Abstract
Background
Epilepsy is one of the most common neurological disorders worldwide, with an age‐adjusted prevalence of 4 to 8 per 1000 population and an age‐adjusted incidence of 44 per 100,000 person‐years in developed countries. Monotherapy represents the best therapeutic option in people with newly diagnosed epilepsy.
Objectives
To assess the efficacy and tolerability of oral clonazepam used as monotherapy for newly diagnosed epilepsy, when compared with placebo or a different anti‐seizure medication.
Search methods
The following databases were searched on 24 July 2018: the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) 1946 to 24 July 2018, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP).
Selection criteria
We included randomized controlled trials (RCTs) or quasi‐RCTs comparing oral clonazepam used as monotherapy treatment (where participants were randomized to treatment with a single drug throughout the study period) versus placebo or a different anti‐seizure medication (active comparator) in people of any age with newly diagnosed epilepsy, defined according to the clinical practical definition proposed by the International League Against Epilepsy (ILAE).
Data collection and analysis
The following outcomes were considered: proportion of participants seizure‐free at one, three, six, 12 and 24 months after randomization; proportion of responders (those with at least a 50% reduction in seizure frequency from baseline to end of treatment); proportion of participants with treatment‐emergent adverse events (TEAEs) during the treatment period or leading to discontinuation during the treatment period; proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons; and improvement in quality of life, as assessed by validated and reliable rating scales.
Two review authors independently screened all titles and abstracts to assess the eligibility of publications identified by the searches. They independently extracted data from trial reports and cross‐checked them for accuracy. Any disagreements between the two authors regarding data extraction were resolved by discussion and consensus. We scrutinized trials and evaluated the methodological quality of all included studies. We used GRADE assessment criteria to evaluate the certainty of the evidence.
Main results
Two randomized controlled trials were included, with a total of 115 participants. One study compared clonazepam to carbamazepine as monotherapy for participants with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy). One study (published as abstract) compared clonazepam to ethosuximide as monotherapy for children with absence seizures. Based on the available data and the details on methodology provided, we judged both studies as being at unclear or high risk of bias for the domains assessed.
In the study comparing clonazepam to carbamazepine, no difference was found between the groups regarding the proportion of participants who were seizure‐free at one month after randomization (risk ratio (RR) 1.97, 95% confidence interval (CI) 0.99 to 3.94; 30 participants; very low‐certainty evidence), three months after randomization (RR 1.19, 95% CI 0.62 to 2.29; 26 participants; very low‐certainty evidence), and six months after randomization (RR 0.50, 95% CI 0.09 to 2.73; 9 participants; very low‐certainty evidence). No statistical difference was found between clonazepam and carbamazepine in terms of proportion of participants with TEAEs leading to discontinuation (RR 2.61, 95% CI 0.80 to 8.52; 36 participants; very low‐certainty evidence) and in terms of dropouts/withdrawals due to side effects, lack of efficacy or other reasons (RR 1.56, 95% CI 0.61 to 4.02; 36 participants; very low certainty evidence). The study did not provide any information on our other prespecified outcomes of interest.
The study comparing clonazepam to ethosuximide did not provide any data on efficacy. The proportion of dropouts/withdrawal was higher in the group receiving clonazepam compared to the group receiving ethosuximide (RR 3.63, 95% CI 1.12 to 11.74; 79 participants; very low‐certainty evidence). No information on other outcomes of interest was provided in this study.
Authors' conclusions
There is only limited and very low‐certainty evidence from randomized controlled trials on the efficacy and tolerability of clonazepam used in monotherapy for the treatment of epilepsy. No difference in efficacy and tolerability was found in a small trial comparing clonazepam to carbamazepine for the treatment of mesial temporal lobe epilepsy. Clonazepam was less well tolerated than ethosuximide in a trial of children with absence seizures, however no comparative data on efficacy were provided. There is currently insufficient evidence to support the use of clonazepam as monotherapy treatment for epilepsy.
Plain language summary
Clonazepam used as single antiepileptic drug to treat people with newly diagnosed epilepsy
Background
Monotherapy (treatment with a single medication) is the best option to treat people with newly diagnosed epilepsy. Clonazepam is a type of medication which can reduce the number of epileptic seizures; it is from a group of medications known as benzodiazepines. We searched electronic databases, with the aim of combining the results from all well‐conducted studies on the topic to determine how effective clonazepam is at reducing the number of seizures in people with newly diagnosed epilepsy.
Study characteristics
We identified only two small trials comparing clonazepam with a different drug in two different epileptic syndromes, mesial temporal lobe epilepsy (the most common and well‐defined focal epilepsy with seizures originating in the internal part of the temporal lobe of the brain) and absence seizures (generalized seizures causing lapses of awareness). In the study conducted in mesial temporal lobe epilepsy, clonazepam was compared to carbamazepine (an antiepileptic drug used to treat focal epilepsy). In the study on absence seizures, clonazepam was compared to ethosuximide (a medication used to treat absence seizures).
Key results
We judged both studies as being of poor quality. The studies did not follow the participants for long enough, and the total of participants was too low to draw definite conclusions on the role of clonazepam used in monotherapy. Results on tolerability were not reported consistently across the studies.
No differences were found between clonazepam and carbamazepine in the proportion of seizure‐free participants; however, this does not mean that clonazepam and carbamazepine have the same efficacy, as the lack of difference can be due to the small number of people included.
The study comparing clonazepam with ethosuximide provided no results on efficacy. No differences were found between the two medications in terms of tolerability. However, the proportion of people who dropped out or withdrew from the study due to side effects, lack of efficacy or other reasons was higher in the clonazepam group compared to the ethosuximide group.
Certainty of the evidence
So far, the evidence on the efficacy and tolerability of clonazepam used as a single antiepileptic drug for the treatment of epilepsy is scarce and of very low certainty; hence insufficient to base decisions on its use in monotherapy.
Summary of findings
Background
Description of the condition
Epilepsy is "a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures" (Fisher 2005). According to the practical definition proposed by the International League Against Epilepsy (ILAE) in 2014, epilepsy can be diagnosed in "any of the following conditions: (1) at least two unprovoked (or reflex) seizures occurring > 24 hours apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome" (Fisher 2014).
