Epilepsy

Despite the advances in anti-epileptic drug (AED) development, there still exists an unmet clinical need for patients with treatment refractive epilepsy. Early evidence of the efficacy of CBD in the treatment of seizures came from small scale clinical trials and parental surveys (1-3).

 In a phase 1, placebo controlled, double blind study, 15 patients with secondary generalised epilepsy where divided into 2 groups receiving 200 – 300 mg of CBD or placebo per day, in addition to their AED therapy. CBD was well tolerated with no serious adverse events (AEs). Of the 8 patients receiving CBD therapy, 4 remained almost free of seizures, while the clinical condition of 3 patients partially improved. CBD had no effect on 1 patient and the condition of all 7 patients on placebo remained unchanged (1). In a retrospective review, 11 patients (6 months – 21 years) with intractable epilepsy were reported to have a significant reduction in seizures after 3 months of CBD (>16:1) therapy. Seizure reduction >75% was reported in 9 out of 11 patients, and 5 patients were seizure free after 3 months (average dose 4-12 mg/kg/day) (2). In an anonymous survey completed by parents of children with severe treatment resistant epilepsies, CBD was reported to reduce seizure frequency and to have a favourable side effect profile (3).

There are multiple limitations to these small-scale studies. Only in recent years has the safety, tolerability and efficacy of CBD for treatment resistant epilepsy been evaluated in larger scale clinical trials.

Efficacy and Safety Data

  1. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Devinsky et al 2016.

Study: Prospective, multicentre, open-label study to assess the safety, tolerability and efficacy of CBD as an adjunct to AED therapy in children and young adults (aged 1- 30 years) with highly treatment-resistant epilepsy.      

Cohort: Total enrolled N = 214.  Safety & tolerability analysis: N = 162 (20% Dravet syndrome, 19% Lennox- Gastaut syndrome, 61% various types of intractable epilepsy). Efficacy analysis N = 137 (23% Dravet syndrome, 22% Lennox-Gastaut   syndrome, 55% various types of intractable epileps

Treatment: Baseline AED regimen & CBD 2–5 mg/kg per day. Up-titrated CBD by 2–5 mg/kg once a week until intolerance or a max dose of 25 mg/kg or 50 mg/kg per day was reached. Mean CBD dose at 12 weeks was 22·9 mg/kg and 22·7 mg/kg in the safety and efficacy analysis groups respectively.

Results: Median change in total seizures: 34·6% reduction. Percentage reduction in focal seizures (n=42; 55·0%), atonic seizures (n=32; –54·3%), tonic seizures (n=65; –36·5%) and tonic-clonic seizures (n=89; –16·0%). A 50% or more reduction in motor seizures was seen in 39% patients, 21% had a reduction of  > 70% and 9% had a reduction of 90% or more. 2% of patients were free of all seizures over the full 12 weeks, 7% were free of all seizures during the final 4 weeks and 11% of patients were free of all motor seizures during the final 4 weeks. 

Adverse Events (AE)Majority of AEs were mild to moderate and transient. Serious AEs possibly related to CBD were recorded in 20 patients and included status epilepticus, pneumonia, diarrhoea, and weight loss.

Conclusion:  Efficacy of CBD was promising.

2. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. Devinsky et al 2017.

 Study: Randomised, double-blind, placebo controlled trial to investigate the efficacy of CBD as an adjunctive therapy in children and young adults (1 – 18 years) with treatment-resistant Dravet Syndrome.

Cohort: Total participants that completed study N = 108. CBD group (completed treatment) N = 52. Placebo group (completed study) N = 56

Treatment: Baseline AED regimen & CBD 20mg/kg per day.

Results:  CBD treatment: 12.4 (median baseline seizures per month) reduced to 5.9. Placebo: 14.9 (median baseline seizures per month) reduced to 14.1.  At least a 50% reduction in convulsive seizure frequency in 43% of CBD group and 27% in placebo group.  An improvement of at least 1 category on the 7-category Caregiver Global Impression of Change scale was reported in 62% of the CBD group compared to 34% of the placebo group (P=0.02).

AEsMild to moderate AEs were reported in 84% of the CBD and 95% of the placebo group. Serious AEs were more common in the CBD group than in the placebo group (16% vs. 5%). AEs led to the withdrawal of 8 patients in the CBD group compared to 1 withdrawal in the placebo group.

Conclusion:  CBD resulted in a greater reduction in convulsive-seizure frequency in patients with Dravet syndrome but was also associated with higher rates of AEs.

CBD- AED Drug-drug interactions.

CBD has been reported to interact with AEDs through CYP metabolism. Serum AED levels were measured during active titration of CBD in refractive epilepsy patients enrolled in an open label study. Increase in the serum levels of rufinamide (p < 0.01), topiramate (p < 0.01), and desmethyclobazam (p < 0.01, active metabolite of clobazam), and a decrease in the levels of clobazam (p < 0.01) was seen with increasing CBD dose in the combined pediatric and adult arms. Furthermore, a significant increase in serum levels of zonisamide (p=0.02) and eslicarbazepine (p=0.04) with increasing CBD dose was seen in the adult arm only. No significant interactions were observed between CBD and the other AEDs investigated, which included valproate, levetiracetam, lacosamide, and perampanel (6). 

Products most prescribed for this condition:
References
  1. Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. 1980; 21:175–185.
  2. Gedde M, Maa E. Whole Cannabis Extract of High Concentration Cannabidiol may calm seizures in highly refractory pediatric patients. American Epilepsy Society Annual Meeting; 2013 December.
  3. Porter, B, Jacobson, C. Report of a parent survey of Cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy and Behavior. 2013 29(3): 574-7.
  4. Devinsky, O; Marsh, E; Friedman, D; Thiele, E; Laux, L; Sullivan, J; Miller, I; Flamini, R; Wilfong, A; Filloux, F; Wong, M; Tilton, N; Bruno, P; Bluvstein, J; Hedlund, J; Kamens, R; Maclean, J; Nangia, S; Singhal, NS; Wilson, CA; Patel, A; Cilio, MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. The Lancet Neurology. 2016. Volume 15, No. 3, p270–278.
  5. Devinsky, Cross, Laux, Marsh, Miller, Nabbout, Scheffer, Thiele, Wright, Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. 2017 N Engl J Med 376;21.
  6. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Sep;58(9):1586-1592.

 

 

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