Treatments For Spas Ti City

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 velocitydependent 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 1 2 3 4

no increase in tone spastic catch more marked increase in tone but limb easily flexed considerable increase in tone, passive movement difficult 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 antispasticity 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 • Systematic review of published & unpublished RCTs of ASAs identified by: – – – –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 Stable spasticity Significant discomfort or functional impairment Ashworth 2+ Spasm score 2+ Stopped previous ASA for 2 weeks

Exclusions • Relapse within 3/12 • Contractures

No information on mobility levels, types of spasm problems 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 Weakness & fatiguability Loss of dexterity Loss of cutaneous reflexes

At rest

Proprioceptive reflexes Increased tendon jerks Clonus Spasticity

During movement (spastic dystonias)

Cutaneous & nociceptive reflexes

Flexor withdrawal reflexes Flexor & adductor spasms Clasp-knife reaction Postive Babinski

Co-contraction Associated reactions Flexor withdrawal reflexes Positive support reaction

Extensor reflexes Extensor spasms Positive support reaction

Extensor thrust Pushing reactions

..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 Stretching Positioning/Seating Splinting & orthoses Strengthening exercises ‘Movement’ re-education Walking aids Electrical stimulation? ‘Psychological’ measures Adjustment to disability Self-management

Medical treatments Oral drugs Focal treatment: BTx, phenol Intrathecal treatment: phenol, baclofen Orthopaedic surgery: soft tissue or bony Rhizotomy: surgical or radiofrequency

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, placebocontrolled, 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!