Epilepsy is one of the most common neurological disorders worldwide, with an age‐adjusted prevalence in developed countries of 4 to 8 per 1000 population (Hauser 1991), and an age‐adjusted incidence of 44 per 100,000 person‐years (Hauser 1993). In low‐ and middle‐income countries its incidence is generally higher, ranging from 100 to 190 per 100,000/year (Sander 1996). It affects people of any age, and in adulthood its incidence and prevalence increase with age (Hauser 1993).
Monotherapy represents the best therapeutic option in people with newly diagnosed epilepsy, and the choice of the initial antiepileptic drug should take into account the person's seizure type and epilepsy syndrome, age, childbearing potential, comorbidities, medical history, tolerability and risk of drug interactions (Perucca 2011).
In this review we investigated the efficacy and tolerability of clonazepam used as monotherapy in people with newly diagnosed epilepsy.
Description of the intervention
Clonazepam, or 5‐(2‐chlorophenyl)‐7‐nitro‐1,3‐dihydro‐1,4‐benzodiazepin‐2‐one, is a drug with anxiolytic and antiepileptic properties. It is rapidly absorbed from the gastrointestinal tract, with an oral bioavailability that is almost complete (more than 85%) and time to peak levels after a single oral dose of one to four hours (Trinka 2016). Clonazepam is extensively bound to plasma proteins (86%) and has no active metabolite. The drug is highly lipophilic, which enables a rapid cross of the blood‐brain barrier, resulting in a rapid onset of action. Clonazepam is eliminated by nitroreduction and has an elimination half‐life of 17 to 55 hours in healthy adults not taking enzyme inducing agents (Trinka 2016).
Clonazepam has a broad‐spectrum efficacy against many seizure types, both generalized and focal, including absences (Sato 1977; Trinka 2016; Wheless 2005). It is particularly effective against myoclonic seizures occurring in different epilepsy types, including progressive myoclonic epilepsies (Browne 1976; Livanainen 1982; Obeso 1995‐1996). Clonazepam is mainly used as an add‐on treatment, but has been proven to be effective also when used in monotherapy. In particular, a paediatric study conducted in 60 children with epilepsy other than infantile spasms, showed that clonazepam monotherapy led to clinical seizure cessation in 71% of the participants with generalized seizures and 89% of focal seizures; the drug was well tolerated, with adverse effects (mainly drowsiness and ataxia) reported in 5% of children (Ishikawa 1985).
Common or clinically relevant adverse events related to clonazepam use include behavioural disorders (irritability, aggressive behaviour, hyperactivity), drowsiness, ataxia, sedation, cognitive dysfunction, and drooling (Browne 1978; Trinka 2016). Adverse effects occur in up to 50% of people treated with this drug (Browne 1978; Trinka 2016), and in some cases may improve after dose reduction and over time due to tolerance. Intolerable adverse effects have been reported in approximately 20% of people with epilepsy (Browne 1978; Keränen 1983).
How the intervention might work
Clonazepam belongs to the drug class of benzodiazepines. Benzodiazepines enhance the binding of the gamma‐aminobutyric acid (GABA) to the GABA‐A receptors, increasing channel opening frequency; this leads to increased chloride conductance and neuronal hyperpolarization, and eventually to enhanced inhibitory neurotransmission and antiepileptic action (Trinka 2016).
Why it is important to do this review
Due to its antiepileptic properties, clonazepam could show promise as monotherapy; monotherapy represents the gold standard of treatment in newly‐diagnosed epilepsy and is preferred over add‐on therapy particularly in this group of people who are not refractory to other treatments.
We planned to comprehensively search and critically assess the scientific literature on the clinical role of oral clonazepam used as monotherapy treatment for people with newly diagnosed epilepsy. In particular, we wanted to evaluate whether high‐quality randomized controlled trials assessing the efficacy and tolerability of this drug are available.
Objectives
To assess the efficacy and tolerability of oral clonazepam used as monotherapy for newly diagnosed epilepsy, when compared with placebo or a different anti‐seizure medication.
Methods
Criteria for considering studies for this review
Types of studies
We included randomized controlled trials (RCTs) or quasi‐RCTs comparing oral clonazepam used as monotherapy treatment (i.e. where participants were randomized to treatment with a single drug throughout the study period) versus placebo or a different anti‐seizure medication (active comparator) in people of any age with newly diagnosed epilepsy, defined according to the clinical practical definition proposed by the ILAE (Fisher 2014). We did not include RCTs assessing the role of clonazepam as treatment of status epilepticus.
We included only RCTs of parallel or cross‐over designs, excluding uncontrolled and non‐randomized trials. We did not exclude trials on the basis of dose, duration of treatment, or length of follow‐up.
Types of participants
We included people with newly diagnosed epilepsy of any type (Scheffer 2016) — defined as two or more unprovoked seizures or a single unprovoked seizure and high risk of seizure recurrence (Fisher 2014) — regardless of sex, age, or ethnicity.
Types of interventions
Clonazepam monotherapy at any dosage versus placebo or a different anti‐seizure drug (active comparator). We also included dose controlled studies (i.e. multiple‐arm trials assessing clonazepam at different dosages).
Types of outcome measures
Primary outcomes
Proportion of participants seizure‐free at one, three, six, 12 and 24 months after randomization
Proportion of responders (defined as those who experienced at least a 50% reduction in seizure frequency from baseline to end of treatment)
-
Proportion of participants with treatment‐emergent adverse events (TEAEs)
during the treatment period
leading to discontinuation during the treatment period
We assessed seizure freedom and proportion of responders both for all seizure types and for specific seizure type (e.g. myoclonic, absence, tonic, atonic, tonic‐clonic, and focal seizures).
For each outcome, we planned to perform an intention‐to‐treat (ITT) primary analysis to include all participants in the treatment group to which they were allocated, irrespective of treatment actually received. We planned to use ITT data in the analysis for all randomly assigned participants recorded during the entire treatment period, including both titration and evaluation phases.
