ArticlePDF Available

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

  • Oxford Centre for Enablement
  • prn Statistical Consulting Services

Abstract and Figures

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.
Content may be subject to copyright.
Author Query Form
Journal Title : Multiple Sclerosis (MSJ)
Article Number : 367462
Dear Author/Editor,
Greetings, and thank you for publishing with SAGE. Your article has been copyedited and typeset, and
we have a few queries for you. Please address these queries when you return your proof corrections.
Thank you for your time and effort.
Please ensure that you have obtained and enclosed all necessary permissions for the reproduction of
artistic works, (e.g. illustrations, photographs, charts, maps, other visual material, etc.) not owned by
yourself, and ensure that the Contribution contains no unlawful statements and does not infringe any
rights of others, and agree to indemnify the Publisher, SAGE Publications Ltd, against any claims in
respect of the above warranties and that you agree that the Conditions of Publication form part of the
Publishing Agreement.
Any colour figures have been incorporated for the on-line version only. Colour printing in the journal
must be arranged with the Production Editor, please refer to the figure colour policy outlined in the e-
Please assist us by clarifying the following queries:
1. Please provide further details for references 2, 7 and 15.
XML Template (2010) [16.4.2010–3:57pm] [1–8]
{SAGE}MSJ/MSJ 367462.3d (MSJ) [PREPRINTER stage]
Research Paper
Multiple Sclerosis
0(00) 1–8
!The Author(s) 2010
Reprints and permissions:
DOI: 10.1177/1352458510367462
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
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.
multiple sclerosis, spasticity, cannabinoids, sativex, delta-9-tetrahydrocannabinol, cannabidiol, nabiximols
Date received: 8th February 2010; accepted: 9th February 2010
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.
Recently, several studies have investigated the effective-
ness of various cannabinoid-containing medications in
patients with multiple sclerosis and spasticity.
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
and how it should be measured. Although the
Ashworth scale
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.
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
XML Template (2010) [16.4.2010–3:57pm] [1–8]
{SAGE}MSJ/MSJ 367462.3d (MSJ) [PREPRINTER stage]
recent study has suggested that the Ashworth scale
should ‘never be used’!
Three randomized, controlled studies
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.
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,
spasticity was the primary variable
and all patients contributed data, whilst in the third
spasticity was one of several primary symptoms
assessed. In this third study
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
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
in one study
and the Modified
Ashworth Scale (MAS)
in the other two.
In one
eight muscle groups were scored using the MAS,
in another 20 muscle groups were scored using the MAS,
and in the third,
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
and seven in
the other two); the analysis simply dichotomized the
data into ‘no change or worse’ and ‘better’.
In two of the studies,
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
and at 14 weeks in the other study.
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.
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
combined; the other study
only had weekly
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.
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.
The pooled effect across
studies was calculated together with 95% CI and the
corresponding p-value.
2Multiple Sclerosis 0(00)
XML Template (2010) [16.4.2010–3:57pm] [1–8]
{SAGE}MSJ/MSJ 367462.3d (MSJ) [PREPRINTER stage]
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.
A total of 189 patients were randomized in the second
337 patients in the third,
and 140 with spastic-
ity as a symptom in the first.
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)
Study 2 Collin et al. (2007)
Study 3 Collin et al. (2009)
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
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
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
Standard error
of difference
95% confidence
interval for difference p-value
Analysis at study endpoint
Nabiximols (N) 356 1.30 0.32 0.145 0.61, 0.04 0.026
Placebo (P) 296 0.97
Analysis at week 6
Nabiximols (N) 356 1.27 0.31 0.140 0.59, 0.04 0.026
Placebo (P) 296 0.95
Treatment difference ¼nabiximols minus placebo.
Intention-to-treat population; Timepoints: week 6 for Wade et al.
and Collin et al.
and weeks 13–14 for Collin et al.
Intention-to-treat population; Timepoints: week 6 for all three studies.
Wade et al. 3
Now Collin et al.
XML Template (2010) [16.4.2010–3:57pm] [1–8]
{SAGE}MSJ/MSJ 367462.3d (MSJ) [PREPRINTER stage]
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-
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]
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
Study 1
31/70 (44%) 21/63 (33%) 1.59 0.79, 3.22
Study 2
48/120 (40%) 14/64 (22%) 2.38 1.19, 4.78
Study 3
51/166 (31%) 42/169 (25%) 1.34 0.83, 2.17
Pooled analysis 130/356 (37%) 77/296 (26%) 1.62
1.15, 2.28* 0.0073
Analysis at week 6
Study 1
31/70 (44%) 21/63 (33%) 1.59 0.79, 3.22
Study 2
48/120 (40%) 14/64 (22%) 2.38 1.19, 4.78
Study 3
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
Intention-to-treat population; Timepoints: week 6 for Study 1 and Study 2 and weeks 13–14 for Study 3.
