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Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis

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  • Oxford Centre for Enablement
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To determine the efficacy of Sativex (USAN: nabiximols) in the alleviation of spasticity in people with multiple sclerosis. The results from three randomized, placebo-controlled, double-blind parallel group studies were combined for analysis. 666 patients with multiple sclerosis and spasticity. A 0-100 mm Visual Analogue Scale (VAS, transformed to a 0-10 scale) or a 0-10 Numerical Rating Scale (0-10 NRS) was used to measure spasticity. Patients achieving a > or =30% improvement from baseline in their spasticity score were defined as 'responders'. Global impression of change (GIC) at the end of treatment was also recorded. The patient populations were similar. The adjusted mean change of the numerical rating scale from baseline in the treated group was -1.30 compared with -0.97 for placebo. Using a linear model, the treatment difference was -0.32 (95% CI -0.61, -0.04, p = 0.026). A statistically significant greater proportion of treated patients were responders (odds ratio (OR) = 1.62, 95% CI 1.15, 2.28; p = 0.0073) and treated patients also reported greater improvement: odds ratio 1.67 (95% CI 1.05, 2.65; p = 0.030). High numbers of subjects experienced at least one adverse event, but most were mild to moderate in severity and all drug-related serious adverse events resolved. The meta-analysis demonstrates that nabiximols is well tolerated and reduces spasticity.
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DOI: 10.1177/1352458510367462
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Meta-analysis of the efficacy and safety
of Sativex (nabiximols), on spasticity
in people with multiple sclerosis
Derek T Wade, Christine Collin,
Colin Stott and Paul Duncombe
Abstract
Objective: To determine the efficacy of Sativex (USAN: nabiximols) in the alleviation of spasticity in people with
multiple sclerosis.
Methods: The results from three randomized, placebo-controlled, double-blind parallel group studies were combined
for analysis.
Patients: 666 patients with multiple sclerosis and spasticity.
Measures: A 0–100 mm Visual Analogue Scale (VAS, transformed to a 0–10 scale) or a 0–10 Numerical Rating Scale
(0–10 NRS) was used to measure spasticity. Patients achieving a 30% improvement from baseline in their spasticity
score were defined as ‘responders’. Global impression of change (GIC) at the end of treatment was also recorded.
Results: The patient populations were similar. The adjusted mean change of the numerical rating scale from baseline in
the treated group was 1.30 compared with 0.97 for placebo. Using a linear model, the treatment difference was
0.32 (95% CI 0.61, 0.04, p¼0.026). A statistically significant greater proportion of treated patients were respon-
ders (odds ratio (OR) ¼1.62, 95% CI 1.15, 2.28; p¼0.0073) and treated patients also reported greater improvement:
odds ratio 1.67 (95% CI 1.05, 2.65; p¼0.030). High numbers of subjects experienced at least one adverse event, but
most were mild to moderate in severity and all drug-related serious adverse events resolved.
Conclusion: The meta-analysis demonstrates that nabiximols is well tolerated and reduces spasticity.
Keywords
multiple sclerosis, spasticity, cannabinoids, sativex, delta-9-tetrahydrocannabinol, cannabidiol, nabiximols
Date received: 8th February 2010; accepted: 9th February 2010
Introduction
Systematic reviews of treatments used in the alleviation
of spasticity, especially in people with multiple sclerosis
(MS), have emphasized the weakness of the evidence
for all currently used systemic drugs such as baclofen,
tizanidine, dantrolene, diazepam, and gabapentin.
1,2
Recently, several studies have investigated the effective-
ness of various cannabinoid-containing medications in
patients with multiple sclerosis and spasticity.
3–10
Their
individual results are consistent but weak. A meta-
analysis of studies using the same preparation might
reduce uncertainty about the effects of cannabinoids.
Meta-analysis of studies investigating drug treat-
ment of spasticity is not easy. Different treatments are
used and the recent trials of cannabinoid medicines
have used preparations that vary both in their active
ingredient(s), in their mode of presentation and in their
route of administration. Second, different measures
were used. This arises from the third difficulty,
namely that there is no agreement on what spasticity
is
11,12
and how it should be measured. Although the
Ashworth scale
13
is the most widely used measure,
there are concerns that it is unreliable and insensitive
and that it only measures passive resistance to move-
ment and not other aspects of spasticity.
