Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy

  • Review
  • Intervention

Authors

  • Graham Powell,

    Corresponding author
    1. The Walton Centre for Neurology & Neurosurgery NHS Foundation Trust, Liverpool, UK
    • Graham Powell, The Walton Centre for Neurology & Neurosurgery NHS Foundation Trust, Lower Lane, Fazakerley, Liverpool, L9 7LJ, UK. g.a.powell@doctors.org.uk.

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  • Matthew Saunders,

    1. Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK
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  • Anthony G Marson

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

Background

Epilepsy is defined as the tendency to spontaneous, excessive neuronal discharge manifesting as seizures. It is a common disorder with an incidence of 50 per 100,000 per year and a prevalence of 0.5% to 1% (Hauser 1993) in the developed world.

Carbamazepine (CBZ) is a widely used antiepileptic drug that is associated with a number of troublesome adverse events including dizziness, double vision and unsteadiness. These often occur during peaks in plasma concentration. The occurrence of such adverse events may limit the daily dose that can be tolerated and reduce the chances of seizure control for patients requiring higher doses (Vojvodic 2002). A controlled-release formulation of carbamazepine delivers the same dose over a longer period of time when compared to a standard formulation, thereby reducing post-dose peaks and potentially reducing adverse events associated with peak plasma levels.

Objectives

To determine the efficacy of immediate-release CBZ (IR CBZ) versus controlled-release CBZ (CR CBZ) in patients diagnosed with epilepsy. The following hypotheses were tested.
(1) For newly diagnosed patients commencing CBZ, how do immediate-release and controlled-release formulations compare for efficacy and tolerability?
(2) For patients on established treatment with immediate-release CBZ but experiencing unacceptable adverse events, what is the effect on seizure control and tolerability of a switch to a controlled-release formulation versus remaining on the immediate-release formulation?

Search methods

We searched the Cochrane Epilepsy Group Specialised Register (5 September 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013) in The Cochrane Library and MEDLINE (1946 to 5 September 2013).

Selection criteria

Randomised controlled trials comparing IR CBZ to CR CBZ in patients commencing monotherapy and patients presently treated with IR CBZ but experiencing unacceptable adverse events.

Primary outcome measures include seizure frequency, incidence of adverse events, proportion with treatment failure and quality of life measures.

Data collection and analysis

The methodological quality of each study was assessed with respect to study design, type of control, method and the concealment of allocation, blinding and completeness of follow up, and the presence of blinding for assessment of non-fatal outcomes. We did not make use of an overall quality score.

Two review authors (GP, MS) independently extracted the data and recorded relevant information on a standardised data extraction form. Results were assessed for inclusion.

The heterogeneity of the included trials resulted in only a narrative, descriptive analysis being possible for both the categorical and time-to-event data.

Main results

Ten trials fulfilled the criteria for inclusion in this review. One trial included patients with newly diagnosed epilepsy and nine included patients on treatment with IR CBZ.

Eight trials reported heterogeneous measures of seizure frequency with conflicting results. A statistically significant difference was observed in only one trial, with patients prescribed CR CBZ experiencing fewer seizures than patients prescribed IR CBZ.

Nine trials reported measures of adverse events. There was a trend in favour of CR CBZ with four trials reporting a statistically significant reduction in adverse events compared to IR CBZ. A further two trials reported fewer adverse events with CR CBZ but the reduction was not statistically significant. One trial found no difference, with a further trial reporting increased adverse events in the CR CBZ group although not statistically significant.

Authors' conclusions

At present, data from trials do not confirm or refute an advantage for CR CBZ over IR CBZ for seizure frequency or adverse events in patients with newly diagnosed epilepsy.

For trials involving epilepsy patients already prescribed IR CBZ, no conclusions can be drawn concerning the superiority of CR CBZ with respect to seizure frequency.

There is a trend for CR CBZ to be associated with fewer adverse events when compared to IR CBZ. A change to CR CBZ may therefore be a worthwhile strategy in patients with acceptable seizure control on IR CBZ but experiencing unacceptable adverse events. The included trials were of small size, poor methodological quality and possessed a high risk of bias, limiting the validity of this conclusion.

Randomised controlled trials comparing CR CBZ to IR CBZ and using clinically relevant outcomes are required to inform the choice of CBZ preparation for patients with newly diagnosed epilepsy.

Résumé

Carbamazépine à libération immédiate et à libération contrôlée dans le traitement de l'épilepsie

Contexte

L’épilepsie se définit par une tendance à une décharge neuronale excessive spontanée se manifestant sous forme de crises. C’est un trouble courant dont l'incidence est de 50 pour 100 000 cas par an avec une prévalence de 0,5 % à 1 % (Hauser 1993) dans les pays développés.

La carbamazépine (CBZ) est un antiépileptique largement employé qui est associé à plusieurs événements indésirables gênants, notamment les vertiges, la diplopie et l'ataxie. Ces événements surviennent souvent au moment des pics de concentration plasmatique. La survenue de ces événements indésirables peut limiter la dose quotidienne tolérée et réduire les chances de contrôler les crises chez les patients nécessitant des doses plus élevées (Vojvodic 2002). Une galénique à libération contrôlée de carbamazépine fournit la même dose sur une période de temps plus longue par comparaison avec une galénique standard, réduisant ainsi les pics post-dose et pouvant diminuer les événements indésirables associés aux pics plasmatiques.

Objectifs

Déterminer l'efficacité de la CBZ à libération immédiate (CBZ LI) par rapport à la CBZ à libération contrôlée (CBZ LC) chez les patients épileptiques diagnostiqués. Les hypothèses suivantes ont été testées.
(1) Pour les patients nouvellement diagnostiqués entamant la CBZ, les galéniques à libération immédiate et à libération contrôlée sont-elles comparables sur le plan de l'efficacité et de la tolérabilité ?
(2) Pour les patients sous traitement établi avec la CBZ à libération immédiate présentant des événements indésirables inacceptables, quel sera l'effet sur le contrôle des crises et sur la tolérabilité d'un passage à une galénique à libération contrôlée versus la poursuite du traitement avec la galénique à libération immédiate ?

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur l'épilepsie (5 septembre 2013), le registre Cochrane des essais contrôlés (CENTRAL) (numéro 8, 2013) dans la Bibliothèque Cochrane et MEDLINE (de 1946 au 5 septembre 2013).

Critères de sélection

Essais contrôlés randomisés comparant la CBZ LI à la CBZ LC chez les patients entamant une monothérapie et chez les patients actuellement traités par la CBZ LI ayant eu des événements indésirables inacceptables.

Les critères de jugement principaux incluent la fréquence des crises, l’incidence des événements indésirables, la proportion d’échec thérapeutique et la qualité de vie.

Recueil et analyse des données

La qualité méthodologique de chaque étude a été évaluée concernant le plan d'étude, le type de contrôles, la méthode et l'assignation secrète, la mise en aveugle et la complétude du suivi ainsi que l’existence d’une évaluation à l’aveugle des critères de jugement autres que le décès. Nous n’avons pas utilisé de score de qualité global.

Deux auteurs de la revue (GP, MS) ont de manière indépendante extrait les données et enregistré les informations pertinentes sur un formulaire d’extraction des données standardisé. Les résultats ont été évalués pour l’inclusion.

En raison de l’hétérogénéité des essais inclus, seule une analyse narrative et descriptive a été possible tant pour les données catégorielles que pour les données sur le délai jusqu’à l’événement.

Résultats Principaux

Dix essais remplissaient les critères d’inclusion dans cette revue. Un seul essai incluait des patients dont le diagnostic d’épilepsie venait d’être posé et neuf essais regroupaient des patients actuellement sous CBZ LI.

