Evidence-based Management of Multiple Sclerosis Spasticity With Nabiximols Oromucosal Spray in Clinical Practice: A 10-year Recap

Abstract

Effective symptomatic management of multiple sclerosis (MS) spasticity remains an unmet need for many patients. The second-line option nabiximols is the most widely investigated of the noninvasive antispasticity medications in this patient population. Clinical evidence accumulated with nabiximols since it was first approved in Europe in 2010 suggests that about 40% of initial responders (i.e., those with ≥20% improvement in their baseline 0–10 Numerical Rating Scale score) may expect to achieve clinically meaningful (≥30% Numerical Rating Scale response) and durable symptomatic improvement in MS spasticity. During 10 years’ routine use of nabiximols, no new safety signals have emerged. Nabiximols-associated improvement in MS spasticity-related symptoms such as pain and sleep disruption suggests a need to track possible therapeutic effects beyond muscle tone control.

Plain Language Summary

Nabiximols contains two main substances from the cannabis plant, called THC and CBD, which work together to provide symptom relief in persons with multiple sclerosis spasticity. Nabiximols is used as ‘add-on’ treatment in patients who are not gaining enough relief from their current antispasticity medication. Many studies of nabiximols have been carried out over the past 20 years. Overall, about 40% of patients with an early response to nabiximols might expect to achieve a noticeable improvement in spasticity that can last for months or years with continued treatment. Real-world use of nabiximols for the past 10 years shows that it is safe. Importantly, nabiximols can provide noticeable relief of other symptoms associated with spasticity such as spasms, pain and disrupted sleep.

Keywords:

• multiple sclerosis spasticity
• nabiximols
• real-world evidence
• spasticity-plus syndrome

Practice points

• At least one third of patients with multiple sclerosis (MS) spasticity derive insufficient benefit from or poorly tolerate conventional oral antispasticity medications, living with the considerable burden of muscle rigidity and associated symptoms.

• Sativex^® (nabiximols) oromucosal spray, containing balanced quantities of δ-9-tetrahydrocannibinol and cannabidiol, is a second-line option for symptomatic management of MS spasticity.

• Findings of the nabiximols clinical trials program have been corroborated by numerous observational real-world studies conducted since nabiximols was first approved for use in 2010.

• More than half of patients who initiate prescribed nabiximols show an initial treatment response, defined as a ≥20% improvement from baseline in their 0–10 Numerical Rating Scale score after a 4-week trial period.

• More than one third of initial responders may expect to achieve clinically meaningful (≥30% Numerical Rating Scale response) and durable symptomatic improvement in MS spasticity beyond 4 weeks.

• Importantly for patients’ autonomy and daily functioning, nabiximols may improve walking ability and does not impair cognition or driving ability.

• During 10 years’ real-world use of nabiximols, no new safety signals or evidence of abuse, tolerance or dependence potential have emerged.

• Official guidelines recognize the role of nabiximols in the symptomatic management of MS spasticity.

• New evidence indicating that nabiximols improves a range of MS spasticity-related symptoms (spasticity-plus syndrome) suggests a potential role in integrated symptomatic management.

Although some multiple sclerosis (MS) symptoms are envisaged as part of an advanced disease course, patients with MS generally perceive a degree of impairment in most domains as early as the first year of onset [1]. Spasticity is a common symptom of MS, present to some extent in around 80% of patients, and tending to worsen over time [1,2]. Spasticity and associated symptoms (e.g., spasms/cramps, pain, bladder dysfunction, sleep disturbances and fatigue) combine to restrict daily activities [3–7], often with economic consequences in terms of impaired working ability, increased care needs and higher health resource consumption [2,6,8,9]. As walking is a priority bodily function for MS patients [10], many patients consider that spasticity contributes to a relevant part of their disability [2,11]. Treatment should aim to relieve the suffering of MS spasticity and associated symptoms and, as much as possible, related mobility limitations, while leaving patients with sufficient muscle tone to cope with the difficulties of progressive paralysis.

MS management is frequently regarded more in terms of disease-modifying therapy than symptomatic treatment. Not all patients with MS spasticity are offered symptomatic treatments [2,4,5,8], and those who are (and their physicians) are frequently dissatisfied with the effectiveness of conventional first-line oral medications [5,7]. Effective symptomatic management of MS spasticity thus remains an unmet need for many patients.

Sativex^® (nabiximols) oromucosal spray is a second-line option for symptomatic management of MS spasticity and has been available in Europe for more than a decade. As of early 2022, nabiximols has been approved for use in 17 European countries and in Canada, Israel, Brazil, Colombia, Chile, New Zealand and others. Nabiximols is indicated as add-on treatment for symptom improvement in adult patients with moderate-to-severe MS spasticity who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy [12].