12,14
Indeed a
Oxford Centre for Enablement, Windmill Road, Oxford, OX3 7LD, UK.
Corresponding author:
Professor Derick Wade MA, MB, BChir, FRCP, MD, Consultant in
Neurological Rehabilitation, Oxford Centre for Enablement, Windmill
Road, Oxford OX3 7LD, UK
Email: derick.wade@noc.nhs.uk
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recent study has suggested that the Ashworth scale
should ‘never be used’!
21
Three randomized, controlled studies
4,6,7
have
recruited similar patients and have used similar mea-
sures of efficacy and the same preparation, nabiximols
(Sativex) which contains two principal cannabinoids –
delta-9-tetrahydrocannbinol (THC) and cannabidiol
(CBD) in a 1 : 1 ratio. All were placebo-controlled
and performed in patients with MS who had insufficient
benefit from their existing anti-spasticity medication.
Nabiximols or placebo was administered as an add-on
therapy, in addition to all existing medications.
Method
The meta-analysis used the original patient data collected
in the three trials. The treatment used was nabiximols
which is a THC : CBD endocannabinoid system modu-
lator prepared under conditions of good manufacturing
practice from extracts of selected chemical varieties (che-
motypes) of cannabis plants (Cannabis sativa L.) with
minor amounts of other cannabinoids and non-cannabi-
noid components (e.g. terpenes) in a solution containing
ethanol, propylene glycol, and peppermint oil flavouring.
It is presented as an oromucosal spray, with each 100 ml
spray containing 2.7 mg of THC and 2.5 mg of CBD.
In two studies,
6,7
spasticity was the primary variable
and all patients contributed data, whilst in the third
study
4
spasticity was one of several primary symptoms
assessed. In this third study
4
only the data from 140 of
the 160 patients randomized who had spasticity as one
of their primary symptoms were used.
Spasticity was assessed using a 100 mm Visual
Analogue Scale (VAS) in one study
4
and a 0–10
Numerical Rating Scale (NRS) in the other two. Data
from the 0–100 VAS were converted to a 0–10 scale
using a simple linear transformation of dividing each
recorded individual observation by 10. The endpoints
used were ‘no problem from spasticity’ and ‘the worst
problem I can imagine’.
Resistance to stretch was measured using the
Ashworth Scale
13
in one study
6
and the Modified
Ashworth Scale (MAS)
14,16
in the other two.
4,7
In one
study
4
eight muscle groups were scored using the MAS,
in another 20 muscle groups were scored using the MAS,
7
and in the third,
6
only muscle groups with an AS score of
2 at baseline were scored throughout the study.
In all studies patients gave a rating of Global
Impression of Change varying from much worse to
much better (five points in one study
4
and seven in
the other two); the analysis simply dichotomized the
data into ‘no change or worse’ and ‘better’.
In two of the studies,
6,7
patients were also asked to
record spasticity using the Numerical Rating Scale on a
daily basis.
The objective of the analysis was to pool and analyse
the data to investigate the efficacy of nabiximols in
comparison with placebo, and to consider data on
safety and adverse effects. All presentations are based
primarily on the intention-to-treat (ITT) population as
reported in the individual study reports.
The statistical methods used were planned prior to
unblinding of the third study, although the sensitivity
analysis at week 6 was added subsequently.
The primary analysis has used data from the pre-
planned final outcome assessment at 6 weeks in two
studies
4,6
and at 14 weeks in the other study.
7
However data from week 6 in the last study have also
been analysed.
The data were analysed using a general linear
model in which the dependent variable was the
change from baseline in spasticity assessment. Fixed
factors included in the model were treatment group
(nabiximols/placebo), study, and the treatment group
by study interaction term. Baseline spasticity was
included as a covariate. Homogeneity of variance
was tested using Brown and Forsythe’s test.
