Keywords:
Cannabidiol - Epilepsy - Efficacy - Safety - Brazil
Palavras-chave:
Canabidiol - Epilepsia - Eficácia - Segurança - Brasil
INTRODUCTION
Approximately 50 million people live with epilepsy worldwide[1]. Epilepsy is not a single disease, but an array of neurological disorders sharing
an enduring predisposition to generate epileptic seizures[2]. Social, physical, psychological, and economic disease substantially create an impact
on affected individuals, their families and caregivers, as well as on society as a
whole[3].
The development of drugs with novel mechanisms to suppress seizure occurrence has
doubled in the past decades, but the proportion of patients with medically refractory
disease has not decreased significantly[4]. Up to 30% of patients with epilepsy still present persistent uncontrolled seizures,
despite adequate trials of two efficacious and tolerated antiseizure medications (ASM),
and this characterizes drug-resistant epilepsy[5],[6].
In 2013, medical use of Cannabis sativa attracted considerable public attention after the successful broadcast experience
of Charlotte Figi in the United States. The five-year girl with Dravet syndrome had
a more than 90% seizure reduction after using a high-CDB-strain cannabis extract[7]. The therapeutic use of the Cannabis plant (also known as marijuana) has been reported
for centuries in anecdotal reports[8]. Since the mid 20th century, more intensive research on cannabidiol (CBD) and delta-9-tetrahydrocannabinol
(THC) Cannabis sativa compounds have provided evidence of their efficacy in treating epilepsy and other
neurological conditions[9]. A better characterization of the endocannabinoid system also expanded the therapeutic
horizon of these compounds. CBD was shown to have a powerful anti seizure effect without
psychoactive effects, compared to THC[9],[10].
In 2014, a systematic review from Cochrane and the American Academy of Neurology showed
lack of evidence to support the use of cannabidiol (CBD) for epilepsy[11]. The four clinical trials then available presented methodological limitations that
underpowered analysis[12]-[15]. Subsequently, five randomized clinical trials, published between 2017 and 2021,
showed evidence of efficacy and safety of CBD in epilepsy related to Dravet syndrome
(DS), Lennox Gastaut syndrome (LGS), and in the tuberous sclerosis complex (TSC)[16]-[20] ([Figure 1]), leading to approval of the highly purified CBD, Epidiolex (GW Pharmaceuticals) by the U.S. Food and Drug Administration (FDA)[21] and by the European Medicines Agency (EMA)[22] as an add-on treatment for these conditions, setting an important milestone in CBD
use in epilepsy treatment. However, there are still no randomized clinical trials
that support CBD use in other treatment-resistant epilepsy etiologies. Currently,
only low-level open-label studies, using heterogeneous compositions, suggest a possible
efficacy in these epilepsy types[23].
Figure 1 CBD efficacy. Reduction in seizure frequency during the 14-week-treatment of the
five randomized clinical trials with cannabidiol in patients with Tuberous Sclerosis
Complex (TSC), Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome (DS). Doses: 10 mg/kg/d
(CBD 10), 20 mg/kg/d (CBD 20), 25 mg/kg/d (CBD 25) and 50 mg/kg/d (CBD 50).
*P < 0.05; **P ² 0.01; *** P ² 0.005 displays the comparisons between CBD groups and corresponding placebo groups.
CANNABIDIOL CLINICAL PHARMACOLOGY
CANNABIDIOL CLINICAL PHARMACOLOGY
CBD molecular structure was described by Mechoulan in 1963[24]. The endocannabinoid complex system was characterized in the 1990s, when cannabinoid
types 1 (CB1) and 2 (CB2), as well as endogenous ligands anandamide and 2-arachidonoylglycerol
- so-called endocannabinoids - were identified[8]. CBD anti-seizure action mechanism remains not fully understood. CBD displays no
effect on cannabinoid receptors (CB1 and CB2), compared to THC, and therefore has
no psychotropic effects[8]. Putative main mechanisms of CBD antiseizure action include modulation of intracellular
calcium (via G protein-coupled GPRR55 receptors, transient receptor potential vanilloid
type 1 TRPV1 channels, and voltage-dependent anion-selective channel protein 1 - VDAC1),
leading to decreased neuronal excitability. Additionally, CBD influences anti-inflammatory
adenosine-associated signaling pathways via equilibrative nucleoside transporter 1
- ENT-1 - inhibition and tumor necrosis alpha factor - TNF-alpha - so resulting in
an antiepileptogenic effect[8],[25],[26].
