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

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Abstract

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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% in the developed world (Hauser 1993).

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 drug 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 review questions were investigated.
(1) For newly diagnosed patients commencing CBZ, how do IR and CR formulations compare for efficacy and tolerability?
(2) For patients on established treatment with IR CBZ but experiencing unacceptable adverse events, what is the effect on seizure control and the tolerability of a switch to a CR formulation versus remaining on the IR formulation?

Search methods

We searched the Cochrane Epilepsy Group Specialized Register (10 November 2014), Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO) 11 November 2014, and MEDLINE (Ovid, 1946 to 11 November 2014).

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 of patients 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 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. The trials 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 the increase was 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, had 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.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Plain language summary

Fast‐release versus slow‐release carbamazepine as medication for patients with epilepsy

Background

Epilepsy is a common brain disorder that is often treated with carbamazepine. With treatment, people often have fewer seizures but many people experience harms or side effects. When carbamazepine is swallowed it is taken into the blood stream quickly and there is a sharp rise of drug levels in the blood. These 'peaks' may be associated with side effects such as dizziness, drowsiness and poor co‐ordination. A type of carbamazepine that releases the medication into the body slowly may lessen these 'peaks' in the blood levels, possibly meaning fewer side effects.

This review compared studies looking at the differences between a 'fast‐release' carbamazepine and a 'slow‐release' carbamazepine.

Participants

To be included in this review, all participants had to be diagnosed with epilepsy and be either just starting carbamazepine treatment or be already on it but with too many side effects. The participants could be any age or gender.

Studies

An initial search was carried out in September 2009 for relevant studies. Ten trials with a total of 296 people with epilepsy were included in the review. All 10 trials were randomised controlled trials (patients were compared in randomly assigned groups). All of the studies had at least two groups, one group taking fast‐release carbamazepine and one group taking slow‐release carbamazepine, and some also had a control group (a group of non‐epileptic people). The searches were updated in July 2011, September 2013 and November 2014, however no new trials were found.

Results

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.

Quality of the evidence

Out of the 10 trials in the review, only one was judged to use good methods, and so the evidence in this review was rated as low quality. It must be stressed that there are not many studies assessing the differences between these two carbamazepine types and more studies are needed before we can make a definitive conclusion about one over the other.

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 small, had poor methodological quality, and possessed a high risk of bias. In addition, this conclusion has been reached following a narrative analysis, which is 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.

Background

Description of the condition

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% in the developed world (Hauser 1993).

Description of the intervention

In the treatment of epilepsy, carbamazepine (CBZ) is one of the first‐line antiepileptic drugs and is of proven efficacy when 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.

How the intervention might work

These adverse events can occur during peaks in plasma concentration 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.

Why it is important to do this review

In this review we have summarised evidence from randomised controlled trials assessing immediate‐release and controlled‐release CBZ in patients with epilepsy. Through assessing the intended effects, including reduction in seizure frequency, and unintended effects, including adverse drug reactions, we aimed to inform clinical decision making in this population.

Objectives

To determine the efficacy of immediate‐release CBZ (IR CBZ) versus controlled‐release CBZ (CR CBZ) in patients diagnosed with epilepsy.

The following review questions were investigated.
(1) For newly diagnosed patients commencing CBZ, how do IR and CR formulations compare for efficacy and tolerability?
(2) For patients on established treatment with IR CBZ but experiencing unacceptable adverse events, what is the effect on seizure control and tolerability of a switch to a CR formulation versus remaining on the IR formulation?

Methods

Criteria for considering studies for this review

Types of studies

(1) Randomised controlled trials (RCTs) comparing IR CBZ to CR 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 could 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 IR CBZ or commencing monotherapy with CR CBZ; or
(2) currently prescribed monotherapy with IR CBZ but experiencing unacceptable adverse events and were being switched to a CR CBZ formulation.

Types of interventions

The intervention group should have received a CR formulation of CBZ and the control group a standard, IR formulation of CBZ.

Types of outcome measures

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

Primary outcomes
Objective 1: analysis of newly diagnosed patients

(1) Time to 12‐month remission

Objective 2: analysis of patients with established epilepsy

(1) Proportion seizure free at six months

Secondary outcomes
For objective 1: analysis of newly diagnosed patients

(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

For objective 2: analysis of patients with established epilepsy

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

Search methods for identification of studies

We carried out searches as follows.

Electronic searches

Searches were run for the original review in September 2009 and subsequent searches were run in July 2011 and September 2013. For the latest update (November 2014) we searched the following databases. There were no language restrictions.

(a) Cochrane Epilepsy Group Specialized Register (10 November 2014) using the search terms (carbam?zepine OR tegretol) AND INREGISTER AND >4/09/2013:CRSCREATED.

(b) Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), 11 November 2014, using the search strategy outlined in Appendix 1.

(c) MEDLINE (Ovid, 1946 to 11 November 2014) using the strategy outlined in Appendix 2.

Searching other resources

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 a future update of this review.

Data collection and analysis

Selection of studies

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 these studies according to pre‐specified selection criteria. Any disagreement concerning eligibility for inclusion was resolved by discussion and a consensus decision made.

Data extraction and management

Two review authors (GP, MS) independently extracted the data and recorded relevant information on a standardised data extraction form. The extracted 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.

Assessment of risk of bias in included studies

Two review authors (GP, MS) independently assessed the methodological quality of all the included studies and recorded their findings on the standardised form. Important aspects of methodology were noted: study design, type of control, method and 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 methodological factors for each study.