Nabiximols is a complex botanical mixture containing balanced quantities of δ-9-tetrahydrocannibinol (THC) and cannabidiol (CBD) as the main active constituents, as well as other plant-derived cannabinoids and non-cannabinoid substances [13]. Nabiximols acts as a modulator of the human endocannabinoid system through interaction with the cannabinoid receptors CB₁ and CB₂. As a partial agonist of CB₁ receptors in particular, THC may modulate the effects of excitatory (glutamic acid) and inhibitory (GABA) neurotransmitters, resulting in muscle relaxation and symptomatic improvement of spasticity [13]. CBD, in contrast, has little affinity for CB₁ and CB₂ receptors and acts as an antagonist at CB₁ receptors. THC and CBD are thought to work synergistically such that CBD counteracts some of the undesirable effects of THC (e.g., psychoactivity, sedation, anxiety) while enhancing its beneficial clinical effects and contributing its own medically beneficial effects, such as analgesia and neuroprotection [13]. Inclusion of CBD in the nabiximols formulation permits administration of pharmacologically active doses of THC while minimizing the risk of associated adverse events. Adverse event risk is also minimized through oromucosal delivery of nabiximols, which facilitates rapid absorption of THC (and onset of therapeutic effect), but at plasma drug concentrations much lower than those associated with inhaled THC [14].

Between 2000 and 2010, nabiximols underwent a large clinical trials program involving more than 2500 MS patients, of whom more than 660 were treated continuously for at least 6 months, yielding more than 1200 patient-years of clinical experience. Vast clinical experience with nabiximols in the post-marketing setting accounts for more than 150,000 patient-years to date, which is important with regard to monitoring of adverse drug reactions and gathering real-world evidence about its effectiveness.

This narrative review examines clinical evidence for nabiximols in the management of MS spasticity, inclusive of all available pre- and post-approval randomized controlled clinical trials (RCTs) and related extension studies, all large observational studies and relevant smaller observational studies (i.e., those investigating clinical parameters) and pharmacovigilance data accumulated during its development and real-world use. In all studies, nabiximols was used as add-on therapy to first-line oral antispasticity medication(s) which had failed to produce an adequate response. Studies selected for inclusion in the review were identified from the reference lists of recent comprehensive reviews on nabiximols’ efficacy and effectiveness [15] and safety [16–19], and supplemented by PubMed literature searches and other references known to the authors.

Nabiximols’ efficacy in clinical trials

Pre-approval RCTs

A large program of pre-approval phase III, multicenter, double-blind, parallel-group RCTs (and associated extension studies) in patients with MS spasticity not fully relieved with current antispasticity therapy showed statistically significant and clinically relevant improvements in MS spasticity and spasticity-associated symptoms compared with placebo (Table 1) [20–25]. These studies were instrumental in gaining regulatory approval for nabiximols and, together, they informed the approved label [12].

Table 1. Efficacy outcomes in randomized controlled trials and associated extension studies of nabiximols oromucosal spray.

Study	Study type	Duration	n	Mean (SD) dose (sprays/day)	Main efficacy outcomes	Ref.
Wade et al. 2004	R, MC, DB, PG	6 weeks	NAB: 80 PLC: 80	NAB: ∼15^† PLC: ∼25^†	Difference in mean spasticity 0–100 VAS score vs PLC: -22.79 (95% CI: -35.52–-10.07; p = 0.001)	[20]
Wade et al. 2006	OL extension	Mean 434 days (range: 21–814)^‡	137	∼11	Large reductions from baseline to 10 weeks in pain (-53%), spasms (-53%), spasticity (-51%), bladder (-55%) symptoms, which were maintained over 1 year of treatment^§	[21]
Collin et al. 2007	R, MC, DB, PG	6 weeks	NAB: 124 PLC: 65	NAB: 9.4 (6.4) PLC: 14.7 (8.4)	Difference in mean spasticity 0–10 NRS score vs PLC: -0.52 (95% CI: -1.029–-0.004; p = 0.048) Difference in ≥30% reduction in mean 0–10 NRS spasticity score vs PLC: 18.1% (95% CI: 4.73 to 31.52; p = 0.014)	[22]
Serpell et al. 2013	OL extension	Mean 334 days (SD: 209)	146	7.3 (4.4)	Mean spasticity 0–10 NRS score (from parent RCT baseline) decreased until about 8 weeks, then was maintained over one year of treatment^¶	[23]
Collin et al. 2010	R, MC, DB, PG	14 weeks	NAB: 167 PLC: 170	NAB: 8.5 (range: 1–22) PLC: 15.4 (range: 2–23)	Difference in mean spasticity 0–10 NRS score vs PLC: ITT analysis: -0.23 (p = 0.219); PP analysis: -0.46 (p = 0.035) Difference in ≥30% reduction in mean 0–10 NRS spasticity score vs PLC: ITT analysis: OR = 1.34 (95% CI: 0.83–2.17; p = 0.23); PP analysis: OR = 1.74 (95% CI: 1.02–2.96; p = 0.040)	[24]
Novotna et al. 2011	Phase A: SB	4 weeks	572	6.9 (1.8)	Change from baseline in mean spasticity 0–10 NRS score: -3.0 (SD: 1.38) ≥20% NRS responder rate: 47.5%	[25]
	R, MC, DB, PG	12 weeks	NAB: 124 PLC: 117	NAB: 8.3 (2.4) PLC: 8.9 (2.3)	Difference in mean spasticity 0–10 NRS score vs PLC: 0.84 (95% CI: -1.29–-0.40; p = 0.0002) ≥30% NRS responder rate vs PLC: 74 vs 51% (OR: 2.73; 95% CI: 1.59–4.69; p = 0.0003)
Markovà et al. 2019	Phase A: SB	4 weeks	190	7.7 (3.0)	≥20% NRS responder rate: 70.5%	[27]
	R, MC, DB, PG	12 weeks	NAB: 53 PLC: 53	7.3 (2.7) 8.5 (3.0)	Difference in mean spasticity 0–10 NRS score vs PLC: -1.9 (p < 0.0001) ≥30% NRS responder rate vs PLC: 77.4 vs 32.1% (OR: 7.0; 95% CI: 2.9–16.7; p < 0.0001)
Notcutt 2012	R, MC, PG, WD	4 weeks	NAB: 18 PLC: 18	NAB: 7.3 PLC: 9.2	Time to treatment failure in favor of NAB: HR = 0.335 (90% CI: 0.162–0.691; p = 0.013)	[29]

† Estimated from a graph.

