Cannabinoid therapy promising in pediatric epilepsy.
SEATTLE -- Cannabinoid therapy holds promise for treating pediatric epilepsy, but more research is needed to assess its safety and efficacy, experts say.
Cannabis contains numerous cannabinoids, including the nonpsychoactive cannabidiol (CBD) and the psychoactive tetrahydrocannabinol (THC).
Two CBD products--an oil-based extract (Epidiolex) and an oral solution (Insys Therapeutics)--have been granted orphan drug status by the Food and Drug Administration for treating some forms of epilepsy. Also, artisanal preparations are available.
However, use and study of cannabinoids in the United States have been complicated by the federal classification of marijuana as a schedule I controlled substance, and the patchwork legal status of medical and recreational use across states.
Investigators reported findings of several clinical studies of cannabinoid therapy in pediatric epilepsy at the annual meeting of the American Epilepsy Society.
Benefits seen in Dravet syndrome
Dr. Orrin Devinsky, director of the comprehensive epilepsy center at the NYU Langone Medical Center, and his colleagues undertook a prospective, open-label, multicenter observational study among pediatric patients with treatment-resistant epilepsy.
In the study, supported in part by GW Pharmaceuticals, 151 patients were treated with Epidiolex, added to their baseline regimen of up to three antiepileptic drugs (AEDs).
The main efficacy analyses based on the 58 patients treated for at least 3 months showed that the median reduction in seizure frequency was about 35% overall and 55% for patients with Dravet syndrome.
The 3-month rate of seizure freedom was 10% overall and 22% in the subset with Dravet syndrome. "These were much higher rates than we would expect, for example, from a placebo response alone," Dr. Devinsky said in a press briefing.
Data from the 40 patients having longer follow-up, at least 16 weeks, showed that the benefit was sustained, indicating that patients did not develop tolerance.
Safety results for all 151 patients showed the most common adverse events were somnolence, seen in 19% of patients, and fatigue, seen in 11%. A single serious adverse event, status epilepticus, was considered possibly related to the CBD.
"Based on the experience at these five sites, in an open-label, nonrandomized controlled trial ... there is good evidence that the Epidiolex 98% product of CBD is an effective drug for many children with treatment-resistant epilepsy, that the patients with Dravet syndrome appear to be the most responsive ones, that the drug overall is quite well tolerated, and most of the side effects when they occur are relatively mild and oftentimes limited," Dr. Devinsky said.
"The critical take-home message is that these are promising early results, but we need controlled trials to know how to move forward," he said, noting that randomized phase III trials are planned in patients with Dravet and with Lennox-Gastaut syndromes.
Classifying CBD as schedule I presents hurdles for researchers and doesn't make sense, said Dr. Devinsky, who disclosed no relevant conflicts.
Impact on levels of AEDs
Investigators led by Dr. Daniel Friedman, director of both the ICU epilepsy monitoring service and the epilepsy consult service at NYU Langone Medical Center, assessed levels of coadministered AEDs in 57 patients from the above study. He noted that such research is important as preclinical data suggest that CBD inhibits enzymes that metabolize commonly used AEDs.
The results showed that over the first 2 months of CBD therapy, 33% of patients on valproate and 24% of patients on clobazam (Onfi) had their doses reduced because they had elevated drug levels or sedation attributed to the drugs, Dr. Friedman reported. But none of the AEDs showed a consistent pattern of change in levels with the addition of CBD.
Data from five patients showed an average threefold increase in the level of the active metabolite of clobazam, N-desmethyldobazam, without any change in levels of the drug itself, suggesting that the CBD was interfering with clearance of the metabolite.
The findings are not definitive, stressed Dr. Friedman, who disclosed no relevant conflicts.
"Until formal drug-drug interaction studies are done, we refrain from any specific advice, except for, make sure if your patients are on CBD, whether they are getting it through artisanal preparations or as part of a compassionate use study, that background AEDs are monitored, and if they are on clobazam, make sure to check the N-desmethyl metabolite level as well," he said.
Do expectations affect results? Dr. Kevin E. Chapman of Children's Hospital Colorado, Aurora, and his colleagues retrospectively studied data for 75 patients who reported using oral cannabis extract.
In Colorado, cannabis is legal for medical and recreational use. But patients must become residents, obtain a prescription from two specialized physicians, get a medical marijuana ID card ("red card"), and buy the product from a dispensary by paying out of pocket.
"We have had a fairly large influx of patients from out of state ever since medical marijuana became legal in our state," Dr. Chapman noted in a press briefing. However, neurologists are often reluctant to raise the topic with patients. "We worry about our own personal DEA licenses if we were to prescribe the medication," he said.
But when they learn patients are starting CBD therapy, "our practice is to encourage families not to make dramatic changes to seizure medications because for us, then it becomes hard to know how many of the problems that they have are from the CBD or how much of the benefit is from the CBD," said Dr. Chapman, who disclosed no relevant conflicts.
Analyses identified only a single predictor of response: moving to the state to obtain the extract. "I think it's understandable that families have high hopes when they move to Colorado that it's going to be effective....
I don't know if there is a bit of bias by families really wanting for it to work and that's part of the reason we saw that," Dr. Chapman said.
Open communication is critical
Dr. Jeffrey Gold, a pediatric neurologist at Rady Children's Hospital in San Diego, and his colleagues reported the case of a boy with Doose syndrome whose seizures resolved after initiation of cannabinoid therapy.
"We face somewhat different challenges in California, where recreational marijuana is not legal. Medical marijuana has some acceptance, but it exists in a nebulous legal area," he noted in the press briefing.
The boy's seizures were refractory to medical therapy and video EEG features suggested a high risk of progression. His parents opted to try CBD instead of the ketogenic diet, the standard of care in such cases.
After starting therapy, the boy had apparent worsening of seizures. Testing revealed that his valproic acid level had risen from 115 to 178 meg / mL, suggesting the CBD was interfering with the drug's clearance.
The valproic acid dose was lowered, and over a 4-month period, the patient became seizure free. "We obtained another EEG which was completely normal, honestly to our surprise," reported Dr. Gold, who disclosed no relevant conflicts. "We wanted to get this report out to the community so that they would know, if families choose to start CBD therapy, we strongly advocate that they share that information with their physicians and that physicians manage the other antiseizure treatments the child is receiving," Dr. Gold said.
"We encourage families to pursue conventional treatment, enroll in clinical trials when they are offered, [and] to get involved with the scientific community," he said. "We need to do it the right way."
Please note: Illustration(s) are not available due to copyright restrictions.
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|Publication:||Clinical Psychiatry News|
|Date:||Apr 1, 2015|
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