Treatments for Spas Ti City

8/14/2019 Treatments for Spas Ti City

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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!

Treatments for Spas Ti City

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