‡ For patients remaining on treatment (n = 79).

§ In patients who completed at least 1 year’s treatment and contributed data to every time point: pain (n = 47), spasm (n = 54), spasticity (n = 66), bladder (n = 57).

¶ For patients with continuous data up to 52 weeks of treatment (n = 55).

DB: Double-blind; HR: Hazard ratio; ITT: Intent-to-treat; MC: Multicenter; NAB: Nabiximols; NRS: Numerical Rating Scale; OL: Open-label; OR: Odds ratio; PG: Parallel group; PLC: Placebo; PP: Per protocol; R: Randomized; RCT: Randomized controlled trial; SB: Single-blind; SD: Standard deviation; VAS: Visual analog scale; WD: Withdrawal.

The first RCT involved 160 patients with various MS-associated symptoms who were treated for 6 weeks with nabiximols or placebo [20]. The primary outcome measure was change in the 0–100 visual analog scale (VAS) score for a patient’s most troublesome symptom (spasticity, spasms, bladder problems, tremor or pain). After 6 weeks’ treatment, significant improvements versus placebo were recorded in VAS scores for MS spasticity (-31.2 vs -8.4%; p = 0.001) and sleep quality (-16.7 vs -9.6%). Post-titration dosages of up to 48 sprays per day (no more than eight sprays per 3-h period) were allowed, although mean dosages were ∼15 and ∼25 sprays per day with nabiximols and placebo, respectively.

In the next major pre-approval clinical trial, 189 patients with MS spasticity were randomized to nabiximols or placebo for 6 weeks [22]. This study was the first to use the patient-rated 0–10 spasticity Numerical Rating Scale (NRS) as the primary efficacy measure, a decision based on its ability to capture patients’ own experience of spasticity over a 24-h period rather than at a moment in time (e.g., with the physician-rated Ashworth Scale). On the basis of data from this study, the NRS was validated for use in MS spasticity, with mean improvements from baseline of ≥20% and ≥30% identified as the minimal clinically important difference and clinically important difference, respectively [26]. After 6 weeks’ treatment, the adjusted mean reduction in the spasticity 0–10 NRS score was significantly greater with nabiximols than with placebo (-1.2 vs -0.6; p < 0.05), and significantly more patients in the nabiximols group were ≥30% NRS responders (40.0 vs 21.9%; p = 0.014). Dosages of up to 48 sprays per day were allowed, and reported mean doses were 9.4 sprays per day with nabiximols and 14.7 sprays per day with placebo [22].

The third major pre-approval study involved 337 patients with MS spasticity treated for 14 weeks with nabiximols or placebo [24]. The maximum allowed dosage in this study was 24 sprays per day, and mean dosages reported for nabiximols and placebo were 8.5 and 15.4 sprays per day, respectively. The study included a responders’ analysis (as a secondary end point) based on patients who achieved ≥30% NRS improvement from baseline. After 14 weeks’ treatment, between-group differences for change from baseline in the NRS score (-1.3 vs -0.8 points; p = 0.035) and responders’ analysis (36 vs 24%; p = 0.040) were statistically significant in the per-protocol population but not in the primary intent-to-treat population. Post hoc analyses indicated that the lack of significance in the intent-to-treat population was due to the moderating effect of having included nonresponder results in the efficacy analyses.

To address this confounding issue, the next major RCT of nabiximols used an enriched study design [25]. Initially, all patients received nabiximols for 4 weeks to identify initial responders (≥20% NRS improvement); nonresponders were discontinued. Of 572 patients who entered the 4-week trial period, 272 (47.5%) were initial responders, and 241 were randomized to nabiximols or placebo. After double-blind treatment for 12 weeks, the NRS score improved by a further 0.04 points in nabiximols-treated patients and deteriorated by 0.81 points in placebo-treated patients, with the between-group difference being highly significant (p = 0.0002). In this study the maximum allowed dosage had been further reduced to 12 sprays per day with a minimum 15-min interval between sprays, and the up-titration phase was extended to 2 weeks at increments of no more than one spray per day. Mean dosages of nabiximols and placebo were 8.3 and 8.9 sprays per day, respectively.

Collectively, these studies provided the necessary supportive evidence for regulatory approval of nabiximols and informed the EU-approved label, which requires that patients achieve ≥20% NRS improvement during an initial 4-week trial of therapy to qualify for continued treatment, at a maximum dosage (after gradual up-titration) of 12 sprays per day [12].

