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Cannabidiol as an Epilepsy Treatment: With and Without Concomitant Clobazam

Cannabidiol as an Epilepsy Treatment: With and Without Concomitant Clobazam

While medical cannabis prescribing in the UK continues to increase, there is one area of medical research that has maintained a particular interest in recent years. Medical cannabis has been found to contribute to a significant reduction in seizures associated with rare forms of treatment-resistant epilepsy – a discovery which helped to change the laws around cannabis in the UK in November 2018.

Medical Cannabis and Treatment-resistant Epilepsy

Lennox-Gastaut and Dravet syndromes are rare forms of childhood epilepsy that are often unresponsive to first-line anti-epilepsy medications. However, a number of cases in recent years have shown the potential of certain cannabis compounds – known as cannabinoids – in the prevention of potentially life-threatening seizures.

In order to build upon the existing clinical and anecdotal evidence, a recent review aimed to understand the anti-seizure potential of cannabidiol (CBD) independently of Clobazam – with which NICE recommends co-prescription. Researchers reviewed the evidence collected in four randomised placebo-controlled clinical. Two of these trials focused on Lennox-Gastaut syndrome and two on Dravet syndrome.

Assessing the efficacy of CBD in Treatment-Resistant Epilepsy

CBD has been approved for use as an epilepsy treatment in the USA, Canada, and parts of Europe in the form of Epidyolex. This medical cannabis product is approved for use in the UK in combination with Clobazam. While previous studies have shown that this combination can be significantly effective in reducing seizure frequency and severity, the efficacy of CBD without concomitant Clobazam requires further observation.

CBD and clobazam have a bi‐directional pharmacokinetic interaction that increases the plasma levels of each drugs’ active metabolites, without having a significant impact on parent compounds. The metabolites that are seen to increase through this interaction (norclobazam and 7‐hydroxy‐cannabidiol (7‐OH‐CBD)) have been found to have an anticonvulsant effect in animal models.

Given this effect, it is crucial to understand the potential effect of CBD treatment when considered independently of clobazam. In addition, the authors of this review aimed to understand the safety and tolerability of CBD both with and without clobazam as well as the exposure-response relationship of the cannabinoid.

The Patient Sample

To address the aims of this review, the researchers analysed the data collected from the four clinical trials in a number of ways. First of all, the patient samples from the individual trials were pooled and divided into sub-groups.

Once the patient samples of the studies were combined, the population for assessment totalled 714. Within this sample, 396 patients were treated for Lennox-Gastaut syndrome, and 318 for Dravet syndrome; 429 patients were treated with add-on CBD (240 with Clobazam and 189 without Clobazam); 285 were treated with add-on placebo.

Clobazam represented the most common anti-epileptic drug that was currently being taken by patients of the sample. 49% of patients with Lennox-Gastaut and 64% of patients with Dravet syndrome were taking the medication. Of the patients not currently using clobazam, around two-thirds had previously tried the ASD and “discontinued its use due to lack of efficacy, tolerability, or [adverse events]”. Patients who were treated without clobazam had a higher baseline frequency of seizures per 28 days (54 without clobazam and 36 without).

Results of the Review

The meta-analysis of the four clinical trials in Lennox-Gastaut and Dravet syndrome revealed a significant reduction in seizures with CBD in comparison to placebo in patients with or without background clobazam therapy. Patients treated with CBD were also more likely to experience at least a 50% reduction in seizure frequency.

This anti-seizure effect was seen to be improved further with the co-administration of clobazam. However, the proportion of patients, compared with placebo, who experienced at least a 50% reduction in seizures were similar with or without Clobazam treatment. This finding suggests that the potential effect modification cannot be fully explained by the interaction between CBD and clobazam.

Conclusions

The collective data from four randomised, placebo-controlled, double-blind clinical trials assessed in this review reveals that CBD may be an effective anti-seizure treatment option both with and without the addition of Clobazam. Furthermore, these findings support the finding of previous animal studies that have found that cannabinoid to be an effective anti-convulsant.

Despite the apparent ability of CBD to reduce seizure frequency in patients with treatment-resistant epilepsy, the researchers stress that the this does not exclude the possibility of significant synergistic effects associated with the combination of the two treatments or between cannabidiol and other anti-epileptic drugs.

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