Two review authors (GP, MS) independently made an assessment of the risk of bias for each trial using the Cochrane 'risk of bias' tool as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We discussed and resolved any disagreements. We rated studies as high, low or unclear for six domains applicable to RCTs: randomisation method, allocation concealment, blinding methods, incomplete outcome data, selective outcome reporting and other sources of bias. We intended to create 'summary of findings' tables and use the GRADE approach for assessing quality of evidence, however this was not appropriate due to the discrepancy between the outcomes of interest in the protocol and the reviewed studies.

Measures of treatment effect

For time‐to‐event data we did not plan to undertake a meta‐analysis using aggregate data, rather we planned to summarise the 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 the review. Similarly, quality of life data were summarised in the text and tables.

Unit of analysis issues

We included crossover trials as well as parallel group trials in the review. However, there were no unit of analysis issues as we could not combine any of the data from the included studies in a meta‐analysis. All findings from the included studies were reported narratively.

Dealing with missing data

We did not seek missing data from the study authors due to the time period when the majority of studies were published. However, contact may be made prior to an update of this review.

Assessment of heterogeneity

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 recruited patient populations 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.

Assessment of reporting biases

Due to the age of the papers, protocols were not requested from the authors. To assess outcome reporting bias we used the ORBIT tool (Kirkham 2010). We originally intended to examine funnel plots to establish any publication bias, however this was not possible.

Data synthesis

No meta‐analyses were carried out, all results were discussed narratively. Comparisons we expected to investigate included:

  1. IR versus CR on time to 12‐month remission;

  2. IR versus CR on proportion seizure free at six months.

Other comparisons included IR versus CR on all secondary outcomes (see Types of outcome measures).

Subgroup analysis and investigation of heterogeneity

We stratified the comparisons made by type of participant, that is newly diagnosed patients and established epilepsy patients.

Sensitivity analysis

No sensitivity analyses were planned.

Results

Description of studies

Results of the search

Searching of the databases as described in Search methods for identification of studies yielded 1963 records, and two additional records were identified from other sources. After the removal of duplicates (861), the remaining 1104 records were screened for potential inclusion: 1081 were excluded for irrelevance. The following assessment for eligibility excluded another 13 (see Figure 1 and Characteristics of excluded studies for reasons of exclusion) leaving a total of 10 to be included in the review. None were included in a meta‐analysis.


Study flow diagram.

Study flow diagram.

Included 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); 20 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 the 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 that were 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 event occurrence.

Excluded studies

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; Ghose 1983; Monaco 1984; 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.

Risk of bias in included studies

See Figure 2 for a summary of the risk of bias in each included study. We allocated each study an overall rating for the risk of bias. One study in this review was rated as low risk of bias (Persson 1990), two as high risk of bias (Nag 1998; Sivenius 1988) and the remainder as unclear risk of bias. See below for specific domain ratings. Across all studies we rated the evidence as unclear risk of bias.


Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

In all trials we rated allocation concealment as unclear risk of bias as the trials did not provide clear methods. For the domain of sequence generation, all except one (Persson 1990) were rated as unclear risk of bias as they did not provide details on the methods used, although all stated that randomisation had been performed. Persson 1990 was rated as low risk of bias due to the use of a computer program for patient randomisation.

Blinding

Four studies were rated as high risk of bias for the blinding domain due to the fact that they were open trials (Nag 1998; Sivenius 1988) or single‐blind (Aldenkamp 1987; Reunanen 1990). The remaining eight trials were adequately blinded, involving identical tablets and packaging.

Incomplete outcome data

All studies in this review were rated as low risk of attrition bias as in each study the number of patients randomised but not included in the analysis was determined not to be significant. Therefore, despite some not reporting missing data, or not carrying out intention‐to‐treat analysis, there were deemed to be no issues with attrition bias.

Selective reporting

Study protocols were not requested due to the time period in which the majority of the studies were published. All but one study (Sivenius 1988) was rated as low risk of bias for this domain. We applied the ORBIT classification system to this study and rated it 'A' due to its lack of reporting analysed adverse effect data; therefore this study was rated as high risk of bias for selective reporting.

Other potential sources of bias

Four studies were rated as unclear risk of bias in this category due to quoting financial support from Ciba‐Geigy Pharmaceuticals, Intas Pharmaceuticals, Shire Pharmaceuticals, all of which produce CR carbamazepine based medications (Browne 1995; Garnett 1998; McKee 1991; Nag 1998).

Effects of interventions

A narrative summary follows concerning the 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 that involved 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 in 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 involvement 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 of the studies 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 those on 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 co‐ordination (3) were experienced during IR CBZ treatment. Dizziness (1), fatigue (4), visual disturbance (2), headache (2), difficulty with co‐ordination (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

Summary of main results

Ten trials were included in this review. All were primarily concerned with comparisons of the pharmacokinetic parameters of IR CBZ and CR CBZ.

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 low 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 have described 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, which was 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, which 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 crossover trial included the largest study sample, 101 patients, and had one of the longest study periods, with 56 days in each treatment arm. Our 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.

Overall completeness and applicability of evidence

For the first objective of this review, the comparison in newly diagnosed patients, only one study fitted the criteria specified in our protocol. Therefore, the evidence for this conclusion is lacking without other studies to support it.

For the second objective, the comparison in patients with established epilepsy, only one study showed any significant difference in seizure frequency between the two groups, with patients in the CR group experiencing a lower mean monthly seizure frequency. In the remaining seven studies that reported seizure frequency there was no significant difference between the two groups. For adverse events, however, five studies reported a significant reduction in named or all adverse events for those patients on CR carbamazepine, with a further two studies reporting the same but without stating significance. The remaining three studies noted no significant differences between adverse events in the two groups.

Quality of the evidence

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.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.