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Treatments for spasticity
Dr David Shakespeare
Consultant in Rehabilitation Medicine
Preston UK
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MS trial of cannabisresults in confusion
(Daily Telegraph, 7/11/2003)
Cannabis helped to relievesymptoms in many patients with MS,
but doctors say today they could find
no physical proof of improvement
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What is spasticity?
Diagnostic definition:
a motor disorder characterised by a velocity-
dependent increase in tonic stretch reflexes thatresults from abnormal intra-spinal processing of
primary afferent input (Young 1994)
Functional definition:
the abnormal motor control caused by an UMNlesion (as in spastic paraparesis)
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Ashworth scale (Ashworth, 1964)
0 no increase in tone
1 spastic catch
2 more marked increase in tone but limbeasily flexed
3 considerable increase in tone, passive
movement difficult
4 limb rigid in flexion or extension
an ordinal level measure of resistance to passive movement
(Pandyan et al, 1999)
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Anti-spasticity agents for
multiple sclerosisDT Shakespeare, C Young, M Boggild Objective: To assess the absolute and
comparative efficacy and tolerability of anti-spasticity agents (ASAs) in MS pts.
Systematic review of published & unpublishedRCTs of ASAs identified by:
MEDLINE, EMBASE
bibliographies of relevant articles
personal communication information from drug companies.
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Selection criteria: Double-blind, RCTs(either placebo-controlled or comparative
studies) of at least seven days duration
Data collection & analysis: separately by
two independent reviewers. Missing data
were collected by correspondence with
principal investigators.
No meta-analysis possible.
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Results
42/175 studies met the inclusion criteria 29 placebo-controlled studies
13 comparative studies.
17/40 studies used the Ashworth scale, but astatistically significant difference between test drugswas only shown in:
3/12 placebo-controlled trials (baclofen, tizanidine, BTx)
0/5 comparative studies
Many studies reported an improvement in unvalidatedself-report scores of spasticity or spasms
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Why was our Cochrane MS spasticity
treatment review so unhelpful? Trials underpowered?
MS is a heterogeneous condition
Would meta-analysis help?
Inadequate outcome measures MS symptoms can vary during the day
Ashworth scale is an ordinal level scale, & problems withvalidation/combined scores
No validated scale for spasms etc
Insensitive functional assessment tools
Confounding factors?
Problems of cross-over trials
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Tizanidine treatment of spasticity
caused by MS (Smith et al, 1994) USA multi-centre, randomised, DB, parallel-group
trial of tizanidine (111) v. placebo (109)
15 weeks: 2 baseline + 3 titration (2-36mg) + 9
plateau + 1 dose tapering + 1 final visit Primary outcomes
Ashworth score (summed score of all limbs)
Patient diary (type & frequency of spasms)
Secondary outcomes inc: Global evaluation by patient and physician (11.5 cm VAS)
Pain & disability due to spasms & clonus (3 point)
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Patient selection
Inclusions
Stable spasticity
Significant discomfortor functionalimpairment
Ashworth 2+
Spasm score 2+
Stopped previous ASA
for 2 weeks
Exclusions
Relapse within 3/12
Contractures
No information onmobility levels, typesof spasm problems
etc
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Ashworth scores
No information on how assessed ?valid
Baseline mean difference between groups: Tiz 14.95, Plac 12.99 (p=0.152)
Reported as mean & SD of change from baselineto end of plateau phase:
Tiz 2.43 (SD 7.83), plac 2.44 (SD 7.30) (p=0.993)
Percentage of patients improved from baseline toend of plateau phase:
Tiz 63%, Plac 57% (p=0.497)
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Patient diary (type & frequency of spasms)
0 = Absent
1 = Provoked by painful stimuli only
2 = Provoked by touch, light pressure and/or occasionallyspontaneous (2/n)
No information on how this data was collected
Data not normally distributed ANOVA showed trend in favour of Tiz (p=0.052)
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Features of the UMN syndrome(Greenwood 1998 & Sheean 2001)
Acute hypotonia
Weakness & fatiguability
Loss of dexterityLoss of cutaneous reflexes
Negative
Proprioceptive reflexes
Increased tendon jerks
Clonus
Spasticity
Flexor withdrawal reflexes
Flexor & adductor spasms
Clasp-knife reaction
Postive Babinski
Extensor reflexes
Extensor spasms
Positive support reaction
Cutaneous & nociceptive reflexes
At rest
Co-contraction
Associated reactions
Flexor withdrawal reflexes
Positive support reaction
Extensor thrust
Pushing reactions
During movement
(spastic dystonias)
Positive
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..but spasticity is not just about reflexes..