Preclinical cannabinoid studies in acute and chronic epilepsy animal models initiated
in the 1970s showed a potential antiepileptic effect[27]. At that time, the proportion of cannabinoid and non-cannabinoid components in the
extract was unknown. When CBD was later isolated, evidence became available of CBD
antiepileptic properties in in vitro and in vivo experimental models[28],[29].
Initial studies in humans have led to a better understanding of CBD pharmacokinetics
and pharmacodynamics[30]. The most common administration route - recreational inhalatory with pulmonary absorption
- was transitioned to the oral route, using an oil-based capsule, which would be more
suitable for studies and for future market distribution as medication. However, oral
biodisponibility of the oral compound was poor, due to low gastrointestinal absorption
related to CBD lipophilic properties, and to first-pass liver effect. All the same,
a rapid absorption peak serum level occurs after two hours after ingestion[31]. Lipophilic properties and high protein affinity allow rapid and high CBD distribution
in the nervous system and in other tissues. CBD accumulation in adipous tissues in
chronic use remains a concern. CBD should preferably be taken with meals. Intranasal
and transdermal routes are still under investigation[32],[33].
CDB metabolism occurs almost exclusively in the liver, through cytochrome P450 enzymes.
CPY2C219 hydrolyzes CBD to 7-hydroxy-cananbidiol (7-OH-CBD), followed by CYP3A4 9-hydroxy-cannabidiol
(7-OH-CBD) formation. 7-OH-CBD is an inactive metabolite, eliminated in the stools,
and to a lesser extent in urine. CBD has a half-life of 18 to 32 hours, allowing a
twice-a-day dose regimen[34]. One third of patients present tolerance, requiring dose increases. CBD strongly
inhibits CYP2C19 and CYP3A4. Drug interactions are a relevant matter in polytherapy
scenarios[35] ([Table 1]).
Table 1
Most used anti-seizure medications (ASMs) pharmacokinetic interaction with cannabidiol
(CBD). No interaction was observed of CBD with carbamazepine, clonazepam, ethosuximide,
lamotrigine, midazolam, phenytoin, vigabatrin.
|
ASMs
|
Type of Evidence
|
Effect of CBD on ASMs
|
Effect of ASM on CBD
|
|
Clobazam
|
RCT
|
↑ [N-CLB]
|
↑ [7-OH-CBD]
|
|
Gabapentin
|
Preclinical
|
↑
|
↔
|
|
Lacosamide
|
Preclinical, observational
|
↑ (preclinical) ↔ (observational)
|
↑ ((preclinical)
|
|
Levetiracetam
|
Preclinical, RCT
|
↔ (preclinical, RCT)
|
↔ (preclinical)
|
|
Oxcarbazepine
|
Preclinical, RCT, observational
|
↑ (preclinical) ↔ (observational)
|
↑ (preclinical)
|
|
Phenobarbital
|
Observational
|
↔ / ↑
|
no studies
|
|
Stiripentol
|
RCT
|
↔ / ↑
|
?#8595;
|
|
Topiramate
|
Preclinical, RCT, observational
|
↑ (observational, preclinical) ↔ (RCT)
|
↑ (preclinical)
|
|
Valproate
|
Preclinical, RCT, observational
|
↔
|
↔
|
↑ elevation of plasma concentration; ↔ no change in plasma concentration; ?#8595;
decrease in plasma concentration; CBD: cannabidiol; RCT: Randomized controlled trial;
ASM: Anti-seizure medication.
