title: Cortical and spinal excitability in patients with multiple sclerosis and spasticity after oromucosal cannabinoid spray.
abstract: BACKGROUND
  Delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) has been recently approved for the management of treatment-resistant multiple sclerosis (MS) spasticity. Although the symptomatic relief of Sativex® on MS-spasticity has been consistently demonstrated, the pathogenetic implications remain unclear and the few electrophysiological studies performed to address this topic yielded controversial results. We therefore aimed to investigate the mechanisms underpinning the modulation of spastic hypertonia by Sativex®, at both central and spinal levels, through an extensive neurophysiological battery in patients with MS.
  
  
  METHODS
  Nineteen MS patients with treatment-resistant spasticity were recruited. Before and after 4weeks of treatment with Sativex® patients were clinically assessed with the Modified Ashworth Scale (MAS) and underwent a large neurophysiological protocol targeting measures of excitability and inhibition at both cortical [e.g., intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)] and spinal level [e.g., H-reflex, H/M ratio and recovery curve of the H-reflex (HRC)]. A group of 19 healthy subjects served as controls.
  
  
  RESULTS
  A significant reduction of the MAS score after 4weeks of Sativex® treatment was detected. Before treatment, an increase in the late facilitatory phase of HRC was recorded in patients compared to the control group, that normalised post treatment. At central level, SICI and LICI were significantly higher in patients compared to healthy subjects. After therapy, a significant strengthening of inhibition (e.g. reduced LICI) and a non-significant facilitation (e.g. marginally increased ICF) occurred, suggesting a modulatory effect of Sativex® on different pathways, predominantly of inhibitory type. Sativex® treatment was well tolerated, with only 3 patients complaining about dizziness and bitter taste in their mouth.
  
  
  CONCLUSIONS
  Our results confirm the clinical benefit of Sativex® on spastic hypertonia and demonstrate that it might modulate both cortical and spinal circuits, arguably in terms of both excitation and inhibition. We suggest that the clinical benefit was likely related to a net increase of inhibition at cortical level that, in turn, might have influenced spinal excitability.
authors: Neuroscience Department, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. Electronic address: giovannamaddalena.squintani@ospedaleuniverona.it.
authors: Giovanna
authors: G
authors: Squintani
authors: Neuroscience Department, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors: Francesco
authors: F
authors: Donato
authors: Neurology Unit, Ospedale Centrale di Bolzano, Italy.
authors: Mara
authors: M
authors: Turri
authors: Neuroscience Department, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors: Luciano
authors: L
authors: Deotto
authors: Neurology Unit, Ospedale Centrale di Bolzano, Italy.
authors: Francesco
authors: F
authors: Teatini
authors: Neuroscience Department, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors: Giuseppe
authors: G
authors: Moretto
authors: Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
authors: Roberto
authors: R
authors: Erro
mesh_terms: D000328:Adult; D000368:Aged; D002185:Cannabidiol; D063385:Cannabinoid Receptor Modulators / Q000008:administration & dosage; D004185:Disability Evaluation; D013759:Dronabinol; D004338:Drug Combinations; D019054:Evoked Potentials, Motor / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006181:H-Reflex / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D009128:Muscle Spasticity / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D059085:Nasal Sprays; D009465:Neuromuscular Agents / Q000008:administration & dosage*; D058993:Oral Sprays; D010936:Plant Extracts / Q000008:administration & dosage*; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D063385:Cannabinoid Receptor Modulators; D004338:Drug Combinations; D059085:Nasal Sprays; D009465:Neuromuscular Agents; D058993:Oral Sprays; D010936:Plant Extracts; D002185:Cannabidiol; D013759:Dronabinol; C587251:nabiximols
keywords: Cannabinoids; Electrophysiology; Inhibition; Multiple sclerosis; Nabiximols; Spasticity