## 2 Materials and Methods  
This was a prospective, observational, multicenter Swiss study conducted between July 2020 and June 2021 collecting data on effectiveness, tolerability, safety and patient's satisfaction related to the use of sabiximabs oro-mucosal spray in the treatment of spasticity, pain and other spasticity related symptoms in MS patients.  
Patients affected with MS according to [PERSON] 2017 [16] were recruited during routine neurologic visits upon decision to start a treatment with nabiximabs. Exclusion criteria for nabiximabs treatment were severe cardiovascular diseases, history of psychiatric diseases, and use of street cannabis and/or other psychoactive drugs. All patients signed an informed consent for the use of their clinical data.  
Demographic and clinical data on patients' age, gender, MS course, and disease duration, were collected at baseline and 12 weeks after starting nabiximabs. A complete neurological examination, including evaluation of disability by Expanded Disability Status Scale (EDSS) [17] and spasticity by Modified Ashworth scale (MAS) [18], was performed by the same neurologist at baseline and after 12 weeks, in order to reduce inter-rater variability. Nabiximabs was initiated as a single spray on the evening of the first day of treatment and was gradually titrated by one additional spray every two days until the 4 th day and then by one additional spray per day according to a prespecified dose escalation protocol (swissmedicinfo.ch) until patients experienced acceptable spasticity and pain relief, unacceptable side effects, or reached the maximum allowed daily dosage of 10 sprays per day. Patients were also asked to complete the self-reported scales for spasticity (Numerical Rating Scale for spasticity [sNRS]), spasticity related symptoms as pain (pNRS), urinary disorders (uNRS), gait impairment (gNRS), treatment satisfaction (tsNRS) and tolerability (tNRS) [19].  
The Modified Ashworth Scale (MAS) is the most widely used clinical scale used to measure the increase of muscle tone. [20] It is a 6-point scale for assessing the degree of spasticity, from 0 referring to \"no increase in muscle tone\" to 5 referring to \"limb is rigid in flexion or extension\" [20]. The maximum MAS Score in this study was 5.  
sNRS is a self-reported scale scoring from 0 (no spasticity) to 10 (worst possible spasticity) widely used to assess MS spasticity evolution during treatment with nabiximabs [19]. For the evaluation of spasticity-related symptoms the pNRS, uNRS, and gNRS, scoring from 0 (no symptoms) to 10 (the worst symptoms), were used [19]. Treatment satisfaction and tolerability were investigated at 12 weeks using treatment satisfaction NRS (tsNRS) scoring from 0 (not satisfied at all) to 10 (very satisfied), and tolerability NRS (tNRS) scoring from 0 (lowest tolerability) to 10 (highest tolerability) [19].  
Patients were defined as responders to nabiximabs in case of an improvement of at least 30% in the sNRS score after 12 weeks of treatment [19,21]. In a further analysis, we defined nabiximabs responders as those patients improving by at least 30% in the pNRS score after 12 weeks of treatment, pain being the most frequent and invalidating spasticity-related symptom [8].  
New neurological symptoms and adverse events were registered during each follow-up visit.  
The aims of our study were to: (a) investigate the effectiveness, tolerability and satisfaction of nabiximabs in a real-life multicentric Swiss cohort of MS patients as monotherapy or with a stable doses of other antispastic medications; (b) explore whether clinical features may predict treatment response.