The use of cannabidiol as a treatment for quantitative seizures reduction in pharmacoresistant epilepsy, a systematic review and meta-analysis.

doi:10.21203/rs.3.rs-4366244/v1

Introduction: Epilepsy is a neurological syndrome, caused by an excess of neuronal discharges due to various etiologies with varying degrees of success in treatment. Currently, a part of the population is pharmacoresistant to the traditional treatment, justifying the search for additional options. One of these alternatives is the cannabidiol - a non-psychoactive component of Cannabis Sativa, with an already tried efficacy, but still needing more studies to quantify this efficacy

Objectives: Gather and analyze efficacy findings of the use of cannabidiol in pharmacoresistant epilepsy.

Methodology: This literature systematic review was made following the PRISMA protocol guidelines. The Google Scholar, Scielo, and PubMed/MEDLINE databases were included. Using the descriptors "Cannabidiol," "Epilepsy," and "Drug Resistant Epilepsy.". This research was registered in the Prospero platform with the identification: CRD42024479643.

Results: 1448 results were found in the PubMed, Virtual Health Library, and Google Scholar databases. 06 studies met the criteria for full-text evaluation and eligibility. Compiled analysis showed that the total number of seizures in patients who received cannabidiol demonstrated a reduction of 41.0875% compared to patients in placebo groups who had an average percentage reduction of 18.1%, a 127% higher response for patients who received the intervention.

Conclusion: Given these results, it is possible to conclude that the therapeutic response of cannabidiol is worthy of consideration in new protocols and of being added to public healthcare systems for its antiepileptic potential; however, the high efficacy rate of the placebo group suggests that other methods of data collection analysis may be employed

Neurology

Epilepsy

Cannabidiol and Pharmacoresistant Epilepsy

Epilepsy is a chronic neurological syndrome that manifests through at least two spontaneous epileptic seizures, which can be classified as partial or complex depending on the affected brain regions. Data from the World Health Organization (WHO) report that approximately 0.7% of the global population is affected, and within its various presentations, causing several impairments for syndrome carriers, impacting their functional and productive capacity (Epilepsy: a public health imperative. Geneva: World Health Organization; 2019).

Approximately 80% of epilepsy cases are adequately treated with monotherapy (Da Silva et al, 2013.). Within the remaining 30%, there is a group of epileptic patients classified as difficult to control, also known as pharmacorresistant, who even with two optimized drugs still experience at least one breakthrough seizure, with some cases reaching thousands monthly (Da Conceição et al, 2017.). Faced with this concern for functional quality of life for the patient and also for their caregivers, multiple therapeutic options are being investigated, with one of the most promising being Cannabidiol (CBD), a phytocannabinoid component of the Cannabis Sativa plant (Maged et al. 2024).

CBD is most relevant for epilepsy as it does not possess the undesired psychoactive effect, while producing anticonvulsant, antidepressant, antipsychotic, and neuroprotective effects. (Meyer et al., 2021) Its antiepileptic potential has been the subject of studies since the 1970s (O'Connell et al, 2016), and in light of a significant number of well-conducted multicenter randomized studies, it becomes pertinent to collect and compile these data toguide the evidence of CBD efficacy for use in patients with pharmacoresistant epilepsy.

Materials and methods

This systematic review and meta-analysis were initiated with the question: "How effective is cannabidiol in reducing seizure frequency in patients with pharmacoresistant epilepsy?" We adopted the PICO (Patient, Intervention, Comparison, Outcome) framework to structure our inquiry. Specifically, we focused on: P: Patients diagnosed with pharmacoresistant epilepsy; I: Treatment regimens including cannabidiol; C: Pharmacoresistant patients administered a placebo as a comparison group; O: The primary outcome measured was the reduction in seizure frequency.

Search strategy

We conducted a search for randomized clinical trial papers in English and Portuguese published from March 2016 to March 2021 in the databases PubMed/Medline, Google Scholar, and Scielo using the following health descriptors: "Cannabidiol," "Pharmacoresistant Epilepsy," and "Drug Resistant Epilepsy." We used the Mendeley Reference Manager® platform for organization and removal of duplicates.

