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Cochrane Database of Systematic Reviews Protocol - Intervention

Diazepam monotherapy for epilepsy

Authors' declarations of interest

Version published: 05 December 2014 Version history

https://doi.org/10.1002/14651858.CD011416

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view the current version 25 June 2021
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy and tolerability of diazepam as monotherapy for the treatment of partial‐onset seizures or generalised tonic‐clonic epilepsy in children and adults in comparison to placebo or any other drug (in monotherapy or combination therapy).

Background

Description of the condition

Epilepsy is one of the most common neurological disorders in the world and is characterised by unprovoked seizures as a result of abnormal and excessive discharge of sets of neurons in the brain without any identifiable cause. Epilepsy accounts for a significant global burden of disease (Sander 1996), and the medical cost of epilepsy in terms of direct (costs incurred for diagnosis and treatment of epilepsy) and indirect costs (lost or reduced earnings and production due to a person being affected by epilepsy including losses of a similar nature incurred by their care‐givers) is quite high. A systematic review on epilepsy health costs in Europe estimated the cost to be 15.5 billion euros in 2004, the majority of them being indirect costs (Pugliatti 2007). A study from India has reported that the total cost per patient with epilepsy amounts to $344 per year which is equivalent to 88% of the mean per capita income in India (WHO 2012). The mean prevalence of epilepsy is estimated to be 0.52% in Europe, 0.68% in the USA and as high as 1.5% in developing nations (Strzelczyk 2008). In 2011, it was estimated to affect about 65 million people globally (Thurman 2011).

Up to 3% of the population is given a diagnosis of epilepsy at some point of their lives. Most of these people go into remission but up to 30% do not respond to monotherapy (Cockerell 1995; Hauser 1993), and often require the use of newer antiepileptic drugs (AEDs) or combination therapies . Newer AEDs as well as combination therapies are costlier than monotherapy and have their own set of adverse drug reaction profiles. Epilepsy is a heterogeneous clinical condition. Seizure types and epilepsy syndromes that determine the choice of therapy as well as prognosis are determined primarily on clinical grounds along with definite roles for electroencephalograms (EEG), and laboratory and radiographic investigations. No single AED is perfect for any particular seizure type/epilepsy syndrome and choice, as well as dosing regimens, have to be individualised based on additional patient factors (age, gender, co‐morbidities, preferences), other co‐prescriptions, cost and the potential for adverse events.

Description of the intervention

Gamma‐aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA‐A and GABA‐B are two classes of receptors for GABA and are found on almost all cortical neurons (Macdonald 2002). Diazepam is the prototype of the class of AEDs named benzodiazepines. Benzodiazepines act by influencing the binding of GABA to GABA‐A receptors. At therapeutic doses, diazepam acts by increasing the frequency of opening of the GABA‐activated chloride (Cl‐) channels, but at higher doses GABA can cause substantial reduction of sustained high‐frequency firing of neurons. Diazepam has a relatively low fractional occupancy to the binding sites and thus acts as an agonist shifting the GABA concentration‐response curve to the left and thereby increasing the amount of current produced by activation of GABA‐A receptors.

Diazepam can be administered orally, intravenously, intramuscularly, per rectally and even intranasally. When administered orally, diazepam is rapidly absorbed and has a fast onset of action. The time to reach peak plasma concentration after drug administration (tmax) is 30 to 90 minutes for oral use and 10 to 60 minutes for rectal use (Patsalos 2014). Diazepam undergoes oxidative metabolism by demethylation and the main active metabolite of diazepam is des‐methyldiazepam. Diazepam has a biphasic half‐life of about one to three days, and two to seven days for the active metabolite des‐methyldiazepam (Riss 2008).

Cognitive impairment, drowsiness, lethargy, and cardiovascular and respiratory depression (particularly on intravenous usage or when used in conjunction with other drugs with similar effects) are the principal adverse effects of diazepam, which limits its use in clinical practice. Tolerance and withdrawal symptoms are also other limitations of the drug.

How the intervention might work

Diazepam was synthesised in the 1960s (as an improvement on the first benzodiazepine to be designed, chlordiazepoxide) by Leo Sternbach (Baenninger 2004). The use of diazepam for acute epileptic attacks began soon after, perhaps solely based on its pharmacokinetic (i.e. absorption, distribution, and excretion of a drug and its metabolites) and pharmacodynamic (i.e. the biological effects of a drug on the body and its mechanism of action) properties (Baenninger 2004). While the costlier and seemingly more promising newer AEDs are being made available to the armoury of clinicians, diazepam, the prototypical benzodiazepine with its well‐understood adverse event profile may provide a viable alternative particularly in low‐ and middle‐income nations due to the cost factor. This is despite the theoretical pharmacokinetic shortcomings such as short duration of action and the potential for adverse outcomes such as sedation and respiratory depression. Diazepam provides some clinical advantages such as rapid onset of action, high efficacy rates, broad spectrum of activity and ease of administration through various routes in addition to the cost advantages (Riss 2008).

