Cannabidiol in addition to current antiepileptic therapy decreases convulsive seizure frequency in children and adolescents with Dravet syndrome and drug-resistant seizures
EBM Focus - Volume 12, Issue 22
- Options for reducing seizures are limited for patients with Dravet syndrome and drug-resistant seizures.
- A recent trial randomized 120 children and adolescents with Dravet syndrome and drug-resistant seizures to cannabidiol vs. placebo in addition to their current antiepileptic therapy for 14 weeks.
- Convulsive seizure frequency was reduced by a median of 38.9% with cannabidiol vs. 13.3% with placebo (p = 0.01). Cannabidiol was associated with more frequent adverse events.
Dravet syndrome is a severe early-onset genetic disorder characterized by difficult-to-control seizures and accompanied by developmental delay, other morbidities, and increased mortality (Can J Neurol Sci 2016 Jun;43 Suppl 3:S3). Treatment is focused on limiting seizures as much as possible, but seizures are often resistant to multiple antiepileptic medications and additional therapies are needed (Can J Neurol Sci 2016 Jun;43 Suppl 3:S13). Cannabidiol, a non-psychoactive cannabinoid, has been suggested as a potential adjunct therapy, but evidence to date has consisted of low-quality randomized trials, observational studies, and uncontrolled trials (Cochrane Database Syst Rev 2014 Mar 5;(3):CD009270, Lancet Neurol 2016 Mar;15(3):270). To assess the potential effects of cannabidiol, a recent trial randomized 120 children and adolescents (mean 10 years old) with Dravet syndrome and drug-resistant seizures to cannabidiol oral solution 20 mg/kg/day vs. placebo in twice daily doses in addition to their current antiepileptic therapy for 14 weeks. All patients had ≥ 4 convulsive seizures (median 13) per month despite taking ≥ 1 antiepileptic medications during a 4-week baseline period, and some were also on a ketogenic diet or were having vagus nerve stimulation. Nonconvulsive seizures were also reported in 65%, and developmental delays were observed in almost all patients, including severe or profound delay in almost half.
Over the 14-week treatment period, the median monthly frequency of convulsive seizures was 5.9 with cannabidiol vs. 14.1 with placebo (statistical comparison not reported). The median reduction from baseline was 38.9% vs. 13.3% (p = 0.01, 95% CI for adjusted median difference 5.4%-41.1%), and a ≥ 50% reduction from baseline was observed in 43% vs. 27% (p = 0.08). Also, the caregivers reported an improved overall condition in 62% vs. 34% (p = 0.02, NNT 4). However, there were no significant differences between groups in the reduction in nonconvulsive seizures, Quality of Life in Childhood Epilepsy score, or Vineland Adaptive Behavior Scales. Adverse events were more frequent in patients with cannabidiol than placebo, including treatment-related events in 75% vs. 36% and events leading to trial withdrawal in 13% vs. 1.7% (statistical comparisons not reported). The most common (in ≥ 15%) adverse events with cannabidiol included somnolence, diarrhea, decreased appetite, elevated liver aminotransferase enzyme levels, fatigue, vomiting, and pyrexia.
This trial, the first high-quality study assessing cannabidiol for seizure control, demonstrated that adjunct cannabidiol decreased convulsive seizure frequency over 14 weeks in children and adolescents with Dravet syndrome and drug-resistant seizures. There is some uncertainty regarding the magnitude of the effect, as the 95% CI for the median difference between groups in convulsive seizure reduction is wide. These results cannot be directly applied to patients without Dravet syndrome, but results from a recent uncontrolled trial (Lancet Neurol 2016 Mar;15(3):270, see EBM Focus 11(3) for our commentary) and observational studies (Epilepsy Behav 2015 Apr;45:49, Seizure 2016 Feb;35:41) suggest that cannabidiol may be beneficial in other patients with drug-resistant seizures. Cannabidiol was associated with increased adverse events, some leading to trial withdrawal, but these must be weighed against the benefits of possible convulsive seizure reduction. Finally, a longer follow-up is needed to determine the long-term risks and benefits of cannabidiol in these patients. Currently cannabidiol is not FDA-approved, but is available in some circumstances through the expanded access program while it continues to be evaluated in clinical trials (FDA website [accessed May 2017]). In addition, in regions where marijuana is approved for medical purposes, there are usually cannabidiol-rich strains available, but the dosing is not standardized and there may be more adverse effects from other compounds in the plant. When available, oral cannabidiol can be considered as an adjunct treatment in young patients with Dravet syndrome and drug-resistant convulsive seizures.