## 4 Discussion  
Efficacy and safety of nabiximabs have been demonstrated in several clinical trials [13; 15; 22; 23; 24] and post-marketing observational studies, particularly as an add on treatment [25; 26; 27; 28; 29]. To date, this is the first real-world study investigating the use of nabiximabs in an MS population that includes a large proportion (43%) of subjects receiving nabiximabs as a monotherapy against spasticity and related symptoms. Firstly, by using the same definition of clinically relevant responder status and the same clinical scores, we found a higher proportion of responders to nabiximabs (48%) compared with pre-approval clinical trials (36-40%) [15; 23] and post-marketing observational studies (30-41%) probably due to different populations and time windows for responder-status evaluation. Actually, previous studies required patients to qualify as early responders, defined as a \(\geq\)20% sNRS improvement at 4 weeks, in order to continue nabiximabs treatment and be evaluated as a \(\geq\)30% sNRS improvement responders at a later time point of 12 weeks [25; 26; 30; 31]. In contrast, we observed all patients until 12 weeks when responder status was evaluated as \(\geq\)30% sNRS improvement. A single Belgian retrospective study found a higher number of treatment responders (74%), possibly confounded by recall bias [32]. Treatment response was consistent among all outcome measures, as responders to nabiximabs also had significantly improved spasticity-related symptoms including pain, as well as spasticity-related urinary and gait problems, compared to non-responders [13; 15; 22; 23]. In line with the registration clinical trial [13; 15; 22; 23; 33; 34] and associated extension studies [33; 34; 35], discontinuation rate in our study was low (5%) and mainly due to dizziness and fatigue. Accordingly, our patients showed a high treatment satisfaction and tolerability scores. However, various side effects have previously been described in the course of nabiximabs therapy. Among these, the most frequent are dizziness and fatigue, followed by dry mouth, balance impairment, nausea, headache, oral pain, somnolence, confusion, depressed mood, constipation, disorientation, dysgeusia, disturbance in attention, euphoric mood, vision blurred, and weakness [10]. Importantly, we conducted an analysis to identify patients' baseline features predicting treatment response. We found that lower EDSS was associated with higher probability of responding to nabiximabs. While this was not confirmed after weighting for other variables, lower EDSS was consistently associated with a reduction of at least 30% in spasticity associated pain. Instead, a post hoc analysis of the SAVANT study showed a reduction in sNRS and pNRS under nabiximabs treatment irrespective of patients' baseline characteristics, including EDSS [36]. This discrepancy might be related to differences in patients' characteristics across studies, and to the observation by [PERSON] et al. that less disabled MS patients are less prone to develop adverse events and discontinue nabiximabs in real world clinical practice [37]. Intriguingly, we did not find evidence of an association between responder status and the use of nabiximabs either as monotherapy or add-on treatment. This suggests that monotherapy with nabiximabs is effective against spasticity at least in some patients. Clinicians could therefore evaluate the opportunity to taper or discontinue other symptomatic therapies for spasticity in selected patients once nabiximabs has been started with beneficial effects. Our study has three main limitations. The first is the small sample size. A larger sample size might have perhaps allowed detection of different responses to nabiximabs in patients treated with high effective disease modifyng therapies (DMTs), those treated with low effective DMTs and patients untreated. The second limitation is the use of a patient-reported outcomes (PROs) measure, as sNRS, to assess the nabiximabs response.