Intention-to-treat population; Timepoints: week 6 for all three studies.
Adjusted for study.
4Multiple Sclerosis 0(00)
XML Template (2010) [16.4.2010–3:57pm] [1–8]
{SAGE}MSJ/MSJ 367462.3d (MSJ) [PREPRINTER stage]
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
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
and a single sub-
ject (of 337) from another study
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).
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
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
31/72 (43%) 18/68 (26%) 2.10 1.03, 4.28
Study 2
66/116 (57%) 31/64 (48%) 1.41 0.76, 2.59
Study 3
72/141 (51%) 56/144 (39%) 1.64 1.02, 2.62
Pooled analysis 169/329 (51%) 105/276 (38%) 1.66
1.19, 2.30
Adjusted for study.
Wade et al. 5
XML Template (2010) [16.4.2010–3:57pm] [1–8]
{SAGE}MSJ/MSJ 367462.3d (MSJ) [PREPRINTER stage]
14-week treatment duration). This dataset is similar in
size to that of the CAMS study dataset (n ¼657).
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
6Multiple Sclerosis 0(00)
XML Template (2010) [16.4.2010–3:57pm] [1–8]
{SAGE}MSJ/MSJ 367462.3d (MSJ) [PREPRINTER stage]
score is inadequate to assess the severity or the degree
of functional impairment of spasticity has recently
been summarized by Fleuren et al.
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,
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-
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.
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.
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.
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
so if there is no benefit at 4 weeks, it could simply be
stopped. The dose needed seems to remain stable once
Finally the side-effects expected seem sim-
ilar to those of most existing medications for the same
1. Shakespeare DT, Boggild M, Young C. Anti-spasticity
agents for multiple sclerosis. Cochrane Database Syst
Rev 2003; 4: CD001332.
2. Beard S, Hunn A, Wight J. Treatments for spasticity and
pain in multiple sclerosis: a systematic review. Health
Technol Assess 2003; 7.
3. Wade DT, Robson P, House H, Makela P, Aram J. A
preliminary controlled study to determine whether whole-
plant cannabis extracts can improve intractable neuro-
genic symptoms. Clin Rehabil 2003; 17: 21–29.
4. Wade DT, Makela P, Robson P, House H, Bateman C.
Do cannabis-based medicinal extracts have general or
specific effects on symptoms in multiple sclerosis? A
double-blind, randomized, placebo-controlled study on
160 patients. Mult Scler 2004; 10: 1–8.
5. Wade DT, Makela PM, House H, Bateman C, Robson P.
Long-term use of a cannabis-based medicine in the treat-
ment of spasticity and other symptoms in multiple scle-
rosis. Mult Scler 2006; 12: 639–645.
6. Collin C, Davies P, Mutiboko IK, Ratcliffe S.
Randomized controlled trial of cannabis-based medicine
in spasticity caused by multiple sclerosis. Eur J Neurol
2007; 14: 290–296.
7. Collin C, Ehler E, Waberzinek G, et al. A double-blind,
randomised, placebo-controlled, parallel-group study of
Sativex, in subjects with symptoms of spasticity due to
multiple sclerosis. Neurol Res 2009; In Press.
8. Zajicek J, Fox P, Nunn A, et al. Cannabinoids for treat-
ment of spasticity and other symptoms related to multiple
sclerosis (CAMS study): Multicentre randomised
placebo-controlled trial. Lancet (North American
Edition) 2003; 362: 1517–1526.
9. Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids
in multiple sclerosis (CAMS) study: safety and efficacy
data for 12 months follow up. J Neurol Neurosurg
Psychiatry 2005; 76: 1664–1669.
10. Vaney C, Heinzel-Guttenbrunner M, Jobin P, et al.
Efficacy, safety and tolerability of an orally administered
cannabis extract in the treatment of spasticity in patients
with multiple sclerosis: a randomized, double-blind,
Wade et al. 7
Health Technol Assess.
2003;7(40):iii, ix-x, 1-111.