Why it is important to do this review

The National Institute for Health and Care Excellence (NICE, UK), in its 2004 guidelines, predicted increased costs for the treatment of epilepsy owing to the trends of prescribing newer and more expensive drugs (NICE 2004). As predicted, five newer and more expensive drugs had been licensed for use in the UK by 2012 (NICE 2012). Diazepam, the prototypical benzodiazepine, is an inexpensive drug that can be administered via various routes, has a broad spectrum of activity and a rapid onset of action. Its role in the management of convulsive status epilepticus (Prasad 2005), and in‐hospital acute tonic‐clonic convulsion (Appleton 2008), is well defined. Diazepam, however, has a short half‐life and concerns have been raised over the potential of benzodiazepines to cause drug‐related withdrawal symptoms and seizure recurrence (NICE 2012). Concerns have also been raised about the potential of drug tolerance and incidences of adverse outcomes such as sedation and respiratory depression with benzodiazepines (Norris 1999). To the best of our knowledge, the efficacy and tolerability of diazepam as a monotherapy has not been evaluated in a systematic review and a Cochrane review would help define the role of diazepam monotherapy in people with epilepsy.

Objectives

To assess the efficacy and tolerability of diazepam as monotherapy for the treatment of partial‐onset seizures or generalised tonic‐clonic epilepsy in children and adults in comparison to placebo or any other drug (in monotherapy or combination therapy).

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi‐RCTs. We will include cross‐over trials . We do not anticipate finding any cluster‐randomised trials on this topic. Section on Unit of analysis issues provides further explanation on this.

Types of participants

Children or adults with partial‐onset seizures or generalised‐onset tonic‐clonic seizures. The therapy may have been instituted after a new diagnosis of epilepsy, a relapse following AED withdrawal or after failure of other therapies. We will not include people with status epilepticus or acute tonic‐clonic seizures in this review.

Types of interventions

Diazepam monotherapy versus placebo or another AED in monotherapy or combination (including diazepam‐containing combination therapy).

Types of outcome measures

Primary outcomes

  • Proportion of people withdrawn from allocated therapy.

Time to withdrawal from allocated therapy is the outcome measure has been recommended by the Commission on Antiepileptic Drugs of the International League Against Epilepsy (ILAE) as a primary outcome since it is an outcome that reflects efficacy as well as tolerability (ILAE Commission 1998). However, most trials typically do not report the statistical information necessary to allow estimation of hazard ratios (Parmar 1998); thus, we will use proportions to allow a maximum amount of evidence to be included in the review.

  • Proportion of people who achieve seizure freedom (remission).

For defining seizure freedom, we will use the ILAE definition of absence of seizures of any type for either 12 months or three times the longest (pre‐intervention) seizure‐free interval, whichever is the longer (Kwan 2010).

Secondary outcomes

  • Validated quality of life measure if available.

  • Serious adverse outcomes (defined as requiring modification in medication or hospitalisation)

Search methods for identification of studies

We intend to identify all relevant trials irrespective of language or publication status (published, unpublished and in progress).

Electronic searches

We will search the following databases:

  • Cochrane Epilepsy Group Specialized Register;

  • Cochrane Central Register of Controlled Trials (CENTRAL; current issue);

  • MEDLINE (Ovid; 1946 to present);

  • SCOPUS (1823 to present);

  • ClinicalTrials.gov (clinicaltrials.gov/);

  • World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP).

Appendix 1 shows the proposed search strategy for MEDLINE. We will modify this strategy for use with the other databases.

Searching other resources

Conference proceedings

We will handsearch published abstracts of conference proceedings and add a full list as an Appendix within the full review.

Researchers, organisations and pharmaceutical companies

We will contact researchers and organisations working in this domain and the trial authors identified by the above‐mentioned methods. We will also write to pharmaceutical companies manufacturing diazepam for unpublished data or ongoing trials.

Reference lists

We will check the reference lists of all included studies and any relevant reviews for more trials.

Data collection and analysis

Selection of studies

Two review authors will independently screen all search results for consideration of inclusion as per eligibility criteria based on title and abstracts. We will obtain full texts of the trial reports whose eligibility is unclear and scrutinise them for inclusion. We will resolve any disagreements by consensus, with one review author acting as arbiter (RJM). We will report the reasons for exclusion in the 'Characteristics of excluded studies' table.

Data extraction and management

Two review authors (SB and RM) will independently extract data from included trials with a pre‐tested data extraction form. We will collect the following data for each of the included studies:

  • Trial design:

    • method;

    • inclusion and exclusion criteria;

    • data for assessment of risk of bias;

    • duration of baseline period;

    • duration of treatment period;

    • duration of 'wash‐out' period in cross‐over studies.

