Sativex in the management of multiple sclerosis-related spasticity: An overview of the last decade of clinical evaluation

Multiple Sclerosis and Related Disorders 17 (2017) 22–31

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Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard

Review article

Sativex in the management of multiple sclerosis-related spasticity: An overview of the last decade of clinical evaluation Sabrina Giacoppo, Placido Bramanti, Emanuela Mazzon

MARK

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IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy

A R T I C L E I N F O

A B S T R A C T

Keywords: Multiple sclerosis Spasticity Sativex Cannabinoids

Background: Spasticity is a common symptom of multiple sclerosis (MS) affecting about 80% of MS patients. Numerous lines of evidence suggest that spasticity due to its complexity is not adequately managed with conventional anti-spastic therapies. Therefore, in order to improve the outcomes for the majority of MS patients, alternative approaches are needed to be discovered. Over the last years, the use of cannabinoid compounds as a potential treatment for MS-related symptoms has aroused great interest, owing to encouraging preclinical and clinical studies. To date, Sativex, an oromucosal spray containing tetrahydrocannabinol and cannabidiol in approximately 1:1 ratio, is the only commercially available formulation containing cannabinoids used as add-on therapy for treatment of spasticity in adult MS patients who are not responding to conventional antispastic therapies. Methods: Here, by performing a literature search, we provided an overview of the last decade of clinical evaluations as well as post-marketing studies about effectiveness and safety of Sativex in the management of MSrelated spasticity. Results: Sativex was proven effective in treating spasticity and also in improving the patient's quality of life. In addition, a low incidence of adverse reactions Sativex-related supports the good safety profile and its tolerability. Conclusion: This review by recognizing the clinical effectiveness of Sativex in spasticity management, opened a new opportunity for many patients with spasticity resistant to common antispastic drugs.

1. Introduction Multiple Sclerosis (MS) is a chronic autoimmune disease of the Central Nervous System (CNS) that causes permanent disability especially in young adults. Although its etiology is not yet been completely understood, several lines of evidence suggest that MS development is due to an aberrant autoimmune response in which T and B lymphocytes destroy myelin sheath surrounding the neurons (Siffrin et al., 2007). This ultimately leads to the main clinical symptoms and neurological deficits of MS (Goldenberg, 2012). According to the National MS Society, spasticity is a common and disabling symptom, affecting approximately 80% of MS patients with a strong impact on patients‘ quality of life (Oreja-Guevara, 2012). A moderate and severe spasticity indeed not only impairs the daily activities but may be also associated with various complications such as painful spasms, bladder dysfunctions, pain, sleep disorders and depression (Flachenecker et al., 2014a; Beard et al., 2003). In MS patients the pathophysiology of spasticity is not completely defined, but is thought to be caused by axonal degeneration or

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malfunction that may be combined with demyelinating plaques within specific descending spinal tracts. This results in a perturbation of inhibitory interneuronal spinal network pathways, that usually causes weakness of flexor muscles with increased “spastic” muscle tone and reduced dexterity of the muscles involved (Sastre-Garriga et al., 2011). Overall, according to a recent definition spasticity is a “disordered sensimotor control resulting from an upper motor neurone lesion, presenting as intermittent or sustained involuntary activation of muscles” (Stevenson, 2010). The current recommended oral therapies for mild to moderate spasticity include baclofen, tizanidine, benzodiazepine, dantrolene sodium, diazepam, clonazepam, gabapentin, and pregabalin (Smyth and Peacock, 2000; Otero-Romero et al., 2016; Paisley et al., 2002). However, these therapeutic options are not completely effective in managing such complex symptoms and also their prolonged use is associated with numerous adverse reactions (Beard et al., 2003; Shakespeare et al., 2003). In addition, the increasing number of patients not responding to treatment, limits their use. For patients with treatment-refractory spasticity intrathecal baclofen, delivered via a programmable

Corresponding author. E-mail addresses: [email protected] (S. Giacoppo), [email protected] (P. Bramanti), [email protected] (E. Mazzon).

http://dx.doi.org/10.1016/j.msard.2017.06.015 Received 24 April 2017; Received in revised form 20 June 2017; Accepted 25 June 2017 2211-0348/ © 2017 Elsevier B.V. All rights reserved.

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2. An overview of the last decade of Sativex clinical evaluation

implanted pump is a valid therapeutic option. Although there is good evidence about its efficacy for managing severe spasticity, the expensive cost, the invasive procedure and the risk of complications (infection or pump dysfunction) greatly limit its use. Also, when spasticity is focal, intramuscular botulinum toxin injections have been shown to be effective in reducing spasticity (Shakespeare et al., 2003; Ward, 2008). However, this treatment is not permanent and is often repeated after a few months. In addition, phenol injections for either a peripheral nerve block or motor point injections are used to provide a temporary reduction in spasticity (Gunduz et al., 1992). Consequently, in order to improve the outcomes for the majority of MS patients, alternative and less invasive approaches are urgently needed. In the last decades, numerous studies have investigated the pharmacological properties of Cannabis sativa in patients with MS (Giacoppo et al., 2014; Leussink et al., 2012; Zettl et al., 2016). In Cannabis sativa there are more than 60 cannabinoids of which the most important is Δ9-tetraidrocannabinol (THC) discovered for the first time in 1964 by Gaoni and Mechoulam (Mechoulam and Gaoni, 1965). Δ9-THC is the most investigated psychoactive cannabinoid with agonist activity on the cannabinoid receptors CB1 and CB2 (Pertwee, 2008). Δ9HC indeed by binding these receptors may modulate the effects of excitatory (glutamic acid-GLU) and inhibitory (gamma-aminobutyricacidGABA) neurotransmitters, leading to muscle relaxation with a subsequent spasticity amelioration (Russo and Guy, 2006). Galenic preparations containing different concentrations of Δ9-THC have been recently developed as additional therapies for the treatment of pain and spasticity correlated to MS. Particularly, galenic formulations were standardized and formally approved in our country from 2013 as a medicine available as prescription-only from specialists in neurology or neuromedicine. These drugs were usually administrated as an oral infusion or vaporization (Notcutt, 2015). Sativex is another emergent therapeutic add-on option for unresponsive spasticity in MS patients, currently approved in several European countries and in particular in Italy since 2013. Sativex was developed following a number of reports about the benefits of street cannabis to treat symptoms such as MS spasticity, along with a better understanding on the endocannabinoid system (Sastre-Garriga et al., 2011). Specifically, it is an oral spray containing a mixture of two extracts in approximately a 1:1 ratio (2.7 mg of Δ9-THC and 2.5 mg of CBD/ 0.1 mL) in an aromatized water-ethanol solution. This oro-mucosal formulation was designed to provide a simple delivery system to enable more convenient and accurate titration. In particular, this route of administration allows rapid and direct access to the circulation through the mucosa with a faster plateau of plasma concentration, avoiding in this way the problems of the oral route. This mode of administration provides also dosing flexibility for patients that can selfmanage the variable nature of their spasticity without resorting to invasive or ineffective drugs. Also, it has been recognized that co-administration of CBD to Δ9-THC allows to overcome the unwanted effects of Δ9-THC alone (Vaney et al., 2004; Perez, 2006). In addition, compared to existing therapies Sativex has the advantage of being a noninvasive treatment for patients. Over the last decade, clinical experience with Sativex in managing MS-related spasticity is growing steadily. The results of both clinical trials and observational post-approval studies to date have demonstrated the efficacy and safety of Sativex_in reducing the severity of symptoms associated with spasticity, leading lastly to a better ability to perform daily activities and an improved perception of patients and their carers regarding functional status (Sastre-Garriga et al., 2011; Zettl et al., 2016). This review focuses on the current knowledge about the pharmacological properties, clinical efficacy as well as tolerability and safety of Sativex in adult patients with MS-related spasticity.