Secondary outcomes
Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons (we used this as a measure of global effectiveness)
Improvement in quality of life, as assessed by validated and reliable rating scales
Search methods for identification of studies
Electronic searches
We searched the following databases on 24 July 2018.
Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), using the search strategy shown in Appendix 1
MEDLINE (Ovid) 1946 to 24 July 2018, using the search strategy shown in Appendix 2
ClinicalTrials.gov, using the search strategy shown in Appendix 3
WHO International Clinical Trials Registry Platform (ICTRP), using the search strategy shown in Appendix 4
Searching other resources
We also did the following.
Handsearched the references quoted in the identified trials
Contacted pharmaceutical companies (Roche) to identify unpublished trials or data missing from articles
Contacted authors and known experts to identify any additional data
Handsearched relevant conference proceedings (American Academy of Neurology (AAN), ILAE)
We did not impose any language restrictions on our searches, and we attempted to obtain translations of retrieved articles where necessary.
Data collection and analysis
Although we planned to perform several data analyses (reported in detail in the review protocol), we did not use most of them due to the small number of studies and data.
Selection of studies
Two review authors (FB, SL) independently screened all titles and abstracts to assess the eligibility of publications identified by the searches. We excluded publications that did not meet the criteria at this stage. After screening, we assessed the full text of potentially eligible citations for inclusion. We listed studies that initially appeared to meet the inclusion criteria but then we later excluded in the Characteristics of excluded studies table. We collated multiple reports of the same study so that each study, rather than each report, was the unit of interest in the review. We also provided any information we could obtain about ongoing studies. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram (Liberati 2009). We resolved any disagreement through discussion.
Data extraction and management
Two review authors (FB and SL) independently extracted data from trial reports onto standardized forms, and cross‐checked them for accuracy. We resolved any disagreement regarding data extraction by discussion and consensus between the review authors.
We extracted the following trial data.
Main study author and age of publication
Total number and demographics of participants for each group (age, sex, weight, height, body mass index, number of seizures in the past three months, number of seizures in the past 12 months, epilepsy duration, type of seizures)
Intervention details (study design; inclusion and exclusion criteria; description of study phases with details on starting and target dose, titration, and length of each phase; primary and secondary endpoints)
Trial methods (method of generating random list; method of concealing randomization; blinding methods)
Definitions of ITT/full analysis, safety, and per‐protocol population adopted in each study
Proportion of participants achieving seizure freedom at one, three, six, 12 and 18 months after randomization in each group
Proportion of responders (those who experienced at least a 50% reduction in seizure frequency from baseline to end of treatment)
Proportion of participants with TEAEs during the treatment period in each group
Proportion of participants with TEAEs leading to discontinuation during the treatment period in each group
Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons
Improvement in quality of life
Assessment of risk of bias in included studies
We scrutinized trials and evaluated the methodological quality of all included studies. Two review authors (FB and SCI) assessed the risk of bias of each trial according to the approaches described in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement regarding data extraction by discussion and consensus between the review authors.
For each study, we evaluated the following characteristics and assigned a judgement of low, high or unclear risk of bias.
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data addressed
Selective reporting (reporting bias)
Other bias, including outcome reporting bias
Measures of treatment effect
We used statistical methods in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), to measure treatment effect.
We planned to use mean differences (MDs) with 95% confidence intervals (CIs) for continuous data (improvement in quality of life, as assessed by validated and reliable rating scales) where we found data provided as means and standard deviations (SDs). Alternatively, if possible, we planned to calculate these data by using conventional statistical formulae. In the event of different quality of life scales, we planned to combine the different scales and present results as standardized mean differences (SMDs). No continuous data were found in the present review, and hence the planned method was not used.
We analyzed dichotomous data by calculating risk ratios (RRs) for each trial with the uncertainty in each trial being expressed using 95% CIs. For individual adverse effects we used 99% CIs to allow for multiple testing. The outcomes that we analyzed as dichotomous data are: (1) proportion of participants seizure free at one, three, six, 12 and 18 months after randomization; (2) proportion of responders (those who experienced at least a 50% reduction in seizure frequency from baseline to end of treatment); (3) proportion of participants with treatment‐emergent adverse events (TEAEs) during the treatment period; (4) proportion of participants with TEAEs leading to discontinuation during the treatment period; and (5) proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons.
Both for dichotomous and continuous data, we planned to calculate a pooled treatment effect across trials; however, due to lack of information and small number of studies we did not do this.
Unit of analysis issues
For any unit of analysis issues, we planned to deal with them using the guidance in theCochrane Handbook (Higgins 2011). We planned to analyze multiple‐armed trials as follows: in the event of dose‐controlled studies with only one control group (i.e. two or more different doses of clonazepam versus control) we planned to "include each pair‐wise comparison separately, but with shared intervention groups divided out approximately evenly among the comparisons" (Higgins 2011), in order to overcome a unit of analysis error. We planned to analyze randomized cross‐over studies in meta‐analyses using the results from paired analyses (Elbourne 2002). However, due to lack of information and small number of studies we did not use these planned methods.
Dealing with missing data
For individual missing data, such as information on dropout or losses to follow‐up, we planned to carry out an ITT analysis, using as the denominator the total number of people who underwent randomization. However, due to lack of information and the small number of studies we did not use this planned method.
Assessment of heterogeneity
We did not implement our planned methods to assess heterogeneity, due to the small number of studies included. Details on assessment of heterogeneity are provided below.
We planned to visually inspect the forest plots to investigate the possibility of statistical heterogeneity. We planned to evaluate statistical heterogeneity using the I2 statistic, which provides an estimate of the percentage of variability due to heterogeneity rather than a sampling error (Higgins 2003). We planned to interpret the level of heterogeneity using I2 according to theCochrane Handbook, as follows: 0% to 40%: might not be important; 30% to 60%: moderate heterogeneity; 50% to 90%: substantial heterogeneity; 75% to 100%: considerable heterogeneity (Higgins 2011).