Long-term extension studies

Open-label extension phases of the first two nabiximols RCTs demonstrated, along with other aspects, that efficacy is maintained in continued treatment responders (Table 1) [21,23]. In the first of these extension studies, 137 of 160 patients in the 6-week parent study proceeded to open-label treatment and 79 (57.7%) continued nabiximols for an average of 434 days (range: 21–814). Among those who completed at least 1 year of treatment, baseline VAS scores for spasticity, pain, spasms and bladder-related problems decreased sharply to week 10, then remained stable at all subsequent evaluation time points [21]. In the second extension study, which specifically tracked evolution in symptomatic relief of MS spasticity, 146 of 189 patients in the 6-week parent study proceeded to open-label treatment with nabiximols. The reduction in the mean baseline spasticity NRS score reached a plateau after about 8 weeks, then was maintained in 55 patients with continuous data up to 52 weeks [23].

Post-approval RCTs

Two post-approval RCTs support the superior efficacy of nabiximols compared with placebo in patients with MS spasticity (Table 1) [27,29].

The post-approval sativex as add-on therapy versus further optimized first-line antispastics (SAVANT) RCT was designed to determine whether adding nabiximols to adjustable first-line antispasticity therapy was superior to adjustable first-line antispasticity therapy alone [27]. To minimize any carryover effects of active treatment during the initial 4-week trial period (n = 191), patients underwent washout. Those eligible after washout (NRS improvement reduced by ≥80%) were randomized to nabiximols (n = 53) or placebo (n = 53). Optimization of the underlying antispasticity medications was permitted in both groups during double-blind treatment. After 12 weeks of double-blind treatment, a significantly greater proportion of patients treated with nabiximols than patients treated with placebo (77.4 vs 32.1%; p < 0.0001) achieved ≥30% NRS improvement (primary efficacy end point), demonstrating the therapeutic gain of adding nabiximols to optimized symptomatic treatment.

A post hoc analysis of SAVANT study data showed that reductions in mean spasticity and pain severity 0–10 NRS scores from the time of randomization (baseline) to the end of double-blind treatment (week 12) were consistent, irrespective of patients’ baseline characteristics (Expanded Disability Status Scale [EDSS] score <6 or ≥6; spasticity NRS score 4–≤6 or >6; spasticity duration <5 or ≥5 years), supporting clinical benefit with nabiximols across a wide range of patients [28]. Mean baseline severity scores for spasticity and pain were halved in all subgroups during nabiximols treatment. From 4 weeks onwards, and despite limited sample sizes, nabiximols significantly reduced mean spasticity 0–10 NRS scores versus placebo in both EDSS subgroups, in the severe spasticity subgroup and in both spasticity duration subgroups. From 4 weeks onwards, nabiximols significantly improved mean pain 0–10 NRS scores versus placebo in the ≥6 EDSS subgroup, in the severe spasticity subgroup and in both spasticity duration subgroups.

The durability of nabiximols’ effect was evaluated in a small, multicenter, placebo-controlled, parallel-group, randomized study by assessing the results of sudden withdrawal [29]. Patients who had gained symptomatic benefit with nabiximols for at least 12 weeks were randomized to continued treatment with nabiximols (n = 18) or switched to placebo (n = 18). The primary end point was time to treatment failure according to predefined criteria: treatment cessation, or worsening of spasticity, or need for additional medication. By the end of the 4-week randomized withdrawal period, the hazard of treatment failure was three times greater for placebo-treated patients (hazard ratio: 0.335; 90% CI: 0.162, 0.691; p = 0.013).

Nabiximols’ effectiveness in daily clinical practice studies

In the post-approval setting over the 10-year period 2011–2021, numerous real-world evidence studies have provided short- and long-term data about the effectiveness of nabiximols in patients with MS spasticity treated in the routine outpatient setting according to the approved label (Supplementary Table 1) [30–55]. The majority of studies used a prospective design without concurrent control or blinding, and most were conducted in Italy or Germany. Study durations were from 1 month to more than 3 years. Reported dosages of nabiximols were generally in the range of 6–7 sprays per day. Response thresholds were ≥20% NRS improvement (initial response) and ≥30% NRS improvement (clinically relevant response).

Real-world observational post-approval studies

A series of large, real-world, multicenter studies showed that a relevant proportion of initial responders to nabiximols maintained ≥30% reduction in spasticity severity with continued treatment (Supplementary Table 1). Prospective studies reported 3-month 30% responder rates of between 30 and 40% [30,32,33], whereas a retrospective registry analysis reported a 3-month 30% responder rate of 74.3% [34]. In longer-term prospective studies, 30% responder rates in treatment continuers were 42.3% at 6 months [33] and 41.2% at 12 months [31].

These outcomes are supported by several single-center studies of nabiximols which document a maintenance of effect in continued treatment responders. A 15-month medical chart-based data collection study from Germany reported on 166 patients who had initiated treatment with nabiximols. At the time of analysis, after a mean follow-up of 9 months, 120 patients remained on treatment, 95 as add-on therapy and 25 as monotherapy, for an overall response rate of 72% [35]. In an Italian cohort of 144 patients with MS spasticity, the 30% responder rate in treatment continuers was 61.9% at week 14; at week 48, the mean NRS score was reduced by 33% from baseline in treatment continuers [36]. Another Italian study, involving 102 patients with severe spasticity at baseline (mean NRS score: 8.7 ± 1.3), reported a 29% reduction by 1 month (p < 0.0001), which was maintained at all evaluation time points up to 1 year in treatment continuers [37]. In a small (n = 50) retrospective study from Italy, nabiximols was effective in 80% of patients according to the prescribing physician’s global impression of therapeutic response. Median treatment duration was 174 days in post-analysis treatment continuers versus 30 days in treatment discontinuers [38].