Huit essais ont fourni des mesures hétérogènes de la fréquence des crises avec des résultats contradictoires. Une différence statistiquement significative a été observée dans un seul essai, les patients auxquels avait été prescrite la CBZ LC ayant moins de crises que les patients sous CBZ LI.

Neuf essais ont fourni des mesures des événements indésirables. Une tendance s’est dégagée en faveur de la CBZ LC, quatre essais mentionnant en effet une diminution statistiquement significative des événements indésirables par rapport à la CBZ LI. Deux autres essais ont signalé un nombre moins élevé d’événements indésirables avec la CBZ LC, mais cette diminution n’était pas statistiquement significative. Un essai n'a fait état d’aucune différence, un autre essai notant une augmentation du nombre d'événements indésirables dans le groupe de la CBZ LC, bien que non statistiquement significative.

Conclusions des auteurs

Actuellement, les données des essais ne confirment ni ne réfutent l’avantage de la CBZ LC par rapport à la CBZ LI pour ce qui est de la fréquence des crises ou des événements indésirables chez les patients dont l’épilepsie vient d’être diagnostiquée.

Pour ce qui est des essais regroupant des patients épileptiques prenant déjà de la CBZ LI, aucune conclusion relative à la supériorité de la CBZ LC pour ce qui est de la fréquence des crises ne peut être tirée.

La CBZ LC a tendance à être associée à un nombre moindre d’événements indésirables par comparaison avec la CBZ LI. Le passage à la CBZ LC peut par conséquent se révéler une stratégie payante pour les patients chez lesquels la CBZ LI offre un contrôle acceptable des crises mais occasionne des événements indésirables inacceptables. Les essais inclus ont été réalisés à petite échelle et avaient une qualité méthodologique insuffisante ainsi qu'un risque de biais élevé, ce qui limite la validité de cette conclusion.

Des essais contrôlés randomisés comparant la CBZ LC à la CBZ LI et utilisant des critères de jugement cliniquement pertinents doivent être menés pour éclairer le choix de la galénique de CBZ à utiliser pour les patients dont l'épilepsie vient d'être diagnostiquée.

Plain language summary

Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy

Epilepsy is a common neurological disorder that is often treated with carbamazepine. With treatment, the number of seizures are often reduced but many people experience side effects. When carbamazepine is taken and it is absorbed into the body quickly there is a sharp rise in blood levels. These 'peaks' may be associated with side effects such as dizziness, drowsiness and lack of coordination. A form of carbamazepine that releases the medication into the body slowly may reduce these 'peaks' in blood levels, reducing the occurrence of side effects.

This review compared studies assessing the differences between a 'fast-release' carbamazepine and a 'slow-release' carbamazepine. Just one of 10 studies found a significant difference between the two carbamazepine types in the number of seizures experienced, with patients prescribed the slow-release carbamazepine experiencing fewer seizures than patients prescribed the fast-release drug. Patients taking 'slow-release' carbamazepine tended to experience fewer side effects. It must be stressed that there are few studies assessing the differences between these two carbamazepine types and more studies are needed before we can make a definitive conclusion.

Résumé simplifié

Carbamazépine à libération immédiate et à libération contrôlée dans le traitement de l'épilepsie

La carbamazépine à libération immédiate et à libération contrôlée dans le traitement de l'épilepsie

L’épilepsie est un trouble neurologique courant qui est souvent traité avec la carbamazépine. Grâce au traitement, le nombre de crises est souvent réduit, mais de nombreuses personnes présentent des effets secondaires. Lorsque la carbamazépine est prise et est absorbée rapidement par l’organisme, une élévation soudaine des taux sanguins est constatée. Ces « pics » peuvent être associés à des effets secondaires tels que des vertiges, une somnolence et un manque de coordination. Une forme de carbamazépine libérant lentement le médicament dans le corps peut réduire ces pics des taux sanguins et ainsi diminuer la survenue des effets secondaires.

Cette revue a comparé des études évaluant les différences entre la carbamazépine « à libération rapide » et la carbamazépine « à libération lente ». Seule une étude sur 10 a fait état d'une différence significative entre les deux types de carbamazépine au niveau du nombre de crises, les patients sous carbamazépine à libération lente ayant moins de crises que ceux prenant le médicament à libération rapide. Les patients sous carbamazépine à libération lente avaient tendance à avoir moins d’effets secondaires. Il convient de souligner que le nombre d’études évaluant les différences entre ces deux types de carbamazépine est peu élevé et que des études supplémentaires doivent être réalisées pour que nous puissions parvenir à une conclusion définitive.

Notes de traduction

Traduit par: French Cochrane Centre 22nd June, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Background

Epilepsy is defined as the tendency to spontaneous, excessive neuronal discharge manifesting as seizures. It is a common disorder with an incidence of 50 per 100,000 per year and a prevalence of 0.5% to 1% (Hauser 1993) in the developed world.

In the treatment of epilepsy, carbamazepine (CBZ) is one of the first-line antiepileptic drugs and is of proven efficacy compared to other standard drugs such as valproate (Marson 2000; NICE 2004). However, CBZ is associated with a number of adverse events including dose-related events such as dizziness, double vision and unsteadiness. These adverse events may also occur during peaks in plasma concentrations of CBZ following ingestion of a dose. The occurrence of such events may limit the daily dose that can be tolerated and reduce the chances of seizure control for patients requiring higher doses (Vojvodic 2002). This problem may be compounded by unpredictable fluctuations of CBZ serum concentrations due to its poor water solubility, which causes slow and irregular absorption. Such problems might be alleviated by prescribing a controlled-release formulation, which delivers the same dose over a longer period of time when compared to a standard formulation, thereby reducing post-dose peaks and potentially reducing adverse events.

CBZ has numerous qualities that may make it a good candidate for a controlled-release preparation. These include a short half-life, lack of first-pass metabolism, a narrow therapeutic index and efficient absorption throughout the gastrointestinal tract (Collins 2000). Several controlled-release preparations are currently available.

In this systematic review we have summarised existing evidence from randomised controlled trials that compared immediate-release and controlled-release CBZ for the treatment of patients with epilepsy.

Objectives

To determine the efficacy of immediate-release CBZ (IR CBZ) versus controlled-release CBZ (CR CBZ) in patients diagnosed with epilepsy. The following hypotheses were tested.
(1) For newly diagnosed patients commencing CBZ, how do immediate-release and controlled-release formulations compare for efficacy and tolerability?
(2) For patients on established treatment with immediate-release CBZ but experiencing unacceptable adverse events, what is the effect on seizure control and tolerability of a switch to a controlled-release formulation versus remaining on the immediate-release formulation?

Methods

Criteria for considering studies for this review

Types of studies

(1) Randomised controlled trials comparing immediate-release CBZ to controlled-release CBZ. Our initial intention was to only include studies with an adequate method of allocation concealment. However, due to the small number of studies identified in the literature searches, studies where the method of randomisation was not clearly stated have also been included.

(2) Studies may be double blind, single blind or unblinded.

Types of participants

Patients of any age and either gender with a diagnosis of epilepsy who were either:
(1) commencing monotherapy with immediate-release CBZ or commencing monotherapy with controlled-release CBZ; or
(2) currently prescribed monotherapy with immediate-release CBZ but experiencing unacceptable adverse events and were being switched to a controlled-release CBZ formulation.

Types of interventions

The intervention group should have received a controlled-release formulation of CBZ and the control group a standard, immediate-release formulation of CBZ.

Types of outcome measures

The outcome measures of interest are listed below for studies addressing each objective.