2.1. Clinical trials on therapeutic efficacy of Sativex The efficacy of Sativex as an add-on therapy for symptom improvement in patients with MS related moderate to severe spasticity has been evaluated in numerous clinical trials since the first reported study in 2003. In this study, Wade and colleagues (Wade et al., 2004) performed a randomized, placebo-controlled, double blind parallel group study involving 160 MS patients of three clinical centers in UK. The authors examined the therapeutic action of Sativex in those patients (N = 80) who experienced spasticity, spasms, bladder dysfunctions, tremor and pain, compared to placebo treated ones (N = 80). In detail, all patients were observed for 10 weeks for the appearance of some symptoms, including disability, cognition, mood, sleep and fatigue. The obtained results showed a reduction of Visual Analog Scale (VAS) (0–100 scale;0 = no spasticity; 100 maximal spasticity) in Sativex group compared with placebo one (−31.2 vs −8.4; P = 0.001) (Wade et al., 2004). Although not statistically significant, an improvement of functional mobility measured by 10 m walking time and an amelioration of bladder control were also found in Sativex patients compared to placebo one. Moreover, MS patients improved quality of sleep following Sativex treatment (P = 0.047). Any significant differences about cognition and mood were observed between the two examined groups (Wade et al., 2004). Following, 86% (137) of the160 MS patients initially recruited were monitored for subsequent extension study performed by the same authors without changes in mean dosages (Wade et al., 2006). Here, it was confirmed effectiveness of long-term use of Sativex (Wade et al., 2006). Specifically, the results obtained after 82 weeks, have proven an improvement in spasticity (mean VAS scores 69.5, 34.2 and 31.8 at double blind baseline, week 10 and week 82, respectively) and trends towards improvement in other MS symptoms in agreement with previous study (Wade et al., 2004). The achieved data emphasized also that the doses of Sativex were maintained constant or slightly decreased over the time entire period of treatment. In addition, it was found that the interruption of Sativex did not cause withdrawal syndrome (Wade et al., 2006). In both these studies, patients were allowed to use a maximum Sativex dose of 12–48 sprays/ day, but a mean of 8.3–9.4 sprays/day was reported (Wade et al., 2004, 2006). In a phase 3, double blind, randomized study, Collin et al. (2007). investigated the efficacy of Sativex into treating the spasticity in MS patients. The trial, multicenter study, involved eight centers in the UK and four centers in Romania with duration of 6 weeks and a total number of 189 patients treated with Sativex (N = 124) or placebo (N = 65) (Collin et al., 2007). More in detail, in this study the primary endpoint was the daily change in the degree of severity of spasticity assessed by a validated visual/numerical rating scales (NRS) (0–11 scale, 0 = no spasticity; 10 maximal spasticity). The efficacy of Sativex was established in MS patients by a reduction of 1.18 points according to the NRS from a value at the baseline of 5.49 points. In the placebo group instead it was found a reduction of NRS score 0.63 points from value in the baseline period of 5.39 points. Specifically, the estimated treatment difference of 0.52 points, in favor of the Sativex group was statistically significant (P = 0.048; 95% CI: −1.029, −0.004 points) In addition, the responder analysis demonstrated that 48 MS patients treated with Sativex exhibited a ≥30% reduction in NRS spasticity compared to 14 in the placebo group (difference in favor of Sativex = 18.1%; 95% CI: 4.73, 31.52; P = 0.014). 21 patients of the Sativex group reported a ≥50% reduction in NRS spasticity compared to 6 patients of the placebo group (difference in favor Sativex = 8.1%; 95% CI: −1.73, 17.98; P = 0.189). The mean sprays/day number was 9.4 (Collin et al., 2007). The secondary endpoint was the measure of spasticity and spasm by using the Ashworth scale (0–4 scale; 0 = no spasticity; 4 maximal spasticity); and the Motricity index that did not 23

