Cannabinoids and epilepsy

INTRODUCTION: Epilepsy affects around 65 million people worldwide, with an incidence of 20-70 new cases per 10,000 individuals per year. Currently, there are multiple antiepileptic treatments, but none of them is curative. 30% of patients are resistant to conventional antiepileptic treatments and have severe conditions with a poor prognosis. Currently, there is increasing pressure on the part of patients, family members and society in general to seek non-traditional therapeutic alternatives for this type of cadres, in addition to easily accessible information and the preponderant role of social networks and social networks. the media. In this context, cannabinoids are positioned as a therapeutic option to be considered in these patients; This makes it necessary to analyze, from a scientific perspective, the available evidence on the effectiveness and safety of the therapeutic use of cannabis or its derivatives in the treatment of epilepsy. The two main biologically active cannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the most abundant psychoactive compound in the plant, being responsible for the cognitive changes and sensoperception commonly associated with the use of marijuana. Tolerance and the psychoactive effects of THC are the critical limiting factors in advancing the potential clinical use of THC. CBD has low affinity for CB1 and CB2 receptors, it counteracts some psychoactive effects of THC and improves its tolerability. Presents anticonvulsant, anti-inflammatory and antitumorigenic effect. Due to the absence of psychoactive properties, the low rate at which tolerance develops, its good safety profile in humans, as well as its efficacy in preclinical studies and some encouraging results in clinical phases, suggest that it could be a safe drug and effective for the treatment of epilepsy. OBJECTIVE: To evaluate the efficacy and safety of cannabinoids in the treatment of epilepsy in patients of any age. MATERIAL AND METHOD: A literature search was carried out using the following keywords: cannabi * AND epilepsy and cannabinoids AND epilepsy. Limits: Human beings, without language restriction. We explored databases Cochrane Collaboration, PubMed, Virtual Health Library (VHL), Central Library of Medicine (RIMA), Epistemonikos, Tripdatabase, UNIVADIS, JAMA Network, Health Technology Assessment Agencies, PROSPERO, Clinicaltrials.gov and manual search . We included 10 studies of 634 trials, published between 1974 and 2016 (3 systematic reviews, 6 descriptive studies and one controlled clinical trial) with the following endpoints: reduction in the frequency of seizures (which was defined in some studies as a proportion of seizure-free patients for 12 months, or three times the longest interval without convulsions and / or proportion of patients presenting ≥50% reduction in the frequency of seizures during the maintenance period) and adverse events. RESULTS: The Devinsky ECCA (2017) included 120 patients with Dravet Syndrome (SD). In the group receiving CBD, the baseline frequency of seizures decreased by 40% in the median compared to the baseline (R25-75 -69.5 to -4.8) and 43% of the patients in the CBD group presented a> 50% reduction in the frequency of seizures. Patients treated with CBD required a smaller amount of rescue drugs. On a scale validated for evaluation by the caregivers, the difference in the general condition of the patients improved. In the study by Devinsky (2016), prospective, open-label, with extended access that included 214 patients, a median change in monthly motor seizures was observed from the baseline of -36.5% (R25-75 -64 , 7 to 0) and 5 patients (4%) were free of motor seizures. For all types of seizures, 37% of patients had a ≥50% reduction, 22% reduction ≥70% and 8% had a response ≥90%. For patients with DS, the reduction of the monthly median in motor seizures was 49.8% (R25-75 -64.3 to -12.4). For patients with Lennox-Gastaut syndrome (SLG) there was a reduction in the median of 36.8% (R25-75 -60.3 to -18.8) in motor seizures and 37% of them had a ≥50% reduction in seizures. The median change in total monthly seizures of all types was -35.5% (R25-75 -55.1 to -16.4). The retrospective study of Tzadok (2016) based on clinical and telephone visits records included 74 patients with refractory epilepsy. Ninety percent of the patients who received CBD had some degree of reduction in the frequency of seizures. 46% of patients reported adverse events (AD) and 14% had to stop treatment. The rest of the studies with their own biases derived from the low methodological quality reported frank improvement of seizures. The majority of the patients were severe, with a long evolution and several treatments with simultaneous antiepileptic drugs, and exposure to CBD occurred after the failure of multiple treatments performed for years. Most studies reported additional benefits in behavior; alertness, language, motor skills, sleep, mood and stereotyped movements. The AEs reported in the studies were mild to moderate and the most frequent (> 10%) were: drowsiness, decreased appetite, diarrhea, fatigue, seizures, changes in appetite, status epilepticus, lethargy, changes in antiepileptic drug concentrations concomitants, impaired gait and sedation. Serious adverse effects were infrequent. DISCUSSION: In the two most recent studies (Devinsky 2017 and 2016) a total of 334 patients with refractory epilepsy, SD and SLG were included. This constitutes a large population, when compared to the population included in the rest of the studies conducted between 1978 and 2016, which include a total of 237 patients. Regarding efficacy, in the study by Devinsky et al (2017) it was shown that 50% of patients with Dravet Syndrome, in treatment with CBD, presented a reduction of approximately 40% in the frequency of seizures. And, in addition, that 50% of patients had a reduction of almost half in the frequency of seizures of all types. It was also concluded that patients treated with CBD required fewer rescue drugs, and that three patients remained seizure-free in the treated group and none in the control group. In the study by Devinsky et al (2016) it was observed that 50% of patients reduced the frequency of monthly motor seizures by approximately 37%. 