title: Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-tetrahydrocannabinol in Patients WithProgressive Multiple Sclerosis.
abstract: The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS).
  
  
  
  This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements.
  
  
  
  Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo. Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands. Electronic address: GvAmerongen@chdr.nl.
authors.forename: Guido
authors.initials: G
authors.lastname: van Amerongen
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Kawita
authors.initials: K
authors.lastname: Kanhai
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Anne Catrien
authors.initials: AC
authors.lastname: Baakman
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Jules
authors.initials: J
authors.lastname: Heuberger
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Erica
authors.initials: E
authors.lastname: Klaassen
authors.affiliation: Echo Pharmaceuticals, Weesp, the Netherlands.
authors.forename: Tim L
authors.initials: TL
authors.lastname: Beumer
authors.affiliation: Department of Neurology and Clinical Neurophysiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Rob L M
authors.initials: RLM
authors.lastname: Strijers
authors.affiliation: Department of Neurology and Clinical Neurophysiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: Killestein
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: van Gerven
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Adam
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands; Department of Neurology and Clinical Neurophysiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Groeneveld
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D013759:Dronabinol / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000150:complications / Q000188:drug therapy*; D009128:Muscle Spasticity / Q000188:drug therapy* / Q000209:etiology; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D000075082:Proof of Concept Study
chemical_list: D013759:Dronabinol
keywords: cannabinoid; multiple sclerosis; pain; spasticity; Δ9-tetrahydrocannabinol