CBD and clobazam (CLB) interactions are well recognized and relevant in clinical practice.
Clobazam is metabolized by the P450 cytochrome complex: CYP3A4 metabolizes CLB to
the active N-methyl clobazam (N-CLB) metabolite, and CYP2C19 metabolizes N-CLB to
an inactive metabolite. CBD inhibits CYP2C19, resulting in increased N-CLB. Likewise,
CLB increases CBD 7-hydroxy-cannabidiol, without increasing CBD levels. These interactions
lead to increased side effects, such as sedation, drowsiness and fatigue. A meta analysis
study demonstrated that CBD anti seizure effect occurred whether or not associated
with CLB[36]. CBD action may be synergistic in the GABA-A receptor, with a possible action on
GPR55 receptor[37].
CBD- valproate interaction is also clinically relevant. CBD does not influence VPA
levels, and VPA does not influence CBD pharmacokinetics. Clinical studies showed increased
liver enzymes, especially when CBD and VPA were used in association, possibly through
potentialization of hepatotoxic effect in the mitochondria[38].
Stiripentol, an antiseizure medication used for Dravet Syndrome (in addition to CLB
and VPA) is also a CYP inhibitor, leading to CLB and N-CLB increases. Stiripentol
does not significantly influence CBD pharmacokinetics, leading to decreased CBD metabolites.
Stiripentol levels are mildly increased, when used in combination with CLB[38].
Drug-to-drug interactions must also be considered not simply for anti seizure medications.
Rapamycin inhibitors, used to treat subependymal giant cell astrocytomas and renal
angiomyolipomas in tuberous sclerosis, in association with CBD, may lead to increased
sirolimus, tacrolimus and everolimus levels, through CYP3A4 inhibition[39]. Methadone[40] and warfarin[41] levels are increased when used in combination with CBD.
EFFICACY AND SAFETY IN CLINICAL TRIALS
EFFICACY AND SAFETY IN CLINICAL TRIALS
Dravet syndrome (DS)
Dravet syndrome is a childhood onset epileptic encephalopathy. Most patients have
a loss-of-function mutation in the voltage gated sodium channel α1 gene (SCN1A gene),
and present prolonged focal and generalized seizures (absences, tonic-atonic, myoclonic
and tonic-clonic seizures). Developmental delay and psychomotor changes are commonly
seen. Two large clinical trials of CBD use in DS were completed - GWCAR1b[16], in 2017 and GWCARE2, in 2020[19].
GWCAR1b enrolled 120 children and adolescents to evaluate efficacy as an add-on medication
against placebo of a 20 mg/kg/d CBD dose at 14 weeks. Mean convulsive seizure reduction
at 14 weeks of treatment was 38.9% versus 13.3% in the control group (p=0.01). There
was a high rate of side effects in the CBD group (93%), compared to 75% in the placebo
group. Eighty nine percent of side effects were deemed mild to moderate. Most common
side effects were drowsiness, diarrhea, hyporexia and fatigue. Drug discontinuation
due to side effects was 13% in the CBD group versus 2% in the placebo group[16].
GWCARE2 studied 199 children using a similar protocol in three groups: CBD 10 mg/kg/d,
CBD 20 mg/kg/d and placebo, in an add-on regimen. Mean seizure reduction was 48.7%,
45.7% and 26.9% respectively, statistically significant for 20 mg/kg (p= 0.03), and
for 10mg/kg (p= 0.01), compared to placebo. An elevated rate of side effects was reported
for all groups: 89.9% in the 20mg/kg group, 87.5% in the 10mg/kg group, and 89.2%
in the placebo group. Ninety two percent of side effects were mild to moderate. Withdrawal
rate was higher in the CBD 20mg/kg/d (9%), compared to 4.5% in the CBD 10 mg/kg/day,
and zero in the placebo group. The most common side effects were hyporexia, diarrhea,
drowsiness and fatigue. The highest incidence of drowsiness and pneumonia was noted
with concomitant clobazam use. Elevated liver enzymes were seen in 12% of patients,
all of them using valproate[19].