  • Participant factors:

    • age;

    • sex;

    • how diagnosis of epilepsy was made;

    • seizure type(s);

    • seizure frequency prior to randomisation;

    • presence of neurological deficit/signs at baseline;

    • co‐morbidities;

    • EEG results at baseline;

    • neuroimaging computed tomography (CT)/magnetic resonance imaging (MRI) scans at baseline.

  • Treatment and follow‐up data:

    • medication dose and route per treatment group;

    • protocol for dosage increase and decrease;

    • data on outcomes and adverse events;

    • description of withdrawals and drop‐outs.

Where data are insufficient or missing, we will contact trial authors for additional information. We will resolve any disagreements by consensus by referring to the trial report with one review author (RB) will act as arbiter. We will report all data collected on data extraction forms in the 'Characteristics of included studies' table.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias of each of the included trials to evaluate the methodological quality following the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will assess the risk of bias on seven domains (random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias).

Measures of treatment effect

For dichotomous outcomes (all primary outcomes and serious adverse events), we will estimate the risk ratio (RR) with 95% confidence intervals (CI). For the continuous outcome (validated quality of life measure), we will calculate the mean differences (MD) between groups and 95% CIs. If the outcomes are measured using different scales, we will calculate the standardised mean difference (SMD) with 95% CI.

Unit of analysis issues

For cross‐over trials, there should be an adequate wash‐out period and careful adjustment for the period effect and sequence effect. If the included studies are not analysed using proper statistical methods, then the estimate will be biased. Therefore, while pooling data from cross‐over RCTs with parallel arms, we will use only data from the first period. We will also perform a sensitivity analysis by using the second period data to access the robustness of the results.

For multiple‐arm studies, we will adjust the data by following methods stated in the Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

We do not anticipate any cluster‐randomised trials, as the intervention is not suitable for this type of design.

Dealing with missing data

We will attempt to obtain missing summary level data from trial authors, wherever possible. We will use intention‐to‐treat analyses. We will assumed participants who are lost to follow‐up or with inadequate seizure data to be non‐responders.

Assessment of heterogeneity

We will test heterogeneity between studies using the Chi2 test for heterogeneity. We will consider a P value of less than 0.10 as statistically significant heterogeneity. We will also examine heterogeneity using the I2 statistic, which we will interpret as follows:

  • 0% to 40%: may not be important;

  • 30% to 60%: represents moderate heterogeneity;

  • 50% to 90%: represents substantial heterogeneity;

  • 75% to 100%: represents considerable heterogeneity.

We will explore the possible cause(s) of heterogeneity, when greater than 60%, by subgroup analyses as described in the Subgroup analysis and investigation of heterogeneity section.

Assessment of reporting biases

We will assess reporting bias using a funnel plot if we include 10 or more studies in our meta‐analysis. If the number of included studies is fewer than 10 in our meta‐analysis then the funnel plot results are likely to be inconclusive (Egger 1997). Where the protocol of trials are available, we will verify the stated outcome against those reported.

Data synthesis

We will examine the similarity across studies in terms of population, interventions and outcomes. If the studies are without clinical heterogeneity, we will perform meta‐analyses using Review Manager 5 (RevMan 2012). For dichotomous outcomes, we will calculate RR and for continuous outcomes, we will calculate MD. If the continuous outcomes are measured using different scales, we will calculate the SMD. We will present all the effect measures with 95% CI. We will use a fixed‐effect model when the I2 statistic is less than 50%, otherwise we will use a random‐effects model and explore the potential cause. We will not pool data where the I2 statistic is greater than 80%.

Subgroup analysis and investigation of heterogeneity

If a sufficient number of studies is available, we plan to perform the following subgroup analyses:

  • paediatric versus adult population;

  • exclusion of trials that have not assessed compliance.

We will explore any other systematic differences between study and participant characteristics by sensitivity analyses.

Sensitivity analysis

We will undertake sensitivity analyses to investigate the robustness of treatment effect estimates by excluding studies with a high risk of bias.

Summarising and interpreting results

We will use the GRADE approach to interpret findings (Schunemann 2011). We will use GRADE Profiler Software (GRADEPro 2004), and import data from Review Manager 5 (RevMan 2012), to create 'Summary of Findings' tables for each comparison included in the review for the primary outcomes.

The 'Summary of findings' table for each comparison will include information on overall quality of the evidence from the trials and information of importance for healthcare decision making. The GRADE approach determines the quality of evidence on the basis of an evaluation of eight criteria (risk of bias inconsistency, indirectness, imprecision, publication bias, effect size, presence of plausible confounding that will change effect and dose‐response gradient). We will use these to guide our conclusions and recommendations.