17
The
interaction term was dropped from the model if not
statistically significant ( p>0.10). The adjusted means
for each treatment group are provided together with
the estimated difference between treatments, 95% con-
fidence intervals (CI) for the difference and corre-
sponding p-value.
In order to assess the time course of effect over the
first 6 weeks of treatment, summary statistics showing
the change from baseline (and standard error) for each
day (1–42) are shown graphically by treatment for two
studies
6,7
combined; the other study
4
only had weekly
assessments.
A ‘responder’ was defined as ‘a patient who experi-
ences a reduction in spasticity score of 30% or greater
from baseline for the period of primary assessment’;
this was derived from a study showing than an 18%
change from baseline was the minimal clinically impor-
tant difference.
18
The analysis was carried out using the
Cochran–Mantel–Haenszel procedure adjusting for
study. The odds ratio (OR) together with 95% CI is
presented. Homogeneity of treatment effect was
assessed using the Breslow–Day test and assessed for
significance at the 10% level.
Due to the differences in Ashworth scales used and
the numbers of muscle groups scored, it was unlikely
that the raw effect size would be the same in the three
studies and hence the analysis was carried out using
summary statistics from the three studies and combin-
ing the standardized effect size. This analysis was car-
ried out according to the methods outlined by
Whitehead and Whitehead.
19
The pooled effect across
studies was calculated together with 95% CI and the
corresponding p-value.
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For all analyses, no imputation was done for sub-
jects where any baseline or endpoint data were missing;
these subjects were excluded from the analyses. Where
subjects failed to complete the study period, then study
endpoints were imputed using a last-observation-
carried-forward approach.
Results
A total of 189 patients were randomized in the second
study,
6
337 patients in the third,
7
and 140 with spastic-
ity as a symptom in the first.
4
In total, 363 patients were
randomized to nabiximols and 303 patients to placebo.
Participants in the three studies were similar in age and
gender distribution and also spasticity severity at base-
line, although patients in the third study had slightly
greater baseline severity scores than patients in the
other two studies. Demographics are summarized for
the three studies by treatment group in Table 1.
The analysis of the outcome assessments of spasticity
using individual patient data and a general linear model
is summarized in Table 2. There was no indication of
any statistically significant study-by-treatment interac-
tion ( p>0.10) or heterogeneity of variance ( p>0.10).
Table 1. Demographics
Study 1 Wade et al. (2004)
4
Study 2 Collin et al. (2007)
6
Study 3 Collin et al. (2009)
7
Variable Statistic Nabiximols Placebo Nabiximols Placebo Nabiximols Placebo
No. of patients N 72 68 124 65 167 170
Gender Female 41 (57%) 44 (65%) 80 (65%) 34 (52%) 106 (63%) 101 (59%)
Age (y) N 72 68 124 65 167 170
Mean 50.8 50.5 49.7 47.8 48.0 47.1
SD 9.09 8.59 10.15 9.46 10.06 9.15
Minimum 27 31 18 20 22 27
Maximum 68 69 69 64 73 77
Spasticity at N 71 67 122 64 166 169
baseline (0–10) Mean 5.96 6.11 5.49 5.39 6.77 6.48
SD 2.176 2.022 1.914 1.912 1.331 1.319
Minimum 0.8 0.8 0.3 1.1 3.0 3.5
Maximum 9.8 9.6 9.2 9.9 10.0 9.5
Ashworth Scale N 68 64 120 64 163 165
at baseline
a
Mean 1.25 1.26 2.41 2.44 1.54 1.45
SD 0.939 1.111 0.454 0.403 0.785 0.722
Minimum 0 0 2.0 2.0 0 0.2
Maximum 3.5 4.8 3.9 3.8 4.4 3.9
a
Modified Ashworth for Study 1 on scale (0–5) for eight muscle groups; Ashworth for Study 2 on scale (0–4) only muscle groups with a score of 2at
baseline assessed; Modified Ashworth for Study 3 on scale (0–5) for 20 muscle groups. Data presented are converted into score/muscle group.