An interim analysis of the long-term three year study, GWPCARE5, was published in
2021. This was an open-label trial that enrolled 315 of the patients that had participated
in GWPCARE1b and GWPCARE2. GWPCARE5 analyzed efficacy data at 156 weeks, and safety
data at 203 weeks. The mean CBD dose was 22 (range 20-24) mg/kg/day, and efficacy
in reducing drop seizures was sustained at 156 weeks: 83% of patients reported an
improved global condition during the whole follow-up period. Approximately 97% of
patients reported side effects. In 72% of those, side effects were mild to moderate.
Most relevant severe side effects were status epilepticus, convulsion, pneumonia and
fever. Increased liver enzymes (three times or more above the upper limit of normal)
was seen in 22% of patients (84% of whom with concomitant valproate use). Abnormal
values were reverted in 86% of cases. Withdrawal rate was 45%. The main reasons for
withdrawal were patient/guardian decision (19%) and side effects (8%)[42].
Post hoc analysis of GWPCARE1b and GWPCARE2 319 patients was published in 2021 and evaluated
time-to-efficacy and side effect duration. CBD led to significant seizure frequency
reduction at two weeks of treatment (bearing in mind that all patients attained a
10 mg/kg/day dose at day seven in both studies). Fifty two percent of patients displayed
side effects within two weeks of dose titration. Most common side effects were drowsiness,
hyporexia and diarrhea, which were resolved within four weeks in most patients[43].
Lennox-Gastaut syndrome (LGS)
Lennox-Gastau is a childhood onset epileptic encephalopathy characterized by significant
cognitive impairment, multiple seizure types, and abnormal EEG findings - background
slowing and slow-spike and wave complexes. Two randomized studies of CBD effect in
an add-on regimen on drop seizures in LGS - GWPCARE3 (17) and GWPCARE4[18] were published in 2018.
GWPCARE3 enrolled 223 patients, randomized to 10 mg/kg/d, 20 mg/kg/d and placebo.
Primary endpoint with median drop seizure reduction was 37.2, 41.9 e 17.2% after 14
weeks of treatment respectively, statistically significant for 20 mg/kg (p= 0.005)
and for 10mg/kg (p=0.002), compared to placebo. A high incidence of side effects was
noted in all groups: 94% in the 20mg/kg group, 84% in the 10mg/kg group and 74% in
the placebo group. Eighty nine percent of side effects were mild to moderate. Most
common side effects were drowsiness, hyporexia and diarrhea. Treatment drop-out rates
were low: 1.5% in the 10mg/kg/d, 7.3% in the 20 mg/kg/d, and 1.3% in the placebo group.
A 50% discontinuation rate was attributed to medication side effects, especially for
important transaminase elevation[17].
GWPCARE4 enrolled 171 patients randomized to CDB 20 mg/kg/d and placebo. Primary endpoint
with median drop seizures reduction was 43.9% and 21.8% (p= 0.0135) at 14 treatment
weeks, respectively. Side effects occurred in 86% of the intervention group and 69%
of the control group. Eighty six percent of side effects were mild to moderate. Most
common side effects were diarrhea, drowsiness, pyrexia, hyporexia, and vomiting. Treatment
withdrawal was higher than in the other randomized controlled trial: 16% in the intervention
group, and 1.2% in the placebo group. Eighty five percent of discontinuation was attributed
to side effects, especially to significant increase in transaminase levels[18].
The final three-year long-term analysis - GWPCARE5 - an open-label trial enrolling
366 of LGS patients that participated in GWPCARE3 and GWPCARE4 was published in 2021.