We planned to combine trial outcomes to obtain a summary estimate of effect (and the corresponding CIs) using a fixed‐effect model, unless there was considerable heterogeneity (that is, I2 greater than 75%). If there was substantial heterogeneity we planned to explore the factors contributing to heterogeneity. If there was substantial heterogeneity that could not readily be explained, we planned to use a random‐effects model. We planned to supplement homogeneity among trial results using a standard Chi2 test and we rejected the hypothesis of homogeneity if the P value was less than 0.10. We planned to assess possible sources of heterogeneity (for example, clinical, methodological or statistical heterogeneity) by using sensitivity analysis as described below.
Assessment of reporting biases
We planned to use a funnel plot to detect reporting biases if sufficient studies (more than 10) were available. We planned to analyze possible sources of funnel plot asymmetry (e.g. publication bias, language bias, citation bias, poor methodological quality, true heterogeneity, etc.) according to the trials. However, due to lack of information and small number of studies we did not use this planned method.
Data synthesis
Provided we thought it clinically appropriate, and no considerable clinical and methodological heterogeneity was found, we planned to synthesize the trial results in a meta‐analysis. We planned to use the Mantel‐Haenszel method for analyzing dichotomous data, and inverse variance for continuous data. However, due to lack of information and small number of studies we did not synthesize the study results in a meta‐analysis.
Subgroup analysis and investigation of heterogeneity
We planned to perform subgroup analysis to separately assess RCTs conducted in paediatric and adult populations, and to assess different doses and lengths of treatment. However, due to lack of information and small number of studies we did not use this planned method.
Sensitivity analysis
In the case of residual unexplained heterogeneity, we planned to evaluate the robustness of the results of the meta‐analysis by comparing fixed‐effect and random‐effects model estimates, removing trials with low methodological quality (i.e. studies with inadequate allocation concealment or lack of blinded outcome assessor). If the conclusions we observed were unchanged, then we would have considered the evidence to be robust. We did not use this method, due to the small number of studies included.
We also planned to use the worst‐case and best‐case scenarios for taking into account missing data, however again we were unable to implement these methods.
Summarizing and interpreting results
The 'Summary of findings' table for each comparison includes information on overall quality of the evidence from the trials and information of importance for healthcare decision‐making. We used the GRADE approach to determine the quality of evidence for each outcome, on the basis of an evaluation of five criteria for RCTs (risk of bias, inconsistency, indirectness, imprecision, publication bias) (Schunemann 2011). If we had serious concerns regarding one of the five criteria, we downgraded the evidence from 'high quality' by one level; if we had very serious concerns we downgraded the evidence by two levels. We used these assessments to guide our conclusions and recommendations.
We used GRADEpro GDT software (GRADEpro GDT 2015), and imported data from Review Manager 5 to create 'Summary of findings' tables for each comparison included in the review for the following primary outcomes (Review Manager 2014).
Proportion of participants seizure‐free at 12 and 24 months after randomization
Proportion of responders (those who experienced at least a 50% reduction in seizure frequency from baseline to end of treatment)
Proportion of participants with treatment‐emergent adverse events (TEAEs) during the treatment period
Proportion of participants with TEAEs leading to discontinuation during the treatment period
Results
Description of studies
We included two randomized controlled trials in the review. One study (Mikkelsen 1981) compared clonazepam to carbamazepine as monotherapy for participants with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy). One study (Sato 1977) compared clonazepam to ethosuximide as monotherapy for children with absence seizures.
The results of Mikkelsen 1981 were published as a full‐length article, whereas those of Sato 1977 were provided as abstract.
Results of the search
The search strategy mentioned above returned 155 records (70 through CRS Web, 75 through MEDLINE, 7 from ClinicalTrials.gov, 3 from the WHO ICTRP), resulting in 77 records after 42 duplicates and 36 irrelevant items were removed. After title and abstract screening, we retrieved six full articles. Of these, we further excluded three records (see Excluded studies). Despite our efforts, we were unable to retrieve the abstract and full‐length report of one study (Miyasaka 1977), which was hence listed among studies awaiting classification (Studies awaiting classification). See Figure 1.
1.
Study flow diagram
Included studies
The first study was a randomized‐controlled trial conducted in 36 previously untreated patients with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy); it compared clonazepam to carbamazepine (Mikkelsen 1981). Patients with progressive brain diseases, presenile dementia, liver and kidney disease and pregnant women were excluded. The study randomly allocated 17 participants to clonazepam and 19 to carbamazepine. After two weeks of titration (further details were not provided), participants received either 6 mg clonazepam or 900 mg carbamazepine, each divided into three daily doses (maintenance dose). In participants younger than 18 years and with a body weight lower than 60 kg, carbamazepine was given at the dose of 15 mg/kg. Dose adjustments were possible “only in agreement with the department”. Occurrence of psychomotor seizures (corresponding to focal seizures with impaired awareness) or grand mal seizures (corresponding to generalized tonic‐clonic seizures) was recorded daily by the participants. The occurrence of headache, dizziness, impaired memory, and irritability was assessed after two weeks, and at one, two, four and six months. The mean age of the 36 included participants (14 males, 22 females) was 22.3 years (range: 6 to 72 years), and the median body weight was 60.5 kg (range: 23.3 kg to 97.5 kg). The median duration of epilepsy was 1.7 years (range: 0 to 10 years), and the median number of seizures per month at baseline was 3.5 (range: 0.5 to 20) in the carbamazepine group and 3.8 (range: 0.4 to 30) in the clonazepam group. At baseline, 7 out of 17 participants in the clonazepam group and 2 out of 19 in the carbamazepine group had experienced grand mal seizures.
The second included study was an RCT which compared clonazepam to ethosuximide for the treatment of children with absence seizures (Sato 1977). The study included 79 children (25 males, 54 females) with absence seizures, aged 5 to 16 years. The study was described as “double‐blind” (no further details were provided), and it lasted 17 weeks. In the study, 43 participants were assigned to clonazepam and 36 to ethosuximide; 30 of the participants in the clonazepam group, and 33 of those in the ethosuximide group, completed the study.
