CLAE 2016 Dr Mark Sadler Dalhousie University Halifax NS Disclosures I have received honoraria from Eisai and UCB Canada I have no disclosures relevant to this presentation Previous Speakers ID: 754787
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The Case Against Medical Marijuana in Epilepsy CLAE 2016
Dr. Mark SadlerDalhousie UniversityHalifax, NSSlide2
DisclosuresI have received honoraria from Eisai and UCB Canada
I have no disclosures relevant to this presentationSlide3
Previous SpeakersDr
Richard McLachlanDr Mac BurnhamDr
Jose Tellez-ZentenoSlide4
The Question: Is Marijuana Useful in the Treatment of Epilepsy?Slide5
Is This Really Even of Interest?Google Search: “Epilepsy” and “Marijuana”Slide6
Is This Even of Interest?
Google Search: “Epilepsy” and “Marijuana”Apparently so (to a lot of people)Slide7
How about EVIDENCE from Medical Literature?(Quick search: PubMed Sept 2016: no filters)Slide8
How about EVIDENCE from Medical Literature?
(PubMed Sept 2016)Filter for past
10 years: 237 reduced to 120Slide9
How about EVIDENCE from Medical Literature?
(PubMed Sept 2016)Past 10 years
Filter forPast 5 years
Comment: The recent literature is growing “like a weed”Slide10
How about EVIDENCE from Medical Literature?(PubMed Sept 2016)
X
XSlide11
EBM: Any Systematic Reviews?Slide12
EBM: Any Systematic Reviews?Slide13
Gloss B, Vickrey B: Cannabinoids for Epilepsy.
(Current as of Sept 2013)Objective: To assess the efficacy and safety of cannabinoids when used as monotherapy or add-on treatment for people with epilepsySlide14
Gloss B, Vickrey B: Cannabinoids for Epilepsy.
(Current as of Sept 2013)Objective: To assess the efficacy and safety of cannabinoids when used as monotherapy or add-on treatment for people with epilepsy
Search Methods: Cochrane Epilepsy Group Specialized Register, Cochrane Central Register of Controlled Trials, MEDLINE (Ovid), ISI Web of Knowledge, CINAHL (EBSCOhost), and ClinicalTrials.gov. In addition, included studies authors personally knew about that were not found by the searches, as well as searched the references in the identified studies.Slide15
Gloss B, Vickrey B: Cannabinoids for Epilepsy.
(Current as of Sept 2013)Selection criteria: Randomized controlled trials (RCTs) whether blinded or notSlide16
Gloss B, Vickrey B: Cannabinoids for Epilepsy.
(Current as of Sept 2013)Selection criteria: Randomized controlled trials (RCTs) whether blinded or notData analysis:
Primary outcome: seizure freedom at one year or more, or three times the longest interseizure intervalSecondary outcome: responder rate at six months or more, objective quality of life data, and adverse events.Slide17
Gloss B, Vickrey B: Cannabinoids for Epilepsy. (Current as of Sept 2013)
RESULTS
4 randomized trial reports that included a total of 48 (!!)patients Each used cannabidiol
as the treatment agent
One report was an abstract; one was a letter to the editor.
Details of randomisation were not included in any study report
No investigation of whether the control and treatment participant groups were the same or different.
“All the reports were low quality”
None of the patients in the treatment groups suffered adverse effects
.Slide18
Gloss B, Vickrey B: Cannabinoids for Epilepsy. (Current as of Sept 2013)
RESULTS
4 randomized trial reports that included a total of 48 (!!)patients Each used cannabidiol (CBD) as the treatment agent
One report was an abstract; one was a letter to the editor.
Details of randomisation were not included in any study report
No investigation of whether the control and treatment participant groups were the same or different.
“All the reports were low quality”
None of the patients in the treatment groups suffered adverse effects.Slide19
Gloss B, Vickrey B: Cannabinoids for Epilepsy. (Current as of Sept 2013)
RESULTS
4 randomized trial reports that included a total of 48 (!!)patients Each used cannabidiol as the treatment agent One report was an abstract; one was a letter to the editor.
Details of randomisation were not included in any study report
No investigation of whether the control and treatment participant groups were the same or different.
“All the reports were low quality”
None of the patients in the treatment groups suffered adverse effects
.Slide20
Gloss B, Vickrey B: Cannabinoids for Epilepsy. (Current as of Sept 2013)
RESULTS
4 randomized trial reports that included a total of 48 (!!)patients Each used cannabidiol as the treatment agent One report was an abstract; one was a letter to the editor. Details of randomisation were not included in any study report
No investigation of whether the control and treatment participant groups were the same or different.