Efficacy data was evaluated at 156 weeks and safety data at 203 weeks. Median dose
was 24 (range 2.5-30) mg/kg/d, and effectiveness in drop seizure reduction was sustained
at 156 weeks. Eighty seven percent of patients reported improved overall conditions
during the whole follow-up period. Ninety six percent of patients reported side effects,
of which 68% were classified as mild and moderate. Most important severe side effects
were convulsion, status epilepticus and pneumonia. Increased transaminases three times
above the upper limit of normal was noted in 15% of patients, of whom 73% were taking
concomitant valproate. Values reverted to normal in 95% of cases. Withdrawal rate
was 33%. Main causes were attributed to patient/guardian decision (13%) and side effects
(10%)[44].
A post-hoc analysis of time to efficacy and side effect duration in the 396 patients
participating in GWPCARE3 and GWPCARE4 was published in 2021. CBD led to significant
reduction of drop seizure frequency at six days after initiating treatment (bearing
in mind that all patients attained at least 10 mg/kg/d dose at day seven in both studies).
Forty five percent of patients reported side effects within two weeks of dose titration.
Most common side effects were drowsiness, hyporexia and diarrhea, which was resolved
within four weeks in more than half of the patients[45].
Tuberous sclerosis complex (TSC)
Tuberous sclerosis is an autosomal dominant disease due to a TSC1 and/or TSC2 gene
mutation leading to rapamycin (mTOR) pathway upregulation, predisposing to benign
tumors (eye, skin, heart, kidney, lung and brain). A randomized controlled trial of
CBD in an add-on regimen in epilepsy related to the TSC complex - GWPCARE6 - was published
in 2020[20].
GWPCARE6 enrolled 224 patients randomized to CDB 25 mg/kg/d, 50 mg/kg/d and placebo.
The primary outcome, mean seizure reduction at 14 weeks of treatment, was 48.6, 47.5
and 26.5%, respectively, statistically significant for 25 mg/kg (p< 0.001) and for
50 mg/kg (p=0.002), compared to placebo. A high incidence of side effects was reported
for all groups: 93% for the 25 mg/kg group, 100% for the 50mg/kg group and 95% for
the placebo group. Eighty eight percent of side effects were considered mild to moderate.
Most common side effects were diarrhea, drowsiness and hyporexia. Treatment withdrawal
was low: 10.7% in the no 25 mg/kg/d group, 13.7% in the 50 mg/kg/d group and 2.6%
in the placebo group. Treatment discontinuation was attributed to medication side
effects in 78% of cases, importantly related to transaminase elevation[20].
A post-hoc analysis GWPCARE6 evaluated 224 patients regarding time to efficacy and
side effect duration. CBD led to important seizure reduction frequency within six
days of treatment initiation at 15 mg/kg/d de CBD, with a more important improvement
in seizure reduction at 10 days, at a 25 mg/kg/d dose. Sixty four percent of patients
reported side effects within two weeks of dose titration. More common side effects
were: drowsiness, hyporexia and diarrhea, which was resolved within four weeks in
about half of the patients[46].
Data regarding CBD efficacy as add-on therapy in Dravet, LGS and tuberous sclerosis
are presented in [Figure 1]. Data regarding tolerability of CBD in the five trials are presented in [Figure 2].
Figure 2 Tolerability profile of Cannabidiol (CBD) during the 14-week-treatment of the five
randomized cannabidiol clinical trials in patients with Tuberous Sclerosis Complex
(TSC), Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome (DS). Doses: 10 mg/kg/d (CBD
10), 20 mg/kg/d (CBD 20), 25 mg/kg/d (CBD 25) and 50 mg/kg/d (CBD 50). A) Withdrawal
analysis; B) Serious adverse events (altered transaminases and pneumonia) and more
common adverse events (decreased appetite, diarrhea, drowsiness)
EVIDENCE IN OTHER EPILEPTIC SYNDROMES
EVIDENCE IN OTHER EPILEPTIC SYNDROMES
Open-label trials with less stringent methodology suggest possible benefits for epileptic
encephalopathies, such as Doose and Aicardi syndromes, CDKL5 deficiency and Dup15q[47]-[50]. A randomized controlled trial for CBD in infantile spasms (GWPCARE7) is currently
in the data analysis phase[51].