Excluded studies
In total we excluded three studies. One article was excluded as it assessed clonazepam as an add‐on treatment (Dahlin 2000); one was excluded because it did not assess the clinical efficacy of clonazepam, but only its effect on epileptiform discharges (Mitsudome 1997); and the last study was excluded because it was not an RCT (Yamatogi 1997). Two expert neuropaediatrics and one expert adult neurologist (Acknowledgements) were contacted by mail (on 26 September 2018 and 8 December 2018) for information on ongoing trials; they kindly replied that they were not aware of any ongoing trial.
Studies awaiting classification
Despite our efforts, we were unable to retrieve the abstract and full‐length report of one study published in 1977 (Miyasaka 1977). According to the title, this study, which is currently listed in Studies awaiting classification, assessed the efficacy of clonazepam compared with nitrazepam in a double blind cross‐over trial conducted in patients with psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy). Should we continue to be unable to contact the study authors in future updates of this review, we will add this as an excluded study.
Risk of bias in included studies
See: Figure 2.
2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Neither of the included studies described the process of random sequence generation or allocation concealment, and so we rated both as being at unclear risk of bias. The studies did not provide enough information to judge whether the baseline characteristics were balanced between treatment groups.
Blinding
Although Mikkelsen 1981 was described as “double‐blind”, it is not clear whether and how this was achieved. The study authors report only that “administration of drugs and clinical examination were performed by two persons to ensure double‐blind conditions” (Mikkelsen 1981). It is unclear whether the two interventions (carbamazepine and clonazepam) were identical. Sato 1977 did not specify blinding.
Incomplete outcome data
Both studies reported the number but not the reasons for participant exclusions or missing data in both intervention arms. We therefore rated them as having a high risk of bias for this domain.
Selective reporting
No protocol was available for either study. We considered that the more clinically relevant outcomes in Mikkelsen 1981 were reported (low risk of reporting bias). No data on efficacy were provided in Sato 1977, so we decided there is a high risk of reporting bias.
Other potential sources of bias
No other bias was detected.
Effects of interventions
Summary of findings for the main comparison. Clonazepam compared to carbamazepine for treating people with newly diagnosed epilepsy.
| Clonazepam compared to carbamazepine for treating people with newly diagnosed epilepsy | ||||||
| Patient or population: people with newly diagnosed epilepsy Setting: outpatients Intervention: Clonazepam Comparison: carbamazepine | ||||||
| Outcomes | Relative effect (95% CI) | Anticipated absolute effects* (95% CI) | Certainty of the evidence (GRADE) | Comments | ||
| Without Clonazepam | With Clonazepam | Difference | ||||
| Proportion of participants seizure‐free at 1 month after randomization № of participants: 30 (1 RCT) | RR 1.97 (0.99 to 3.94) | Study population | ⊕⊝⊝⊝ VERY LOW 1 | |||
| 36.8% | 72.6% (36.5 to 100) | 35.7% more (0.4 fewer to 108.3 more) | ||||
| Proportion of participants seizure‐free at 3 months after randomization № of participants: 26 (1 RCT) | RR 1.19 (0.62 to 2.29) | Study population | ⊕⊝⊝⊝ VERY LOW 1,2 | |||
| 53.3% | 63.5% (33.1 to 100) | 10.1% more (20.3 fewer to 68.8 more) | ||||
| Proportion of participants seizure‐free at 6 months after randomization № of participants: 9 (1 RCT) | RR 0.50 (0.09 to 2.73) | Study population | ⊕⊝⊝⊝ VERY LOW 1,2 | |||
| 66.7% | 33.3% (6 to 100) | 33.3% fewer (60.7 fewer to 115.3 more) | ||||
| Proportion of participants seizure‐free at 12 months after randomization ‐ not reported | ‐ | ‐ | ‐ | ‐ | ||
| Proportion of participants seizure‐free at 24 months after randomization ‐ not reported | ‐ | ‐ | ‐ | ‐ | ||
| Proportion of participants with treatment‐emergent adverse events (TEAEs) during the treatment period ‐ not reported | ‐ | ‐ | ‐ | ‐ | In the only study included, all participants (except one receiving carbamazepine) had at least one side effect (no further details provided). The duration of side effects was generally short, without significant difference between clonazepam and carbamazepine for sedation, headache, dizziness, irritability and other complaints. | |
| Proportion of participants with treatment‐emergent adverse events (TEAEs) ‐ Leading to discontinuation during the treatment period № of participants: 36 (1 RCT) | RR 2.61 (0.80 to 8.52) | Study population | ⊕⊝⊝⊝ VERY LOW 1,2 | |||
| 15.8% | 41.2% (12.6 to 100) | 25.4% more (3.2 fewer to 118.7 more) | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio; | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect | ||||||
1 Study conducted in a very small population. No calculation of sample size was made. Very wide confidence intervals, indicative of imprecise results
2 High risk of attrition bias and reporting bias; unclear risk of selection and performance bias
Summary of findings 2. Clonazepam compared to ethosuximide for treating people with newly diagnosed epilepsy.
| Clonazepam compared to ethosuximide for treating people with newly diagnosed epilepsy | ||||||
| Patient or population: people with newly diagnosed epilepsy Setting: outpatients Intervention: clonazepam Comparison: ethosuximide | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with ethosuximide | Risk with Clonazepam | |||||
| Proportion of participants seizure‐free at 1 month after randomization | Outcome not reported | n/a | ||||
| Proportion of participants seizure‐free at 3 months after randomization | Outcome not reported | n/a | ||||
| Proportion of participants seizure‐free at 6 months after randomization | Outcome not reported | n/a | ||||
| Proportion of participants seizure‐free at 12 months after randomization | Outcome not reported | n/a | ||||
| Proportion of participants seizure‐free at 24 months after randomization | Outcome not reported | n/a | ||||
| Proportion of responders (those with at least a 50% reduction in seizure frequency from baseline to end of treatment) | Outcome not reported | n/a | ||||
| Proportion of participants with treatment‐emergent adverse events (TEAEs) during the treatment period | Outcome not reported | n/a | In the only study included, drowsiness and ataxia were common side effects and seemed dose‐related (no further details were provided). | |||
| Proportion of participants with TEAEs leading to discontinuation during the treatment period | Outcome not reported | n/a | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect | ||||||
Two comparisons were available: (1) clonazepam versus carbamazepine, and (2) clonazepam versus ethosuximide.