Neurol Res. 2010
Mar 19. [Epub
ahead of print] -
available - online -
due to be printed
hard copy in the
June 2010 issue of
Neurol Res
XML Template (2010) [16.4.2010–3:57pm] [1–8]
{SAGE}MSJ/MSJ 367462.3d (MSJ) [PREPRINTER stage]
placebo-controlled, crossover study. Mult Scler 2004; 10:
11. Lance JW. Symposium synopsis. In: Feldman RG,
Young RR, Koella WP (eds) Spasticity: disordered
motor control. Chicago: Chicago Year Book Publishing
Co, 1980, p.485–495.
12. Pandyan A, Johnson G, Price C, Curless R, Barnes M,
Rodgers H. A review of the properties and limitations of
the Ashworth and modified Ashworth Scales as measures
of spasticity. Clin Rehabil 1999; 13: 373–383.
13. Ashworth B. Preliminary trial of carisoprodol in multiple
sclerosis. Practitioner 1964; 192: 540–542.
14. Morris S. Ashworth and Tardieu scales; their clinical rel-
evance for measuring spasticity in adult and paediatric
neurological populations. Phys Ther Rev 2002; 7: 53–62.
15. Fleuren JFM, Voerman GE, Erren-Wolters CV, et al.
Stop using the Ashworth Scale for the Assessment of
Spasticity. J Neurol Neurosurg Psychiatry 2009; published
online (September.
16. Bohannon RW, Smith MB. Interrater reliability of a
modified Ashworth scale of muscle spasticity. Phys
Ther 1987; 67: 206–207.
17. Brown MB, Forsythe AB. Robust Tests for Equality of
Variances. JAMA 1974; 69: 364–367.
18. Farrar J, Troxel A, Stott C, Duncombe P, Jensen P.
Validity, reliability, and clinical importance of change
in a 0–10 Numeric Rating Scale measure of spasticity: a
post hoc analysis of a randomized, double-blind, placebo-
controlled trial. Clin Ther 2008; 30: 974–985.
19. Whitehead A, Whitehead J. A general parametric
approach to the meta-analysis of randomised clinical
trials. Stat Med 1991; 10: 1665–1677.
20. Farrar JT, Young Jr JP, LaMoreaux L, Werth JL, Poole
RM. Clinical importance of changes in chronic pain
intensity measured on an 11-point numerical pain rating
scale. Pain 2001; 94: 149–158.
21. Anwar K, Barnes M. A Pilot Study of a Comparison
Between a Patient Scored Numeric Rating Scale and
Clinician Scored Measures of Spasticity in Multiple
Sclerosis. NeuroRehabilitation 2009; 24: 333–340.
22. Pandyan AD, Gregoric M, Barnes MP, et al. Spasticity:
clinical perceptions, neurological realities and meaningful
measurement. Disabil Rehabil 2005; 27: 2–6.
23. Altman DG. Personal communication.
8Multiple Sclerosis 0(00)
J Neurol Neurosurg
Psychiatry. 2010
... 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). ...
Full-text available
Background: Cannabis refers to a plant in the family Cannabaceae, which has been used medically, recreationally, and industrially. The last two decades, in particular, have seen a large increase in the volume of literature on this topic. The present bibliometric analysis aims to capture the characteristics of scholarly journal publications on the topic of cannabis and cannabinoid research. Methods: Searches were run on the Scopus database on April 02, 2021, as follows "(TITLE (cannabi* OR hashish OR marijuana OR marihuana)) AND ( LIMIT-TO ( DOCTYPE,"ar" ) OR LIMIT-TO ( DOCTYPE,"re" ) )". Results were exported on the same day to prevent discrepancies between daily database updates. Only "article" and "review" publication types were included; no further search limits were applied. The "article" publication type includes publications featuring original research, whereas "review" includes reviews and conference papers. The following data were collected: number of publications (in total and per year), authors, and journals; open access status; publications per journal; journals publishing the highest volume of literature and their impact factors, language of publication; document type; publication country; author affiliations; funding sponsors; most highly cited publications; and most highly published authors. Trends in this subset of publications were identified and presented. Bibliometric networks were constructed using the software tool VOSviewer. Results: A total of 29 802 publications (10 214 open access), published by 65 109 authors, were published in 5474 journals from 1829 to 2021. The greatest number of publications was published over the last 20 years. The journal that published the largest number of publications was Drug and Alcohol Dependence (n = 705). The most productive countries included the USA (n = 12 420), the UK (n = 2236), and Canada (n = 2062); many of the most common institutional affiliations and funding sponsors originated from these countries. Conclusions: The number of publications published on the topic of cannabis follows an upward trend. Over the past 20 years, the volume of cannabis research has grown steeply, which can be attributed to a large amount of funding dedicated to researching this topic. Future research should continue to investigate changes in the publication characteristics of emerging research, as the volume of publications on this topic is expected to rapidly grow.