In adult patients with focal refractory epilepsy, CBD studies are scarce and evidence
for CBD efficacy is still lacking[52]. Fragmentary evidence is based on observational studies, case reports and subgroup
analysis. CBD doses ranged from 5-50 mg/kg/day, with improved seizure control. Among
different etiologies CBD use has been reported in Sturge-Weber syndrome, focal cortical
dysplasia, lissencephaly, brain tumor-related epilepsy, and frontal and temporal lobe
epilepsy of unknown etiology. In the emergency setting and status epilepticus treatment,
benefit has been reported in children with febrile infection-related epilepsy syndrome
(FIRES)[53] and in a case report of a young man with new-onset refractory status epilepticus
(NORSE)[54] presented significant improvement that was temporally related to CBD initiation.
Adverse effects profile does not differ from those reported on the DS and LGS trials.
Reported side effects include: drowsiness, gastrointestinal symptoms, hyporexia and
weight loss[47]-[50].
EVIDENCE FOR SYNTHETIC CANNABIDIOL
EVIDENCE FOR SYNTHETIC CANNABIDIOL
Epidiolex® is the only Cannabidiol-based medication used in randomized controlled
clinical trials. Epidiolex® is a purified product directly extracted from the Cannabis plant. There is a current debate regarding the efficacy of synthetic CBD. An open-label
study showed similar efficacy and safety profiles[55],[56]. A more widespread use of synthetic CBD is still viewed with hesitancy. Proponents
for natural CBD argue for a possible “entourage effect”, that proposes that different
Cannabis components could enhance antiepileptic effect, not properly assessed in current studies.
Some put forward the argument that plant-derived Cannabis would be more natural, with fewer side effects[57]. Synthetic Cannabis may be more appropriate for large-scale production, possibly
with less environmental impact.
CURRENT BRAZILIAN STATUS
Federal Medicine Council (Conselho Federal de Medicina) resolution number 2113 of
October 30th, 2014 set the rules for compassionate CBD use as a medical therapy, restricted
to the treatment of childhood and adolescence epilepsy refractory to conventional
therapies[58]. Individuals or their legal proxies were allowed to import CBD for personal use,
under prescription of a licensed professional. The patient was required to fill in
a form in the National Sanitary Agency (Anvisa). Due to the morosity of paperwork
for importation licensing and to high demand, Anvisa authorized production and utilization
of cannabinoid medications in Brazil in 2019, but did not register cannabinoids as
a medication, but rather as a product under different regulatory rules[59]. Brazil followed similar models as other countries, such as Canada, Germany, Portugal
and Australia with the intent of allowing faster and more widespread access to the
population. Brazil did not register cannabidiol as a medication, but as a Cannabis
product. A Collegiate Board Resolution 327/2019 created this novel category to allow
for a faster approval of quality products, which are subject to all requirements for
approval as a medication, except for the requirement of complete safety and efficacy
data. These products are not subject to price control by the Anvisa Medication Market
Regulation Chamber. In order to receive approval to commercialize in the Brazilian
Medication Market, the pharmaceutical industry must apply for a special authorization
adhering to prerequisites such as holding a Good Practice Certificate for the Production
of Medications. Prati-Donaduzzi was the first pharmaceutical company to be authorized
to produce and commercialize cannabidiol in Brazilian pharmacies. Cannabis products,
composed exclusively of Cannabis sativa-derived products, must predominantly contain CBD, with no more than 0.2% tetrahydrocannabinol
(THC). CBD concentrations above 0.2% should be destined to patients under palliative
care, in clinically irreversible or terminal conditions. Other requirements for approval
as a product include sanitary license to manufacture and import limited to five unextendable
years. Imported Cannabis products must be approved for use in their country of origin
and a box warning reading “this product was not evaluated for efficacy and safety
by Anvisa” is required, thus placing responsibility for efficacy and safety upon the
prescribing physician and the manufacturer, and requiring that the patient or legal
proxy sign an informed consent form. Prescription requires a special controlled medication
formulary, and can be acquired in regular pharmacies[59].