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In addition, the fact that the initial responders can be identified in a 4 week trial period could explain the time required for the license. For this study 572 patients of 52 centers across Europe (18 centers in UK, 11 in Spain, 10 in Poland, 8 in the Czech Republic and 5 in Italy) were enrolled. Among these, 272 patients were identified as responder since had a ≥20% reduction of spasticity in the NRS score. More in detail, an improvement in spasticity of 3.01 ± 1.38 points according to NRS from a value in the baseline of 6.91 ± 1.25–3.90 ± 1.51 was recorded in this first phase. Moreover, the daily number of Sativex sprays was 6.9 ± 1.78. Following, 241 MS patients that meet entry criteria continued the study and were randomized in Sativex or placebo groups. During study phase 2 (12 weeks), for these patients it was found that Sativex group improved spasticity measured by Modified Ashworth scale (MAS) (0–10 scale; 0 = no spasticity; 10 maximal spasticity) by 0.04 units from a baseline of 3.87 points, while the placebo group worse of 0.81 points from a baseline of 3.92 score (P = 0.094). Specifically, the estimated treatment difference between the two groups in mean spasticity NRS was 0.84 points (95% CI: −1.29 to −0.40; P = 0.0002). Responder analysis showed also that 74% of MS patients treated with Sativex had an improvement of 30% in spasticity compared with 51% in placebo group (74% vs. 51%: odds ratio 2.73 [95% CI 1.59–4.69]: P = 0.0003). The mean daily sprays number was 8.3 ± 2.43 in Sativex group compared with 8.9 ± 2.31 in the placebo group. Moreover, a total of 56 patients (45%) who received Sativex were classed as > 50% responders compared with 39 ones (33%) on placebo. This approached statistical significance (P = 0.061). In addition to spasticity severity, Sativex was found to improve other spasticity-related symptoms including spasm frequency (P = 0.005), sleep disturbance (P < 0.0001) Barthel activities of daily living (P = 0.0067), Physician Global Impression of Change (P = 0.005), Subject Global Impression of Change (P = 0.023) and Carer Global impression of Change (GIC) in Function (P = 0.005). Interestingly, other secondary end-points of responder analysis including MAS, 10 m walking time, quality of life and mood assessments were in favor of Sativex, without reaching statistical differences (Novotna et al., 2011). The same authors performed a meta-analysis on 666 MS patients who have previously enrolled in the above clinical trials, confirming that Sativex is well tolerated and it is able to reduce spasticity (Wade et al., 2010). Vachová et al. (2014) in a multicenter phase 4, double blind randomized, placebo controlled study evaluated for 50 weeks the efficacy of long-term Sativex use on the severity of spasticity in 121 MS patients (62 receiving Sativex, 59 receiving placebo), that did not relieved with conventional anti-spasticity therapy. This study firstly showed that long-term treatment with Sativex was not associated with cognitive impairment or relevant changes in mood in MS patients. In parallel, the efficacy of Sativex on spasticity reduction was demonstrated by looking to the patients, physicians and careers GIC compared with placebo (P = 0.001, P = 0.002 and P = 0.014, respectively), chosen as secondary endpoints. The remaining secondary outcomes such as MAS and 10 m walking time were not statistically significant, but in favor of Sativex treatment. The mean daily spray number decreased gradually from 7.6 ± 3.1–6.4 ± 3.1 sprays in the Sativex group, while remained 9.5 ± 2.4 in placebo group.Vachová et al. (2014). All clinical studies here described are summarized in Table 1.

reveal statistical significance (Collin et al., 2007). Overall, the achieved data showed that statistically significant differences were observed in patients reported scales of spasticity but not by looking at objective measurements. In the subsequent non-comparative open-label extension of this study (Serpell et al., 2013), a total of 146 patients from the previous study continued the study for 52 weeks. Among these patients, 82 patients completed the study and 52 took Sativex for more than 1 year. In 55 (90%) patients a reduction of NRS spasticity severity score from 5.6 at the double-blind baseline to 4.0 at the end of the study period was found. During this time period the number of sprays taken by patients decreased slightly from 7.29/day (week 4) to 6.34/day (week 52). Only 10% of patients withdrew from the study due to the lack of efficacy (Serpell et al., 2013). After that, in 2010, Collin et al. (2010) performed another multicenter, double-blind, randomized, placebo-controlled, parallel-group study on 337 MS patients treated with Sativex (N = 167) or placebo (N = 170) lasting 15 weeks. Here, authors showed that in the per-protocol (PP) analysis (79% of subjects) the mean baseline NRS spasticity score, the primary end-point, was significantly reduced in favor of Sativex group compared to placebo group (−1.3 versus −0.8 points; p = 0.035). Among the responders patients (≥30% reduction in NRS spasticity), 98%, 94% and 73% exhibited improvements of 10%, 20% and 30%, respectively, at least once during the first 4 weeks of treatment. The mean of Sativex sprays/day number was 8.5 (Collin et al., 2010). In parallel, intention-to-treat (ITT) analysis showed a non-significant amelioration in NRS score, in favor of Sativex. Other secondary measures of spasticity including 10 m walking test, MAS, sleep quality, pain, tremor, spasm and bladder symptoms showed a not statistically significant trends favoring Sativex. In addition, the ITT population did not show any difference in the carer global impression of change (CGIC), whereas it was in favor of Sativex in the PP population (P = 0.013). Authors suggest that the difference between PP and ITT outcomes may be explained by the behavior of patients that were withdrawn from the PP analysis, which in the Sativex group was largely a cohort of patients not following dosage instructions as well as poor responders (Collin et al., 2010). In a clinical trials setting, it can be difficult showing clear-cut efficacy in a population of patients where a proportion may lack the capacity to respond to treatment. Indeed, the studies so far discussed have included all patients that met entry criteria, but in this way the average response includes not only the effect of the treatment in those who respond to it but also in those who do not respond, underestimating the real effect of treatment. Starting from this, Novotna et al. (2011). in a phase 3 placebo-controlled trial used an enriched enrollment design to evaluate the efficacy of Sativex in the treatment of spasticity only in MS patients who had shown the capacity to respond to treatment (Novotna et al., 2011). More in detail, this study included a first phase in single-blind (4 weeks) to identify patients sensible to Sativex. The patients were not aware whether they were taking placebo or Sativex, administered as adjunctive therapy to the ongoing oral antispasmodic drugs. In this way, subjects lacking the capacity to respond were not randomized and were therefore not exposed to the hazards of continued treatment. In addition, the purpose of keeping the subjects blind to treatment during the first phase of study allowed to reduce the impact of any expectation that the patients might have about the efficacy of the treatment administered and also to reduce the potential for unblinding during the following phase. In other words this method allows to determine the effectiveness of Sativex in a way that more tightly reflects good clinical practice. Importantly, this type of study design not eliminate the placebo response. Indeed, by including only those patients who have demonstrated the capacity to respond, it is more likely to enhance the placebo response (Novotna et al., 2011). Hence the differences between pharmacological treatment and placebo could be a reflection of effectiveness in the population intended for treatment.