1. Clonazepam versus carbamazepine
Data on this comparison were provided in Mikkelsen 1981.
Primary outcomes
1.1. Proportion of participants seizure‐free at one month after randomization
The duration of treatment differed considerably among study participants. Furthermore, only 17 out of 19 participants in the carbamazepine group and 11 out of 17 in the clonazepam group were treated for longer than 30 days (one month). Among these, eight in the carbamazepine group and seven in the clonazepam group were seizure‐free. No statistical difference was found between the groups (RR 1.97, 95% CI 0.99 to 3.94; 1 study, 30 participants); Analysis 1.1. We downgraded the certainty of the evidence from 'high' to 'very low' for serious risk of attrition bias and imprecision of effect estimates.
1.1. Analysis.
Comparison 1 Clonazepam versus carbamazepine, Outcome 1 Proportion of participants seizure‐free at 1, 3 and 6 months after randomization.
1.2. Proportion of participants seizure‐free at three months after randomization
The duration of treatment differed considerably among study participants. Furthermore, only 15 out of 19 participants in the carbamazepine group and 11 out of 17 in the clonazepam group were treated for longer than 90 days (three months). Among these, eight in the carbamazepine group and seven in the clonazepam group were seizure‐free. No statistical difference was found between the groups (RR 1.19, 95% CI 0.62 to 2.29; 1 study; 26 participants); Analysis 1.1. We downgraded the certainty of the evidence from 'high' to 'very low' for serious risk of attrition bias and for imprecision of effect estimates.
1.3. Proportion of participants seizure‐free at six months after randomization
The duration of treatment differed considerably among study participants. Furthermore, only 6 out of 19 participants in the carbamazepine group and 3 out of 17 in the clonazepam group were treated for longer than 180 days (six months). Among these, four in the carbamazepine group and one in the clonazepam group were seizure‐free. No statistical difference was found between the groups (RR 0.50, 95% CI 0.09 to 2.73; 1 study; 9 participants); Analysis 1.1. We downgraded the certainty of the evidence from 'high' to 'very low' for serious risk of attrition bias and for imprecision of effect estimates.
1.4. Proportion of participants seizure‐free at 12 months after randomization
Data on this outcome were not provided.
1.5. Proportion of participants seizure‐free at 24 months after randomization
Data on this outcome were not provided.
2. Proportion of responders (those with at least a 50% reduction in seizure frequency from baseline to end of treatment)
Data on this outcome were not provided.
3. Proportion of participants with treatment‐emergent adverse events (TEAEs) during the treatment period or leading to discontinuation during the treatment period
The study reported that except for one participant receiving carbamazepine, all participants had at least one side effect during the study period. The duration of side effects was generally short, and no significant difference was found between clonazepam and carbamazepine in terms of sedation, headache, dizziness, irritability and other complaints. Three out of 19 participants in the carbamazepine group discontinued the treatment because of mental disturbances (one participant) or exanthema (two participants). In the clonazepam group, 7 out of 17 participants discontinued the drug due to mental disturbances (2), ataxia and mental disturbances (2), dizziness (1) or impotence and sedation (1). No statistical difference was found between the groups (RR 2.61, 95% CI 0.80 to 8.52; 1 study; 36 participants); Analysis 1.2. We downgraded the certainty of the evidence from 'high' to 'very low' for serious risk of attrition bias and for imprecision of effect estimates.
1.2. Analysis.
Comparison 1 Clonazepam versus carbamazepine, Outcome 2 Proportion of participants with treatment‐emergent adverse events (TEAEs).
Secondary outcomes
1. Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons
Seven participants allocated to clonazepam were withdrawn during the study, all of them for adverse effects. In the carbamazepine group, five participants were withdrawn (three for adverse effects, one for seizure worsening, and one because the treatment was found to be "superfluous"). No statistical difference was found between the groups (RR 1.56, 95% CI 0.61 to 4.02; 1 study; 36 participants); Analysis 1.3.
1.3. Analysis.
Comparison 1 Clonazepam versus carbamazepine, Outcome 3 Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons.
2. Improvement in quality of life
Data on this outcome were not provided.
2. Clonazepam versus ethosuximide
Data on this comparison were provided in Sato 1977.
Primary outcomes
1.1. Proportion of participants seizure‐free at one month after randomization
Data on this outcome were not provided.
1.2. Proportion of participants seizure‐free at three months after randomization
Data on this outcome were not provided.
1.3. Proportion of participants seizure‐free at six months after randomization
Data on this outcome were not provided.
1.4. Proportion of participants seizure‐free at 12 months after randomization
Data on this outcome were not provided.
1.5. Proportion of participants seizure‐free at 24 months after randomization
Data on this outcome were not provided.
2. Proportion of responders (those with at least a 50% reduction in seizure frequency from baseline to end of treatment)
Data on this outcome were not provided.
3. Proportion of participants with treatment‐emergent adverse events (TEAEs) during the treatment period or leading to discontinuation during the treatment period
Data on this outcome were not provided. The study authors reported only that drowsiness and ataxia were common side effects and seemed dose‐related. Withdrawal from clonazepam therapy was most commonly related to behavioural changes (i.e. hyperactivity, short attention span, and uninhibited and aggressive behavior) and occasionally to increased seizure frequency.
Secondary outcomes
1. Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons
Thirteen participants out of 43 in the clonazepam group did not complete the study (reasons were not provided); in the ethosuximide group, three out of 36 participants did not complete the study (reasons were not provided). The proportion of dropouts/withdrawal was higher in participants receiving clonazepam compared to participants receiving ethosuximide (RR 3.63, 95% CI 1.12 to 11.74; 1 study; 79 participants); Analysis 2.1. We downgraded the certainty of the evidence from 'high' to 'very low' for serious risk of attrition and reporting bias, and for imprecision of effect estimates.
2.1. Analysis.
Comparison 2 Clonazepam versus ethosuximide, Outcome 1 Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons.
2. Improvement in quality of life
Data on this outcome were not provided.