Study selection

Two reviewers conducted the study selection independently, discrepancies between findings were resolved through consensus between the two parties and the review of a third observer. The selected articles were included for meeting the following criteria: Use of cannabidiol as a new intervention, Patients with pharmacoresistant epilepsy, double-blind randomized clinical trials, and the possibility of quantitatively calculating the change in the number of seizures. Other works that did not fit into these categories or for which it was not possible to obtain the quantity of convulsive seizures were excluded.

Data extraction and reporting of bias risk

Using a standardized form, the 2 reviewers extracted the following data: Study name and year, number of participants and their subgroups, study intervention strategy and results, consisting of the difference between the number of seizures before and after the introduction of intervention with cannabidiol or placebo. Subsequently, the third observer compared the results obtained to evaluate discrepancies.

Statistical analysis

The data was compiled and tabulated in spreadsheets using Excel on the Windows® platform. Subsequently, the meta-analysis was conducted using the RevMan® 5.4 platform, calculating forest plot models

Level of evidence and risk of biases

The quality of the studies was analyzed using the RevMan® 5.4 criteria for assessing risk of bias: Selection, Performance, Detection, Attrition, and Reporting, in which all selected studies were classified as low risk due to the good description of methodology among all of them. These data are reported in the meta-analysis graphs.

The search yielded 1448 records. After filtering by a 10-year publication period and by inclusion, exclusion, and duplicate removal criteria, 119 articles remained, which were analyzed and read in full. 6 studies were selected for analysis and comparison. Of the analysed studies, 3 of them had the population of patients diagnosed with Dravet Syndrome, other 3 of them with patients diagnosed with Lennox-Gastaut Syndrome. 4 of the 6 studies had branchs for different dosages of CBD, with 3 of them comparing doses of CBD10 and CBD 20, with the sole exception the study that compared CBD 25 and CBD 50 for the Tuberous Sclerosis Complex diagnosys. All of them followed a similar procedure of previous seizure quantity measurement, blinding process, intervention methods and periods with a follow-up period after said intervention. Some studies had a branching of placebo groups, while other don’t, so for the comparision process, placebo groups where equally divided and their results we’re accommodated for it