2.2. Everyday clinical practice studies Since Sativex was approved in European countries for the management of MS-related spasticity, numerous observational post-approval studies have been performed to monitor its use in everyday clinical practice (Fernandez, 2016). In this context, the observational, prospective study (Mobility Improvement 2 (MOVE) 2) have proved very useful in confirming the efficacy of Sativex in MS patients resistant to the current antispasmodic therapy. 24

25 337 Sativex (N = 167) Placebo (N = 170)

15 weeks

Double-blind, randomized, placebo-controlled, parallel-group study

189 Sativex (N = 124) Placebo (N = 65)

6 weeks

Phase 3, double blind, randomized study

146

137

82 weeks

Open-label long-term study

52 weeks

160 Sativex (N = 80) Placebo (N = 80)

10 weeks

Randomized, placebocontrolled, double blind parallel group study

Non-comparative open-label extension

Number of MS patients

Study duration

Study design

Table 1 Summary of the clinical studies.

8.5

6.34

9.4

8.3–9.4

8.3–9.4

Mean Sativex sprays/day Reduction of VAS spasticity severity score in Sativex group compared with placebo one (−31.2 vs −8.4; P = 0.001); Improvement of quality of sleep in Sativex group compared with placebo one (P = 0.047); Improvement of functional mobility measured by 10 m walking time and amelioration of bladder control and quality of sleep in favor of Sativex group compared to placebo (not statistically significant). Improvement in spasticity (mean VAS scores 69.5, 34.2 and 31.8 at 0, 10 and week 82, respectively); pain (mean VAS scores 68.1, 31.9 and 26.4 at 0, 10 and 66 weeks, respectively); spasm (mean VAS scores 65.1, 30.7 and 26.7 at 0, 10 and 66 weeks, respectively); bladder dysfunction (65.6, 29.5 and 23.5 at 0, 10 and 74 weeks, respectively. NRS spasticity score reduced from 5.49 to 4.31 in the Sativex and from 5.39 to 4.76 in the placebo group a small numerical estimated treatment difference of 0.52 points, in favor of Sativex (P = 0.048; 95% CI: −1.029, −0.004 points) (ITT analysis). Responder analysis favored Sativex group: 48 patients achieved ≥30% reduction in mean NRS score vs placebo (difference in favor of Sativex = 18.1%; 95% CI: 4.73, 31.52; P = 0.014). 21 patients of the Sativex group reported a ≥50% reduction in NRS spasticity vs placebo (difference in favor Sativex = 8.1%; 95% CI: −1.73, 17.98; P = 0.189. Ashworth scale and Motricity Index favored Sativex group but not statistically significant. Reduction of NRS spasticity severity score from 5.6 at the double-blind baseline to 4.0 at the end of the study period. Reduction of NRS spasticity severity score (−1.3 versus −0.8 points; P = 0.035) in Sativex group (PP analysis). Reduction, but not statistically significant, of NRS spasticity severity score in Sativex group (ITT analysis). The secondary measures of spasticity including 10 m walking time, MAS, sleep quality, pain, tremor, spasm and bladder symptoms showed nonsignificant trends favoring Sativex group. The CGIC it was in favor of Sativex in the PP population (P = 0.013), whereas did not show any difference in the ITT population.

Clinical Outcome

(continued on next page)

Collin et al., 2010

Serpell et al., 2013

Collin et al., 2007

Wade et al., 2006

Wade et al., 2004

Ref.

S. Giacoppo et al.

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Number of MS patients Phase A 572 Phase B 241 Sativex (N = 124) Placebo (N = 117)

121 Sativex (N = 62) Placebo (N = 59)

Study duration

Phase A 4 weeks Phase B 12 weeks

50 weeks

Study design

Phase 3, double-blind, randomized, placebocontrolled, parallel-group study

Phase 4, double blind randomized, placebo controlled study

Table 1 (continued)

7.6–6.4

8.3

Mean Sativex sprays/day Reduction of NRS spasticity severity score of 3.01 ± 1.38 points from a value in the baseline of 6.91 ± 1.25–3.90 ± 1.51 in Sativex group (Phase A). Reduction of NRS spasticity score in Sativex group (mean spasticity 0.84 points; 95% CI: −1.29 to −0.40; P = 0.0002) (Phase B-ITT analysis). Responder analysis favored Sativex group; 74% of patients had an improvement of 30% in spasticity compared with 51% in placebo group (74% vs. 51%: odds ratio 2.73 [95% CI 1.59–4.69]: P = 0.0003); 45% of patients were classed as > 50% responders compared with 33% on placebo (P = 0.061). MAS score improved of 0.04 units from a baseline of 3.87 points, while the placebo group worse of 0.81 points from a baseline of 3.92 score (P = 0.094). Significant differences in favor of Sativex were found about: spasm frequency (P = 0.005), sleep disturbance (P < 0.0001), Barthel index (P = 0.0067), physician GIC (P = 0.005), patient GIC (P = 0.023) and carer GIC (P = 0.005) (Phase B-ITT analysis). Improvement in spasticity was measured by the patient GIC (P = 0.002), physician GIC (P = 0.0001) and carer GIC (P = 0.014) was found in Sativex group compared to placebo. MAS score and 10 m walking time were not statistically significant, but in favor of Sativex treatment.

Clinical Outcome

Vachová et al., 2014

Novotna et al., 2011

Ref.

S. Giacoppo et al.

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According to the physician's judgement, 65.4% of patients were considered responders after the first month of treatment, aligning with the proportion of patients reaching IR (70.5%), whereas 9.3% were considered partial responders, suitable to become responders in a longer follow-up (Patti et al., 2016). The data are recorded also after 12 and 24 weeks from baseline. showing a gradually reduction of NRS spasticity score from baseline value was recorded after 12 weeks (from 7.5 to 5.1; P < 0.0001) and after 24 weeks (from 7.5 to 4.8; P < 0.0001). These results suggest that a significant MS spasticity NRS reduction is obtained during the first month and that it is maintained or slightly enhanced over time. The mean dosage of Sativex was of 6.8 sprays/day. In everyday clinical practice studies it was found that patients used lower Sativex sprays/day than in clinical trials (6.7 vs. 8.3 sprays/day), suggesting that increasing the number of doses does not necessarily improve the treatment efficacy. All Everyday clinical practice studies here discussed are summarized in Table 2.