Discussion
Summary of main results
Data from RCTs available in the scientific literature on clonazepam monotherapy for epilepsy are scarce and of low quality. In this systematic review of the literature we did not find significant differences for most outcomes; furthermore, there were too little data to draw any conclusions on the role of clonazepam monotherapy for epilepsy. Clonazepam is usually considered as a therapeutic option to be used as adjunctive treatment in epilepsy, particularly for treating myoclonic seizures (Trinka 2016). Furthermore, as for any other benzodiazepine, the chronic use of clonazepam can be associated with tolerance, leading to reduced efficacy over time (Trinka 2016). This may partially explain the paucity of RCTs available in the literature so far.
Overall completeness and applicability of evidence
We identified only two RCTs on clonazepam used as monotherapy for treating epilepsy (Mikkelsen 1981; Sato 1977). Both studies were conducted several years ago. The studies assessed the efficacy and tolerability of this drug in two different epileptic syndromes, mesial temporal lobe epilepsy and absence seizures, and used different comparators (carbamazepine and ethosuximide, respectively). The results of one study were published as a full‐length article (Mikkelsen 1981), whereas those of the other were provided as abstract (Sato 1977).
Certainty of the evidence
Based on the available data and the details on methodology provided, we judged both studies as having unclear and high risk of bias for most domains. The length of follow‐up and the total number of participants were insufficient to draw definite conclusions on the efficacy of this drug used as monotherapy.
No statistical differences were found between clonazepam and carbamazepine in terms of the proportion of seizure‐free participants (Mikkelsen 1981). However, these results could be due to there being inadequate statistical power to detect a statistically significant and clinically relevant difference between the tested drugs, considering the low number of participants included and the wide confidence intervals which are indicative of imprecision of the results and limited data available.
In the GRADE assessment the certainty of the evidence for the individual outcomes on seizure‐freedom (at one, three and six month(s) after randomization) was downgraded by one level to reflect the fact that this study was subject to a high risk of attrition bias; the evidence was further downgraded for imprecision of the results. Overall, we judged the certainty of the evidence to be very low, which means that we have very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of effect.
Similarly, when assessing the certainty of the evidence for TEAEs leading to discontinuation, we downgraded the GRADE assessment by two levels to reflect the high risk of attrition bias and imprecision of the results. Therefore, we judged the certainty evidence for this outcome to be very low (i.e. the data do not provide a reliable indication of the likely effect; and the true effect is likely to be substantially different from the estimate of effect).
No data on efficacy in the comparison between clonazepam and ethosuximide were provided (Sato 1977).
No significant differences in tolerability were found between clonazepam and carbamazepine or ethosuximide, although again the negative results can be due to low statistical power, linked to imprecision of the results and limited data available). However, the proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons was higher in the clonazepam group compared to the ethosuximide group (Sato 1977). It should be noted, however, that in this study data on tolerability were not reported systematically. Accordingly, we downgraded our GRADE assessment of the certainty of the evidence for this outcome by two levels to reflect the high risk of attrition and reporting bias, and the imprecision of the results. Hence, we judged the certainty evidence for this outcome to be very low (i.e. the data do not provide a reliable indication of the likely effect; and the true effect is likely to be substantially different from the estimate of effect).
Potential biases in the review process
There were no potential biases during the review process.
Agreements and disagreements with other studies or reviews
In the literature there is currently no other systematic review assessing the efficacy and tolerability of clonazepam used as monotherapy for epilepsy.
Authors' conclusions
Implications for practice.
The current evidence from randomized controlled trials on the efficacy and tolerability of clonazepam used in monotherapy for the treatment of epilepsy is scarce and of very low quality. No difference in efficacy and tolerability was found in a small trial comparing clonazepam to carbamazepine for the treatment of mesial temporal lobe epilepsy. Clonazepam was less well tolerated than ethosuximide in a trial conducted in children with absence seizures, but no comparative data on efficacy were provided. So far, there is insufficient evidence to support the use of clonazepam as monotherapy treatment for epilepsy.
Implications for research.
Further adequately powered randomized controlled trials are required to provide data on the efficacy and tolerability of clonazepam as monotherapy for epilepsy. However, it is unlikely that such studies will be conducted, as benzodiazepines — including clonazepam — are not considered as monotherapy antiepileptic drugs in epilepsy. However, this belief is not substantiated by high‐quality evidence, but is mainly based on clinical experience. Hence, the role of clonazepam used as monotherapy for treating people with newly diagnosed epilepsy remains to be clarified in clinical research.
Acknowledgements
We thank Dr Ronit Pressler (Great Ormond Street Hospital, London, UK), Dr Hans Hartmann (Clinic for Pediatric Kidney, Liver and Metabolic Disorders, Hannover Medical School, Hannover, Germany), and Prof Eugen Trinka (Department of Neurology, Christian‐Doppler‐Klinik, Paracelsus Medical University, Salzburg, Austria) for kindly replying to the mail we sent them to obtain information on any ongoing trials on clonazepam monotherapy in epilepsy.
We, and the Cochrane Epilepsy Group, are grateful to the following peer reviewers for their time and comments: Richard Appleton, Sarah Moore and Sarah Nevitt.
This review was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Epilepsy Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service (NHS) or the Department of Health.
Appendices
Appendix 1. Cochrane Register of Studies (CRS Web) search strategy
1. MeSH DESCRIPTOR Clonazepam Explode All AND CENTRAL:TARGET
2. (Antilepsin or Chlonazepam or Cloazepam or Clonazepam* or Clonex or Clonopin or Iktorivil or Klonopin or Kriadex or Landsen or Paxam or Petril or Ravotril or Rivatril):AB,KW,MC,MH,TI AND CENTRAL:TARGET
3. #1 OR #2 AND CENTRAL:TARGET
4. ((adjunct* or "add‐on" or "add on" or adjuvant* or combination* or polytherap*) not (monotherap* or alone or singl*)):TI AND CENTRAL:TARGET
5. #3 NOT #4 AND CENTRAL:TARGET
6. MESH DESCRIPTOR Epilepsy EXPLODE ALL AND CENTRAL:TARGET
7. MESH DESCRIPTOR Seizures EXPLODE ALL AND CENTRAL:TARGET
8. (epilep* OR seizure* OR convuls*):AB,KW,MC,MH,TI AND CENTRAL:TARGET
9. #6 OR #7 OR #8 AND CENTRAL:TARGET
10. #5 AND #9 AND CENTRAL:TARGET
Appendix 2. MEDLINE (Ovid) search strategy
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 or pragmatic clinical trial).pt. or (randomi?ed 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$).tw.
