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What is the role of cannabidiol in refractory epilepsy?

LaFleur, Kathryn M.; Nemec, Eric C. II, PharmD, MEHP, BCPS

Journal of the American Academy of PAs: March 2019 - Volume 32 - Issue 3 - p 16–18
doi: 10.1097/01.JAA.0000553393.36249.df
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ABSTRACT The FDA recently approved the first cannabidiol oral medication to treat refractory epilepsy in patients with Dravet syndrome and Lennox-Gastaut syndrome. This article describes the safety and efficacy of cannabidiol treatment in patients with refractory epilepsy.

At the time this article was written, Kathryn M. LaFleur was a student in the PA program at Sacred Heart University in Fairfield, Conn. Eric C. Nemec II is director of research and assessment and a clinical associate professor in the PA program at Sacred Heart University. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Mary Lou Brubaker, PharmD, PA-C, department editor

Figure

Figure

A 7-year-old girl diagnosed with Dravet syndrome has been experiencing seizures refractory to three different antiepileptic medications. Her parents have explored alternative treatment options, including the ketogenic diet, without success. They are not comfortable with their daughter undergoing surgery or vagus nerve stimulation at such a young age. What other treatment options are available for patients with refractory epilepsy?

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A NEW OPTION

Dravet and Lennox-Gastaut syndromes are severe epileptic syndromes that become apparent in early childhood. Dravet syndrome is due to a mutation in the SCN1A gene; Lennox-Gastaut syndrome has several causes and is characterized by drop seizures that can lead to fall injuries.1,2 These syndromes affect patients' quality of life and may increase their mortality risk. Of the 3.4 million patients in the United States with active epilepsy, about one-third have a form of refractory epilepsy, also called drug-resistant, uncontrolled, or treatment-resistant epilepsy.3,4 According to the International League Against Epilepsy, patients are considered to have drug-resistant epilepsy if they do not achieve sustained freedom from seizures after adequate trials of two appropriate antiepileptic drugs (alone or as combination therapy) that were tolerated.5

In June 2018, a nonpsychoactive form of cannabis called cannabidiol was approved by the FDA as a potential treatment for patients with Dravet or Lennox-Gastaut syndromes.6 Cannabidiol is a phytocannabinoid derived naturally from the cannabis plant that lacks the psychoactive or psychotropic effects typically seen in its phytocannabinoid counterpart delta-9-tetrahydrocannabinol (THC).7,8 Because artisanal cannabidiol preparations are unregulated, the cannabidiol and noncannabidiol concentrations can vary widely among dispensaries, leading to variable dosing depending on the product.9 The FDA approval helps standardize the dosing and expands legal access to patients in states that do not have access to medical marijuana.

Unlike THC, cannabidiol does not activate CB1 and CB2 receptors in the endocannabinoid system, which likely accounts for its lack of psychotropic activity; however, the exact mechanism of action of cannabidiol as an antiepileptic is not fully understood.7 Cannabidiol may prevent neuronal hyperexcitability by modulating neuron activity and also may regulate the release of gamma-aminobutyric acid (GABA) and glutamate.7,10

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INDICATIONS

Cannabidiol is indicated for patients age 2 years and older who have seizures associated with Dravet or Lennox-Gastaut syndrome. The 100 mg/mL oral solution can be taken concomitantly with antiepileptic medications. The recommended initial oral treatment is 2.5 mg/kg twice daily, which can be increased weekly by 2.5 mg/kg twice daily as needed to a maximum dose of 10 mg/kg twice daily.11 Slower titration and lower maximum daily dosing may be necessary in patients with preexisting hepatic impairment or those taking certain antiepileptic drugs. Obtain liver function tests before the patient starts cannabidiol, and repeat these tests after 1 month, 3 months, and 6 months of treatment and as clinically indicated.11

Several studies have demonstrated modest efficacy of cannabidiol (defined by a 50% or greater reduction in seizure frequency), with three of the studies each reporting 50% or greater success.12-14 In two additional studies, a portion of the study population became seizure-free with cannabidiol treatment.2,15 In a study on patients ages 2 to 55 years with Lennox-Gastaut syndrome, cannabidiol demonstrated significant reduction of both drop and nondrop seizures in the treatment group compared with the placebo group.16 Although most of the studies demonstrated seizure reduction, one reported that 11% of patients experienced no change in seizure frequency and another reported treatment had no beneficial effect on seizure frequency in nearly 23% of patients.8,14