Table 2. Pooled analysis of individual spasticity assessment using Visual Analogue Scale (VAS)/Numerical Rating Scale (NRS) data
using a linear model
Treatment N
Adjusted mean
change from baseline Treatment difference
a
Standard error
of difference
95% confidence
interval for difference p-value
Analysis at study endpoint
b
Nabiximols (N) 356 1.30 0.32 0.145 0.61, 0.04 0.026
Placebo (P) 296 0.97
Analysis at week 6
c
Nabiximols (N) 356 1.27 0.31 0.140 0.59, 0.04 0.026
Placebo (P) 296 0.95
a
Treatment difference ¼nabiximols minus placebo.
b
Intention-to-treat population; Timepoints: week 6 for Wade et al.
4
and Collin et al.
6
and weeks 13–14 for Collin et al.
7
c
Intention-to-treat population; Timepoints: week 6 for all three studies.
Wade et al. 3
Now Collin et al.
2010
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However, the primary analysis based on the individual
study endpoint and the ITT population showed a sta-
tistically significant difference in favour of nabiximols
compared with placebo (difference 0.32, 95% CI
0.6, 0.04; p¼0.026). Analyses using the week-6 end-
point for all studies rather than the individual study
endpoints gave very similar results. Meta-analyses
using the summary statistics from each study gave the
same results (data not shown).
Figure 1 uses the summarized daily scores from 526
patients (n¼291 nabiximols, n¼235 placebo) over the
first 42 days from the two studies with daily record-
ing
6,7
to show the change from baseline in spasticity
score. Both groups improved during the first week;
the change in the placebo group remained relatively con-
stant from around day 10 until day 42 whilst the nabix-
imols group continued to show improvement up to day
16 and the improvement is maintained thereafter. The
maximum difference between nabiximols and placebo is
achieved after approximately 2 weeks treatment.
At the end of study time-point, 130 (37%) of 356
patients with post-randomization efficacy data avail-
able were responders on nabiximols and a pooled anal-
ysis using the Cochran–Mantel–Haenszel procedure in
SAS (version 9.1, SAS Institute Inc, USA) adjusting for
the study endpoint showed this proportion to be sig-
nificantly greater than the 77 responders out of
296 patients (25%) on placebo ( p¼0.0073; Table 3).
Mean (±SE) spasticity NRS scores days 1 to 42 (ITT) [6, 7]
–1.6
–1.4
–1.2
–1
–0.8
–0.6
–0.4
–0.2
0
0 5 10 15 20 25 30 35 40 45
Study day
Sativex Placebo
Change from baseline in mean spasticity NRS score (±SE)
Figure 1. Change from baseline in spasticity over time.
Table 3. Responder analysis (30% or more reduction from baseline in spasticity assessment)
N (%) with 30% reduction in spasticity
Study Nabiximols Placebo Odds ratio 95% confidence interval p-value
Analysis at study endpoint
a
Study 1
4
31/70 (44%) 21/63 (33%) 1.59 0.79, 3.22
Study 2
6
48/120 (40%) 14/64 (22%) 2.38 1.19, 4.78
Study 3
7
51/166 (31%) 42/169 (25%) 1.34 0.83, 2.17
Pooled analysis 130/356 (37%) 77/296 (26%) 1.62
c
1.15, 2.28* 0.0073
Analysis at week 6
b
Study 1
4
31/70 (44%) 21/63 (33%) 1.59 0.79, 3.22
Study 2
6
48/120 (40%) 14/64 (22%) 2.38 1.19, 4.78
Study 3
7
44/166 (27%) 38/169 (22%) 1.24 0.76, 2.05
Pooled analysis 123/356 (35%) 73/296 (25%) 1.57
#
1.11, 2.23* 0.014
a
Intention-to-treat population; Timepoints: week 6 for Study 1 and Study 2 and weeks 13–14 for Study 3.
b
Intention-to-treat population; Timepoints: week 6 for all three studies.
c
Adjusted for study.
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The point estimate of the odds ratio (OR) was 1.62
(95% CI 1.15, 2.28) indicating that the probability of
getting a response of 30% or more improvement in
spasticity score was 62% greater with nabiximols than
placebo.