10. 7 or 8 or 9
11. exp *Pre‐Eclampsia/ or exp *Eclampsia/
12. 10 not 11
13. exp Clonazepam/
14. (Antilepsin or Chlonazepam or Cloazepam or Clonazepam$ or Clonex or Clonopin or Iktorivil or Klonopin or Kriadex or Landsen or Paxam or Petril or Ravotril or Rivatril).tw.
15. 13 or 14
16. 6 and 12 and 15
17. exp *anxiety disorders/ or exp *mood disorders/ or exp *"schizophrenia and disorders with psychotic features"/ or exp *Alcohol‐Related Disorders/
18. 16 not 17
19. ((adjunct$ or "add‐on" or "add on" or adjuvant$ or combination$ or polytherap$) not (monotherap$ or alone or singl$)).ti.
20. 18 not 19
21. remove duplicates from 20
Appendix 3. ClinicalTrials.gov search strategy
Interventional Studies | Epilepsy | Clonazepam
Appendix 4. ICTRP search strategy
Condition: epilepsy
Intervention: clonazepam
Recruitment status: All
Phases: 2, 3, 4
Data and analyses
Comparison 1. Clonazepam versus carbamazepine.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Proportion of participants seizure‐free at 1, 3 and 6 months after randomization | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Seizure freedom at 1 month after randomization | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.97 [0.99, 3.94] |
| 1.2 Seizure freedom at 3 months after randomization | 1 | 26 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.62, 2.29] |
| 1.3 Seizure freedom at 6 months after randomization | 1 | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.5 [0.09, 2.73] |
| 2 Proportion of participants with treatment‐emergent adverse events (TEAEs) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Leading to discontinuation during the treatment period | 1 | 36 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.61 [0.80, 8.52] |
| 3 Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons | 1 | 36 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.56 [0.61, 4.02] |
Comparison 2. Clonazepam versus ethosuximide.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons | 1 | 79 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.63 [1.12, 11.74] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Mikkelsen 1981.
| Methods | Randomized‐controlled trial comparing clonazepam to carbamazepine in previously untreated participants with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy) | |
| Participants | 36 previously untreated participants (14 males, 22 females) with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy) Mean age of the 36 included participants was 22.3 years (range: 6 years to 72 years) Median body weight was 60.5 kg (range: 23.3 kg to 97.5 kg) Median duration of epilepsy was 1.7 years (range: 0 years to 10 years) Median number of seizures per month at baseline was 3.5 (range: 0.5 to 20) in the carbamazepine group and 3.8 (range: 0.4 to 30) in the clonazepam group Seventeen participants allocated to clonazepam and 19 to carbamazepine |
|
| Interventions | Clonazepam versus carbamazepine Two weeks of titration (details not provided) Maintenance: 6 mg clonazepam or 900 mg carbamazepine, each divided into three daily doses. In participants younger than 18 years and with a body weight lower than 60 kg, carbamazepine was given at the dose of 15 mg/kg. Dose adjustments were possible “only in agreement with the department”. |
|
| Outcomes | Occurrence of psychomotor seizures (corresponding to focal seizures with impaired awareness) or grand mal seizures (corresponding to generalized tonic‐clonic seizures) was recorded daily by the participants. Occurrence of headache, dizziness, impaired memory, and irritability was assessed after 2 weeks, and at 1, 2, 4 and 6 months. |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No information provided |
| Allocation concealment (selection bias) | Unclear risk | No information provided |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No information provided |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No information provided |
| Incomplete outcome data (attrition bias) All outcomes | High risk | This study reported the number but not the reasons for participant exclusions or missing data in both intervention arms. |
| Selective reporting (reporting bias) | Low risk | No protocol was available. We considered that the more clinically relevant outcomes were reported. |
Sato 1977.
| Methods | Randomized controlled trial comparing clonazepam to ethosuximide for the treatment of children with absence seizures | |
| Participants | Seventy‐nine children (25 males, 54 females) with absence seizures, aged 5 to 16 years Forty‐three participants assigned to clonazepam and 36 to ethosuximide |
|
| Interventions | Clonazepam (dose not reported) versus ethosuximide (dose not reported) | |
| Outcomes | Not explicitly reported. Data on adverse effects are provided; no data on efficacy are provided | |
| Notes | This trial was available as an abstract only | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No information provided |
| Allocation concealment (selection bias) | Unclear risk | No information provided |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No information provided |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No information provided |
| Incomplete outcome data (attrition bias) All outcomes | High risk | This study reported the number but not the reasons for participant exclusions or missing data in both intervention arms. |
| Selective reporting (reporting bias) | High risk | No data on efficacy (a clinically relevant outcome) were provided. |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Dahlin 2000 | Clonazepam not used in monotherapy |
| Mitsudome 1997 | This study did not assess the clinical efficacy of clonazepam, but only its effect on epileptiform discharges. |
| Yamatogi 1997 | This study was not randomized |
Differences between protocol and review
In the "Summary of findings table" we provided data on short‐term efficacy outcomes, and not only those on the long‐term time points as prespecified for inclusion in the protocol.
Contributions of authors
Francesco Brigo and Simona Lattanzi selected the studies for possible inclusion and extracted data. Francesco Brigo wrote the review. Stanley C Igwe and Nicola L Bragazzi critically revised it.
Sources of support
Internal sources
No sources of support supplied
External sources
National Institute for Health Research (NIHR), UK.
Declarations of interest
FB: has received speaker's honoraria and travel support from Eisai and UCB Pharma. He has also acted as a consultant for EISAI. SCI: none known. NLB: none known. SL: none known.
New
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