Effect of THC-CBD oromucosal spray (Sativex) on measures of spasticity in multiple sclerosis: A doubleblind, placebo-controlled, crossover study

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.