In this kind of studies, the data collected in daily practice, allow to complement the results of clinical trials providing informations from larger population and under prescribed condition use, without any criteria of inclusion typical of clinical trials (Fernandez, 2016). Generally, the experimental design consists of a baseline visit (enrollment), 1-month visit, to find Sativex responder patients, defined as patients who had a ≥ 20% improvement of spasticity in the NRS, and 3-months visit (Trojano, 2016). The first MOVE 2 conducted in Germany, involved 276 MS patients from 42 specialized centers for a follow-up period of 3 months (Flachenecker et al., 2014b). The disability of enrolled MS patients was evaluated by using the Expanded Disability Status Scale (EDSS) score. In particular, patients showed a mean EDSS score of 6.0 (range1.0–9.0), a mean spasticity 0–10 NRS score of 6.1 (P < 0.0001) and a mean MAS score of 3.0 (P < 0.0001) (Flachenecker et al., 2014b). Sativex was administered to patients in concurrency with other antispasmodic drugs with a mean of daily sprays of 6,9 ± 2.8 after 1 month and 6.7 ± 2.9 after 3 months. This study was subsequently extended to several other countries in the European Union, like Italy. The Italian study MOVE 2, an interim analysis, involved 322 patients with moderate to severe MS spasticity from 33 specialized centers (Trojano and Vila, 2015). For these patients a mean EDSS score was not available, a mean spasticity 0–10 NRS score decreased by −19.1% (−1.6 points, P < 0.0001) and the mean MAS decreased from 2.6 to 2.3 points (P < 0.0001) from baseline to month 3 of treatment. By comparing the two populations examined, it was found a considerably higher proportion of patients in MOVE 2-Italy who had an initial response to Sativex treatment. 82.9% of MS-Sativex treated patients recorded a spasticity reduction of at least 20% in their NRS score after 1 month of treatment (P < 0.0001) and 24.6% of patients showed a spasticity reduction of at least 30% in NRS score after 3 months (P < 0.0001). In both MOVE 2-Germany and MOVE 2-Italy, the mean 0.3-point decrease in the MAS score observed from baseline to month 3 (P < 0.0001). In addition, spasticity-related symptoms, such as spasms, fatigue, pain, sleep quality and bladder dysfunction were significantly improved by Sativex at 3 months, as well as the activities of daily living (P < 0.001 vs. baseline). Achieved data suggest that add-on Sativex is an effective and well-tolerated treatment option for patients with treatment-resistant MS spasticity in everyday clinical practice (Trojano, 2016; Vermersch and Trojano, 2016). Interestingly, MS patients used a low average of Sativex sprays per days (6.9 ± 2.1) demonstrating that the number of sprays does not improve the response to the treatment. Overall, quality of life was found improved. A recent prospective, observational, multicentre study was performed on 205 patients with treatment-resistant MS spasticity enrolled at 13 specialist MS centers across Spain (Oreja-Guevara et al., 2015). This study confirmed that Sativex as add-on therapy showed sustained anti-spasticity benefit in a relevant proportion (60.5%) of Spanish patients with MS-related spasticity treated for up to 12 months in everyday clinical practice. The mean dosage of Sativex remained stable for the entire duration of the study with a mean of 6.6 sprays/day (range: 1–14 sparys/say) (Oreja-Guevara et al., 2015). Recently, it was conducted an Italian observational, prospective multicenter study involving 30 centers specialized in MS in order to evaluate the efficacy of Sativex in 1615 MS patients (Patti et al., 2016). Specifically, this study was a trial single blind in the first phase and a double-blind randomized in the second phase. As already reported by Novotna et al. (2011), this study allows to identify the initial responders that can continue either with Sativex treatment or placebo. The effectiveness of Sativex was evaluated by using two parameters: the initial response (IR) defined as an improvement of NRS spasticity of ≥ 20% and the clinically relevant response (CRR), defined as an improvement of NRS spasticity of ≥ 30%. At the end of the 4-week trial period, it was observed that 70.5% of patients reached the IR threshold and that 28.2% had already reached the CRR threshold with a mean NRS score reduction of 22.6% compared to baseline (from 7.5 to 5.8; P < 0.0001).

2.3. Post-marketing evaluations on walking improvements with Sativex The outcomes used in both clinical trials and in everyday clinical practice studies, so far, reflect the efficacy of Sativex on spasticity management. However, data leading to approval and clinical practice use of Sativex, although widely recognized, are based on subjective evaluations, including NRS, VAS, Ashworth scores and MAS. On the other hand, it has led to less information about the functional effects towards walking function. Until now the functional mobility was evaluated predominantly as a secondary outcome. Instead, walking difficulties related to spasticity are common in MS patients. Problems with walking can make it more difficult to socialize or continue working and can cause other aches and pains through the strain the person puts on their body as they try to walk in a normal and steady manner. In this context, we looked to a recent study of 2015 conducted in an Italian monocentric cohort of MS patients that evaluated the walking improvements following Sativex treatment (Coghe et al., 2015). Specifically, this study involved 20 MS with a mean EDSS of 6.1 ± 1.4. Here, it was found that Sativex has a positive impact on patients’ ambulation abilities. More in detail, authors evaluated spatialtemporal and kinematic variations by means of three-dimensional gait analysis, showing an increase speed (+15%; P < 0.001), cadence (+6%; P < 0.001) and stride length (+10%; P < 0.001) after treatment with Sativex. Regarding the kinematics results, the Gait Profile Score (GPS) was reduced by 10% (P < 0.001). The improvements are particularly important in strategic joint actions, namely, pelvic tilt, pelvic rotation, pelvic obliquity, hip rotation and knee flexion-extension. Interestingly, authors found an amelioration, but not statistically significant, in parameters of walking also in NRS non-responder patients. In this case, authors suggest that the functional response could be attributed to a limited usefulness of NRS in targeting walking impairment, or it could be interpreted as an effect on the ambulation that goes beyond the simple muscle reduction (Coghe et al., 2015). Therefore, it is conceivable that Sativex may act more deeply in the mechanisms of stiffness and movement regulation in spasticity and improved walking ability that is imperceptible to the patients. The results of a recent post-marketing study in which the changes in motor functions following Sativex were examined are reported by Ferre et al. (2016). In particular, the authors investigated the efficacy and safety of Sativex in a real-life monocentric Italian cohort of 144 MS patients, with a mean EDSS of 6.5 (range 2.0–8.5). Here, the ambulatory function was assessed using the 10 m walking time and ambulation index in 69 MS patients. After 4 weeks of Sativex treatment it was found an improvement in the 10 m walking time, being 25.5 s (SD: 18.9 s) at baseline and 21.6 (SD: 13.8 s) (P < 0.001) as well as a significant reduction of the ambulation index (P = 0.03), with nine responders displaying a reduction of ≥1 point. At the end of study (14 weeks) these parameters remained stable, despite median EDSS 27