Objective 1: analysis of newly diagnosed patients

(1) Time to 12-month remission
(2) Proportion seizure free at six months
(3) Proportion seizure free at 12 months
(4) A 50% or greater reduction in seizure frequency
(5) Proportion with treatment failure (inadequate seizure control, adverse events, or both) at six months
(6) Proportion with treatment failure (inadequate seizure control, adverse events, or both) at 12 months
(7) Incidence of adverse events
(8) Quality of life measures

Objective 2: analysis of patients with established epilepsy

(1) Proportion seizure free at six months
(2) Proportion seizure free at 12 months
(3) A 50% or greater reduction in seizure frequency
(4) Proportion with treatment failure (inadequate seizure control, adverse events, or both) at six months
(5) Proportion with treatment failure (inadequate seizure control, adverse events, or both) at 12 months
(6) Incidence of adverse events
(7) Quality of life measures

Search methods for identification of studies

We carried out searching as follows.

(1) Electronic databases

Searches were run for the original review in September 2009 and subsequent searches were run in July 2011. For the latest update (September 2013) we searched the following databases. There were no language restrictions.

(a) Cochrane Epilepsy Group Specialised Register (5 September 2013) using the search terms (carbamazepine OR tegretol) AND INREGISTER AND >2010:YR.

(b) Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013) in The Cochrane Library using the search strategy outlined in Appendix 1.

(c) MEDLINE (Ovid) (1946 to 5 September 2013) using the strategy outlined in Appendix 2.

2) Other sources

We did not contact pharmaceutical companies or researchers in the field due to the time period when the majority of studies were published. However, contact may be made prior to an update of this review.

Data collection and analysis

Selection of trials

Two review authors (GP, MS) screened all the titles, abstracts and keywords of publications identified by the searches to assess their eligibility for inclusion. Publications that clearly did not meet the inclusion criteria were excluded at this stage. A paper copy of the full publication of each relevant study was obtained. Both review authors assessed studies according to pre-specified selection criteria. Any disagreement concerning eligibility for inclusion was resolved by discussion and a consensus decision made.

Assessment of methodological quality

Two review authors (GP, MS) independently assessed the methodological quality of all the included studies and recorded their findings on a standardised form. Important aspects of methodology were noted: study design, type of control, method and the concealment of allocation, blinding and completeness of follow up, and the presence of blinding for assessments of non-fatal outcomes. We did not make use of an overall quality score but described each of the above methodological factors for each study.

Data extraction

Two review authors (GP, MS) independently extracted the data and recorded relevant information on a standardised data extraction form. The results were compared to assess agreement. The data reported by published sources were used for analysis in this review. Both review authors pilot tested the data collection form on a sample study and found it to be suitable. Disagreement or uncertainty concerning results was resolved by discussion and a consensus decision made.

Data analysis

For categorical data, we planned to express relative treatment effects as risk ratios with 95% confidence intervals (CI). Clinical heterogeneity was assessed by comparing study designs and the patient populations recruited among the trials. Statistical heterogeneity, where appropriate, was to be assessed using the I2 statistic where a value of greater than 70% was taken to indicate statistical heterogeneity. If heterogeneity was present, its significance was considered and a decision made as to whether meta-analysis was appropriate. If so, a random-effects model would be used.

For time-to-event data we did not plan to undertake a meta-analysis using aggregate data, rather summarising trial results in text tables. Due to the small number of trials identified, we did not explore the possibility of obtaining individual patient data to include in a meta-analysis using inverse variance methods. This may be considered in an update of this review. Similarly, quality of life data were summarised in the text and tables.

Results

Description of studies

Twenty-three trials were identified as potentially eligible for inclusion in this review. Two trials were not published in English and could not be included due to restrictions that prevented their translation (Dam 1980; Remy 1990). However, these trials may be included in an update of this review. Eleven trials were excluded as they did not meet the eligibility criteria. Four trials did not include CR formulations of CBZ (Dam 1981; Thakker 1991), two of which were concerned with the dose frequency of IR CBZ (Ghose 1983; Monaco 1984). Three trials did not make the required treatment comparison, two trials involved a comparison of two CR CBZ formulations (Jensen 1990; Scheuch 1992) and one trial compared CR CBZ to sodium valproate (Sobaniec 2004). There was no mention of randomisation in two trials (Bojinova 1997; Pieters 1992). One trial was observational in design, involving a treatment cohort with no control group (Mirza 1998), and a further trial did not report any relevant outcome measures (Ramsay 1989). Additional details can be found in the table Characteristics of excluded studies.

Ten trials fulfilled the criteria for inclusion in this review. One trial concerned patients with newly diagnosed epilepsy and was included under the first objective (Nag 1998). Twenty patients with ages ranging from 16 to 35 years were recruited. The remaining nine trials included patients currently treated with IR CBZ and were included under the second objective. In total, 296 patients with ages ranging from 6 to 69 year were recruited into these 10 trials. One trial included children in addition to adult patients (Kaski 1991). Summary information on the trials included in this review can be found in the Characteristics of included studies table. In addition, more detailed information, particularly concerning interventions and results of each study, can be found in Appendix 3.

Included trials were primarily concerned with the pharmacokinetic parameters of both CBZ and its predominant metabolite, CBZ epoxide. The clinical parameters that were of interest in this review were generally considered as secondary outcomes within the included studies and there was significant heterogeneity with respect to the outcomes reported. The clinical outcomes reported included mean seizure frequency, total number of seizures experienced in each study arm, mean total number of seizures per patient in each study arm, total incidence of adverse events reported in each study arm, total number of patients reporting adverse events, and total scores of inventories designed to quantify adverse events occurrence.

Many of the outcomes specified in the protocol of this review were not measured. The studies were predominantly designed as randomised cross-over trials. The duration of treatment in each arm ranged from two weeks to three months. No trial reported follow up beyond study completion. Categorical data including the proportion seizure free and the proportion with treatment failure, both at six and 12 months, were therefore not reported. In addition, time-to-event data were not reported.

Detailed statistical analysis, including meta-analysis, was not appropriate. Therefore, the analysis used in this review is largely narrative.

Risk of bias in included studies

One study used an adequate randomisation procedure involving a computer-generated random sequence, adequately concealed allocation, and was double blind with identical tablets and containers (Persson 1990). The methods of randomisation and allocation concealment were unclear for the remaining nine trials, although all stated that randomisation had been performed. Eight trials were adequately blinded, involving identical tablets and packaging; the remaining two trials were considered unblinded (Nag 1998; Sivenius 1988).

Effects of interventions

A narrative summary follows concerning results for each relevant outcome. More detailed results can be found in the 'Additional tables' section.

Objective 1: analysis of newly diagnosed patients

Seizure frequency

No data relating to seizure frequency were reported in the one trial involving patients with newly diagnosed epilepsy (Nag 1998).

Incidence of adverse events

One unblinded parallel trial was identified involving 20 adult patients with newly diagnosed epilepsy (Nag 1998). During the 20-day study period, a total of four adverse events were reported in patients prescribed IR CBZ: diplopia, rash and two reports of sedation. Two adverse events, sedation and diplopia, were reported in patients prescribed CR CBZ. The significance of the difference between groups was not reported.

Objective 2: analysis of patients with established epilepsy

Seizure frequency

The occurrence of seizures during each treatment period was reported heterogeneously. The majority of studies where seizures were recorded reported the mean number of seizures per patient during each study period.

  • Garnett 1998 reported an increased mean number of seizures per patient during CR CBZ treatment. A mean 2.8 seizures per patient (range 0 to 29) occurred in patients prescribed CR CBZ compared to 1.6 (range 0 to 18) in patients prescribed IR CBZ during each two-week treatment arm. This difference was not statistically significant. The CBZ dose remained stable throughout the study period.