Treatment discontinuation studies

Three publications have examined treatment discontinuation rates in patients with MS spasticity who began treatment with nabiximols (Supplementary Table 1) [39–41].

Two of these analyses utilized data collected prospectively in the Italian Medicine Agency’s (Agenzia Italiana del Farmaco, AIFA) e-Registry; until 2020, data collection was mandatory for all patients in Italy starting nabiximols treatment. In the first analysis, 631 of 1597 patients (39.5%) discontinued nabiximols within the first 6 months of treatment, 333 of them (20.8% of the population) within 4 weeks and 422 (26.4%) within 6 weeks [39]. A subsequent analysis involving 1845 AIFA e-Registry patients found that about one-half (48%) had discontinued nabiximols by 18 months, most within 3–6 months of treatment start and mainly due to ‘loss of effect’ or insufficient effect. Multivariate analysis showed that higher baseline spasticity NRS scores and a greater NRS response during the first 4 weeks were factors associated with treatment continuation at 18 months [40].

A retrospective analysis reported continuation rates in 396 Italian patients with MS spasticity treated with nabiximols. After 4 weeks (titration phase), 266 patients (67.2%) continued with treatment. After 19 ± 21 months (treatment phase), 136 (51.1%) of initial persisters remained on treatment. Higher EDSS scores (p = 0.04) and cognitive impairment (p = 0.005) at baseline were predictive of treatment discontinuation during follow-up [41].

Gait analysis studies

Three studies from Italy conducted gait analyses to determine the effect of nabiximols on walking ability (Supplementary Table 1) [42–44]. 3D gait analysis (spatial-temporal and kinematic) in 20 patients with MS spasticity treated with nabiximols for 1 month identified improvements versus baseline in speed, cadence and stride length, while dynamics for pelvic area movements, hip rotation and knee flexion-extension moved closer to physiological values [42]. A study which used robot-aided gait training to improve functional ambulation in patients with MS spasticity reported significant improvements in the Functional Independence Measure and 10-meter walking test (both p < 0.001) in 20 patients treated with nabiximols for 6 weeks compared with 20 matched controls. Clinical findings were supported by a more evident reshaping of intracortical excitability measured in the nabiximols group versus the control group [43]. A third study which used clinical scales and 3D gait analysis to evaluate the effects of nabiximols on walking and balance in patients with MS spasticity recorded significant improvements from baseline in a few clinical and kinematic parameters after 45 min in the nabiximols-treated (n = 22) versus the control (n = 10) group. The absence of any significant differences in the results measured at 45 min and at 4 weeks suggested that the effects of nabiximols persisted over time [44].

Muscle elastography study (experimental)

Clinical scales used to assess spasticity, including the spasticity 0–10 NRS and modified Ashworth Scale, harbor a degree of subjectivity. In an attempt to quantify objective changes in spasticity severity, an Italian study used real-time elastography ultrasound to evaluate muscle fiber status in MS spasticity patients (n = 55) treated with nabiximols. After 4 weeks’ treatment, the 20% NRS responders (65% of patients) had significant (p < 0.0001) mean reductions of 1.87 points in their 0–10 NRS score and 1.97 points in their muscle elastography MS scores. An interesting finding was the significant mean reduction in muscle elastography MS scores (0.8; p = 0.002) also in nonresponders according to NRS change criteria (Supplementary Table 1) [45].

Study of effect with combined physiotherapy

An observational, multicenter study from Italy demonstrated the benefit of associated physiotherapy programs on the effectiveness and persistence of nabiximols treatment in patients with MS-related spasticity. At week 4, 77% of 290 evaluable patients had reached ≥20% NRS improvement, including 22% with ≥30% NRS improvement. Patients receiving physiotherapy had a higher probability of achieving ≥30% NRS improvement (odds ratio: 2.6; 95% CI: 1.3–5.6; p = 0.01) and a lower probability of discontinuing nabiximols treatment by 3 months (hazard ratio: 0.41; 95% CI: 0.23–0.69; p = 0.001; Supplementary Table 1) [46].

Studies of effect on activities of daily living

Two studies have examined the effect of nabiximols on activities of daily living in MS patients during long-term use (Supplementary Table 1) [47,48]. In the first study, 124 long-term (mean: 30 months) users of nabiximols, 92 of whom had MS spasticity, completed a questionnaire. According to the survey results, daily activities associated with the most improvement were holding a glass, standing up, and sitting in a chair or lying in a bed with comfort. Carers identified improvements in assisted activities such as washing, dressing, communicating and transferring (e.g., moving from wheelchair to bed) [47]. The second study compared daily functioning in a small sample of patients with MS spasticity (n = 32) prior to the start of nabiximols treatment (assessed retrospectively using recall) with that at the ‘present moment’ using a 16-item activities of daily living survey. Daily functioning was maintained or slightly improved with nabiximols across treatment time (mean: 31.9 months) including a significant improvement in ‘standing up’ (p < 0.05) and trends toward improvements in several other daily activities [48].