... The recent FDA's approval of a CBD extract (brand name: Epidiolex ® ), as a prescription medicine for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients 1 year of age and older, has boosted the interest in CBD as a potential therapeutic candidate for other diseases, including neurodegenerative diseases. Moreover, diverse drugs containing CBD in various formulations have been proposed or are actively under development, such as Sativex ® , an oromucosal spray composed of CBD and THC, for the treatment of spasticity and pain related to MS [79,124], PTL101, a CBD-embedded oral gelatin matrix pellet for the adjunctive treatment of pediatric epilepsy [125,126], and Zygel TM (ZYN002), a CBD-formulated transdermal gel for the treatment of Fragile X syndrome [127,128]. ...
Full-text available
(‒)-Cannabidiol (CBD) is one of the major phytocannabinoids extracted from the Cannabis genus. Its non-psychoactiveness and therapeutic potential, partly along with some anecdotal-if not scientific or clinical-evidence on the prevention and treatment of neurological diseases, have led researchers to investigate the biochemical actions of CBD on neural cells. This review summarizes the previously reported mechanistic studies of the CBD actions on primary neural cells at the in vitro cell-culture level. The neural cells are classified into neurons, microglia, astrocytes, oligodendrocytes, and neural stem cells, and the CBD effects on each cell type are described. After brief introduction on CBD and in vitro studies of CBD actions on neural cells, the neuroprotective capability of CBD on primary neurons with the suggested operating actions is discussed, followed by the reported CBD actions on glia and the CBD-induced regeneration from neural stem cells. A summary section gives a general overview of the biochemical actions of CBD on neural cells, with a future perspective. This review will provide a basic and fundamental, but crucial, insight on the mechanistic understanding of CBD actions on neural cells in the brain, at the molecular level, and the therapeutic potential of CBD in the prevention and treatment of neurological diseases, although to date, there seem to have been relatively limited research activities and reports on the cell culture-level, in vitro studies of CBD effects on primary neural cells.
... Previous studies on the effect of CBM for NP and spasticity have shown limited and conflicting evidence. Among these studies, those that investigated the effect of cannabis (smoked) or CBM on spasticity in pwMS have indicated a small positive effect [30][31][32][33][34][35][36]. In Denmark and several other countries, the oromucosal spray nabiximols (a cannabis extract product containing CBD and THC) has been approved as an add-on therapy for spasticity for pwMS if other treatments are ineffective [37]. ...
Full-text available
Disease or acquired damage to the central nervous system frequently causes disabling spasticity and central neuropathic pain (NP), both of which are frequent in multiple sclerosis (MS) and spinal cord injury (SCI). Patients with MS and SCI often request treatment with cannabis-based medicine (CBM). However, knowledge about effects, side effects, choice of active cannabinoids (Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) alone or in combination), and doses of CBM remains limited. Using a double-blind, parallel design in a national multicenter cohort, this study examines the effect of CBM on spasticity and NP. Patients are randomized to treatment with capsules containing either THC, CBD, THC and CBD, or placebo. Primary endpoints are patient-reported pain and spasticity on a numerical rating scale. Other endpoints include quality of life and sleep, depression and anxiety, and relief of pain and spasticity. Side-effects of CBM are described. In a sub-study, the pharmacodynamics (PD) and pharmacokinetics (PK) of oral capsule CBM are examined. We expect that the study will contribute to the literature by providing information on the effects and side-effects of CBD, THC, and the combination of the two for central neuropathic pain and spasticity. Furthermore, we will describe the PD/PK of THC and CBD in a patient population.
... Examples include oral formulations of dronabinol (dose 10-20 mg) and nabilone (dose 1-2 mg, taken twice daily) that can be prescribed for the treatment of nausea and vomiting associated with cancer chemotherapy and anorexia associated with weight loss in patients with HIV 224,225 . Nabiximols is a plant-based formulation that contains THC and CBD in a 1:1 ratio and is indicated for the treatment of pain and spasticity in patients suffering from multiple sclerosis 226,227 . Nabiximols is available as a spray that is administered under the tongue or on the inside of the cheeks. ...
Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis‐related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis. Acute cannabis exposure modulates numerous aspects of neurocognitive function; however, the effects experienced by individuals are highly variable. Ramaekers and colleagues here review the neural basis of cannabis-induced neurocognitive changes and response variability, and consider the legal, therapeutic and societal implications.
Full-text available
Kenevirin tıpta yeri
Plants of Cannabis sativa L. (Cannabaceae) produce an array of more than 160 isoprenylated resorcinyl polyketides, commonly referred to as phytocannabinoids. These compounds represent molecules of therapeutic importance due to their modulation of the human endocannabinoid system (ECS). While understanding of the biosynthesis of the major phytocannabinoids Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) has grown rapidly in recent years, the biosynthetic origin and genetic regulation of many potentially therapeutically relevant minor phytocannabinoids remains unknown, which limits the development of chemotypically elite varieties of C. sativa. This review provides an up-to-date inventory of unusual phytocannabinoids which exhibit cannabimimetic-like activities and proposes putative metabolic origins. Metabolic branch points exploitable for combinatorial biosynthesis and engineering of phytocannabinoids with augmented therapeutic activities are also described, as is the role of phytocannabinoid remodelling to accelerate therapeutic portfolio expansion in C. sativa.
Background: Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required. Objectives: To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS. Search methods: We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews. Selection criteria: We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS. Data collection and analysis: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence. Main results: We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female. The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies. Critical outcomes • Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I2 = 67%; moderate-certainty evidence). 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. Important outcomes • PGIC: cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I² = 0%; moderate-certainty evidence). 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). Authors' conclusions: Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies.
Full-text available
Telekia speciosa (Schreb.) Baumg., porodica Asteraceae se tradicionalno koristi kao lijek za bronhijalnu astmu u zemljama Balkanskog poluostrva. Cilj istraživanja je da se odredi ukupan sadržaj fenola i antioksidativni kapacitet metanolnih ekstrakata nadzemnih dijelova i korijena T. speciosae sakupljene u ljeto i jesen 2015. godine na Karauli, Olovo, Bosna i Hercegovina (BiH) te da se analiziraju fenolne kiseline u pomenutim ekstraktima. Za određivanje ukupnog sadržaja fenola i in vitro antioksidativnog kapaciteta u ekstraktima, korištene su spektrofotometrijske metode. Fenolne kiseline su analizirane pomoću RP-HPLC metode. Ukupan sadržaj fenola za T. speciosa ekstrakte je bio od 28,84 do 146,06 mg galne kiseline po g ekstrakta. IC50 vrijednosti su bile od 112,57 do preko 800,00 µg ml-1 dok su se FRAP vrijednosti kretale od 189,31 do 1329,56 µmol Fe2+ po g ekstrakta. Sadržaj hlorogenske kiseline je bio od 26,80 do 968,80 mg po 100 g ekstrakta. Ekstrakti korijena T. speciosae imali su statistički značajno veći antioksidativni kapacitet u poređenju sa nadzemnim dijelovima biljke dok je antioksidativni kapacitet ekstrakata sakupljenih u ljeto statistički značajno veći veći u odnosu na ekstrakte sakupljene u jesen. Statistički značajna razlika u sadržaju hlorogenske kiseline u ekstraktima nadzemnog dijela i korjena T. speciosae između ljeta i jeseni može se objasniti razlikom u temperaturi, različitom stepenu vlage i deponovanju aktivnih supstanci u korijenu tokom zimskog perioda. Koliko nam je poznato, hemijski sastav korijena kao i antioksidativni kapacitet ekstrakata T. speciosae do sada nisu istraživani. Hlorogenska kiselina prisutna u ekstraktima daje mogućnost za dalja ispitivanja i širu primjenu T. speciosae zbog njenog različitog farmakološkog djelovanja.
Full-text available
Many studies have been performed on the methodological qualities of the (modified) Ashworth Scale but overall these studies seem inconclusive. The aim of this study was to investigate the construct validity and inter-rater reliability of the Ashworth Scale (AS) for the assessment of spasticity in the upper and lower extremities. A cross-sectional study on spasticity in the elbow flexors (part 1) and knee extensors (part 2) was carried out. In both parts AS was assessed while muscle activity and resistance were recorded simultaneously in patients with upper motor neuron syndrome. Each patient was measured by three raters. 30 patients participated, 19 in each part of the study. For elbow flexor muscles, AS was not significantly associated with electromyographic parameters, except for rater 2 (rho = 0.66, p<0.01). A significant moderate association was found with resistance (0.54< or = rho < or =0.61, p<0.05). For knee extensors, AS scores were moderately associated with muscle activity (0.56< or = rho < or =0.66, p<0.05) and also with resistance (0.55< or = rho < or =0.87, p<0.05). The intraclass correlation coefficient for absolute agreement was 0.58 for elbow flexors and 0.63 for knee extensors. In linear mixed model analysis, the factor rater appeared to be highly associated with AS. The validity and reliability of the AS is insufficient to be used as a measure of spasticity.