At the 6-week time-point, the proportion of respon-
ders on nabiximols (123 of 356) was also significantly
greater than the proportion of responders on placebo
(p¼0.014). The estimate of the odds ratio based on the
week-6 endpoint was very similar (OR ¼1.5, CI 1.11,
2.23) to that of the end of study time-point. The anal-
ysis did not indicate any heterogeneity of treatment
effect across the three studies for the analysis based
on either time endpoint ( p>0.10).
The analysis of Global Impression of Change was
carried out using the Cochran–Mantel–Haenszel proce-
dure in SAS adjusting for study. The results are sum-
marized in Table 4. The analysis did not indicate any
heterogeneity of treatment effect across studies
(p>0.10). The odds ratio of seeing an improvement
in Global Impression of Change on nabiximols com-
pared with placebo was 1.66 (95% CI 1.19, 2.30) and
was statistically significant ( p¼0.0036).
In the analysis of the Ashworth Scale score results,
the meta-analysis was based on the standardized effect
size in the three studies due to the different scoring
systems used. There was no statistically significant dif-
ference between treatments ( p¼0.75). It is of note that
seven of 140 subjects from one study
4
and a single sub-
ject (of 337) from another study
7
were assessed at base-
line as having a zero Ashworth Score. All subjects had
been clinically diagnosed as suffering from spasticity
and all provided a self assessment of spasticity and/or
spasms which identified them as suffering from spastic-
ity. In neither study was a positive Ashworth score a
criterion for inclusion.
The incidence of treatment emergent, treatment-
related adverse events are presented in Table 5. Two
hundred and eighty-eight (79.3%) patients treated
with nabiximols experienced at least one event, com-
pared with 169 (55.8%) placebo patients. Most adverse
events (AEs) were mild or moderate in severity in both
treatment groups (84.6% versus 93.4%). There were
21/363 (5.8%) subjects in the nabiximols group with
serious adverse events (SAEs), compared with 13/303
(4.3%) in the placebo group. All treatment-related
SAEs resolved.
The following system organ classes had greater than
a 3% difference in incidence of AEs between nabiximols
and placebo: nervous system disorders (54.5% versus
26.4%); gastrointestinal disorders (29.6% versus
19.4%); general disorders and administration site reac-
tions (29.2% versus 19.1%) psychiatric disorders
(18.5% versus 5.6%); ear and labyrinth disorders
(nabiximols versus placebo: 7.4% versus 2.3%); and
musculoskeletal and connective tissue disorders (5.5%
versus 2.0%). Overall, the single most common adverse
reaction in the nabiximols group was dizziness, in 32%
of patients, compared with 11% of placebo patients.
There were few treatment-emergent AEs which led
to cessation of therapy (Table 6). Forty patients
(11.0%) withdrew from treatment on nabiximols. The
most frequent events leading to withdrawal were
nausea in 10 subjects, dizziness in nine subjects, and
vertigo in three subjects. No other AE accounted for
more than two withdrawals. This compares with 11
patients (3.6%) who withdrew from treatment with pla-
cebo. The most common AEs leading to withdrawal in
the placebo group were urinary tract infection (in three
patients) dizziness and vomiting (in two subjects each).
Discussion
This meta-analysis of individual patient data from 666
patients with multiple sclerosis who had spasticity not
adequately controlled using existing treatments and
were then given nabiximols (363) or placebo (303)
shows that there is a definite reduction in patient-
reported problems; that the effects of nabiximols are
usually evident within 3 weeks; and that about one-
third of people given nabiximols as an add-on will
gain at least a 30% improvement from baseline. The
treatment appears reasonably safe. The three studies
providing these data
4,6,7
were randomized, double-
blind, placebo-controlled, parallel-group studies (two
studies of 6-week treatment duration and the other of
Table 4. Global Impression of Change (GIC) Improved versus Not Improved
N (%) with any improvement (intention-to-treat population) 95% confidence
Study Nabiximols Placebo Odds ratio interval p-value
Study 1
4
31/72 (43%) 18/68 (26%) 2.10 1.03, 4.28
Study 2
6
66/116 (57%) 31/64 (48%) 1.41 0.76, 2.59
Study 3
7
72/141 (51%) 56/144 (39%) 1.64 1.02, 2.62
Pooled analysis 169/329 (51%) 105/276 (38%) 1.66
a
1.19, 2.30
a
0.0036
a
Adjusted for study.