Multiple Sclerosis and Related Disorders 17 (2017) 22–31

NRS score reduction compared to baseline from 7.5 to 5.8 (P < 0.0001) after 4 weeks; from 7.5 to 5.1 (P < 0.0001) after 12 weeks and from 7.5 to 4.8 (P < 0.0001) after 24 weeks.

Patti et al., 2016

persisted unchanged throughout the study period (Ferre et al., 2016). In general this study suggest that Sativex is an effective, safe and welltolerated therapeutic strategy in MS patients. Interestingly, its efficacy is especially evident during the first months but persist up to 1 year of follow-up. In addition, MS patients with shorter disease duration seem to respond better to the treatment. Future studies could provide more information on the effectiveness of Sativex in improving movement disabilities and reduced walking ability. 2.4. Electrophysiological studies Despite the proven efficacy of Sativex in reducing spasticity in MS patients, little is known about the neurophysiological correlates of such effects. In this context, Koch et al. (2009) explored effects of Sativex on continuous transcranial magnetic theta burst stimulation TBS (cTBS) and intermittent TBS (iTBS) in 10 MS patients. Authors found that following cTBS, Sativex administration caused persisting increase of motor-evoked potentials (MEPs) after 4 weeks of treatment. More in detail, in comparison with baseline evaluation, MEP amplitudes were increased at all the time points explored (0–5, 7–12, 13–18, and 19–24 min after TBS; P < 0.05), suggesting the important role of cannabinoid system in the modulation of synaptic plasticity and at least in amelioration spasticity. Moreover, a recent a randomized, double-blind, placebo-controlled, crossover study of 2015 investigated the beneficial action of Sativex on neurophysiological measures of spasticity and corticospinal excitability in MS patients (Squintani et al., 2016). This study involved 19 MS unresponsive to conventional antispastic treatments with a mean Expanded Disability status Scale (EDSS) of 6.1 ± 1.4. The patients were clinically evaluated by MAS score and underwent a neurophysiological protocol targeting for measures of excitability and inhibition at both cortical, (intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)) and spinal level (Hreflex, H/M ratio and recovery curve of the H-reflex (HRC)) both before and after 4 weeks of treatment with Sativex. Results showed that Sativex leads to a decrease in muscle tone with consequent amelioration of spasticity as measured with MAS score from 1.1 ± 0.6–0.7 ± 0.5 (P = 0.005). By looking to neurophysiological data, it was found a significant strengthening of inhibition shown by reduced LICI and a nonsignificant facilitation, shown by non-significant increased ICF, whereas no differences as to both H-reflex and H/M ratio were observed. Thus, these data suggest a modulatory effect of Sativex on different pathways, mainly of inhibitory nature. Moreover, Russo et al. (2015) studied the role of Sativex in improving the spasticity by corticospinal modulation in 30 MS patients. In Sativex-treated patients, the spasticity was evaluated by using the MAS, NRS, Penn Spasm frequency scale (PSFS), bladder control scale (BLCS) and 10 m walking time. The patients were subjected also to a neurophysiological examination. Specifically, electrophysiological parameters including motor threshold, motor evoked potentials amplitude, intracortical excitability, short intracortical inhibition, sensory-motor integration, and Hmax/Mmax ratio were recorded at baseline and after one month of treatment. The results achieved after one month of treatment have demonstrated a significant improvement in spasticity, as proven by the NRS score that decreased from baseline of 8.3 ± 0.5–5.5 ± 0.4 (P < 0.01). The MAS also decreased from 4.0 ± 0.7–3.0 ± 0.9compared to baseline (P < 0.05). PSFS and BLCS decreased respectively from 2.8 ± 0.5 and 15.0 ± 2.0–2.2 ± 0.3 and 11.0 ± 1.0 from baseline (P < 0.05). The time for the 10 m walking test decreased from 98.0 ± 9.0–69.0 ± 7.0 s (P < 0.01) in Sativex group. In addition, Sativex was capable to modulate both cortical excitability, as shown by the increase of short intracortical inhibition (P = 0.0002) and reduction of intracortical facilitation and the spinal excitability (P = 0.01), as shown by the slight but significant reduction of Hmax/Mmax ratio implicated in spasticity pathophysiology (P = 0.05).

205

1615

12 months

24 weeks

Prospective, observational, multicentre study Observational, prospective multicenter study

6.8

322 3 months MOVE 2-Italy

6.6

Oreja-Guevara et al., 2015

Flachenecker et al., 2014b

Statistically significant reduction of NRS spasticity severity score (mean NRS score of 6.1; P < 0.0001) and MAS score (mean MAS of 3.0; P < 0.0001). NRS spasticity severity score decreased by −19.1% (−1.6 points, P < 0.0001) and the mean modified Ashworth score decreased from 2.6 to 2.3 points (P < 0.0001) from baseline to month 3. Improvement in spasticity and in other MS symptoms (Statistics not provided). 335 3 months MOVE 2-Germany

6.9 (after 1 month) and 6.7 (after 3 months) 6.9

Trojano and Vila, 2015

Ref. Study duration Study design

Table 2 Overview of the everyday clinical practice studies.