  • Persson 1990 reported an increased mean number of seizures per patient for the IR CBZ treatment group: 2.2 compared to 1.2 during CR CBZ treatment. These figures were only derived from the first month of the three-month treatment period. This was not statistically significant. There were no statistically significant differences between the mean number of seizures per month per patient for IR CBZ (1.34) and CR CBZ (1.24). The CBZ dosage remained the same throughout the study period.

  • McKee 1991 reported an increased mean number of seizures per patient during treatment with CR CBZ: 3.8 (SD 0.9) compared to 2.8 (SD 1.2) during treatment with IR CBZ (95% CI -0.7 to 2.8). The CBZ dose remained stable during the four-week study period. Seizure frequency was not statistically significantly different for either CBZ formulation when compared to baseline.

  • Browne 1995 reported a lower mean monthly seizure rate during IR CBZ treatment: 0.41 compared to 0.53 during treatment with CR CBZ. SDs or CIs were not given for these estimates. The CBZ dose remained stable during each 56-day study arm. The difference was not statistically significant.

Seizure frequency was reported in the following studies.

  • Canger 1990 reported a statistically significant reduction in mean monthly seizure frequency during treatment with CR CBZ: 6.3 (SD 9.8) compared to 9.3 (SD 15.6) during treatment with IR CBZ. The CBZ dose remained stable during the one-month study period.

  • Kaski 1991 reported the total number of seizures during the 10-week study period: 44 (range 9 to 133) in patients prescribed CR CBZ compared to 42.7 (range 4 to 107) in patients prescribed IR CBZ. This difference was not statistically significant. The CBZ dose remained stable throughout the study period.

The total numbers of seizures during each study group were reported in the following studies.

  • Reunanen 1990 reported an increased total number of seizures during treatment with IR CBZ: 56 seizures compared to 31 during treatment with CR CBZ in each two-week treatment arm. The CBZ dose remained stable throughout the study period. This difference was not statistically significant.

  • Sivenius 1988 reported identical total numbers of seizures during each treatment period. Nine seizures occurred during treatment with both CBZ formulations in each two-week study period. The CBZ dose remained stable throughout the study period.

Incidence of adverse events

Adverse events were reported heterogeneously in the studies included in this review. The following studies used various inventories designed to assess adverse events as a result of antiepileptic drugs. Total scale scores were calculated following completion to allow the comparison of these psychometric outcomes between groups.

  • McKee 1991 reported significantly lower cognitive adverse event scores at one hour with CR CBZ compared to IR CBZ. In addition, reaction times were shorter at one and four hours with CR CBZ, again statistically significant.

  • Aldenkamp 1987 reported increased performance in various tests of cognitive function in patients taking CR CBZ. Statistical significance was not stated.

  • Persson 1990 reported lower scores on a combined systemic toxicity and neurotoxicity scale in patients taking CR CBZ compared to IR CBZ. The difference was statistically significant.

Numerous studies reported the individual numbers of adverse events reported.

  • Browne 1995 reported that four patients experienced six adverse events when prescribed CR CBZ: dizziness (2 patients), diplopia (1), headache (1), nausea (1) and vomiting (1). Five patients experienced five adverse events when prescribed IR CBZ: dizziness, drowsiness, hand tremor, stomach cramps and vomiting. These differences were not statistically significant.

  • Reunanen 1990 reported 19 adverse events during IR CBZ treatment compared to 12 with CR CBZ. Dizziness (7 patients), fatigue (4), visual disturbance (4), headache (1) and difficulty with coordination (3) were experienced during IR CBZ treatment. Dizziness (1), fatigue (4), visual disturbance (2), headache (2), difficulty with coordination (1), nausea (1) and gastric discomfort (1) were experienced during CR CBZ treatment. The difference was statistically significant for dizziness, reported seven times during IR CBZ treatment and just once during CR CBZ treatment.

  • Garnett 1998 reported one adverse event: somnolence during IR CBZ treatment.

The following studies reported the number of patients experiencing adverse events.

  • Sivenius 1988 reported that four patients in each treatment group experienced adverse events. No further details concerning the individual adverse events were reported.

  • Canger 1990 stated that 26 patients reported intermittent adverse events with IR CBZ whereas six patients reported adverse events with CR CBZ. No further details concerning the individual adverse events were reported. The difference was statistically significant.

Discussion

Ten trials were included in this review. All were primarily concerned with comparisons of the pharmacokinetic parameters of both IR CBZ and CR CBZ. Few of the clinical outcomes pre-specified in the protocol of this review were measured in these trials. The overall methodological quality of the trials included in this review was poor, as was the reporting of important methodological factors. The risk of bias was low in only one of the 10 trials included in this review (Persson 1990). The methods of randomisation and allocation concealment were unclear in the remaining nine trials, whilst eight trials were adequately blinded.

Only one trial involving patients with newly diagnosed epilepsy was identified (Nag 1998). This trial involved only 20 patients and reported a total of six adverse events, four occurring during IR CBZ treatment. Given the small number of patients and small number of events, no conclusions can be drawn regarding the comparative tolerability of IR CBZ and CR CBZ. Measures of seizure frequency, quality of life measures and time-to-event data were not reported.

Eight of the included trials reported measures of seizure frequency in patients with an established diagnosis of epilepsy and currently treated with IR CBZ. Measures were heterogeneous and we describe general trends. Three trials reported a reduced occurrence of seizures in patients taking CR CBZ, which was statistically significant in one trial. In addition, three trials reported a reduced occurrence of seizures in patients taking IR CBZ, statistically significant in one trial. The remaining two trials reported no difference in seizure occurrence between the two formulations. There appears to be no difference between formulations in controlling the occurrence of seizures. However, the absence of further statistical analyses, methodological limitations and risk of bias limit the accuracy of these narrative conclusions.

Eight of the included trials reported data concerning adverse events in patients with an established diagnosis of epilepsy and already prescribed IR CBZ. Although methods of reporting differed greatly and measures could not be statistically combined, four of the trials found a significantly reduced incidence of adverse events in patients taking CR CBZ compared to IR CBZ. A further two trials reported a lower incidence with CR CBZ that did not reach statistical significance. Of the remaining two trials, one found no difference between the two CBZ formulations and one reported a reduced incidence in patients taking IR CBZ (Browne 1995). Interestingly this cross-over trial included the largest study sample, 101 patients, and one of the longest study periods with 56 days in each treatment arm. This narrative analysis suggests a reduced incidence of adverse events and therefore superiority of CR CBZ compared to IR CBZ when considering adverse events. These results do not however provide robust evidence due to the heterogenous methods of reporting that prevented further statistical analysis of the results, inherent limitations in methodological quality, and the risk of bias present in many of the trials included in this review.

Authors' conclusions

Implications for practice

Existing randomised controlled trials comparing IR CBZ to CR CBZ have not focused on clinical outcomes. At present, data from trials do not confirm or refute an advantage for CR CBZ over IR CBZ concerning seizure frequency or adverse events in patients with newly diagnosed epilepsy.

Trials involving patients with an established diagnosis of epilepsy and already prescribed IR CBZ were more numerous. No conclusions can be drawn concerning superiority with respect to seizure frequency.

There is a trend for CR CBZ to be associated with fewer adverse events when compared to IR CBZ. This difference was statistically significant in four of the eight trials. However, the included trials were of small size, had poor methodological quality, and possessed a high risk of bias. In addition, this conclusion has been reached following a narrative analysis, inherently less reliable and less accurate than using statistical techniques. Nevertheless, in patients currently prescribed IR CBZ and experiencing unacceptable dose-related adverse events, changing to CR CBZ may be worthwhile and should be considered by the clinician when faced with this scenario.

Implications for research

Randomised controlled trials comparing CR CBZ to IR CBZ and using clinically relevant outcomes are required to provide evidence to inform the choice of CBZ preparation for patients with newly diagnosed epilepsy.