“All the reports were low quality”
None of the patients in the treatment groups suffered adverse effects.Slide21
Gloss B, Vickrey B: Cannabinoids for Epilepsy. (Current as of Sept 2013)
RESULTS
4 randomized trial reports that included a total of 48 (!!)patients Each used cannabidiol as the treatment agent One report was an abstract; one was a letter to the editor. Details of randomisation were not included in any study report
No investigation of whether the control and treatment participant groups were the same or different.
“All the reports were low quality”
None of the patients in the treatment groups suffered adverse effects.Slide22
Gloss B, Vickrey B: Cannabinoids for Epilepsy. (Current as of Sept 2013)
RESULTS
4 randomized trial reports that included a total of 48 (!!)patients Each used cannabidiol as the treatment agent One report was an abstract; one was a letter to the editor. Details of randomisation were not included in any study report
No investigation of whether the control and treatment participant groups were the same or different.
“All the reports were low quality”
None of the patients in the treatment groups suffered adverse effects.Slide23
Gloss B, Vickrey B: Cannabinoids for Epilepsy. (Current as of Sept 2013)
RESULTS
4 randomized trial reports that included a total of 48 (!!)patients Each used cannabidiol as the treatment agent One report was an abstract; one was a letter to the editor. Details of randomisation were not included in any study report
No investigation of whether the control and treatment participant groups were the same or different.
“All the reports were low quality”
None of the patients in the treatment groups suffered adverse effects.Slide24
Gloss B, Vickrey B: Cannabinoids for Epilepsy. (Up-to-date Sept 2013)
CONCLUSIONS
No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol
was safely administered to small numbers of patients generally for short periods of time, and so the safety of long term
cannabidiol
treatment cannot be reliably assessed.Slide25
The Trial: Lancet Neurology 2016;15:270-78 (online December 23, 2015)Slide26
MethodsDevinsky et al 2016
Multicenter ( N= 11); recruitment over 12 months; US of APatients 1-30 yearsSevere medically resistant epilepsy
Uncontrolled, open label, add on CBD 2-5mg/kg titrated to 25-50 mg/kgPrimary objective: Safety and tolerability of CBDPrimary efficacy endpoint: “Median % change in the mean monthly frequency of motor seizures at 12 weeks”Slide27
Results: Patients:Min 12 weeks F/U
Slide28
PatientsSlide29
Adverse Events (in > 5% of 162 patients):
Somnolence = 25%Decreased appetite = 19%Diarrhoea = 19%Fatigue = 13%Convulsion = 11%Status epilepticus = 8%
A few others…Slide30
Treatment emergent Serious Adverse Effects*(*Investigator reports possibly related to CBD use)
Status epilepticus: 6%Diarrhoea: 2%Several other single instances… Slide31
EfficacyBaseline median monthly f of motor seizures = 30
At 12 weeks = 15.8Median change in monthly motor seizures = - 36.5% 39% of patients had a reduction of 50% or more of motor seizures (5 patients seizure free = 4%) Slide32
Critique and Commentary
Authors’ comments cautious; conservative; acknowledged deficienciesA study of purified “CBD” not “marijuana”No control group;
Unblinded* (see next slide)Short baseline period (4 weeks)About 1/3 of patients had an INCREASE in Sx
f and 1/3 had < 50%
Sx
reduction (Bauer PB, Sander JW Lancet Neurology 2016. Letter to editor).
Effect of CBD on
clobazam
metabolite (N-
desmethyl
clobazam
): Post hoc analysis
70 patients WITH
clobazam
: 51% had >50% reduction in
Sx
f
67 patients NOT taking
clobazam: 27% had > 50% reduction in Sx fSlide33
Importance of Blinding & Placebo: Example(Press CA et al. Epilepsy and Behavior 2015)
Retrospective study of oral cannabis extracts (OCEs) in Rx of pediatric epilepsy in Colorado75 patients of whom 1/3 reported a >50% reduction in Sx
fMajor Result:If parents MOVED to Colorado for OCEs: 47% responder rate vs 22% if already lived in ColoradoSlide34
Return to The Question: Is Marijuana Useful in the Treatment of Epilepsy?
CBD: Worthy of a double blind placebo controlled trial: Sure
√“Marijuana” in various other forms: NO RELIABLE EVIDENCE“Regular marijuana”:Dose?Mode of administration? Smoke: lung function
etc
“Lot-to-lot” variation in concentration?
Adverse effects . See
Volkow
et al NEJM 2016
Therefore: use of “regular” marijuana outside of a clinical trial is…Slide35