2.1. Search Strategy

To ensure the quality of our systematic review and meta-analysis, Cochrane methodology recommendations and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement have been followed [12, 13]. We registered the protocol for our analysis to PROSPERO (International prospective register of systematic reviews) (CRD42021282177) and followed the protocol without deviations.

We followed the “PICO-S” (i.e. population, intervention, comparator, outcome, study design) approach for the formulation of the clinical question and defining the eligibility criteria. The population included adult patients (age ≥ 18 years), diagnosed with MS, receiving adequate disease-modifying and antispastic therapy, but with inadequate spasticity response. The intervention was nabiximols as an add-on treatment, while the comparator was a placebo as an add-on treatment. The primary outcome was the spasticity response rate. The secondary outcomes were the change of spasticity and spasticity-related parameters, such as spasticity NRS or VAS; mAS, timed 10-m walk, subject global impression of change (SGIC), sleep disturbance, Barthel Index for Activities of Daily Living (ADL) and quality of life. Regarding study design, only blinded, randomized, placebo-controlled trials were eligible for analysis. Any other study designs were deemed ineligible.

The search was performed within the Web of Science, MEDLINE (via PubMed), Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases on the 15^th of October, 2021. The following search key was used: (multiple sclerosis OR “disseminated sclerosis” OR “encephalomyelitis disseminata”) AND (nabiximols OR Sativex); without filters or restrictions.