In the Brazilian Public Healthcare System (Unified Health System - SUS), the Clinical
Protocol and Therapeutic Directives - Protocolo Clínico e Diretrizes Terapêuticas
(PCDT) for epilepsy, published in 2018, included the following anti seizure medications:
sodium valproate, carbamazepine, clobazam, clonazepam, ethosuximide, phenytoin, phenobarbital,
gabapentin, lamotrigine, levetiracetam, primidone, topiramate and vigabatrine[60]. Cannabis products are not listed in the medication list offered by SUS at no cost.
The National Commission for Technology Incorporation - Comissão Nacional de Incorporação
de Tecnologias (CONITEC) - following an intensive study of current evidence and cost-benefit
analysis of the only available Cannabis product licensed at the time for commercialization
in Brazil recommended to SUS against incorporation of this CBD product in 2022. Three
studies from 2017 and 2018 on efficacy and safety - GWPCARE3 and CWPCARE4 involving
Lennox-Gastaut patients and GWPCARE1b involving Dravet patients, were evaluated[61]. Cost-benefit studies were performed with an estimate cost of 1850.41 Brazilian
Reais (including taxes), or approximately US$379.95 for a 30ml 200mg/ml vial at an
annual cost of R$74,865 per patient (US$15,373), with an annual budget impact of 70
to 80 million reais (US$14 to 16 million). Cannabidiol received a 0.32 QALY value
(quality-adjusted life year - in which 1 QALY indicates one year of perfect healthy
life). Cannabidiol currently presents a higher cost than standard treatment, with
an investment of 1600 Brazilian Reais (approximately US$334) to prevent an epileptic
seizure and R$ 3,6 million or US$764,000) for each QALY point increase - well above
standard QALY of 0,7 to 3 per capita Gross National Product PIB required for approval
of a medication in the public National Health System in Brazil. Additionally, variability
of Cannabis products presentation, lack of proof of equivalence and interchangeability
between products and those used in clinical trials, as well as uncertainty regarding
efficacy and Cannabis products magnitude of effect for the proposed use were further
limitations for approval for Cannabis products in the Brazilian Public System.
In the Private Healthcare System in Brazil, CDB products are still not included in
the National Agency for Supplementary Healthcare Mandatory coverage procedures for
Healthcare plans.
Internationally, cannabidiol use for refractory epilepsy was evaluated by Agencies
in England (National Institute for Health and Care Excellence - NICE), Scotland (Scottish
Medicines Consortium - SMC) and Argentina (Administracion Nacional de Medicamentos,
Alimentos y Tecnologia Médica - ANMAT)[43]. Following approval of Epidiolex, these agencies strongly recommended its exclusive use for Dravet[38],[39] and Lennox-Gastaut syndromes[38],[40].
As of February 2022, in Brazil, 14 Cannabis-derived products can be manufactured and
commercialized in pharmacies, including: Canabidiol Prati-Donaduzzi (20 mg/mL; 50
mg/mL and 200 mg/mL); Cannabidiol NuNature (17,18 mg/mL); Cannabidiol NuNature (34,36
mg/mL); Cannabidiol Farmanguinhos (200 mg/mL); Cannabidiol Verdemed (50 mg/mL); Cannabis
sativa Extract Promedio (200 mg/mL); Cannabis sativa Extract Zion Medpharma (200 mg/mL);
Cannabidiol Verdemed (23,75 mg/mL); Cannabis sativa Extract Alafiamed (200 mg/mL);
Cannabis sativa Extract Greencare (79,14 mg/mL); Cannabis sativa Extract Ease Labs
(79,14 mg/mL); Canabidiol Belcher (150 mg/mL); Cannabidiol Aura Pharma (50 mg/mL);
and Cannabidiol Greencare (23,75 mg/mL)[62]. Efforts have been made to facilitate the import of a 288 Cannabidiol product list,
including Epidiolex, through an online form[63].