Number of MS patients

Mean Sativex sprays/day

Clinical outcome

S. Giacoppo et al.

28

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Russo et al., 2015

In a recent paper, the same authors examined the effect of Sativex on functional and psychological status in 61 MS patients that before the enrollment did not use Sativex or other cannabinoid-based medications (Russo et al., 2016). Among these, 45 MS patients were considered as responders to Sativex administration. Thus, these MS patients underwent a neurological and neurophysiological examinations. The authors demonstrated a significant NRS and MAS decrease after 1 and 6 months of Sativex administration. In addition, any significant neurobehavioral impairment was observed in all the MS patients (Russo et al., 2016). A summary of the electrophysiological studies is provided in Table 3. 3. Adverse events of Sativex in MS patients

1 month Observational single group, interventional single center

Not available

Sativex was generally well tolerated in patients with MS-related spasticity as proven in several clinical studies as well as in everyday clinical practice observations. However, as any pharmacological treatment, Sativex can cause unwanted side effects. These may vary from person to person, and not everyone can get them. The most common adverse reactions, affecting less than 1 in 10 people and usually reported during the first 4 weeks, were dizziness, fatigue, anxiety, depression, constipation or diarrhea, nausea, vertigo, headache, dry mouth, somnolence and urinary tract infections. All these adverse effects are most often described as mild or moderate severity and their incidence can be significantly reduced by gradual “up-titration”. Moreover, uncommon side effects, affecting less than 1 in 100 people, including allergic phenomena, euphoria, psychosis, panic, hallucinations, paranoia, suicidal ideation, memory changes and cognitive decline were also observed. These events generally disappeared when Sativex dose is reduced or treatment is interrupted (Aragona et al., 2009). Constantinescu (2006) reported a collection data from randomizedcontrolled clinical trials involving 930 MS patients, of which 444 patients continued long-term extension studies. Authors reported that the most common adverse reactions, affecting less than 1 in 10 people, were dizziness (27.5%), diarrhea (13.1%), fatigue (11%) and nausea (10.85%). All these adverse effects are most often described as mild or moderate severity. In addition, 17.1% serious adverse events were recorded, but only 3.8% of these were correlated to Sativex treatment. Likewise, Pozzilli (2013) in a symposium paper of 2013, by collecting safety data from phase 3 studies (Wade et al., 2004; Collin et al., 2007; Novotna et al., 2011) suggested good tolerability to Sativex under clinical trial conditions. 805 MS patients subjected to Sativex administration reported dizziness, fatigue and somnolence as the most common treatment-related adverse events. However, the majority of these reactions were mild or moderate severity and resolved quickly, indeed their appearance decreased after introduction of the recommended gradual up-titration schedule for Sativex. In addition, by looking to the long-term studies on Sativex it was showed that the improvement in spasticity continued throughout the trial so there was no evidence that patients became tolerant to Sativex or needed to increase the dose (Serpell et al., 2013). Moreover, other MS symptoms remained stable throughout the studies. Interestingly, there is no evidence of psychological or psychiatric problems as showed in an 8 week randomized, double blind, placebo-controlled crossover study (Aragona et al., 2009). Here, Sativex treatment did not found to cause psychopathology nor cognitive decline in MS patients who have never used cannabis. Likewise, an open-label long-term study with 137 MS patients as well as a randomized, placebo-controlled study involving 60 patients demonstrated no evidence of withdrawal symptoms even though Sativex treatment was stopped quite suddenly (Wade et al., 2006; Notcutt et al., 2012). Overall, the adverse events rate observed in the observational studies was lower than in the randomized clinical trials, although that is often due to different patient perception and a less controlled environment. In the MOVE-2 study (Flachenecker et al., 2014b), above described, the majority of MS patients did not exhibited adverse

30

19 1 month Randomized, double-blind, placebo-controlled, crossover study

6.9

Koch et al., 2009

In comparison with baseline evaluation, MEP amplitudes were increased and not decreased 7–12, 13–18, and 19–24 min after TBS (P < 0.05). Amelioration of spasticity as measured with MAS score from 1.1 ± 0.6–0.7 ± 0.5 (P = 0.005). No differences as to both H-reflex and H/M ratio were observed Significant reduction of NRS spasticity score from baseline of 8.3 ± 0.5–5.5 ± 0.4 (P < 0.01). The MAS also decreased from 4.0 ± 0.7–3.0 ± 0.9 compared to baseline (P < 0.05). PSFS and BLCS decreased respectively from 2.8 ± 0.5 and 15.0 ± 2.0–2.2 ± 0.3 and 11.0 ± 1.0 from baseline (P < 0.05). Reduction of 10 m walking test from 98.0 ± 9.0–69.0 ± 7.0 s (P < 0.01). Increase of short intracortical inhibition (P = 0.0002). Reduction of intracortical facilitation (P = 0.01). Mild but significant Hmax/Mmax ratio reduction (P = 0.05). 10 1 month Observational study

10.5

Ref. Clinical outcome Mean Sativex sprays/day Number of MS patients Study duration Study design

Table 3 Summary of the electrophysiological studies.

Squintani et al., 2016

S. Giacoppo et al.

29

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S. Giacoppo et al.

safety profile and its tolerability. In the light of the described findings, we believe that Sativex could represent new opportunity for many patients affecting by different conditions in which with spasticity is resistant to common antispastic drugs. Finally, we strongly hope that further studies will be performed in order to confirm the efficacy of Sativex as add-on therapy in many disabling diseases.

reactions correlated to Sativex. Also here, the most common side effects were dizziness, fatigue, drowsiness, nausea and dry mouth. 3.1. Post-marketing evaluations on safety of Sativex The benefit-risk profile for Sativex was also confirmed by postmarketing evaluations. Specifically, an observational post-marketing registry to collect safety data from patients who have been prescribed Sativex was designed with the objective of monitoring its long-term safety in clinical practice after its approval in the European countries (Etges et al., 2016). This registry was opened in the UK in 2010, followed by Germany in 2012, and was extended to include Switzerland in 2015. The results were published on 2016. Overall, it contains data for a total of 941 MS patients (761 from UK, 178 from Germany and 2 from Switzerland). More in detail, the collected informations about suspected adverse reactions were related to areas of special attention, including clinically significant adverse events, falls, important psychiatric/psychotic events (mood changes, memory impairment, confusion/disorientation), suicidal thoughts or attempted suicide, changes in driving ability, and the potential for abuse, dependence, or misuse. The collected data show that 60% of patients were reported as continuing treatment, the 83% were reported as benefiting from the treatment, while 32% interrupted treatment due to the lack of effectiveness or to adverse reactions. In agreement with the previous studies, the most common treatment-related adverse events were dizziness and fatigue. Moreover, psychiatric adverse events of clinical importance were recorded in 6% of the patients, 6% reported falls requiring medical attention, and suicidality was reported in 2%. Driving ability was described to have worsened in 2% of patients, but improved in 7%. There were also no indications to indicate abuse, diversion, or dependence (Eltayb et al., 2013). Post-marketing data suggest also that effectiveness of Sativex under clinical practice conditions is equivalent to its efficacy in clinical trials. Similarly, the Spanish safety study involved 207 patients from 13 MS centers across Spain reported a data collection about safety of Sativex. No new safety findings were reported after 6 and 12 months (Fernandez, 2014; Oreja-Guevara et al., 2013). The study was completed by 64% of patients with a mean daily doses of 6.6 sprays/day. Interestingly, a total of 5 psychiatric/psychotic incidences but no incidences of suicidal thoughts, attempts, abuse, misuse or indication of driving impairment was recorded. Taken together, these data suggest that treatment with Sativex is commonly well tolerated. However, patients should be controlled by their treating physician, mainly in the initial trial period, to identify and resolve possible occurring adverse reactions.