Wade et al. 5
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14-week treatment duration). This dataset is similar in
size to that of the CAMS study dataset (n ¼657).
8
The subjects enrolled in these studies were those who
were not adequately controlled by existing anti-spasticity
medication (i.e. were treatment-resistant), and who
had significant residual spasticity. It is of note that
eight subjects overall entered the study despite
having a baseline Ashworth Score of zero. In seven
of the eight subjects the Ashworth Score was assessed
as being at least 1 later in the study. On one hand, it
could be questioned whether these patients did indeed
have spasticity; on the other hand, a positive
Ashworth Score was not an entry criterion and it
may be that patients with spasticity may, on occasion,
be assessed as having an Ashworth score of zero. The
consensus in the literature that a single Ashworth scale
Table 5. Adverse events: treatment emergent, treatment-related adverse events
Nabiximols (n¼363) Placebo (n¼303)
System organ class N%N%
Subjects with an event 288 79.3 169 55.8
Cardiac disorders 5 1.4 2 0.7
Ear and labyrinth disorders 27 7.4 7 2.3
Eye disorders 14 3.9 4 1.3
Gastrointestinal disorders 110 29.6 61 19.4
General disorders and administration site conditions 106 29.2 58 19.1
Hepatobiliary disorders 1 0.3 0 0
Infections and infestations 8 2.2 5 1.7
Injury, poisoning, and procedural complications 5 1.4 6 2.0
Investigations 10 2.8 2 0.7
Metabolism and nutrition disorders 11 3.0 1 0.3
Musculoskeletal and connective tissue disorders 20 5.5 6 2.0
Nervous system disorders 198 54.5 80 26.4
Psychiatric disorders 67 18.5 17 5.6
Renal and urinary disorders 8 2.2 1 0.3
Reproductive system and breast disorders 1 0.3 1 0.3
Respiratory, thoracic, and mediastinal disorders 11 3.0 8 2.6
Skin and subcutaneous tissue disorders 5 1.4 2 0.7
Vascular disorders 6 1.7 3 1.0
Table 6. Adverse events: treatment emergent, adverse events leading to withdrawal
Nabiximols (n¼363) Placebo (n¼303)
System organ class N%N%
Subjects with an event 40 11.0 11 3.6
Ear and labyrinth disorders 3 0.8 0 0
Eye disorders 1 0.3 0 0
Gastrointestinal disorders 20 5.5 3 1.0
General disorders and administration site conditions 5 1.4 2 0.7
Infections and infestations 4 1.1 4 1.3
Neoplasms (benign, malignant, and unspecified) 2 0.6 0 0
Nervous system disorders 19 5.2 4 1.3
Psychiatric disorders 7 1.9 0 0
Renal and urinary disorders 3 0.8 0 0
Respiratory, thoracic, and mediastinal disorders 1 0.3 1 0.3
Vascular disorders 1 0.3 0 0
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score is inadequate to assess the severity or the degree
of functional impairment of spasticity has recently
been summarized by Fleuren et al.
15
This meta-analysis should be put in the context of
other studies of treatments for spasticity. The evidence
supporting botulinum toxin as a treatment for focal
spasticity is strong, particularly in the arm; the evidence
supporting other anti-spastic drugs and physical meth-
ods is weak. The numbers of patients involved in most
past studies have been small, the measures used have
not included detailed assessment of patient experience
and the standard of the designs low (most studies were
carried out many years ago).
