Naturally occurring cannabinoid compounds may help reduce the frequency of seizures in rare forms of pediatric, drug-resistant epilepsy, new research suggests.
One cannabinoid in particular, cannabidiol (CBD), was associated with a 50% lower seizure frequency compared with placebo, results of a systematic review show.
“Given the small amount of high-quality evidence available, our clinical message to neurologists is that CBD products may be considered for use in young people with refractory forms of epilepsy — most notably Dravet and Lennox-Gastaut syndromes,” study investigator Emily Stockings, BPsychHons, PhD, National Drug and Alcohol Research Centre at UNSW in Sydney, Australia, told Medscape Medical News
The study was published online March 6 in the Journal of Neurology, Neurosurgery & Psychiatry.
Not a Replacement for Standard Therapy
Between 70% and 80% of patients with new-onset epilepsy achieve complete seizure control with antiepileptic drugs, the investigators note. For the 20% to 30% who are drug resistant, “there is great interest in investigating novel agents to reduce seizure frequency and severity.”
CBD and cannabidivarin have shown antiseizure effects in both in vivo and in vitro models, but investigators point out they did not produce euphoric or psychoactive effects.
In addition, researchers note that cannabinoids have been proposed as an adjunctive treatment for epilepsy and that parents of children with epilepsy report using CBD products.
To examine the safety and efficacy of cannabinoids as adjunctive treatments for treatment-resistant epilepsy, the investigators analyzed data from a total of 36 studies.
Of these, 6 were randomized controlled trials (RCTs) with a total of 555 patients (mean age, 16.3 years) with drug-resistant epilepsy. Two RCTs examined Lennox-Gastaut syndrome, one examined Dravet syndrome, and the remaining studies reported on “mixed” epilepsy syndromes.
The remaining 30 studies were observational and included 2865 patients with drug-resistant epilepsy and a mean age of 15 years.
Nine of these non-RCT studies examined Dravet syndrome, either primarily or as part of a subgroup within a larger sample, 8 examined Lennox-Gastaut syndrome, 4 examined Doose syndrome, and the remaining studies examined mixed epilepsy syndromes. Two studies did not specify epilepsy subtype.
They found CBD products were associated with a 50% or greater reduction in seizure frequency in 49% of patients.
Complete freedom from seizures was a secondary outcome, observed in 4.9% and 5.8% of participants in 2 high-quality RCTs. In addition, 8.5% of patients achieved this outcome from pooled data in 8 observational studies.
A total of 12 observational studies included quality-of-life measures. Again by pooling the data, investigators found that quality of life improved in 56% of the patients taking adjunctive cannabinoids.
“It is very important for clinicians to be aware that almost all studies used CBD in addition to existing standard antiepileptic drugs, so there is little evidence to support CBD as a replacement for standard antiepileptic drugs,” Stockings said.
Risk for side effects, including dizziness and drowsiness, was a significant 24% higher among patients taking adjunctive cannabidiol. Also, the risk for serious side effects was twice as high among those taking CBD, the researchers note.
Stockings further cautioned about potential drug-drug interactions. For example, clobazam, which is commonly used to treat Lennox-Gastaut syndrome, and CBD are both metabolized in the cytochrome P450 pathway. Clinicians should therefore closely monitor patients, including through re-evaluation of treatment response (including any side effects), after 12 weeks of therapy.
Not Without Risk
“The authors show that the 36 available studies vary significantly in quality, and there is a great deal of heterogeneity in populations studied that make it difficult to make confident statements about overall efficacy of cannabinoids, though the available evidence supports the efficacy of cannabidiol,” said Daniel Friedman, MD, from the NYU Langone Health’s Comprehensive Epilepsy Center in New York City. Friedman was not affiliated with the study.
“The authors point out that cannabidiol is not without risk and about 1 of every 23 patients in randomized controlled trials experienced a serious adverse effect. This is also important because there is a perception in the public that compounds derived from cannabis are safe,” Friedman told Medscape Medical News.
This review also points out that there are no high-quality studies with which to assess the efficacy of cannabis plant extracts and cannabidiol/tetrahydrocannabinol mixtures in the treatment of epilepsy, he said.
“This is particularly important because in many of the states that have legalized cannabis for medical use, cannabis plant extracts are the only product available to patients at this time. It is therefore difficult to counsel patients about risks and benefits of these products because good-quality data is unavailable.”
Stockings and her team noted some additional high-quality randomized controlled trials that were underway at the time of the review.
“We will be interested to see if the outcomes of these trials are consistent with the existing evidence,” she said.
Stockings says her next research project is to review the evidence for medicinal cannabis in the treatment of chronic, noncancer pain, “with findings due to be released soon.”
Stockings has disclosed no relevant financial relationships. The National Drug and Alcohol Research Centre at the University of New South Wales is supported by funding from the Australian Government under the Substance Misuse Prevention and Service Improvements Grants Fund. Friedman has served on an advisory board for GW Pharmaceuticals. He also performed study quality monitoring for Zynerba on behalf of the nonprofit Epilepsy Study Consortium, which provides NYU with payments to support his salary.
J Neurol Neurosurg Psychiatry. Published online March 6, 2018. Full text
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