrition and no need for intention to treat analysis

Selective reporting (reporting bias)Low riskComment - no selective outcome reporting

Other biasLow riskNone identified

Starreveld 1989

MethodsDouble-blind placebo-controlled cross-over trial.
Baseline = 8 weeks.
No titration period.
Treatment phase 1 and 2 = 16 weeks.


ParticipantsSingle Canadian centre.
Total randomised 34; all with drug-resistant partial epilepsy; numbers of randomised participants into individual treatment sequence groups not available.
38% male.
Age range within 15 to 60 years.
Other AEDs: most participants on 1 to 2.
Baseline seizure frequency: data not available.


Interventions1) Flunarizine 15 mg per day.

2) Placebo.


OutcomesFollowing outcomes were reported:

1) Total seizure frequency on each treatment phase.

2) 25%, 25 to 49%, and 50% or greater reduction in seizure frequency.

3) Treatment withdrawal.

4) Adverse effects.

5) Serum concentration of flunarizine and concomitant AEDs.


NotesWe were not able to acquire the data from the first treatment phase for meta-analyses for any of the outcomes.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of randomisation therefore uncertain risk of bias

Allocation concealment (selection bias)Unclear riskQuote - "randomised"

Comment - No details of method of allocation concealment therefore uncertain risk of bias

Blinding (performance bias and detection bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Blinding of participants and personnel (performance bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Blinding of outcome assessment (detection bias)
Seizure Reduction
Unclear riskQuote - "Blinded"

Comment - No details of method of blinding therefore uncertain risk of bias

Incomplete outcome data (attrition bias)
Seizure Reduction
High riskComment - Missing data was mentioned but no intention to treat analysis performed

Selective reporting (reporting bias)High riskComment- Did not report primary and secondary outcomes for first phase of the study

Other biasLow riskNone identified

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Binnie 1985Not RCT due to lack of randomisation. Three patient arms from a previous study were entered into this study as one arm. Placebo was not mentioned in the methods.

Cavazzuti 1986Some participants received study medication for less than 8 weeks.

Handforth 1995The paper reports results from a previous RCT and then presents the results of an open-label extension study.

Malashkhia 1996Although this study was a randomised trial, it was not a placebo-controlled trial and all concurrent AEDs were substituted with phenobarbitone rather than being kept unchanged.

Meyer 1995This trial did not investigate for 50% or greater reduction in seizure frequency. We were also unable to acquire the proportion of participants having treatment withdrawn and the proportion of participants experiencing individual adverse effects in individual treatment groups in the first treatment phase.

Sasso 1993This trial did not investigate for 50% or greater reduction in seizure frequency. We were also unable to acquire the proportion of participants having treatment withdrawn and the proportion of participants experiencing individual adverse effects in individual treatment groups.

Treiman 1993Pilot study to assess concentration treatment for 34 days. Not RCT, concentration-controlled study.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Andrade 2012

MethodsRandomised double-blind interventional controlled trial.

Participants18 to 60 year old patients with refractory epilepsy. Both genders included.

InterventionsDrug: Verapamil (80 mg TID).

Drug: Placebo (TID).

OutcomesPrimary outcome measures:

  • percentage reduction of seizure frequency (time frame: 3 months) (designated as safety issue: No) after 3 months of treatment compared to baseline.

NotesTaking place in Toronto.

 
Comparison 1. Flunarizine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 50% or greater reduction in seizure frequency193Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.59, 3.96]

    1.1 Controlled plasma flunarizine concentration at 60 ng/ml
193Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.59, 3.96]

 2 Treatment withdrawal4247Risk Ratio (M-H, Fixed, 95% CI)7.11 [1.73, 29.30]

    2.1 15 mg per day
130Risk Ratio (M-H, Fixed, 95% CI)6.13 [0.86, 43.86]

    2.2 Dose by body weight (BW): 5 mg/d for BW less than 20 kg, 10 mg/d for BW 20-40 kg, 15 mg/d for BW more than 40k
134Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 Dose by body weight (BW): 10 mg/d for BW less than 70 kg, 15 mg/d for BW more than 70 kg
190Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.4 Controlled plasma flunarizine concentration at 60 ng/ml
193Risk Ratio (M-H, Fixed, 95% CI)8.17 [1.06, 62.78]