Studies takeways and reviewers’ notes

Main Author	Year	Patients Quantity	Intervention Method	Results Reviewer 1	Results Reviewer 2
Devinsky	2017	120 Patients diagnosed with Dravet Syndrome were included, of these 61 received cannabidiol and the rest were assigned to the placebo group.	The patients who underwent the intervention received a dose of CBD20 in two daily doses for 14 weeks and, in the end, both the treatment and placebo groups had their doses reduced by 10% per day for 10 days.	The average monthly number of seizures among patients who underwent intervention was reduced by 38.9%. The placebo group showed a reduction of 13.3%. In the classification of seizure subtypes, the Odds Ratio favored the treatment, except for the number of absence seizures, which favored the placebo group.	The average monthly number of crises among patients who received intervention was reduced by 38.9%. Meanwhile, the placebo group had a reduction of 13.3%.
Devinsky	2018	225 patients with the diagnosis of Lennox-Gastaut Syndrome were divided into 3 groups; 76 to receive CBD20, 73 to receive CBD10, and 76 for the placebo group.	The treatment was administered in two daily doses, starting with 2.5mg/kg/day and increased by 2.5 or 5mg depending on the assigned group until reaching the target dose.	The CBD 20 group showed a reduction of 41.9% in the total number of seizures, the CBD 10 group showed a reduction of 37.2%, and the placebo group had a reduction of 17.2%. The Odds ratio was positive for the treatment group, with 3.85 and 3.27 for the 20 and 10 groups, respectively.	The group that received CBD 20 recorded a reduction of 41.9% in its total seizures, while the CBD group 10 recorded a reduction of 37.2%. Furthermore, the placebo group saw a reduction of 17.2%.
Thiele	2018	Of a total of 171 patients diagnosed with Lennox-Gastaut Syndrome, 86 were selected for the intervention and the remainder received placebo	Patients were treated for 14 weeks, with 2 weeks of dose escalation to 2.5mg/kg, followed by 12 weeks of receiving 20mg/kg/day in two daily doses, a 10-day titration phase with a 10% reduction in dose. dose per day and a 4-week follow-up period	The intervention group showed a 41.2% reduction in the total average number of seizures, while the placebo group showed a 13.7% reduction. There was also a discrepant response between the intervention group, 44% of participants reported a reduction in the number of seizures, and 24% of patients in the placebo group reported the same thing. 3 patients in the cannabidiol group remained without insensible seizures in the maintenance phase	The odds ratio for reducing the number of crises was positive for cannabidiol in the comparisons of percentage of crisis reduction. 1.96; 2.76; 3.43 for reductions of up to 25%, 50% and 75% respectively
Miller	2020	198 patients diagnosed with Dravet Syndrome, 66 were assigned to the CBD10 group, 67 to the CBD20 group and 65 to the two placebo groups of both doses	The dose was administered twice a day, starting with 2.5mg/kg/day until reaching the dose of CBD10 or CBD20 on the 7th or 11th day respectively. Then followed by 12 weeks of dose maintenance, 10 days of titration until the dose was zero and 4 weeks of follow-up	The CBD10 group showed a 48.7% reduction in total seizures, the CBD20 showed a 45.7% reduction and the two placebo groups showed a reduction of 29.8% and 25.7% between the two groups	The CBD 10 group was 6.56% more effective than the CBD 20 with a 48.7% reduction compared to the 45.7% reduction. Furthermore, the proportion of patients who achieved a reduction of at least 50% in the number of seizures for the CBD10 group was 43.9%, 49.3% for the CBD20 group, 26.2% for the sum of the two placebo groups
Privitera	2021	396 patients diagnosed with Lennox-Gastaut Syndrome were divided into 3 groups, namely CBD10, CBD20 and placebo with 73,162 and 161 participants respectively	The dose was administered twice a day, starting with 2.5mg/kg/day until reaching the dose of CBD10 or CBD20 on the 7th or 11th day respectively. Then followed by 12 weeks of dose maintenance, 10 days of titration until the dose was zero and 4 weeks of follow-up	The CBD 10 Group showed a 56.4% reduction in the total number of crises while the CBD20 showed a 47.3% reduction and the placebo group showed a 17% reduction. At the end of 28 days, between Placebos, CBD 10 and CBD 20, 14.3%, 34.2% and 41.4% of the groups had achieved a reduction of at least 50% in the number of crises, respectively	The CBD 10 Group recorded a 56.4% reduction in the total sum of seizures during the intervention while the CBD 20 showed a 47.3% reduction, and the placebo group demonstrated a 20.1% reduction.
Thiele	2021	224 patients diagnosed with tuberous sclerosis complex were randomized, 75 to CBD25, 73 to CBD50 and 76 received placebo	Patients started with a dose of CBD 5, receiving an increment of 5mg/kg/day until reaching a dose of CBD25 on the 9th day and CBD50 on the 29th, receiving maintenance treatment for 12 weeks after reaching the established dose, followed by 10 days of titration of the dose and 4 weeks of follow-up	The CBD25 group showed a 47.5% reduction in total crises, the CBD 50 showed a 26.5% reduction. The placebo groups of CBD 25 and CBD 50 had a reduction of 30.1% and 28% respectively	The group receiving CBD25 saw a 47.5% drop in total seizures, while the CBD50 group saw a 26.5% reduction. The placebo groups associated with CBD25 and CBD50 experienced a decrease of 30.1% and 28%, respectively.
Caption: CBD5 - Dose of 5mg/kg/day; CBD 10 - Dose of 10mg/kg/day; CBD 20 - Dose of 20mg/kg/day; CBD25 - Dose of 25mg/kg/day; CBD 50 - Dose of 50mg/kg/day

Meta-analysis

The main takeway for the analyzed results is the efficacy of CBD in reducing the amount of seizures, with the advantage for the higher dose of 20mg/kg/day compared to the 10mg/kg/day, but these improvement was of 12% considering all the analyzed studies, this systematic review didn’t taken in account the side-effects that also are progressive to the higher dose.

The only diagnoses that were repeated between different studies to make comparisons were Lennox-Gastaut and Dravet syndromes, in which doses of 10 and 20/mg/kg/day were compared, in Lennox-Gastaut, the study by Devinsky et al. 2018 showed better seizure control with a higher dose, while Privitera et al. 2021 showed the opposite, in Dravet there was only 1 study that compared different doses, which favored the lower one.