Study dosing among children varied; however, most studies administered an average dose of 10 mg/kg/day. In a study that used higher dosing (25 mg/kg/day), participants required a dose reduction due to adverse reactions and intolerance.12 Although cannabidiol's antiepileptic mechanism of action is not well known, it is metabolized by the cytochrome P450 pathway, raising concern for interactions with drugs metabolized by CYP2 C19.17 Studies that included monitoring of patient blood serum levels reported elevated liver transaminase and bilirubin (particularly in patients taking valproate), and increased clobazam levels in patients also taking cannabidiol. In addition to adverse reactions, studies also demonstrated unintended positive effects observed in children including improvements in appetite, behavior, sleep quality, and cognitive function.6,8,13 Clinical trials did not include patients older than age 55 years; therefore, cannabidiol should be used cautiously in these patients as it is unknown if they will respond differently than younger patients.11 Dose selection for an older patient typically should start at the low end of the dosing range and be titrated cautiously.11

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CONCLUSION

For patients with refractory epilepsy, adding cannabidiol to the treatment regimen could prove beneficial and could delay or eliminate the need for surgery. The positive benefits associated with seizure control are not limited to decreased morbidity and mortality but include improved physical and cognitive function and improved quality of life.18 Because cannabidiol is a Schedule V controlled substance, physician assistants (PAs) should face few barriers to prescribing it, even in states that restrict PAs' prescriptive authority for medical marijuana.19,20 One foreseeable issue clinicians may encounter in prescribing cannabidiol is a requirement of prior authorization for insurance approval. However, insurance coverage policies and product pricing are yet to be determined.

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REFERENCES

1. Dravet Syndrome Foundation. What is Dravet syndrome? http://www.dravetfoundation.org/what-is-dravet-syndrome. Accessed November 26, 2018.
2. Devinsky O, Patel AD, Cross JH, et al Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378(20):1888–1897.
3. Zack MM, Kobau R. National and state estimates of the numbers of adults and children with active epilepsy: United States, 2015. MMWR Morb Mortal Wkly Rep. 2017;66(31):821–825.
4. Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol. 2017;8:301.
5. Kwan P, Arzimanoglou A, Berg AT, et al Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE commission on therapeutic strategies. Epilepsia. 2010;51(6):1069–1077.
6. US Food and Drug Administration. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm. Accessed November 26, 2018.
7. Anderson C, Evans VF, DeMarse TB, et al Cannabidiol for the treatment of drug-resistant epilepsy in children: current state of research. Pediatr Neurol. 2017;15(4):143–150.
8. Neubauer D, Perković Benedik M, Osredkar D. Cannabidiol for treatment of refractory childhood epilepsies: experience from a single tertiary epilepsy center in Slovenia. Epilepsy Behav. 2018;81:79–85.
9. Porcari GS, Fu C, Doll ED, et al Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: practical experiences in a tertiary medical center. Epilepsy Behav. 2018;80:240–246.
10. Perucca E. Cannabinoids in the treatment of epilepsy: hard evidence at last. J Epilepsy Res. 2017;7(2):61–76.
11. Epidiolex prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed November 26, 2018.
12. Kaplan EH, Offermann EA, Sievers JW, Comi AM. Cannabidiol treatment for refractory seizures in Sturge-Weber syndrome. Pediatr Neurol. 2017;71:18–23.e2.
13. Hausman-Kedem M, Menascu S, Kramer U. Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents: an observational, longitudinal study. Brain Dev. 2018;40(7):544–551.
14. Tzadok M, Uliel-Siboni S, Linder I, et al CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience. Seizure. 2016;35:41–44.
15. Devinsky O, Cross JH, Laux L, et al Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–2020.
16. Thiele EA, Marsh ED, French JA, et al Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085–1096.
17. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246–1251.
18. Rosenberg EC, Louik J, Conway E, et al Quality of life in childhood epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia. 2017;58(8):e96–e100.
19. US Drug Enforcement Administration. FDA-approved drug Epidiolex placed in schedule V of Controlled Substance Act. http://www.dea.gov/press-releases/2018/09/27/fda-approved-drug-epidiolex-placed-schedule-v-controlled-substance-act. Accessed November 26, 2018.
20. American Academy of PAs. PA prescribing authority by state. http://www.aapa.org/pa_prescribing_chart. Accessed November 26, 2018.
Keywords:

cannabidiol; cannabis; epilepsy; refractory epilepsy; Dravet syndrome; Lennox-Gastaut syndrome

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