 3 Adverse effects1Risk Ratio (M-H, Fixed, 99% CI)Subtotals only

    3.1 Altered concentration
193Risk Ratio (M-H, Fixed, 99% CI)2.38 [0.44, 12.99]

    3.2 Blurred vision
193Risk Ratio (M-H, Fixed, 99% CI)4.09 [0.85, 19.73]

    3.3 Diplopia
193Risk Ratio (M-H, Fixed, 99% CI)1.63 [0.42, 6.42]

    3.4 Dizziness
193Risk Ratio (M-H, Fixed, 99% CI)1.82 [0.72, 4.61]

    3.5 Fatigue
193Risk Ratio (M-H, Fixed, 99% CI)1.66 [0.59, 4.64]

    3.6 Irritability
193Risk Ratio (M-H, Fixed, 99% CI)3.07 [0.60, 15.68]

    3.7 Vomiting
193Risk Ratio (M-H, Fixed, 99% CI)4.09 [0.57, 29.16]

    3.8 Insomnia
193Risk Ratio (M-H, Fixed, 99% CI)2.72 [0.52, 14.33]

 
Comparison 2. Nimodipine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 50% or greater reduction in seizure frequency117Risk Ratio (M-H, Fixed, 95% CI)7.78 [0.46, 130.88]

 2 Treatment withdrawal117Risk Ratio (M-H, Fixed, 95% CI)2.25 [0.25, 20.38]

 
Summary of findings for the main comparison. Flunarizine versus placebo for drug-resistant epilepsy

Flunarizine versus placebo for drug-resistant epilepsy

Patient or population: patients with drug-resistant epilepsy
Settings: Out-patient
Intervention: Flunarizine versus placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlFlunarizine versus placebo

50% or greater reduction in seizure frequency
Number of seizures
13 per 10020 per 100
(8 to 51)
RR 1.53
(0.59 to 3.96)
93
(1 study)
⊕⊕⊕⊕
high
1 Study did not find a significant difference in seizure reduction

Treatment withdrawal
Number of withdrawals
2 per 10012 per 100
(3 to 49)
RR 7.11
(1.73 to 29.30)
247
(4 studies)
⊕⊕⊕⊝
moderate1
1 study found a significant difference in treatment withdrawal. 3 did not find a significant difference in treatment withdrawal.

Adverse effects - Blurred vision
No of patients with blurred vision
6 per 10026 per 100
(5 to 100)
RR 4.09
(0.85 to 19.73)
93
(1 study)
⊕⊕⊕⊕
high
1 study did not find a significant difference in blurred vision.

Adverse effects - Dizziness
No of patients with dizziness
19 per 10035 per 100
(14 to 88)
RR 1.82
(0.72 to 4.61)
93
(1 study)
⊕⊕⊕⊕
high
1 study did not find a significant difference in dizziness.

Adverse effects - Fatigue
No of patients with fatigue
17 per 10028 per 100
(10 to 79)
RR 1.66
(0.59 to 4.64)
93
(1 study)
⊕⊕⊕⊕
high
1 study did not find a significant difference in fatigue

Adverse effects - Irritability
No of patients with irritability
6 per 10020 per 100
(4 to 100)
RR 3.07
(0.6 to 15.68)
93
(1 study)
⊕⊕⊕⊕
high
1 study did not find a significant difference in Irritablity.

Adverse effects - Vomiting
No of patients with vomiting
4 per 10017 per 100
(2 to 100)
RR 4.09
(0.57 to 29.16)
93
(1 study)
⊕⊕⊕⊕
high
1 study did not find a significant difference in vomiting.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 3 studies did not report outcomes adequately and intention-to-treat analysis not employed adequately
 
Summary of findings 2. Nimodipine versus placebo for drug-resistant epilepsy

Nimodipine versus placebo for drug-resistant epilepsy

Patient or population: patients with drug-resistant epilepsy
Settings: Out-patient
Intervention: Nimodipine versus placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlNimodipine versus placebo

50% or greater reduction in seizure frequency
Number of seizures
0 per 1000 per 100
(0 to 0)
RR 7.78
(0.46 to 130.88)
17
(1 study)
⊕⊕⊕⊝
moderate1
1 study did not find a significant difference in seizure reduction.

Treatment withdrawal
Number of withdrawals
11 per 10025 per 100
(3 to 100)
RR 2.25
(0.25 to 20.38)
17
(1 study)
⊕⊕⊕⊝
moderate1
1 study did not find a significant difference in treatment withdrawal.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 This study had missing data and did not employ an intention-to-treat analysis, dropouts were excluded from the analysis
 
Table 1. 50% responders and treatment withdrawal outcomes of cross-over trials

TrialParticipants (n)50% responder (n)

Alving 1989 (FZN)Total randomised participants = 29, completing study = 22, having treatment withdrawn = 7, excluded from analysis = 7.4 participants had 50% SZ reduction on FZN. Overall no significant reduction in SZ frequency on FZN compared with PCB.

