Abstract
Review evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy. Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL). Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5–55 years). Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17). CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs. Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed.
Background
The International League Against Epilepsy (ILAE) defines epilepsy as a disease of the brain, diagnosis of which requires: (a) at least two unprovoked seizures occurring >24 hours apart; (b) one unprovoked seizure and a probability for further seizures of at least 60%, occurring over the next 10 years or (c) the diagnosis of an epilepsy syndrome.1 Between 70% and 80% of patients with new-onset epilepsy achieve complete seizure control using antiepileptic drugs such as valproate or carbamazepine.2 In 20%–30% who are drug-resistant,3 4 there is great interest in investigating novel agents to reduce seizure frequency and severity. For the purposes of this review, the ILAE’s definition of drug-resistant epilepsy—the failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drugs (AEDs) schedules (as either monotherapies or in combination) to achieve seizure freedom5—is used. For the 30% of patients who experience drug-resistant epilepsy, the efficacy of alternative and adjunctive therapies is likely to be of great interest.
Preclinical studies suggest that naturally occurring cannabinoids (phytocannabinoids) have anticonvulsant effects which are mediated by the endocannabinoid system.6 Cannabidiol (CBD) and cannabidivarin have shown antiseizure effects in both in vivo and in vitro models. In contrast to tetrahydrocannabinol (THC), CBD does not produce euphoric or intrusive psychoactive side effects when used to treat seizures.7 Cannabinoids have been proposed as an adjunctive treatment for epilepsy7 and parents of children with epilepsy report using CBD products.8–10 There are a number of phase III human trials underway of CBD as an adjunctive therapy for treatment resistant paediatric and adult epilepsies.11 12
Recently Israel, the Netherlands, Germany and Canada have legislated to allow the use of cannabinoids for medicinal purposes. In Australia, Federal and state legislation that allows doctors to prescribe cannabinoids is being implemented. Systematic reviews are required to synthesise the evidence for individual conditions for which cannabinoids may be used to inform clinical practice and patient guidance.
This review considers evidence on the safety and efficacy of cannabinoids as adjunctive treatments for drug-resistant epilepsy. As previous reviews noted a lack of controlled studies,13 14 we synthesised evidence from randomised controlled trials (RCTs) and observational studies.[…]
TBI Rehabilitation 