Acknowledgements

Alison Beamond and Rachael Kelly provided invaluable help with the searches and administrative aspects of this review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. CENTRAL search strategy

The following search strategy was used for the latest update.

#1 (epilep* or seizure* or convuls*):ti,ab,kw (Word variations have been searched)

#2 MeSH descriptor: [Epilepsy] explode all trees

#3 MeSH descriptor: [Seizures] explode all trees

#4 (#1 or #2 or #3)

#5 carbam?zepine or tegretol

#6 MeSH descriptor: [Carbamazepine] explode all trees

#7 #5 or #6

#8 #4 and #7 from 2011, in Trials

The following was the original search strategy.

#1 (carbamazepine or tegretol)
#2 MeSH descriptor Carbamazepine explode all trees
#3 (#1 OR #2)
#4 MeSH descriptor Epilepsy explode all trees
#5 MeSH descriptor Seizures explode all trees
#6 epilep* or seizure* or convulsion*
#7 (#4 OR #5 OR #6)
#8 (#3 AND #7)

Appendix 2. MEDLINE search strategy

The following search strategy was used for the latest update.

This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomized trials (Lefebvre 2011).

1. (randomized controlled trial or controlled clinical trial).pt. or (randomized or placebo or randomly).ab.

2. clinical trials as topic.sh.

3. trial.ti.

4. 1 or 2 or 3

5. exp animals/ not humans.sh.

6. 4 not 5

7. exp Epilepsy/

8. exp Seizures/

9. (epilep$ or seizure$ or convuls$).tw.

10. 7 or 8 or 9

11. exp Pre-Eclampsia/ or exp Eclampsia/

12. 10 not 11

13. (carbam?zepine or tegretol).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

14. exp Carbamazepine/

15. 13 or 14

16. 6 and 12 and 15

17. limit 16 to ed=20110701-20130905

The following was the original search strategy.

The filter to identify randomised controlled trials was taken from the Cochrane highly sensitive search strategy for MEDLINE as set out in Appendix 5b of the Cochrane Handbook for Systematic Reviews of Interventions (version 4.2.4, updated March 2005) (Higgins 2005).

1. randomized controlled trial.pt.

2. controlled clinical trial.pt.

3. exp Randomized Controlled Trials/

4. exp Random Allocation/

5. exp Double-Blind Method/

6. exp Single-Blind Method/

7. clinical trial.pt.

8. Clinical Trial/

9. (clin$ adj trial$).ab,ti.

10. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ab,ti.

11. exp PLACEBOS/

12. placebo$.ab,ti.

13. random$.ab,ti.

14. exp Research Design/

15. or/1-14

16. (animals not humans).sh.

17. 15 not 16

18. (carbamazepine or tegretol).tw.

19. exp Carbamazepine/

20. 18 or 19

21. exp Epilepsy/

22. exp Seizures/

23. (epilep$ or seizure$ or convuls$).tw.

24. 21 or 22 or 23

25. 17 and 20 and 24

Appendix 3. Summary tables of included studies

Aldenkamp 1987

ObjectiveMethodQuality assessmentParticipants
2

RCT, cross-over single blind, participants blinded.

Each arm of at least 1 month duration IR CBZ versus CR CBZ.

Outcome measures to assess cognitive side effects:

- 15-word Test: Verbal memory

- Complex Figure Test: Nonverbal memory

- Stroop Word Colour Test: Attention

- WISC-R maze: Concentration

- Perceptual Speed: Visual scanning ability

Tests to assess performance related to fluctuations in serum CBZ level:

- Tapping Task: Motor speed

- Corsi’s Block Tapping Test: Memory span

- Computerised Visual Searching Task: Visual-spatial information processing

No follow up beyond completion

Compliance not assessed

Randomisation stated but method unclear

Concealment of allocation unclear

Blinding: tablets administered in same tablet form and dose frequency

Not analysed as intention-to-treat

11 patients with a diagnosis of epilepsy. Partial in 8, generalised in 2, multifocal in 1

5 male, 6 female

Age (mean) 32.1

Age (range) 16-58

Mean age of onset of epilepsy 11.6 years (range birth-25)

Patients treated with CBZ for at least 1 year

Non-medication control group for cognitive testing standards was matched to epilepsy group for sex, age, educational level

 

Interventions/protocolResultsOther

Patients randomised to receive either CR or IR CBZ in same tablet form and dose frequency.

400mg CBZ given bd at 9.00AM and 7.00PM.

At a non-specified day during the study period, the psychological tests were administered 6 hourly.

The non-medication control group followed the same test scheme for 1 day.

 

Summary:

CR CBZ produced overall increases in performance over IR in the following tests:

- 15 word test (direct and delayed recall) for verbal memory

- Complex figure test (recall) for non-verbal memory

- Stroop Colour Word Test for attention

- Perceptual speed for visual scanning ability

CR CBZ produced superior results in all tests assessing differences in performance relating to fluctuations in serum level:

- Tapping task (dominant and non-dominant hands) for motor speed

- Corsi’s Block Tapping Test for memory span

- Computerised Visual Searching Task for visual-spatial information processing

 

 

Browne 1985

ObjectiveMethodQuality assessmentParticipants
2

RCT cross-over

56-day treatment arms, no washout period.

Double blind including participant, but unclear whether outcome assessor or the clinician responsible for patients care is blinded.

Relevant outcomes include seizure frequency recorded continuously in a diary and adverse events assessed periodically during interim follow-up appointments.

No follow up beyond study completion reported.

Compliance was assessed.

Randomisation stated, method unclear

Concealment of allocation unclear

Participants blinded. Study is double blind but unclear whether outcome assessor or the clinician responsible for patients care is blinded

Not analysed as ‘intention to treat’

 

Patients diagnosed with partial or generalised epilepsy prescribed monotherapy with CBZ 200 mg tablets either tds or qds in a stable regimen for at least 3 months

No more than 3 seizures in each of the 3 months prior to enrolment

101 patients enrolled, 87 completed both arms

Both groups were statistically comparable. Mean age group 1 was 34, group 2 was 32 years

 

Interventions/protocolResultsOther

During the 21-day run-in period patients continued their usual regimen of IR CBZ.

Day 22: patients were randomised to receive either IR or CR CBZ at their usual daily dose. Group 1: IR CBZ given every 12 hours plus placebo. Group 2: CR given every 12 hours plus placebo.

Day 78: patients were crossed over to alternate arm, no washout period mentioned. 

Mean CBZ dose 1084 mg (range 400-2000).

No change in pattern of seizure frequency observed overall during both arms. 74% during CR and 77% during IR, the seizure rate did not exceed that at baseline.

 Mean monthly seizure rate 0.53 during CR, 0.41 during IR. Statistical significance is not reached.

Adverse events:

- CR: 4 patients reported 6 adverse events, dizziness, (2) diplopia, headache, nausea and vomiting.

- IR: 5 patients reported 5 adverse events, dizziness, drowsiness, hand tremor, stomach cramps and vomiting.

No adverse events were clinically significant or required discontinuation of therapy.

96% of patients were compliant at any study visit.

 

 

Canger 1990

ObjectiveMethodQuality assessmentParticipants
2

RCT double blind, cross-over.

CBZ monotherapy at individualised doses for 1-month study period following 2-month dose finding phase.

No washout period stated.

Compliance was assessed prior to the study and non-compliant patients excluded.

Relevant outcomes include seizure frequency recorded continuously in a seizure diary, and side effects assessed by direct enquiry according to a form.