There are no other meta-analyses of anti-spastic
drug treatments. This meta-analysis was possible
because similar methods and measures were used and
all the data were held by one organization. This meta-
analysis is unusual in that it can report upon additional
features. First the speed of response to medication can
be given; most people who will benefit do so within
4 weeks. No other studies have such detailed informa-
tion. Second the effects and safety over a longer
period than that included in most studies can be
reported; the side-effects are common but rarely suffi-
cient to stop treatment. Third, it can estimate the
number of patients who have intractable spasticity
who nonetheless might respond, about one-third. Of
course this one third may include some placebo respon-
ders but in clinical practice this applies to all drugs
prescribed and is no different in this case.
The 0–10 Numeric Rating Scale is recommended as a
preferred outcome measure in the assessment of inter-
ventions in chronic pain,
20
but has not been widely used
in studies of anti-spasticity medications. It has the ben-
efit of allowing the patient to express their own daily
experience of spasticity and has recently been vali-
dated.
17,21
The homogeneity of the Numeric Rating
Scale data seen in this meta-analysis adds to the evi-
dence that it is a suitable assessment tool and possibly
an alternative to the Ashworth Scale which several
research groups have criticized.
15,22
The potential weaknesses and limitations of this
study are as follows. The studies were sponsored by
the manufacturer who also has the data. However anal-
ysis was undertaken by an independent company and
the company have not controlled the analysis or writ-
ing. The reader will have to judge how much influence
there has been. Second, though the studies were similar
in most aspects, there were slight differences in mea-
surement techniques and times. However the degree
of similarity is far greater than in most meta-analyses
undertaken and the supplementary analyses suggest
that the differences were not material. With any medi-
cine that has central nervous system effects, there is a
possibility that patients may become unblinded to
treatment allocation. There is no evidence that this
has occurred with nabiximols to an extent that affects
the outcome of these studies.
23
This meta-analysis has
not investigated the long-term effects of nabiximols but
a long-term, open-label study has suggested that the
effect persists with needing any increase in dose.
5
The results would suggest that nabiximols has a role
in the management of spasticity that is not adequately
controlled using other available treatments, and that a
4-week trial would be justified. Other studies have
shown that it can be stopped suddenly without risk
5
so if there is no benefit at 4 weeks, it could simply be
stopped. The dose needed seems to remain stable once
established.
5
Finally the side-effects expected seem sim-
ilar to those of most existing medications for the same
problem.
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... Belendiuk et al. (2015) also explored the use of cannabis as a treatment for multiple sclerosis. Studies have reported that cannabis administered orally or sublingually may relieve common symptoms of MS, such as muscle spasticity (Lakhan and Rowland 2009;Novotna et al. 2011;Wade et al. 2010) and lead to improvement in the long term (Notcutt et al. 2012;Serpell et al. 2013). However, there is also evidence of a decrease in cognitive function in patients with multiple sclerosis who The most common author keywords for this subset of publications (n = 29 802). ...
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The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo. • Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity. • Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I² = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people. 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The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement. • HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I2 = 0%; low-certainty evidence); • SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I² = 0%; low-certainty evidence); • AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I² = 63%; low-certainty evidence); • Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I² = 0%; low-certainty evidence); • Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence). 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To assess the validity and reliability of a Numeric Rating Scale (NRS) for the measurement of spasticity in multiple sclerosis. Longitudinal study with multiple comparators over two clinic visits. Rehabilitation Centre in the North East of England, UK. A total of thirty-five patients, with a diagnosis of multiple sclerosis (MS) that were attending a rehabilitation clinic. The test/re-test reliability of the NRS showed there was a high correlation between the two visits (r = 0.672). Construct validity was assessed by examining the relationship between the mean spasticity NRS and each of the other spasticity assessment tools. There was a statistically significant correlation between subject's mean NRS diary scores and the Modified Ashworth Scale scores at both visits (Visit 1, r = 0.459, p = 0.0056; Visit 2, r = 0.446, p = 0.0106). There was a moderate, statistically significant correlation between the mean NRS diary scores and the Tardieu Scale (Visit 1, r = 0.429, p = 0.0113; Visit 2, r = 0.407, p = 0.0209). The spasticity NRS has been shown to be a valid and reliable tool in the assessment of spasticity with a moderate to high level of correlation with other clinician rated instruments used to assess spasticity.