Alternative formulations of Levene's test statistic for equality of variances are found to be robust under nonnormality. These statistics use more robust estimators of central location in place of the mean. They are compared with the unmodified Levene's statistic, a jackknife procedure, and a χ2 test suggested by Layard which are all found to be less robust under nonnormality.
The commonest bedside tool for assessing spasticity is the Ashworth Scale. Recently, particularly in the paediatric literature, the Tardieu Scale has gained favour because it can quantify spasticity. Also, preliminary findings suggest that it is more reliable than the modified Ashworth Scale. Fundamental to the clinical examination of spasticity and hypertonia is a clear understanding of the terminology and the mechanical and neurophysiological changes that accompany upper motor neuron lesions. With these objectives in mind, the literature was reviewed in order to examine the clinical relevance of the Ashworth and Tardieu Scales.
Meta-analysis provides a systematic and quantitative approach to the summary of results from randomized studies. Whilst many authors have published actual meta-analyses concerning specific therapeutic questions, less has been published about comprehensive methodology. This article presents a general parametric approach, which utilizes efficient score statistics and Fisher's information, and relates this to different methods suggested by previous authors. Normally distributed, binary, ordinal and survival data are considered. Both the fixed effects and random effects model for treatments are described.
Muscle spasticity is common in multiple sclerosis (MS), occurring in more than 60% of patients. To compare Sativex with placebo in relieving symptoms of spasticity due to MS. A 15-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy. The primary endpoint was a spasticity 0-10 numeric rating scale (NRS). Intention-to-treat (ITT) analysis showed a non-significant improvement in NRS score, in favor of Sativex. The per protocol (PP) population (79% of subjects) change in NRS score and responder analyses (> or =30% improvement from baseline) were both significantly superior for Sativex, compared with placebo: -1.3 versus -0.8 points (change from baseline, p=0.035); and 36% versus 24% (responders, p=0.040). These were supported by the time to response (ITT: p=0.068; PP: p=0.025) analyses, carer global impression of change assessment (p=0.013) and timed 10-meter walk (p=0.042). Among the subjects who achieved a > or =30% response in spasticity with Sativex, 98, 94 and 73% reported improvements of 10, 20 and 30%, respectively, at least once during the first 4 weeks of treatment. Sativex was generally well tolerated, with most adverse events reported being mild-to-moderate in severity. The 0-10 NRS and responder PP analyses demonstrated that Sativex treatment resulted in a significant reduction in treatment-resistant spasticity, in subjects with advanced MS and severe spasticity. The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status.
Background: Multiple sclerosis is associated with muscle stiffness, spasms, pain, and tremor. Much anecdotal evidence suggests that cannabinoids could help these symptoms. Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis. Methods: We did a randomised, placebo-controlled trial, to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity. 630 participants were treated at 33 UK centres with oral cannabis extract (n=211), Δ9-tetrahydrocannabinol (Δ9-THC; n=206), or placebo (n=213). Trial duration was 15 weeks. Our primary outcome measure was change in overall spasticity scores, using the Ashworth scale. Analysis was by intention to treat. Findings: 611 of 630 patients were followed up for the primary endpoint. We noted no treatment effect of cannabinoids on the primary outcome (p=0·40). The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0·32 (95% CI −1·04 to 1·67), and for those taking Δ9-THC versus placebo it was 0·94 (−0·44 to 2·31). There was evidence of a treatment effect on patient-reported spasticity and pain (p=0·003), with improvement in spasticity reported in 61% (n=121, 95% CI 54·6–68·2), 60% (n=108, 52·5–66·8), and 46% (n=91, 39·0–52·9) of participants on cannabis extract, Δ9-THC, and placebo, respectively. Interpretation: Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale. However, though there was a degree of unmasking among the patients in the active treatment groups, objective improvement in mobility and patients' opinion of an improvement in pain suggest cannabinoids might be clinically useful.
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.