 

Randomised, method unclear

Concealment of allocation unclear

CBZ formulations were indistinguishable in taste and physical appearance

Outcome assessor blinded to treatment

Not analysed as intention to treat

48 patients, 21 male, 27 female

Treated with CBZ monotherapy for 3 months or greater with inadequate seizure control or intermittent side effects

Exclusion criteria: oto-vestibular disease or poor pre-study compliance

Age: mean 34.2, range 18-64 years

No withdrawals

2 generalised, 46 partial seizures

Duration of epilepsy mean: 17.7 range: 1.5-44

CBZ daily dose (mg) mean: 1.125, range: 400-2.400

   

Interventions/protocolResultsOther

Each period of cross over consisted of a 2-month optimal dose finding phase. The dose was altered to reach the highest best tolerated in patients with seizures or lowest effective dose in patients with side effects.

The 1-month maintenance phase was used for statistical analysis during which the dose was not altered.

Seizure frequency was recorded throughout the maintenance phase in a seizure diary.

Side effects were checked by direct enquiry according to a form assessing the most common effects. In addition, at the end of each period a global evaluation of tolerability was assessed.

 

CBZ total daily dose (mg) significantly (P=0.001) higher with CR CBZ: 1558.3±735.7 versus IR 1310.4±481.7.

CR CBZ had significantly reduced number of administrations. 38 patients managed a bd regimen compared to 15 on IR (P=0.001)

Mean monthly seizure frequency was significantly reduced with CR: 6.3±9.8 versus 9.3±15.6 (P=0.013)

6 patients reported intermittent side effects with CR whereas 26 reported with IR (P=0.001)

Global evaluation of tolerability significantly better in CR CBZ group (P=0.001).

 

 

Garnett 1998

ObjectiveMethodQuality assessmentParticipants
2

RCT cross-over, double blind

2 weeks each arm

Dose was according to existing CBZ therapy. Patients were assigned to 800, 1200 or 1600mg/day.

Relevant outcomes:

Incidence of adverse events

Seizure frequency

No follow up beyond study completion.

Compliance was assessed.

Randomisation stated, method unclear

Concealment of allocation: Identical capsules used and covered in powder and packaged in identical blister packs. Placebo tablets appeared the same and were packaged in the same blister packs

Double blind: participant and outcome assessor

Not analysed as intention to treat

Adult patients with a diagnosis of epilepsy prescribed IR CBZ at a stable and therapeutic dose for at least 30 days

24 patients were included. 1 patient was excluded from pharmacokinetic analysis due to blood sampling problems

Mean age: 36.1±8.1 (range 21-54) years

13 F 11 M

CBZ dose (mg)

800: 9 patients

1200: 9 patients

1600: 6 patients

Interventions/protocolResultsOther

CBZ dose was determined according to patients pre-study dose: either 800, 1200 or 1600mg was administered. If a change was required the dose was kept the same for 30 days prior to starting the study.

IR CBZ was divided into 4 doses/day.

CR CBZ was divided into 2 doses/day.

Placebo tablets were used during the CR CBZ arm.

The occurrence of seizures and adverse events was recorded throughout the study periods. Method not stated.

No patient was withdrawn from the study because of increased seizure frequency or adverse events.

Mean number of seizures during the study periods:

CR CBZ: 2.8±6.2

IR CBZ: 1.6±3.9

However, 2 patients reported over half the total number of seizures.

1 adverse event, somnolence, was reported during the IR CBZ treatment period.

Compliance was assessed by pill counts and was of a high level and similar for both groups.

Concomitant use of additional AEDs was allowed but the dosing remained constant.

9 patients received concomitant AEDs.

 

 

Kaski 1991

ObjectiveMethodQuality assessmentParticipants
2

RCT cross-over.

Baseline period for 2 months, each treatment arm 10 weeks long.

Daily CBZ dose kept the same as prior to study.

Seizure frequency is the single relevant outcome, recorded by experienced nurses both day and night. Participants remained in the institution for the duration of the study.

No follow up beyond study completion.

Randomisation stated but method unclear

Concealment of allocation: IR CBZ, CR CBZ and placebo tablets looked identical

Participants blinded but unclear whether outcome assessor or clinician responsible for participants care is blinded

Mentally retarded patients px CBZ at a therapeutic serum level for at least 2 months and with at least 4 seizures per month despite therapy were eligible

21 patients enrolled, 1 withdrawn

Mean age: 24.9±10.3 (range 6-38) years

11 F, 9 M

18 patients experienced secondary generalised, and 2 primary generalised seizures

Mean CBZ dose: 780.0±370.8 mg

 

Interventions/protocolResultsOther

2 10-week arms followed 2-month baseline period where usual CBZ treatment was given: IR was divided into 3 daily doses, CR was divided into 2 daily dosages with 1 placebo tablet.

Tablets were taken at the same times during both arms.

No washout period.

Seizure frequency was recorded by experienced nurses both day and night. Participants remained in the institution for the duration of the study.

 

 

1 patient was withdrawn due to appendicitis.

Mean total number of epileptic seizures were equivalent:

CR: 44.0

IR: 42.7.

Over time there was a significant trend for less seizures during CR CBZ (P=0.01).

During last 2 weeks of therapy, seizure frequency was significantly lower during CR CBZ (P=0.02).

There were no significant differences between the mean totals for different types of seizure. 

This trial involved mentally retarded patients, only 2 of which were prescribed CBZ monotherapy.

Many patients were prescribed additional non-antiepileptic medications.

 

McKee 1991

ObjectiveMethodQuality assessmentParticipants
1

RCT, cross-over.

Study period: 8 weeks, 4 weeks in each arm.

Patients stabilised on maximally tolerated doses of CBZ monotherapy for 3 months minimum. Previous attempts at increasing the dose resulted in neurotoxic adverse events.

Relevant outcomes:

Seizure frequency

Incidence of cognitive adverse effects.

No follow up beyond study completion.

Compliance was assessed by a tablet count following the study.

Randomisation stated, method unclear

Participant and outcome assessor blinded

Concealment of allocation is unclear

Not analysed as intention to treat

Adult patients with an existing diagnosis of epilepsy

25 patients were included. 9 reported generalised seizures, 16 complex partial

12 M, 13 F

Age range: 18-53 years

4 patients were excluded from analysis: 3 did not comply with the protocol and 1 experienced inadequate seizure control during the IR CBZ phase

Mean CBZ dose: 1076mg

Range: 600-2000mg

Interventions/protocolResultsOther

Patients continued to take their usual CBZ dose for 3-month baseline period during which seizure frequency was recorded.

CR CBZ: taken twice daily with 2 placebo tablets in all patients.

IR CBZ: qds in 4, tds in 8 and bd in 1. Placebo tablets were given if required.

No mention of appearance of tablets.

Seizure frequency charts were completed throughout the trial.

Compliance was assessed following each treatment arm.

Cognitive function tests were performed at 1, 4 and 8 hours following the morning dose at baseline and following each treatment arm.

 

There were no differences in cognitive function between baseline and after 4 weeks treatment with IR CBZ. Reaction times using Leeds Psychomotor Tester were shorter after CR CBZ:

Mean time±SD after 1 hour:

IR CBZ: 0.51±0.19s

CR CBZ: 0.46±0.15s (P<0.01).

Mean time±SD after 4 hours:

IR CBZ: 0.49±0.15s

CR CBZ: 0.45±0.1s (P<0.05).

Adverse event scores were lower with CR CBZ at 1 hour:

8.7±7 with IR CBZ compared to 6.6±6.3 with CR CBZ  (P<0.05).

Seizure frequency was higher with CR CBZ:

2.8±1.2 with IR CBZ compared to 3.8±0.9 with CR CBZ (P<0.01).

However, control was not statistically worse than baseline.

Compliance was good following tablet counts.