Study of effect on goal attainment

A prospective pilot study assessed the evolution of patient-selected spasticity-related Goal Attainment Scale (GAS) item scores during nabiximols treatment in 21 patients with MS spasticity. A clinically meaningful and significant (p = 0.0060) increase was recorded in the overall unweighted GAS score from baseline (mean: 32.1; standard deviation: 3.4) to month 3 (mean: 43.6; standard deviation: 14.6), indicating that GAS methodology can be applied to MS management in daily practice (Supplementary Table 1) [49].

Study of effect on spasticity-plus syndrome

The ‘spasticity-plus syndrome’ has recently been described and recognizes the association of MS spasticity with other symptoms [56,57]. Two AIFA e-Registry analyses have investigated the evolution of predefined MS spasticity-related symptoms (spasms/cramps, clonic movements, sleep disturbances, urinary dysfunction, pain, depressed mood, trigeminal neuralgia) in patients with moderate-to-severe MS spasticity receiving nabiximols in daily clinical practice (Supplementary Table 1) [50,51]. In the first analysis, 627 of 1432 patients (43.8%) who completed a 4-week trial of therapy, including 543 (86.6%) ≥20% NRS responders and 84 (13.4%) NRS nonresponders (change <20%), reported amelioration of at least one spasticity-related symptom [50]. A more recent analysis involving 1138 patients confirmed the resolution of MS spasticity-associated symptoms over the longer term (18 months) in treatment continuers. Although the mean number of spasticity-associated symptoms was reduced to a greater extent from baseline to 18 months in patients with ≥20% or ≥30% NRS response, a reduction was also observed in NRS nonresponders (change <20 or <30%, respectively) [51].

Studies of effect on cognition & driving ability

Studies of the effect of nabiximols on cognition reported no detrimental effects during treatment for up to 1 year (Supplementary Table 1) [52–54]. The first major study, a RCT from the Czech Republic, concluded that nabiximols (n = 62) was non-inferior to placebo (n = 59) based on the absence of any significant between-treatment difference for the change from baseline to end of treatment in the Paced Auditory Serial Addition Test I and II combined total score. Nabiximols was also non-inferior to placebo with regard to mood changes assessed using the Beck Depression Inventory II [52]. An observational study involving 45 nabiximols responders (from an enrolled sample of 61 patients) found no significant differences from baseline to 6 months in a range of cognitive tests (Montreal Cognitive Assessment, attentive matrices, trial making test [A, B and BA], Babcock Story Recall Test, Zung-Sas Scale and Multiple Sclerosis Quality of Life) which focused on domains most commonly impaired in MS [53]. More recently, an observational pilot study from Italy involving 20 patients with MS spasticity found significant improvements from baseline in the Symbol Digit Modalities Test and California Verbal Learning Test with nabiximols at 6 (p < 0.001) and 12 months (p = 0.020), and no changes in other measures of processing speed and verbal memory assessments or in the visual memory assessment [54].

A pilot study from Germany which assessed driving ability in 33 patients who initiated treatment with nabiximols for MS spasticity identified no differences from baseline (pre-treatment) after 4–6 weeks of treatment using a battery of standardized computerized driving tests (Supplementary Table 1) [55].

Safety & tolerability

The first published review of nabiximols’ safety, based on manufacturer-supplied integrated analyses from the clinical trials program in patients with mainly MS spasticity, included studies that allowed a maximum dosage of up to 48 sprays per day [16]. Across studies, treatment-related adverse events (AEs) occurring more frequently with nabiximols (n = 805) than with placebo (n = 741) included dizziness (24.8 vs 7%), fatigue (11.1 vs 6.6%) and somnolence (8.1 vs 1.9%). These events tended to occur during the first 4 weeks of exposure, were usually mild to moderate in severity and resolved quickly. To minimize the likelihood of AEs, the final pre-approval clinical trial of nabiximols limited the dose to a maximum of 12 sprays per day and extended the up-titration period to 14 days (or longer if necessary) [25]. These changes to nabiximols posology were ultimately incorporated into the nabiximols approved label [12].

Pharmacovigilance data accumulated during short- and long-term use of nabiximols in daily practice support the safety profile reported in RCTs. A systematic review of real-world publications (n = 14 observational studies and treatment registries) found no new or unexpected AEs or safety signals during routine use of nabiximols over 10 years, including AEs of special interest (e.g., psychiatric events, falls); abuse, tolerance or dependence potential; and driving impairment [17].

Recent in-depth analyses of nabiximols’ safety in patients with MS spasticity provide further evidence that it is generally well tolerated [18,19]. In placebo-controlled RCTs and associated extension studies (n = 15), discontinuation rates due to AEs were 5.4 and 2.8% with nabiximols and placebo, respectively. The treatment-related AEs reported most frequently and most consistently across studies were dizziness, nausea and fatigue. Overall, 32 treatment-related serious AEs were reported in 23 of 666 patients (3.5%) treated with nabiximols and showed no particular pattern [18]. Similarly, the most common AEs reported consistently across observational studies of nabiximols (n = 20) were dizziness, fatigue and somnolence. Treatment-related serious AEs were rare (39 of 137 events reported in 4351 patients) and, where specified, were resolved [19].

A small pilot study (n = 52) involving patients with oral cavity complaints while using nabiximols showed that chewing sugar-free gum and/or refrigerating the bottle could improve taste perception and alleviate oral mucosal symptoms (e.g., dry mouth, irritation and pain) [58].

