Treatments for spasticity

Dr David Shakespeare
Consultant in Rehabilitation Medicine
Preston UK
 ‘MS trial of cannabis
results in confusion’
(Daily Telegraph, 7/11/2003)

‘Cannabis helped to relieve

symptoms in many patients with MS,
but doctors say today they could find
no physical proof of improvement’
 What is spasticity?
• Diagnostic definition:
– ‘a motor disorder characterised by a velocity-
dependent increase in tonic stretch reflexes that
results from abnormal intra-spinal processing of
primary afferent input’ (Young 1994)
• Functional definition:
– the abnormal motor control caused by an UMN
lesion (as in spastic paraparesis)
 Ashworth scale (Ashworth, 1964)
0 no increase in tone
1 spastic catch
2 more marked increase in tone but limb
easily 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)
 Anti-spasticity agents for
multiple sclerosis
DT 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• Systematic review of published & unpublished
RCTs of ASAs identified by:
– MEDLINE, EMBASE
– bibliographies of relevant articles
– personal communication
– information from drug companies.
• 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.
 Results
• 42/175 studies met the inclusion criteria
– 29 placebo-controlled studies
– 13 comparative studies.

• 17/40 studies used the Ashworth scale, but a

statistically significant difference between test drugs
was only shown in:
– 3/12 placebo-controlled trials (baclofen, tizanidine, BTx)
– 0/5 comparative studies

• Many studies reported an improvement in unvalidated

‘self-report’ scores of spasticity or spasms
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 with
validation/combined scores
• No validated scale for spasms etc
• Insensitive functional assessment tools
• Confounding factors?
• Problems of cross-over trials
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)
 Patient selection
Inclusions Exclusions
• Stable spasticity • Relapse within 3/12
• Significant discomfort • Contractures
or functional
impairment
• Ashworth 2+ No information on
• Spasm score 2+ mobility levels, types
• Stopped previous ASA of spasm problems
for 2 weeks etc
 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 baseline

to 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 to

end of plateau phase:
• Tiz 63%, Plac 57% (p=0.497)
Patient diary (type & frequency of spasms)
0 = Absent
1 = Provoked by painful stimuli only
2 = Provoked by touch, light pressure and/or occasionally
spontaneous (<5/d and/or <2/n)
3 = Provoked by passive movements and/or frequently
spontaneous (>5/d and/or >2/n)

• No information on how this data was collected

• Data not normally distributed

• ANOVA showed trend in favour of Tiz (p=0.052)
 Features of the UMN syndrome
(Greenwood 1998 & Sheean 2001)

Negative Positive

Acute hypotonia At rest During movement

Weakness & fatiguability (spastic dystonias)
Loss of dexterity
Loss of cutaneous reflexes

Proprioceptive reflexes Cutaneous & nociceptive reflexes Co-contraction Extensor thrust

Increased tendon jerks Associated reactions Pushing reactions
Clonus Flexor withdrawal reflexes
Spasticity Positive support reaction

Flexor withdrawal reflexes Extensor reflexes

Flexor & adductor spasms Extensor spasms
Clasp-knife reaction Positive support reaction
Postive Babinski
..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 (Rosenfalck
1980)

• Changes in & around joints (Akeson 1987)

 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
Inter-disciplinary spasticity treatment
Physical measures Medical treatments
Stretching Oral drugs
Positioning/Seating Focal treatment: BTx, phenol
Splinting & orthoses Intrathecal treatment: phenol, baclofen
Strengthening exercises Orthopaedic surgery: soft tissue or bony
‘Movement’ re-education Rhizotomy: surgical or radiofrequency
Walking aids
Electrical stimulation?

‘Psychological’ measures
Adjustment to disability
Self-management
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
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 with
2/52 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 & other
measures (inc Ashworth how scored?)
 Randomised crossover trials
• Comparison at individual rather than group
level
• 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
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)
• Prospective, DB, RCT of BTx v. placebo
injections with standardised assessments every 3
weeks for 12 weeks
• Adults with focal hypertonia of UL or LL, after
multi-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
• DB, RCT of 22 patients with IT pump for
13/52 with baclofen or placebo, then 52/52
with baclofen open label
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!