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Sativex® and clinical–neurophysiological measures of spasticity in progressive multiple sclerosis

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Abstract

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.

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Acknowledgments

The authors would like to thank Content Ed Net (Madrid, Spain) for editorial assistance with the manuscript and Mrs Raffaella Battisti, Mrs Simona Albanesi and Mr Ennio Comi, Neurological Department, Hospital San Raffaele, for their help in managing study logistics.

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Authors and Affiliations

  1. Neurological Department and INSPE-Institute of Experimental Neurology, Scientific Institute Hospital San Raffaele, Via Olgettina 60, 20132, Milan, Italy

    Letizia Leocani, Arturo Nuara, Elise Houdayer, Ubaldo Del Carro, Stefano Amadio, Laura Straffi, Paolo Rossi, Vittorio Martinelli & Giancarlo Comi

  2. Biostatistics Unit, Department of Health Sciences (DISSAL), University of Genova, Genoa, Italy

    Irene Schiavetti & Maria Pia Sormani

  3. Global Medical Affairs, Almirall S.A., Barcelona, Spain

    Carlos Vila

  4. Vita-Salute University San Raffaele, Milan, Italy

    Letizia Leocani, Arturo Nuara & Giancarlo Comi

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  1. Letizia Leocani
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  2. Arturo Nuara
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Correspondence to Letizia Leocani.

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Conflicts of interest

The study was sponsored by Laboratorios Almirall S.A., Barcelona, Spain. L Leocani has received honoraria/research/travel support from Abbvie, Almirall, Merck Serono and Novartis, unrelated to the present study. A Nuara reports no disclosure. E Houdayer reports no disclosure. I Schiavetti reports no disclosure. U Del Carro reports no disclosure. S Amadio reports no disclosure. L Straffi reports no disclosure. P. Rossi reports no disclosure. V. Martinelli has received compensation for consulting or travel support from Biogen Idec, Genzyme, Merck Serono, TEVA, Novartis, Bayer, Sanofi-Aventis. C Vila is a full-time employee of Laboratorios Almirall S.A., Barcelona, Spain. MP Sormani has received compensation for consulting services and/or speaking activities from Merck Serono, TEVA, Genzyme, Novartis, Biogen Idec, Synthon, Roche, and Actelion. G Comi has received compensation for consulting services and/or speaking activities from Novartis, Teva, Sanofi, Genzyme, Merck Serono, Biogen, Bayer, Serono Symposia International Foundation, Almirall, Chugai and Receptos. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent was obtained from the participants involved.

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Leocani, L., Nuara, A., Houdayer, E. et al. Sativex® and clinical–neurophysiological measures of spasticity in progressive multiple sclerosis. J Neurol 262, 2520–2527 (2015). https://doi.org/10.1007/s00415-015-7878-1

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  • DOI: https://doi.org/10.1007/s00415-015-7878-1

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