Place in guidelines

Clinical practice guidelines from official medical associations in several EU countries reflect the positioning of nabiximols in the management of MS spasticity based on available evidence and aligning with its approved label [59–65]. Guideline recommendations are supported by endorsements from non-medical organizations [66,67]. All recommendations acknowledge the role of nabiximols in the management of MS spasticity after failure of first-line therapies (mainly baclofen and tizanidine).

A practical example of nabiximols’ positioning is provided in the recently updated MS Spasticity Management Guidelines from the German Neurological Society [65]. Recommendations for antispasticity medications are as follows:

• Baclofen (on-label; evidence class Ib–II). Recommendation grade A;

• Tizanidine (on-label; evidence class Ib). Recommendation grade A;

• Gabapentin for painful spasms. Dosage from 1200 mg/d to 2700 mg/d (off-label; evidence class Ib). Recommendation grade A;

• Nabiximols oromucosal spray (2.7 mg THC + 2.5 mg CBD) evidence class Ia. Recommendation grade A;

• Dantrolene, tolperisone, benzodiazepines. Not well documented.

Notably, nabiximols has the same recommendation grade (grade A) as conventional treatments, but a higher evidence class (Ia), reflecting the quality of evidence accumulated throughout the clinical trials program.

Discussion

Depending on their severity, MS spasticity and associated symptoms can profoundly impair patients’ daily functioning, adding to overall disease burden and reducing quality of life. In many patients, conventional first-line options such as baclofen and tizanidine (and gabapentin for neuropathic pain) [68] are only modestly effective and often poorly tolerated [69]. Nabiximols addresses this unmet need by offering an option for adjunctive therapy to first-line agents in patients with inadequately controlled moderate-to-severe MS spasticity, as reflected by its positioning in numerous official guidelines and agency endorsements [59–67].

Given the wealth of data accumulated with nabiximols during its development and 10 years of post-approval use in patients with MS spasticity, we considered it timely to review the available evidence. Studies were conducted across Europe, and participating patients were mainly of Caucasian origin. The majority of real-world data derives from Italy and Germany. Across the reviewed studies, sociodemographic and clinical features of patient cohorts were representative of the MS spasticity population; that is, age range of about 45–55 years, two-thirds women, MS disease duration of 10–15 years, baseline 0–10 MS spasticity NRS scores of 4–6 (moderate) or >6 (severe) and mean EDSS scores of 5 or 6 (data not shown). Analyses of gender differences in response to nabiximols were not reported in any clinical trials or observational studies.

The nabiximols clinical trials program established its efficacy versus placebo for reducing MS spasticity (muscle rigidity and spasms) severity and a range of associated symptoms (e.g., pain, urinary dysfunction and sleep disturbances) in 30% (clinically relevant) NRS responders [24,25]. Each clinical trial led to refinements in the design of subsequent trials, successively defining optimal use of nabiximols and informing the EU-approved label [12]. Extension studies showed that benefit was maintained in treatment continuers [21,23], including prolonged control of spasticity-associated symptoms [21]. A placebo-controlled randomized withdrawal study confirmed that nabiximols was responsible for symptomatic relief of MS spasticity [29].

Collectively, data from clinical trials and observational studies indicate that about 40% of initial responders to nabiximols will achieve sustained clinically relevant ≥30% NRS improvement with continued treatment. Symptomatic relief is noticeable within 4 weeks in treatment responders and is maintained over the longer term at the optimal dose reached during titration. Mean doses of 6–7 sprays per day were recorded across a wide range of clinical practice studies [30,32–34,36,37,39,40], with no evidence of a need to increase dosages during continued use for 1 year or more [31,26,37,40].

Apart from early nonresponders who are deemed to discontinue nabiximols after the 4-week trial period, longer-term follow-up indicates that about one-half of initial responders will discontinue treatment within the first 6 months, mainly due to loss of effectiveness and/or adverse effects [40,41]. Factors associated with an increased probability of continuing nabiximols treatment, such as higher baseline NRS scores and a greater initial NRS response, emphasize the importance of early monitoring of patients to identify those most likely to benefit [39,40].

In contrast to conventional oral medications indicated for symptomatic treatment of MS spasticity, nabiximols has been investigated for its potential impact on several functional measures associated with MS spasticity. Nabiximols was shown to improve some walking parameters [34–42], enhance the benefits of concurrent physiotherapy [46] and improve or maintain patients’ ability to carry out activities of daily living [47,48]. Whether improvement in spasticity severity (and motor function) occurs via nabiximols-mediated modulation of corticospinal excitability remains to be determined, however, as evidence regarding its effects on neurophysiological measures of spasticity is inconsistent [70–72]. A small observational study reported a detrimental effect of nabiximols on postural control at 1 year in treatment continuers (n = 11) versus treatment quitters (n = 11), which the investigators hypothesized was due to cannabis-influenced maladaptive changes in disease-modified brains of MS patients [73]. Given the small sample size and lack of a control group, further research is required to confirm these findings.

AIFA e-Registry analyses found that nabiximols improved a number of spasticity-related symptoms (e.g., sleep disturbances, clonic movements, bladder dysfunction, pain) during up to 18 months’ treatment, including in nonresponders according to NRS response criteria [50,51]. The findings suggest that the therapeutic benefit of nabiximols may extend beyond muscle tone control, irrespective of NRS response, although this requires confirmation in placebo-controlled RCTs before any conclusions can be drawn.