The only study involving the Brazilian population was carried out in 1980. This study
evaluated 15 patients with at least one focal temporal lobe seizure per week evolving
to bilateral tonic clonic seizures for at least one year. Patients were randomized
to receive 200-300 mg/day of cannabidiol (manufactured in Israel). Four patients showed
a marked improvement in an up-to-18-week follow-up. Limitations include the fact that
criteria for refractory epilepsy were not established at the time, and medications
used included primidone, phenobarbital, phenytoin and clonazepam, some in monotherapy.
Doses were not presented in the paper, hindering evaluation as to whether anti seizure
medication dosage was optimized[12]. No other population observational or interventional study has been performed in
Brazilian subjects so far.
For literature searches, we employed descriptors chosen based upon scientific-technical
MeSH (Medical Subjective Heading) and DeCS (Descriptor in Health Sciences) terms,
such as “Cannabis”, “Cannabis sativa”, “Cannabidiol”, “Epilepsy” and “Brazil”, in
English, Portuguese and Spanish. To our knowledge, there is currently only one ongoing
clinical trial with Brazilian subjects (NCT02783092) recruiting two- to 18-year-old
patients with refractory epilepsy fulfilling ILAE (International League Against Epilepsy)
criteria[64]. This study will evaluate clinical response to purified CBD available in Brazil,
at 5-25 mg/kg/day doses. This study was initiated in 2019, with completion foreseen
in the fourth quarter of 2021[64].
PROPOSED ALGORITHM FOR CBD USE IN REFRACTORY EPILEPSY
PROPOSED ALGORITHM FOR CBD USE IN REFRACTORY EPILEPSY
A proposed algorithm for CBD use in medically refractory epilepsy is presented in
[Figure 3]
[65].
Figure 3 Algorithm for use of CBD in epilepsy. Adapted from von Wred R et al (2021)[65].AEDs: antiepileptic drugs; DS: Dravet Syndrome; LGS: Lennox-Gastaut Syndrome; TSC:
Tuberous Sclerosis Complex; VNS: vagus nerve stimulation; DBS: deep brain stimulation;
FDA US: Food and Drug Administration; EMA: European Medicine Agency; ANVISA: Brazilian
Health Regulatory Agency; CBD: cannabidiol; VPA: valproate; CLB: clobazam; ULN: upper limit of normal.
In conclusion, epilepsy burden, especially medically refractory epilepsy, affects
patients and families, particularly for medically refractory epilepsy[66]. CBD offers hope in treating epilepsy. Current evidence demonstrates efficacy and
safety in prescribing CBD for Dravet and Lennox-Gastaut syndrome and Tuberous Sclerosis
Complex. Newer randomized studies are currently underway to evaluate CBD use in other
epilepsy types. Caution is advised against indiscriminate CBD use. CBD has a powerful
marketing appeal that may risk foregoing significant lacunae in scientific knowledge
that need to be clarified and better understood in order to delineate rational CBD
use in epilepsy. Medically refractory epilepsy encompasses a heterogenous group of
conditions, and currently available RCT results should not be automatically extrapolated
to other epilepsy conditions.
CBD access is hindered by elevated costs that cannot be afforded by the majority of
the Brazilian population. In addition to acquisition of further scientific knowledge
regarding Cannabis products, public healthcare policies must be implemented to allow
widespread access to Cannabis products in Brazil and worldwide. Production of purely
synthetic products with equivalent efficacy compared to natural Cannabis products may decrease production cost, and, consequently, price. Recently approved
legislation and resolutions should facilitate a growing scientific knowledge of Cannabis-derived
products, as well as facilitating promotion of strategies to a more widespread use
of these products.
Lastly, current CBD prescription patterns raise concerns as to indiscriminate use.
Individual clinical and pharmacological responses must be strictly evaluated to allow
scientifically-based CBD use. Careful dose titration and side-effects monitoring are
key to maximizing tolerability of Cannabis products. Patient and family expectations
of treatment results (sometimes previously artificially inflated) must be adjusted
in order to promote better quality of life for people with medically refractory epilepsy.