Another point addressed in several studies is the level of response between patients, which is unequal even among those with the same diagnosis. In Devinsky et al. 2017, it was reported that some patients in the intervention group had a reduction of more than 75% in the number of seizures and 10 of them were completely free of seizures during the study period, while 8 did not show any improvement and 1 of them even had an increase in the total number of seizures. In this work, the terms Good and Bad Responders were cited among the works analyzed, to classify patients who had a reduction greater or less than 50% of the total number of crises, respectively. The term began to be used in subsequent studies and it is still unclear why a patient responds well to treatment, but it is possible to state that the majority of patients qualify as good responders.

Among the cases analyzed, more studies are needed to evaluate the disparity in effectiveness between patients with the same diagnosis and ways to identify which would be “good responders” in order to introduce the right medication to the right patient.

Regarding the discussion of possible biases, it is necessary to comment on the following topics: Methodology, authorship and response levels. The methodology of all the studies that were selected are very similar, they all carried out a period of 28 to 30 days for baseline metrics of the total number of patients' seizures measured by the patients themselves or their guardians, this is the first point to be discussed because the metric of reduction in the placebo groups, which showed an average reduction of 18.1%, may be a result of the way in which the seizures were measured, since because these were double-blind studies and because epilepsy is a disabling disease, which causes great distress to the patient and the family, everyone wants to see the improvement, in Thiele et al. 2018, it is even commented how many of the patients who were included in the study moved to the North American state of Ohio to participate in the study, all this level of effort on the part of the families reflects the desire for these patients to have a better quality of life and may be one of the reasons for such significant efficacy in the placebo groups. Secondly, the studies, despite being from different authors, have many of the co-authors participating in other publications, precisely because they are multicenter studies, these researchers end up being involved in parts of these studies since there are not many centers with the structure and number of patients to carry out highly relevant studies, as an example, Elizabeth Thiele who is the author of 2 of the 6 selected works and is also co-author of 2 others, while mentioning this, there is nothing to question of the reported methodology, quality of the works or the data reported, these are just worthy points to be cited.

About the CBD use in Brazil, its use still depends on extremely individual criteria, not being part of official treatment algorithms, being assessed on a case-by-case basis and with difficult access. The characteristics mentioned above make it difficult to place cannabidiol within a treatment algorithm, with therapeutic testing being widely used to assess response and continuity, given the cost of continuous use and especially at SUS level, in 2024 the drug is not yet described in the RENAME (National List of Essential Medicines), and it is only possible to receive the medication through the SUS with court decisions or by participating in special groups to receive the medication. Furthermore, there were still no double-blind controlled studies carried out in Brazil at the time of publication of this study, all the drugs used in the analyzed studies and those used in the country need to be imported, these two factors hinder their full adoption in the national territory due to price and availability, these two points need to be discussed so that CBD can be adopted in greater quantities in the national territory and studies adapted to the local reality can be carried out.

Given the results seen in the studies analyzed, it is possible to conclude that cannabidiol added to the treatment of patients with pharmacoresistant epilepsy is beneficial in most cases. The doses of 10 and 20mg/kg/day were compared in 5 or the 6 studies, with a better result in seizure control for the higher dose, but the lower one also showed a good enough result to be considered in treatment and guidelines as well.

Ethics approval and consent to participate - Not applicable

Consent for publication - Not applicable

Availability of data and materials – All data used in this manuscript is available in on the analyzed and already published studies

Competing interests - The authors declare that they have no competing interests

Funding – All funding was provided by the authors

Authors' contributions – VGO was the main writer and the reviewer Nº1 in the table. NBA was the reviewer Nº 2. GCR was the 3 reviewer that compiled the notes of both reviewers and made the table. BFOS was the thesis advisor providing guiding and necessary instruction in the making of the manuscript and the methodology of the systematic review and metanalisys

Acknowledgements - Not applicable

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The authors declare no competing interests.

The use of cannabidiol as a treatment for quantitative seizures reduction in pharmacoresistant epilepsy, a systematic review and meta-analysis.

Status:

Version 1

Abstract

Figures

Introduction

Methodology

Results

Studies takeways and reviewers’ notes

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1