Battaglia 1991 (FZN)Total randomised participants = 20, completing study = 13, having treatment withdrawn = 7, excluded from analysis = 7.1 participant had 50% SZ reduction on FZN. Overall no significant reduction in SZ frequency on FZN compared with PCB.

Fröscher 1988 (FZN)Total randomised participants = 30, completing study = 22, having treatment withdrawn = 8, excluded from analysis = 8.PCB-FZN sequence (n = 13): 2 patients had 50% SZ reduction on FZN. Overall significant reduction in SZ frequency on FZN compared with PCB. // FZN-PCB sequence (n = 9): 1 pt had 50% SZ reduction while 5 had SZ increase on FZN. Overall no significant SZ reduction on FZN compared with PCB.

Keene 1989 (FZN)Total randomised participants = 34, completing study = 34, having treatment withdrawn = 0, excluded from analysis = 0.5 participants had 50% SZ reduction on FZN. 8 participants had 50% SZ reduction on PCB compared with baseline.

Moglia 1986 (FZN)Total randomised participants = 90, completing study = 90, having treatment withdrawn = 28, excluded from analysis = 28.14 participants had 50% SZ reduction on FZN. Overall significant SZ reduction on FZN compared with baseline.

Overweg 1984 (FZN)Total randomised participants = 33, completing study = 30, having treatment withdrawn = 3, excluded from analysis = 3.7 participants had 50% SZ reduction while 9 participants had SZ increase on FZN. Overall significant SZ reduction on FZN compared with PCB.

Starreveld 1989 (FZN)Total randomised participants = 34, completing study = 25, having treatment withdrawn = 0, excluded from analysis = 9.5 participants had 50% SZ reduction on FZN. Overall no significant SZ reduction on FZN compared with PCB.

Larkin 1992 (NFD)Total randomised participants = 22, completing study = 21, having treatment withdrawn = 1, excluded from analysis = 1.2 participants had 50% SZ reduction on NFD. 2 participants had 50% SZ reduction on PCB compared with baseline. No significant difference in SZ reduction between NFD and PCB.

Larkin 1991 (NMD)Total randomised participants = 22, completing study = 17, having treatment withdrawn = 5, excluded from analysis = 5.7 participants had 50% reduction in partial SZ, 1 had 50% reduction in tonic-clonic SZ on NMD. 5 participants had 50% reduction in partial SZ, 1 had 50% reduction in tonic-clonic SZ on PCB compared with baseline. No significant difference in SZ reduction between NMD and PCB.

 FZN: flunarizine
NFD: nifedipine
NMD: nimodipine
PCB: placebo
SZ: seizure
 
Table 2. Numbers of participants experiencing adverse effects in cross-over trials

Adverse effectsAlving 1989
(n = 29)
Battaglia 1991
(n = 20)
Fröscher 1988
(n = 30)
Keene 1989
(n = 34)
Moglia 1986
(n = 90)
Overweg 1984
(n = 23)
Starreveld 1989
(n = 34)
Larkin 1992
(n = 22)
Larkin 1991
(n = 22)

Change in moodFZN = 4 : PCB = 2NFD = 0 : PCB = 1

Change in appetiteFZN = 7 : PCB = 6FZN = PCBNFD = 0 : PCB = 1

DrowsinessFZN = 1 :
PCB = 0
FZN = 16 : PCB = 0FZN = 1 :
PCB = 0
FZN = PCBNFD = 0 : PCB = 1

Dry mouthNFD = 1 : PCB = 1

FatigueFZN = 8 : PCB = 4

HeadacheFZN = 4 : PCB = 5FZN = PCBNFD = 2 : PCB = 0

IrritabilityFZN = 9 : PCB = 5

Poor memoryNFD = 1 : PCB = 0

TirednessApproximately the same extent in both FZN and PCB

TremorFZN = 3 : PCB = 2

VertigoFZN = PCB

Weight changeFZN = PCB

OtherFZN = 8 : PCB = 8No significant side effects were reported by any patients during the FZN phase compared with the PCB phase.Neither NMD nor PCB significantly changed the severity of the following side effects compared with baseline period: agitation, double vision, flushing, headache, itching, nausea, palpitation, poor concentration, sedation, unsteadiness.

 FZN: flunarizine
NFD: nifedipine
NMD: nimodipine
PCB: placebo