title: Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes.
abstract: Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ(9) -tetrahydrocannabinol and cannabidiol (THC/CBD) oromucosal spray in patients with multiple sclerosis (MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo-allocated patients. The overall mean therapeutic gain of THC/CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27-point improvement on the spasticity 0-10 Numerical Rating Scale (NRS; ~-20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid-based medications are being investigated.
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D002185:Cannabidiol / Q000008:administration & dosage*; D002986:Clinical Trials as Topic; D013759:Dronabinol / Q000008:administration & dosage*; D006801:Humans; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D009128:Muscle Spasticity / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D009465:Neuromuscular Agents / Q000008:administration & dosage*; D058993:Oral Sprays; D015990:Placebo Effect
chemical_list: D009465:Neuromuscular Agents; D058993:Oral Sprays; D002185:Cannabidiol; D013759:Dronabinol
keywords: Endocannabinoid system; Multiple sclerosis; Placebo; Spasticity; Δ9-tetrahydrocannabinol and cannabidiol