Changes in muscle ultrastructure type I (SO) fibre predominance (Dattola 1993)
remodelling of connective tissue (Williams 1984)
reduced muscle compliance or thixotropy (Tardieu 1982)
loss of sarcomeres (Goldspink 1990)
Changes in motor unit activity reduced numbers of motor units (Stein 1990)
variability in motor unit activation prevents fusion (Rosenfalck1980)
Changes in & around joints(Akeson 1987)
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Spasticity management as a
component of neuro-rehabilitation Within a dynamic, biopsychosocial model,
identify the functional problem(s)
Treat any exacerbating factors pain, bowels, bladder, pressure sores...
B-interferon, SSRIs
Define the spasticity treatment goals
focal, segmental or generalised? Inter-disciplinary management plan
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Inter-disciplinary spasticity treatment
Physical measuresStretching
Positioning/Seating
Splinting & orthoses
Strengthening exercises
Movement re-educationWalking aids
Electrical stimulation?
Medical treatmentsOral drugs
Focal treatment: BTx, phenol
Intrathecal treatment: phenol, baclofen
Orthopaedic surgery: soft tissue or bony
Rhizotomy: surgical or radiofrequency
Psychological measures
Adjustment to disabilitySelf-management
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Examples of MS spasticity scenarios
Tight, painful, spastic flexed arm
Deteriorating mobility with an assymetric
stiff-legged gait Wheelchair-bound MS patient with
troublesome extensor spasms
Bed-bound MS patient with severe flexor &
adductor posturing
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A preliminary controlled study to determine whether
whole-plant cannabis extracts can improve
intractable neurogenic symptoms (Wade et al, 2003)
Consecutive series of DB, randomised, placebo-controlled, single-patient crossover trials with2/52 treatment periods
No washout 24 patients: 18 MS, 4 SCI, 1 BPI, 1 NF/amp
20 completed inc 14 MS
Outcome measures: VAS scored daily
2 weekly assessor: numerical symptom scales & othermeasures (inc Ashworth how scored?)
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Randomised crossover trials
Comparison at individual rather than grouplevel
Inappropriate if 1st treatment alters patients for 2nd phase
Requires half the number of patients!
Must use statistics for paired data (e.g.paired t-test or McNemar test)
Not 2-sample t-test on active v. placebo results!
Carryover effect? Bias if discard 2nd period results if evidence of carryover
Meta-analyses involving cross-over trials: methodological issues.
Elbourne et al (2002) Int J Epidemiol 31: 140
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Do cannabis-based medicinal extracts have general or
specific effects on MS symptoms. A DB, randomised,
placebo-controlled study on 160 patients (Wade e al, 2004)
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Prospective, DB, RCT of BTx v. placeboinjections with standardised assessments every 3weeks for 12 weeks
Adults with focal hypertonia of UL or LL, aftermulti-disciplinary assessment
Outcomes: Modified Ashworth Scale
Percentage passive range of joint movement
Subjective rating of problem severity LL: Rivermead motor assessment scale
UL: Nine hole peg test
Modified Goal Attainment Scale
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DB, RCT of 22 patients with IT pump for
13/52 with baclofen or placebo, then 52/52
with baclofen open label
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Some thoughts on how to optimise the
chance of getting useful information
from spasticity treatment trials
Define your spasticity scenario
Choose an appropriate range of validated
outcome measures Define the optimal inter-disciplinary
management plan
Describe everything which might impact on
spasticity & control for what you can
Proper power calculations!