Aim of this randomized, double-blind, placebo-controlled, cross-over study is to investigate cannabinoid-induced changes in neurophysiological parameters in a group of 40 patients with secondary or primary progressive Multiple Sclerosis (MS).
Conference»Joint Americas Committee for Treatment and Research in Multiple Sclerosis ACTRIMS—European Committee for Treatment and Research in Multiple Sclerosis ECTRIMS Meeting
Background: THC-CBD oromucosal spray (Sativex) has proven effective in reducing symptoms associated with spasticity in multiple sclerosis-MS. Little is known on the correlates of such effects on objective measures of spasticity (e.g. spinal H reflex) or corticospinal excitability. Objectives: to assess clinical-neurophysiological correlates of Sativex on spasticity in MS. Methods: Subjects with progressive MS (43, 20 females, EDSS 3.5-6) and clinical evidence of spasticity (modified Ashworth scale-MAS >1) were randomized to a 2-week titration plus 2-week stable dose of either active THC-CBD (Sativex) or placebo formulation, followed by a second cross-over cycle after 2-week washout, in a double-blind fashion. Clinical-neurophysiological measures were obtained before and at the end of each phase: MAS, spasticity and pain numeric rating scales-NRS, 10-mt walk, fatigue severity scale, bilateral soleus H/M ratio; Motor Evoked Potential amplitude at 120% threshold and 100% stimulator output, and intracortical inhibition/facilitation. Five subjects dropped (2 during real treatment: 1 for dizziness, 1 subjective weakness; 3 on post-real washout: 1 acute pancreatitis, 1 to enter a rehabilitation program, 1 for family reasons), 4 were not analyzed due to positive THC urine testing on washout. The effect of treatment on changes from baseline was tested using paired Student's t; treatment sequence effect was tested using repeated measures ANOVA, after verifying homogeneity of baselines between subgroups and over time. Results: A significant treatment effect was found on MAS with higher improvement after real vs placebo (-1.51 ± 2.20 vs 0.16±2.55; p = 0.009); improvement in MAS and in NRS spasticity were significantly correlated (r 0.38, p 0.025). MAS responders (at least 20% improvement) were significantly more frequent during real treatment (41.2%) vs placebo (11.8%; χ2=5.56, p 0.018). Neurophysiological measures did not significantly differ according to treatment and were not significantly correlated crosssectionally/ longitudinally with clinical parameters, except for a trend between percent changes in MAS and in H/M (r 0.34, p 0.051). Conclusions: Our findings confirm clinical beneficial effect of THC-CBD on MS spasticity. The lack of corresponding changes on corticospinal excitability and on the monosynaptic component of the stretch reflex point to the relevance of other spinal and supraspinal mechanisms involved in spasticity physiopathology.
Despite the proven efficacy of Sativex(®) (9-delta-tetrahydrocannabinol plus cannabidiol) oromucosal spray in reducing spasticity symptoms in multiple sclerosis (MS), little is known about the neurophysiological correlates of such effects. The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity (H/M ratio) and corticospinal excitability in patients with progressive MS. This was a randomized, double-blind, placebo-controlled, crossover study. Consecutive subjects with progressive MS and lower limb spasticity referred to our center were randomized to 4 weeks' treatment (including 2 weeks' titration) with Sativex or placebo, with crossover after a 2-week washout. Clinical and neurophysiological measures (H/M ratio and cortical excitability) of spasticity were assessed. The H/M ratio was the primary outcome, with sample size calculation of 40 patients. Of 44 recruited patients, 34 were analyzed due to 6 drop-outs and 4 exclusions, which lowered the power of the study to show differences between treatments. Neurophysiological measures did not differ significantly according to treatment and did not correlate significantly with clinical response. Response on the modified Ashworth scale (at least 20 % improvement) was significantly more frequent after Sativex than placebo (50 vs 23.5 %; p = 0.041; McNemar). Side effects did not differ significantly according to treatment. Our findings confirm the clinical benefit of Sativex on MS spasticity. The lack of corresponding changes in corticospinal excitability and on the monosynaptic component, of the stretch reflex, although in a limited sample size, points to the involvement of other spinal and supraspinal mechanisms in the physiopathology of spasticity in progressive MS.
Aim of this randomized, double-blind, placebo-controlled, cross-over study is to investigate cannabinoid-induced changes in neurophysiological parameters in a group of 40 patients with secondary or primary progressive Multiple Sclerosis (MS).