39% of patients had a> 50% reduction in the frequency of motor seizures and 37% of patients had a> 50% reduction for all types of seizures. 56% of patients with atonic frames reduced the frequency of seizures by more than 50%, and almost 10% of patients remained seizure-free. In the patients with SLG it was observed that 50% achieved a reduction close to 40% in the frequency of motor crises; however, no patient remained crisis-free. Atonic attacks were reduced, but no reduction was observed in tonic-clonic seizures. Only a minority of parents were able to provide specific doses of CBD (ie, mg of CBD per day). The changes perceived in the frequency of the crises were observed quickly, since 86% of the patients reported improvement or worsening within 14 days. Other beneficial effects of treatment with CBD have also been reported, such as the improvement seen in behavior, alertness, language, communication and motor skills. Surveys of parents and caregivers are in agreement with the findings previously described. The dose of CBD proved to be safe, in a fairly wide range between 0.5 and 30 mg / kg / day, although some patients should have received doses of 50 mg / kg / day. With respect to the formulations based on mixtures of CBD and THC, the concentration of the latter did not exceed 1%. The AEs most frequently described (> 10%) were drowsiness, decreased appetite, fatigue, diarrhea, convulsions, appetite change, lethargy, gait disturbances, sedation and irritability. The AEs were more frequently reported during the first 14 days of titration of the dose. Most reported events were mild or moderate and transient. The patients included in most of the studies evaluated were severe patients, with refractory epilepsy, in treatment with at least three antiepileptic drugs and other therapeutic options such as surgery for epilepsy, the ketogenic diet or vagal stimulation, without achieving control. adequate of crises. In Devinsky et al (2017) almost all patients had a moderate and severe maturational delay. In all the studies the use of cannabinoids is considered as a coadjuvant and synergistic treatment with the basic treatment, which in most cases allows to suppress a drug or reduce its dose, with the consequent benefit. The use of cannabis as the sole medication or as the first therapeutic option has never been considered. With regard to methodological quality, the only controlled clinical trial was Devinsky et al (2017) that included only patients with Dravet syndrome, while the rest of the studies included in the table are descriptive studies that lack a control group and are low. methodological quality. The descriptive studies included patients with tonic, atonic, clonic or tonic-clonic seizures, Dravet Syndrome, Lenox-Gastaut and Doose among others. Although there is little evidence and low quality, since the beginning of the use of cannabinoids in epilepsy, in the last three years the anticonvulsive effect of CBD has been demonstrated in patients with DS and a frankly beneficial effect in the rest of the refractory epilepsies. treatment in children and young people, with a very reasonable range of safety. The main limitations of these studies are the financing by the industry (GW) which has been declared in the studies of Devisnky et al 2016 and 2017. The relative ease in obtaining the artisan oil, in no case should lead us to suppose that its development without control can ensure the adequate provision of the CBD active ingredient to the population. Risks include: the technical impossibility of ensuring proper manufacturing, precise composition and delivered dose, type of suitable and predictable crop of the plant, absence of contaminants and many other random variables that threaten any therapeutic attempt that can be considered effective and safe. CONCLUSIONS: The use of CBD in standardized and controlled formulations (obviously, this excludes home preparations), in a concentration of 99% and never less than 96% with respect to THC, as an adjuvant treatment in refractory or drug-resistant epilepsy in children and young people, has shown to have an anticonvulsant effect mainly in motor crises and should be considered as an effective and safe option in the treatment of this type of patients. Beyond its proven anticonvulsant efficacy, it allows in most cases to reduce the dose of other anticonvulsant drugs and their adverse effects, which results in an improvement in the quality of life of patients and their caregivers. The medicinal use of cannabinoids and their non-addictive compounds must be considered within the therapeutic arsenal of controlled use, in the treatment of refractory epilepsy.