Conflict of interest The authors declared no potential conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. Acknowledgements This study was supported by funds of Pharmacovigilance multiregional project entitled “EVALUATION AND RECOGNITION OF ADVERSE REACTIONS IN PATIENTS WITH MULTIPLE SCLEROSIS PHARMACOLOGICALLY TREATED” of 2010/2011 of Agenzia Italiana del Farmaco (AIFA). References Aragona, M., Onesti, E., Tomassini, V., et al., 2009. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study. Clin. Neuropharmacol. 32, 41–47. Beard, S., Hunn, A., Wight, J., 2003. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol. Assess. 7 (iii, ix-x, 1–111). Coghe, G., Pau, M., Corona, F., et al., 2015. Walking improvements with nabiximols in patients with multiple sclerosis. J. Neurol. 262, 2472–2477. Collin, C., Davies, P., Mutiboko, I.K., Ratcliffe, S., Sativex Spasticity in, M.S.S.G., 2007. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur. J. Neurol. 14, 290–296. Collin, C., Ehler, E., Waberzinek, G., et al., 2010. A double-blind, randomized, placebocontrolled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol. Res. 32, 451–459. Constantinescu, C.S.S.N., 2006. Long-term open-label treatment with Sativex® in patients with multiple sclerosis. Mult. Scler. 12. E Eltayb, A., Etges, T., Wright, S., 2013. An observational post-approval registry study of patients prescribed Sativex (R). results from clinical practice. Mult. Scler. J. 19, 480. Etges, T., Karolia, K., Grint, T., et al., 2016. An observational postmarketing safety registry of patients in the UK, Germany, and Switzerland who have been prescribed Sativex(R) (THC: CBD, nabiximols) oromucosal spray. Ther. Clin. Risk Manag. 12, 1667–1675. Fernandez, O., 2014. Advances in the management of MS spasticity: recent observational studies. Eur. Neurol. 72 (Suppl 1), 12–14. Fernandez, O., 2016. THC:CBD in Daily Practice: Available Data from UK, Germany and Spain. Eur. Neurol. 75 (Suppl 1), 1–3. Ferre, L., Nuara, A., Pavan, G., et al., 2016. Efficacy and safety of nabiximols (Sativex ((Rativex((Sativex((R))) on multiple sclerosis spasticity in a real-life Italian monocentric study. Neurol. Sci. 37, 235–242. Flachenecker, P., Henze, T., Zettl, U.K., 2014a. Spasticity in patients with multiple sclerosis–clinical characteristics, treatment and quality of life. Acta Neurol. Scand. 129, 154–162. Flachenecker, P., Henze, T., Zettl, U.K., 2014b. Nabiximols (THC/CBD oromucosal spray, Sativex) in clinical practice–results of a multicenter, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity. Eur. Neurol. 71, 271–279. Giacoppo, S., Mandolino, G., Galuppo, M., Bramanti, P., Mazzon, E., 2014. Cannabinoids: new promising agents in the treatment of neurological diseases. Molecules 19, 18781–18816. Goldenberg, M.M., 2012. Multiple sclerosis review. PT 37, 175–184. Gunduz, S., Kalyon, T.A., Dursun, H., Mohur, H., Bilgic, F., 1992. Peripheral nerve block with phenol to treat spasticity in spinal cord injured patients. Paraplegia 30, 808–811. Koch, G., Mori, F., Codeca, C., et al., 2009. Cannabis-based treatment induces polarityreversing plasticity assessed by theta burst stimulation in humans. Brain Stimul. 2, 229–233. Leussink, V.I., Husseini, L., Warnke, C., Broussalis, E., Hartung, H.P., Kieseier, B.C., 2012. Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity. Ther. Adv. Neurol. Disord. 5, 255–266. Mechoulam, R., Gaoni, Y., 1965. A total synthesis of Dl-Delta-1-tetrahydrocannabinol, the active constituent of Hashish. J. Am. Chem. Soc. 87, 3273–3275. Notcutt, W., Langford, R., Davies, P., Ratcliffe, S., Potts, R., 2012. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex (nabiximols). Mult. Scler. 18, 219–228. Notcutt, W.G., 2015. Clinical use of cannabinoids for symptom control in multiple

4. Conclusion Complexity of spasticity poses several problems in its clinical management and has a strong impact on the patients' quality of life and in particular on normal daily activities. In the last years, a growing interest is focused on the combination drug approach with existing medications in order to maximize the therapeutic efficacy and minimize the adverse effects commonly observed with conventional therapies. In this context, Sativex represents a valid therapeutic option when the conventional therapies have been ineffective or not tolerated. In addition, compared to existing therapies Sativex has the advantage of being a non-invasive treatment for patients. The numerous evidences so far have demonstrated the efficacy of Sativex as adjunctive therapy in MS patients resistant to existing therapies, especially regarding global improvement in patients’ and caregiver's perception. Overall, during Sativex treatment patients reported outcome measures (PROMs) such as NRS and VAS scores, compared to the lack of efficacy found in objective measures, like MAS. Unfortunately, there are still few informations about the functional effects towards walking function. In addition, a low incidence of adverse reactions Sativex-related supports the good 30

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