Cognitive impairment can affect up to two-thirds of patients with MS [74–76], and there is evidence linking the use of inhaled cannabis with further deficit in cognitive domains commonly affected in this population (e.g., information processing speed, working memory, executive functions) [77–81]. Although nabiximols is formulated to avoid the high plasma THC concentrations associated with the use of inhaled cannabis [82], it is important nonetheless to ascertain its cognitive tolerability. A small pilot RCT involving 17 cannabis-naive patients with MS spasticity reported no significant differences in Paced Auditory Serial Addition Test scores between nabiximols and placebo after 3 weeks’ crossover treatment [83]. Since then, longer-term studies of cognitive function in MS patients have reported no evidence of cognitive impairment or significant changes in mood between nabiximols and placebo after 1 year [52], no differences compared with baseline after 6 months [53] and a possible beneficial effect within 6 months on one measure of processing speed and one of auditory verbal memory which remained stable at 1 year [54], although the possibility of a practice effect in this latter study cannot be ruled out. The findings of these studies are supported by a recent systematic review and meta-analysis which found no consistent evidence to suggest that nabiximols causes cognitive impairment or cognitive AEs at approved doses in MS patients during up to 12 months’ follow-up [84]. Another functional study showed that nabiximols had no adverse effect on driving ability during the first few weeks of initial exposure [55]. Nevertheless, the contribution of physical or cognitive disability to the likelihood of patients discontinuing nabiximols [41] highlights the importance of interacting closely with such patients to facilitate treatment persistence and maximize benefit.

AEs such as dizziness and fatigue are relatively common with nabiximols during the early stages of treatment, but their likelihood can be reduced by adhering to the approved dosage and titration schedule [12]. Safety studies, registry analyses and comprehensive safety reviews have identified no new safety concerns or evidence of abuse, diversion or dependence during routine clinical use of nabiximols [17,19]. The positive benefit:risk balance of nabiximols for treatment of MS spasticity is reflected by the lack of relevant changes to the EU-approved label since 2010.

Conclusion

After 10 years of post-approval experience and more than 150,000 patient-years of exposure, we can conclude that nabiximols is a solid option for the management of MS spasticity in patients who fail to respond adequately to treatment with first-line antispasticity agents.

Future perspective

Nabiximols is the most investigated noninvasive treatment option for MS spasticity. Evidence for its benefit is consistent across a wide range of pre- and post-approval studies. Notably, nabiximols as adjunctive therapy addresses an unmet need for meaningful and durable symptomatic relief of MS spasticity in a relevant proportion of initial responders, with no safety concerns beyond its known safety profile. This level of consistency allows clinicians to set reasonable expectations with patients about the potential benefits of nabiximols and can allay any residual concerns about prescribing a cannabinoid-based medication.

Looking ahead, confirmation of the existence of a spasticity-plus syndrome and the role of nabiximols in managing the syndrome may have important implications for future management of MS spasticity. The spasticity-plus syndrome was initially conceptualized on the basis of clinical trial reports of improvement with nabiximols in other spasticity-related symptoms (e.g., pain, sleep disturbance, bladder dysfunction), suggesting a link between these symptoms and increased muscle tone as well as possible mediation in a similar part of the brain stem [56]. AIFA e-Registry analyses involving large cohorts of patients with MS spasticity have indeed documented the presence of symptom clustering and of short- and long-term resolution of associated symptoms in ≥20% and ≥30% NRS responders and in nonresponders [50,51]. The findings suggest that an assessment of clinical benefit with nabiximols may need to consider evolution in related symptoms, not spasticity alone. Using appropriate assessment tools, patients who show improvement or resolution of associated symptoms might be candidates for continued nabiximols treatment, irrespective of their spasticity improvement status based on current NRS thresholds. This is an intriguing concept, as it may extend the opportunity for benefit with nabiximols to a wider group of patients with MS spasticity; however, well-controlled clinical studies are required to confirm any potential role for nabiximols in the integrated management of MS spasticity-associated symptoms.

Other potential research avenues for nabiximols include investigating its earlier use in MS spasticity (before patients become poorly responsive to other treatments) and exploring its use in conditions other than MS that involve spasticity.

Author contributions

A Chan and C Vila Silván fulfilled ICMJE criteria for authorship, which involved initial drafting and critical review of the manuscript during its development and approving the final version for submission.

Acknowledgments

This review article is based on proceedings of a virtual ‘product theater’ presentation held as part of the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), 13–15 October 2021, Vienna, Austria.

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/nmt-2022-0002

Financial & competing interests disclosure

A Chan has received speaker’s/board honoraria from Actelion (Janssen/J&J), Almirall, Bayer, Biogen, Celgene (BMS), Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Roche and Teva, all for hospital research funds; and has received research support from Biogen, Genzyme and UCB, the EU and the Swiss National Foundation. C Vila Silván is a fulltime employee of Almirall SA. Almirall is a partner of GW Pharmaceuticals (developer of Sativex) in Europe. 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.

Writing assistance for this article was provided by K Dechant ISMPP CMPP™ on behalf of Content Ed Net (Madrid, Spain) with funding from Almirall SA. (Barcelona, Spain).