Patients were prescribed CBZ monotherapy.

Concomitant medication is not stated.

Nag 1998

ObjectiveMethodQuality assessmentParticipants
1

RCT, parallel.

The length of the study period is not stated but final measurements are taken on the 20th day. It can be assumed this is the length of the study period.

For both CR and IR CBZ, the target dose administered was 200mg tds.

Relevant outcomes:

Incidence of adverse effects.

No follow up beyond study completion.

Compliance is mentioned in the method but has not been reported in the results.

Randomisation stated, method unclear

Concealment of allocation: drugs given in plastic containers to ensure compliance but no mention of drug appearance

This study can be considered unblinded

Not analysed as intention to treat

Adult patients with a new diagnosis of partial seizures with no previous prescription of AED therapy

20 patients were included. No withdrawals are mentioned.

IR CBZ group:

Mean age: 20.32±8.28

(range 16-34) years

3 F, 7 M

CR CBZ group:

Mean age: 22.48±9.23

(range 18-35) years

2 F, 8 M

Interventions/protocolResultsOther

CBZ doses in both groups given in increments:

100mg bd for 2 days

200mg bd for 2 days

200mg tds.

The drugs were given in plastic containers to ensure compliance.

There is no mention of placebo tablets or the appearance of the tablets themselves.

The occurrence of adverse events has been reported but there is no mention of how they were assessed.

4 patients reported adverse events in the IR CBZ group:

Sedation was present in 2

Diplopia/ataxia in 1

Skin rash in 1.

2 patients reported adverse events in the CR CBZ group:

Sedation in 1

Diplopia/ataxia in 1.

 

This study is unblinded and of small sample size.

Patients were not prescribed any other concurrent medication.

Discrepancies between results reported in text and that stated in tables.

 

Persson 1990

ObjectiveMethodQuality assessmentParticipants
1           

RCT, cross-over.

Study period: 2 month baseline followed by 3 months in each arm.

Adult patients with epilepsy with few or no seizures and with subjectively moderate to severe adverse events caused by IR CBZ were entered into the trial.

Relevant outcomes:

Seizure frequency

Incidence of adverse effects.

No follow up beyond study completion.

Compliance was not assessed.  

Randomisation performed by a computer program

Participant and outcome assessor blinded

Concealment of allocation was adequate: IR CBZ and CR CBZ tablets looked identical and were supplied in identical containers with appropriate labels

Not analysed as intention to treat

21 adult patients with epilepsy with few or no seizures and with subjectively moderate to severe adverse events caused by IR CBZ. 1 withdrew due to ataxia

9 M, 11 F

Age: Mean: 43.35±15.7 (range 20-69) years

Duration of epilepsy:

Mean: 17.7±14.4 (range 0.5-47)

4 patients interrupted treatment during IR CBZ due to adverse events but tolerated SR CBZ. 1 patient interrupted treatment during both arms due to adverse events

Mean CBZ dose: 682mg (range 300-1100mg)

 

Interventions/protocolResultsOther

Patients continued to take their usual CBZ dose for 2-month baseline period.

Total daily dose and dosing frequency was kept unchanged throughout study. There was no mention of placebo tablets.

Adverse events were assessed at monthly visits by the study investigators using the Questionnaire on Systemic Toxicity (STRS) and Neurotoxicity Rating Scales (NTRS). Mean values for each arm were used in the analysis.

Seizure frequency charts were completed throughout the trial and registered at each monthly visit.

 

 

1 patient withdrew during IR CBZ due to ataxia and did not continue. 

STRS mean total scores:

IR CBZ:   12.1±19.0

CR CBZ:  8.3±18.6 (P=0.09).

NTRS mean total scores:

IR CBZ:   80.3±66.2

CR CBZ:  47.2±39.5 (P=0.04).

NTRS + STRS mean total scores:

IR CBZ:   92.5±68.8

CR CBZ:  55.5±46.4 (P=0.04).

Statistically significant reductions in subscores for the occurrence of GI problems, disturbance of vision, speech and motor function, dizziness and headache.

Seizure frequency:

2.2 per patient during first month of IR CBZ

1.2 per patient during first month of CR CBZ.

No significant differences in mean seizure frequency per month.

11 patients preferred CR CBZ, 3 preferred IR CBZ, and 6 had no preference. (P=0.0176).   

9 patients were prescribed additional AEDs, the dose of which was unaltered throughout.

Concomitant medication is not stated.    

 

Reunanen 1990

ObjMethodQuality assessmentParticipants
2

RCT, cross-over.

2 weeks in each treatment arm with no washout period. IR CBZ versus CR CBZ.

Single blind: outcome assessor blinded.

Outcomes include clinical parameters such as total seizure incidence and total incidence of reported adverse effects. Data was recorded for these parameters throughout the study period.

No follow up beyond study completion reported.

Compliance not assessed.

Randomised, method unclear

Concealment of allocation unclear

Observer blinded to treatment, drugs were given in identical containers

Not analysed as intention to treat

21 patients diagnosed with epilepsy and experiencing simple or complex partial seizures, on stable CBZ therapy for at least 3 months

3 withdrawals

18 evaluated: 10 females, 8 males

Mean age: 42 (±10) years

Interventions/protocolResultsOther

CBZ given in identical containers during each 2-week study period.

Both controlled and immediate release were given at 12 hourly intervals.

Dose was kept the same as before the study. Mean: 644±200mg.

Throughout study period seizures and subjective adverse effects reported by patients were recorded. Dizziness, fatigue, movement disorders and visiual disturbance received ‘special attention’.

Patient preference was sought at the end of the study.  

Wilcoxons’s signed rank and McNemar’s tests were used to test the significance of differences between the treatment periods.

During immediate-release CBZ 12 generalised, 25 complex partial and 8 simple partial, totalling 56 seizures were recorded.

During controlled release CBZ, 2 generalised, 18 complex partial and 11 simple partial, totalling 31 seizures were recorded. The difference did not reach significance P=0.093.

Adverse effects were reported 12 times during CR and 19 times during IR CBZ.

Dizziness was reported 7 times during IR and once during CR, P=0.034.

12 patients reported no adverse effects during CR compared to 9 during IR.

Only 11 patients prescribed monotherapy.

 

Sivenius 1988

ObjectiveMethodQuality assessmentParticipants
2

RCT, cross-over,

2 weeks each arm.

Dose remained the same as prior to study.

Relevant outcomes:

Incidence of adverse effects

Seizure frequency.

No follow up beyond study completion.

Compliance was assessed.

Randomisation stated, method unclear

Concealment of allocation: drugs given in identical containers, no mention of appearance of drugs or inclusion of placebo tablets

This study can be considered unblinded

Analysed as intention to treat

Adult patients with a diagnosis of epilepsy prescribed CBZ monotherapy at a stable and therapeutic dose for 6 months minimum were eligible

24 patients were included. 2 excluded due to compliance issues, 1 due to protocol violation and 1 due to difficulties in analysis

Mean age: 36.9 (range 18-62) years

Mean CBZ dose (mg) 615.0 (range 300-1100)

9 F, 11 M

 

Interventions/protocolResultsOther

CBZ dose remained the same as prior to study.

IR CBZ was divided into 3 doses.

CR CBZ was divided into 2 doses.

The drugs were given in identical containers.

There is no mention of placebo tablets or the appearance of the tablets themselves.

The occurrence of seizures and adverse effects was recorded during the study periods. Method not stated. Special attention was paid to dizziness, fatigue and visual disturbance.

Patient preference was determined following study completion.

9 seizures during each treatment arm.

Fatigue was the most common adverse effect, occurring in 4 patients in each group. There was ‘practically no difference in adverse effects between the 2 treatment periods’.

