The Role of SAtivex® in Robotic-Rehabilitation
The Role of SAtivex® in Robotic-Rehabilitation
Spasticity is frequently experienced by people with Multiple Sclerosis (MS), negatively
 impacting on patient's motor functional outcome, including walking. Currently, none of the
 available MS disease-modifying medications has been shown to stop or reverse gait disability.
 Recently the nabiximols has been tested for the treatment of spasticity and walking
 impairment in MS. Nabiximols (trade name Sativex®) is an oromucosal spray formulation
 containing 1:1 fixed ratio of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)
 derived from cloned Cannabis sativa L. plant. The main active substance, THC, acts as a
 partial agonist at human cannabinoid receptors (CB1 and CB2), and may modulate the effects of
 excitatory (glutamate-GLU-) and inhibitory (gamma-aminobutyric acid -GABA-)
 neurotransmitters, leading to muscle relaxation, which in turn is responsible for spasticity
 improvement. Cannabinoid receptors may modulate both excitatory and inhibitory transmission
 at central synapses, and have been heavily implicated, in animal models, in multiple forms of
 synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD).
 Indeed, in a previous study implying transcranial magnetic stimulation (TMS) technique, it
 has been hypothesized that the activation of cannabinoid receptors by Sativex® could modulate
 the balance between LTP and LTD like plasticity by changing the state of cortical
 excitability. In a recently study it has been proposed that Sativex may modulate the cortical
 excitability changing the activity of inhibitory GABAergic cortico-cortical synapses. Aim of
 our study is to clarify the role of Sativex coupled to a robotic neurehabilitation training
 in MS patients in improving the motor outcome, by means of clinical, kinematic, beside some
 neurophysiological and measures.
Forthy MS patients affected by gait disturbances and moderate-severe spasticity will be
 enrolled: 20 out of them in treatment with Sativex (Group A) considered as responders and 20
 treated only with the most common antispastic used in MS (Group B). All the 40 subjects,
 divided into two groups (A: Sativex+Lokomat Training and B: other antispastic+Lokomat
 Training), will perform a neurorobotic-assisted gait training (RAGT, each session will last
 at least 45', 3 times per week, for a total amount of 20 treatment's sessions). All patients
 will undergo a complete blind physical and neurological examination, including evaluation of
 disability by means of the Expanded Disability Scale (EDDS) and assessment of spasticity
 using the Modified Ashworth Scale (MAS) and the numerical rating scale (NRS). To clarify the
 role of Sativex® in improving spasticity gait-related symptoms the following scales will be
 also administered: ten meters walking test (10wt), Ambulation Index (AI). Quality of life
 will be evaluated by means of MSQOL 54. The skilled clinician will be blind to the drug
 treatment.Moreover, some electrophysiological parameters to test cortical excitability will
 be also evaluated: motor evoked potentials (MEP) amplitude, short intracortical inhibition
 (SICI) and facilitation (ICF) from the abductor pollicis brevis muscle (APB) of the most
 affected side. The same assessment will be applied in baseline, at the end of the robotic
 training (T1) and 30 days after the end of the nerehabilitation training (T2).
Inclusion Criteria:

 Inclusion criteria were:

 -  age of 18-65 years,

 -  diagnosis of definite relapsing-remitting or primary-progressive Multiple Sclerosis,
 -absence of clinical relapses from no gadolinium enhanced lesions on brain and spinal
 cord MRI performed at least six months prior to study entry,

 -  no mood or sleep disorders (Hamilton score of <17),

 -  a moderate to severe spasticity in at least two districts of upper and/or lower limbs;
 -absence of clinical or neuroradiological relapses from at least six months prior to
 study entry,

 -  Expanded Disability Status Scale (EDSS) total score between 3.5 and 7.0,

 -  no history of psychosis,

 -  no presence of pace-maker, aneurysms clips, neurostimulator or brain/subdural
 electrodes (safety TMS procedure),

 -  right handedness,

 -  central conduction time in upper limbs of <8 ms;

 -  no robotic gait traing contraindications.

 Exclusion Criteria:

 -  History of psychosis,

 -  presence of pace-maker, aneurysms clips, neurostimulator or brain/subdural electrodes
 (safety TMS procedure),

 -  central conduction time in upper limbs of <8 ms;

 -  robotic gait traing contraindications.