Adjunctive Use of Cannabidiol: A Joint Action to Patch Up Drug-Resistant Epilepsy

Abstract

Commentary

Despite the advent of numerous second-generation anti-seizure medications (ASMs) in the past 3 decades, one third of persons with epilepsy still experience disabling seizures.^1,2When nonpharmacological (e.g., ketogenic diet) or surgical (e.g., destructive or neuromodulatory) treatment options are not available, indicated or desired, these patients inevitably rely on further trials of the approved ASMs, at times in different formulations, doses, or indications than the labeled ones.

Cannabidiol (CBD), a nonpsychotropic phytocannabinoid, was first approved in 2018 in oral form as an adjunct treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex.^3 –9Its synergistic promise for seizure frequency reduction in conjunction with more commonly prescribed ASMs through interaction with serotonin, opioid, and non-endocannabinoid G protein-coupled receptors, in addition to its potential benefit in mood, sleep, appetite, spasticity and hence, overall quality of life, made it appealing for children with such developmental epileptic encephalopathies (DEEs).^3 –9The current 2 studies^10,11investigate whether its therapeutic spectrum can be extended to other seizure types, through other formulations and across the age spectrum.

The first study¹⁰is a double-blind, placebo-controlled, multicenter, randomized clinical trial (RCT) of transdermally administered CBD conducted in 14 epilepsy centers in Australia and New Zealand on adult patients with drug-resistant focal epilepsy. A total of 188 participants were randomized in 195 mg/daily or 390 mg/daily of CBD versus placebo for 12 weeks, while being maintained on a stable ASMs regimen that excluded clobazam. Participants completing that double-blind period were offered enrollment into a 2-year open-label extension (OLE) of 390 mg CBD daily, during which medication adjustments, including CBD increments, were permitted. The findings were analyzed for both study periods in terms of efficacy, safety, and pharmacokinetics. While no statistically significant reduction in seizure frequency compared to placebo was noted during the RCT stage, nearly 60% of the participants demonstrated at least 50% seizure frequency reduction 6 months into the OLE. Notwithstanding the possibility of a pervasive high placebo effect and the influence of other ASMs adjustments, this positive response sustained in the long run. No dose-relationship response was observed, and plasma levels were highly variable. During the RCT stage, treatment-emergent adverse events occurred in approximately 9% more patients in the treatment groups compared to placebo, they were mild to moderate, and they were not dose related. The vast majority of participants continued in the OLE stage, where excellent tolerability and safety were also noted, both on clinical as well as paraclinical (e.g., liver function tests) grounds, even when higher CBD doses were used.¹⁰

The second study¹¹is a retrospective, multicenter study from 16 epilepsy centers in Germany providing real-world data on the add-on use of oral CBD. The study cohort comprised of 311 patients, almost a quarter of whom were adults. Three quarters of the patients were drug-resistant on polypharmacy (including nearly 46% on clobazam) and two-thirds of them had epilepsy syndromes other than the approved CBD indications. Cannabidiol was used off-label in >90% of cases (i.e., for different seizure types, ages or doses than approved for, or without clobazam that is required in the European labeling due to previously established synergistic effect) with a median end dose of 17.8 mg/kg/day.¹¹One-third of the cohort terminated the treatment for various reasons, including lack of efficacy, poor tolerability, pregnancy, suboptimal compliance, and insurability. In the end of the follow-up period of nearly 16 months, approximately 37% of the whole cohort experienced >50% seizure frequency reduction, typically those on higher doses, regardless of seizure type or comedication with clobazam. Factoring in the retrospective study design, adverse effects were observed in nearly 47% of the patients, foremost in the form of sleepiness and diarrhea. Within the confines of inconsistent CBD plasma levels collection, these were not dose-dependent, and their profile did not differ between in-label versus off-label use. Liver enzymes elevation was observed rarely, typically in conjunction with valproate administration. Conversely, improvement of soft signs (e.g., mood, sleep, appetite, spasticity) was seen in 41% of the patients.¹¹

Notably, both studies^10,11share common points. They are both industry-sponsored, multicenter investigations that provide evidence on the adjunctive use of CBD for focal seizures also in adults. Additionally, the former¹⁰informs on its transdermal application. In that sense they cumulatively raise 3 important questions: (1) How does CBD work, both in terms of safety and tolerability, compared to other ASMs; (2) How does CBD work for alternative seizure types and populations than those originally approved for; (3) How does CBD work as a transdermal gel compared to its approved oral version?

The first question is hard to answer with the available data in hand, as CBD has only been used as adjunctive treatment and no head-to-head comparisons have ever been done with other ASMs.^1,2Yet, the accumulated evidence from the initial RCTs and OLEs^3 –9suggest fairly similar rates of seizure response, at least as a second-line treatment, and satisfactory tolerability.^1,2One should not discount, however, the high public expectations of cannabis that may result in higher response rates in retrospective or open-label studies and the potential of regression to the mean in patients with high seizure counts at baseline.¹²

Preliminary data to answer the second and third question are provided by the studies discussed herein,^10,11as well as a prior nonrandomized controlled trial on the use of transdermal gel for children with DEEs.¹²In adults, the transdermal formulation in the OLE of the first study¹⁰resulted in fairly similar efficacy for focal seizures compared to the oral formulation evaluated in a mixed pediatric and adult population in the real world experience of the second study.¹¹A prior study on the use of CBD gel in skin patches for children with DEEs¹²led to a comparable 50% responder rate of approximately 40% compared to the DS⁴and LGS⁶studies conducted with the oral formulation. Despite the lack of a dose–response effect,¹⁰the measured plasma concentrations with transdermal administration overlapped with those observed with oral CBD.⁸Tolerability of the transcutaneous delivery both in the adults with focal seizures¹⁰and in children with DEEs¹²was linked to lower rates of discontinuation compared to its oral counterparts for these indications.^3 –9,11The reduced rates of liver function test elevation and gastrointestinal adverse effects with the transdermal application may be attributable to the reduced first-pass metabolism.¹⁰

In conclusion, these 2 studies^10,11converge with the extant literature that: (1) CBD is a reasonably safe and well tolerated adjunct for drug resistant epilepsy (DRE), with RCT based data for its proven-albeit not mind-boggling efficacy in DEEs in the pediatric population and preliminary, open-label/real world data for a fairly similar efficacy in focal seizures in the adult population and (2) transdermal delivery of ASMs may be an alternative option for patients facing difficulties with oral administration, with potentially better tolerability compared to oral formulation, at least in the case of CBD. Foremost, they highlight the need for further research on CBD to clarify the optimal dose and delivery mode in other populations (e.g., elderly), for additional indications (e.g., autoimmune or tumoral epilepsy), its comparative effectiveness and standalone efficacy earlier on in the disease process (e.g., monotherapy), the optimal combination with other pharmacological (e.g., pharmacodynamic interactions with ASMs) and nonpharmacological (e.g., ketogenic diet) treatments, its interaction with drugs used for other medical comorbidities (e.g., cardiovascular or neoplastic diseases), the need for drug level monitoring, the role in addressing common epilepsy-related comorbidities (e.g., mood problems), the long-term efficacy and tolerability (e.g., potential impact on bone health and teratogenicity), its cost-effectiveness, as well as any effect on the mechanisms underlying epileptogenesis and pharmacoresistance.

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