50% of patients preferred CR CBZ

20% preferred IR CBZ

30% had no preference.

 

 

3 patients were prescribed other non-antiepileptic medication.

This study is unblinded and of small sample size.

 

 

What's new

Last assessed as up-to-date: 5 September 2013.

DateEventDescription
5 September 2013New citation required but conclusions have not changedNo new trials identified. Conclusions remain the same.
5 September 2013New search has been performedSearches updated 5 September 2013.

History

Protocol first published: Issue 2, 2008
Review first published: Issue 1, 2010

DateEventDescription
21 July 2011New search has been performedSearches updated 21 July 2011; no new trials identified.

Contributions of authors

Graham Powell identified the studies, assessed their methodological quality, extracted the data and composed the review.

Matthew Saunders identified the studies, assessed their methodological quality and extracted the data.

Declarations of interest

None known

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aldenkamp 1987

MethodsMethods of randomisation and concealment of allocation not stated. Single blind, identical tablets and dose frequency
ParticipantsPatients with a diagnosis of partial or generalised epilepsy. 11 patients were enrolled and completed both study periods. Mean age: 32.1 (16-58) years
InterventionsBoth CR and IR CBZ administered as 400mg tablets twice daily. Order determined by randomisation
OutcomesIncidence of cognitive adverse events
Notes 

Browne 1995

MethodsMethods of randomisation and concealment of allocation not stated. Double blind, no further information given
ParticipantsPatients diagnosed with partial or generalised epilepsy prescribed monotherapy with CBZ 200mg tablets either tds or qds as a stable regimen for at least 3 months. Participants must not have had more than 3 seizures in each of the 3 months prior to enrolment. 101 patients enrolled, 87 completed both study arms. Mean age for group 1 was 34 years, group 2 was 32 years
InterventionsMonotherapy at usual daily dose with IR and CR CBZ, order determined by randomisation. Mean daily dose: 1084mg (range 400-2000mg)
Outcomes

Seizure frequency

Incidence of adverse events

Notes 

Canger 1990

MethodsMethods of randomisation and concealment of allocation not stated. Double blind, no further information given
ParticipantsAdult patients with epilepsy treated with CBZ monotherapy for at least 3 months with either inadequate seizure control or intermittent adverse events. 48 patients were enrolled and completed both study arms. Mean age: 34.2 (18-64) years
InterventionsMonotherapy with either CR or IR CBZ during each study arm. Optimal doses and frequencies of administration were determined over the initial 2 months of each study period. Mean daily dose: 1.125mg (400-2400mg)
Outcomes

Seizure frequency

Incidence of adverse events

Notes 

Garnett 1998

MethodsMethod of randomisation and concealment of allocation not stated. Double blind, identical capsules and blister packs
ParticipantsAdult patients with a diagnosis of epilepsy prescribed IR CBZ at a stable and therapeutic dose for at least 30 days. 24 patients were enrolled, 23 were included in the analysis. Mean age: 36.1 (21-54) years
InterventionsCBZ dose was determined according to pre-study dose. If a change was required the dose remained the same for 30 days prior to commencing the study. 9 patients were prescribed 800mg, 9 patients 1200mg and 6 patients 1600mg daily. IR CBZ was administered four times daily, CR CBZ twice daily with 2 placebo tablets
Outcomes

Seizure frequency

Incidence of adverse events

Notes 

Kaski 1991

MethodsMethod of randomisation and concealment of allocation not stated. Double blind, no further information given
ParticipantsMentally retarded patients prescribed CBZ at a therapeutic serum level for at least 2 months and with at least 4 seizures per month despite treatment. 21 patients enrolled, 20 patients completed both arms. Mean age 24.9 (6-38) years
InterventionsUsual daily CBZ dose divided into tds for IR CBZ and bd with placebo tablet for CR CBZ. Order determined by randomisation. Mean daily dose: 780mg
OutcomesSeizure frequency
Notes 

McKee 1991

MethodsMethod of randomisation and concealment of allocation not stated. Double blind: participant and outcome assessor
ParticipantsAdult patients with an existing diagnosis of partial or generalised epilepsy prescribed CBZ at a stable dose. 25 patients enrolled, 21 included in the final analysis Age range: 18-53 years
InterventionsIR CBZ either qds, tds or bd. CR CBZ bd. In all cases placebo tablets were included where necessary to total 4 tablets taken per day. Mean CBZ dose: 1076mg (600-2000mg)
Outcomes

Seizure frequency

Incidence of cognitive adverse events

Notes 

Nag 1998

MethodsMethods of randomisation and concealment of allocation not stated. Unblinded
ParticipantsAdult patients with a new diagnosis of partial seizures with no previous history of antiepileptic drug treatment. 20 patients were enrolled and completed the study period. IR CBZ group mean age: 20.32 (16-34) years. CR CBZ group mean age: 22.48 (18-35) years
InterventionsEither CR or IR CBZ treatment initiated in dose increments to a maximum of 200mg 3 times daily
OutcomesIncidence of adverse events
Notes 

Persson 1990

MethodsRandomisation performed by a computer program. Concealment of allocation unclear. Double blind: identical tablets and containers
ParticipantsAdult patients with epilepsy with few or no seizures treated with IR CBZ and experiencing moderate to severe adverse events. 21 patients were enrolled, 20 completed both study arms. Mean age: 43.35 (20-69) years
InterventionsParticipants continued to take their usual dose at the same dose frequency throughout study period and in both study arms. Treatment with IR and CR CBZ as monotherapy, order determined by randomisation. Mean CBZ dose: 682mg (300-1100mg)
Outcomes

Seizure frequency

Incidence of adverse events

Notes 

Reunanen 1990

MethodsMethod of randomisation and concealment of allocation not stated. Double blind, no further information given
ParticipantsPatients diagnosed with partial epilepsy and experiencing seizures prescribed a stable CBZ dose for at least 3 months. 21 patients enrolled, 18 completed both treatment arms. Mean age: 42 years
InterventionsBoth IR and CR CBZ were administered bd. Order determined by randomisation. Dose remained same as prior to study. Mean dose: 644mg
Outcomes

Total number of seizures

Total incidence of adverse events

Notes 

Sivenius 1988

MethodsMethod of randomisation and concealment of allocation not stated. Study unblinded
ParticipantsAdult patients with a diagnosis of epilepsy prescribed CBZ monotherapy at a stable, therapeutic dose for at least 6 months. 24 patients enrolled. 22 completed both study arms. Mean age: 36.9 (range 18-62) years
InterventionsCBZ dose remained same as prior to study. IR CBZ divided into 3 daily doses. CR CBZ divided into 2 daily doses. Mean daily dose: 615mg (300-1100mg)
Outcomes

Seizure frequency

Incidence of adverse events

Notes 

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bojinova 1997There was no mention of randomisation
Dam 1980Study not published in English. Translation will be sought for an update of this review
Dam 1981It is unclear whether a controlled-release preparation of CBZ was used. Further information will be sought and this study will be included in an update of this review, if eligible
Ghose 1983This study concerned dose frequency of IR CBZ
Jensen 1990This study involved a comparison of two CR CBZ preparations
Mirza 1998Observational study involving one treatment cohort without comparison group
Monaco 1984This study concerned dose frequency of IR CBZ
Pieters 1992There was no mention of randomisation
Ramsay 1989No relevant outcome measures were reported
Remy 1990Study not published in English. Translation will be sought for an update of this review
Scheuch 1992This study involved a comparison on two CR CBZ formulations
Sobaniec 2004This study compared CR CBZ to sodium valproate
Thakker 1991It is unclear whether a controlled-release preparation of CBZ was used. Further information will be sought and this study will be included in an update of this review, if eligible

Ancillary