Cannabidiol Use in Refractory Epilepsy

Marcia L. Buck, PharmD, FCCP, FPPAG, BCPPS

Disclosures

Pediatr Pharm. 2018;24(11) 

In This Article

Clinical Experience

The efficacy and safety of CBD was evaluated in three phase 3 randomized, double-blind, placebo-controlled trials.[2] Two 14-week trials were conducted in patients 2 to 55 years of age with LGS. In the first study, 171 patients were randomized to receive CBD 20 mg/kg/day or placebo. The second study enrolled 225 patients who were randomized to CBD either 10 mg/kg/day or 20 mg/kg/day or placebo. After baseline assessment, each study consisted of a 2-week dose titration followed by a 12-week maintenance period. In both, 94% of the patients were taking one or more antiseizure drugs at baseline. The most common agents, in order of frequency, were clobazam, valproate, levetiracetam, lamotrigine, and rufinamide. The primary outcome for both studies was the median percent change in frequency of atonic, tonic, or tonic-clonic seizures from baseline per 28 days. Secondary endpoints included change in total seizure frequency and change in Global Impression of Change (S/CGIC) scores.

Both studies documented a significantly greater reduction seizure frequency with CBD compared to placebo. In Study 1, the median percent change was -44 in the CBD 20 mg/kg/day group, compared to -22 in the controls (p = 0.01). In study 2, the median percent change was -37 in the CBD 10 mg/kg/day group, -42 in the CBD 20 mg/kg/day group, and -17 in the controls (p < 0.01 for both CBD groups compared to placebo). These reductions were seen within the first month of treatment and persisted throughout the 14-week treatment period. There were also significant reductions in total seizure frequency. In Study 1, the median reduction was 41% in the CBD 20 mg/kg/day group, compared to 14% in the controls (p < 0.01) In Study 2, the median reduction was 36% in the CBD 10 mg/kg/day group, 38% in the CBD 20 mg/kg/day group, and 18% in the controls (p < 0.01 for both groups). Improvement in S/CGIC scores were also greater in the patients given CBD. In Study 1, the final mean score was 3.0 in the CBD 20 mg/kg/day group, indicating slight improvement, and 3.7 in the controls, indicating no improvement (p < 0.01). In Study 2, S/CGIC scores were 3.0, 3.2, and 3.6 in the CBD 10 mg/kg/day, CBD 20 mg/kg/day, and placebo groups, respectively (p < 0.01 and p=0.04). In Study 1, three patients (4%) in the CBD 20 mg/kg/day group became seizure-free, while in Study 2, three of the 73 patients (4%) in the CBD 10 mg/kg/day group, five of the 76 patients (7%) in the CBD 20 mg/kg/day group, and one of the 76 controls became seizure-free.

The third premarketing study evaluated the effectiveness of CBD in 120 children and adolescents with Dravet syndrome.[2] All patients had continued seizures while receiving one or more antiseizure medication, vagal nerve stimulation, or a ketogenic diet. They were randomized to either CBD 20 mg/kg/day or placebo, with assessment, titration, and maintenance phases similar to the first two studies. The primary outcome was median percent change in convulsive seizures from baseline per 28 days. As in the LGS studies, there was a significant improvement in the CBD group as early as 4 weeks after starting treatment which continued throughout the study, with a median change of -39 compared to -13 for the controls (p = 0.01). Four of the 60 patients in the CBD group (6.7%) were seizure-free during the maintenance period; none of the controls were seizure-free.

In a new paper in Epilepsy & Behavior, Szaflarski and colleagues from the University of Alabama published a single-center prospective open-label study describing their early experience as one of several CBD expanded access programs in the United States.[7] A total of 72 children (mean age 10 + 5 years) and 60 adults with refractory seizures were included in the analysis. Treatment was initiated with a dose of 5 mg/kg/day and titrated to a maximum of 50 mg/kg/day. Patients were assessed at 12, 24, and 48 weeks. Most patients (77%) continued treatment after the last evaluation. Mean Chalfont Seizure Severity Scale (CSSS) scores decreased from 80.7 to 39.2 at 12 weeks (p < 0.0001) and remained stable thereafter. Seizure frequency per 14 days declined from a mean of 144.4 at baseline to 52.2 days at 12 weeks (p = 0.01) and remained stable. While most patients experienced benefit, 23 (17%) discontinued treatment due to lack of efficacy. Adverse effects declined throughout the study, likely the result of both acclimation to the sedative effects of CBD and the reduction in the doses of valproate and clobazam necessitated by the introduction of CBD.

The investigators from the University of Alabama CBD program also recently published a case series of three patients treated for seizures associated with brain tumors.[8] The patients, 40, 30, and 17 years of age, who had refractory seizures associated with ganglioglioma (in the first two cases) and an oligodendroglioma were treated and assessed as in the previous paper. Mean seizure frequency decreased by 58%, 94%, and 21% in the three patients, respectively. All had improvement in CSSS scores.

Two other papers representing cumulative data from multiple expanded access sites add further evidence of the utility CBD in refractory seizures. Devinsky and colleagues described 55 patients with seizures associated with genetic mutations, including CDKL5 deficiency disorder, Aicardi syndrome, Dup15q syndrome, and Doose syndrome who were treated with CBD between 2014 and 2016.[9] The median percent change in convulsive seizure frequency from baseline was 51.4% at week 12 (IQR 9–85%) and 59.1% at week 48 (IQR 14–86%). An additional report from Gofshteyn and colleagues described the use of CBD for seven children with febrile infection-related epilepsy syndrome (FIRES).[10] All patients had refractory seizures despite other antiseizure drugs, immunotherapy, vagal nerve stimulation, or the ketogenic diet. Six patients showed improvement in both seizure frequency and duration after starting CBD. One patient expired during treatment. Of those surviving until the end of the study, one showed no improvement, but five became ambulatory, including one was able to walk with assistance. Four regained the ability to speak. Initiation of CBD also allowed the weaning of other antiseizure drugs, with a mean reduction of four drugs per patient.

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