Spasticity Update

Michael Saulino, MD PhD Physiatrist MossRehab Assistant Professor Physical Medicine and Rehabilitation Thomas Jefferson University Hospital

CME Disclosures 1

• Speaker’s bureau for Jazz Pharmaceuticals• Speaker’s bureau and clinical investigator for

Medtronic, Inc• Speaker’s bureau for Ipsen• Consultant for SPR therapeutics and

Myoscience

CME Disclosures 2

• Will discuss off label and investigational indications for medications and devices

• All activities are reviewed by Albert Einstein Healthcare Network’s conflict of interest committee

• Honoraria are paid directly to PMR department

Surgery

ITB

NeurolyticBlockade

OralMedications

PhysicalMeasures

Removal ofNoxious Stimuli

Synergistic Model of Spasticity Management

Surgery

ITB

NeurolyticBlockade

OralMedications

PhysicalMeasures

Removal ofNoxious Stimuli

Synergistic Model of Spasticity Management

Oral Pharmacological Options • Baclofen (Lioresal) *• Diazepam (Valium)• Neurontin (Gabapentin)• Clonidine (Catapress)• Tizadine (Zanaflex) *• Dantrolene (Dantrium) *

* FDA approved for spasticity

Baclofen (Lioresal)• Racemic GABA B receptor agonist• Both pre- and post-synaptic activity resulting in inhibition

of both monosynaptic and polysynaptic reflexes at the spinal level

• R enatomier considered to the 5-6 times more potent

Baclofen Several pharmacologic limitations:

Only absorbed in the upper small intestineSaturable active transport mechanismShort half life (3-4 hrs)Requires frequent administrations for effectivenessSustained release formulation unachievable

Arbaclofen Placarbil• Improved absorption of R enatomoer by disguising it

as a nutrient which uses an active transport mechanism• Compared with immediate-release baclofen,

arbaclofen has a flatter pharmacokinetic profile and more sustained plasma levels allowing less frequent dosing

Arbaclofen SCI Trial• Double-blind, placebo-controlled crossover study • 37 SCI patients >1 year after injury, Ashworth > 2 after washout• Arbaclofen 10, 20, or 30 mg BID or placebo • Primary end point: Difference in Ashworth scale

Arbaclofen SCI Trial

Arbaclofen SCI Trial

Arbaclofen SCI Trial

ArbaclofenInitial SCI trial suggests efficacy of BID dosing and

improved tolerability compared to immediate release racemic oral baclofen

Ongoing trial in multiple sclerosis• Currently ongoing at 35 sites in US • Randomizing 200 patients • 4 treatments: placebo, 15 mg, 30 mg, or 40 mg

twice daily over 8 weeks • Followed by an on open label study

Botulinum Neurotoxin

• The most potent neurotoxin known • Derived from Clostridium botulinum • Variations in the polypeptide sequence produce

different serotypes of toxin, referred to as types A, B, C1, D, E, F and G

• The different serotypes can evoke different immune responses; for each serotype, multiple packaging and formulation options exist, adding to the variability

Mechanism of action

Mechanism of action

Toxin Formulations Available in US

• Only Onabotulinumtoxin A (Botox) is approved for adult upper extremity spasticity

Toxin Dilution Reasonable Max Dosing

Onabotulinumtoxin A 25-100 units/ml 400 U / limb 600 U / session

Abobotulinumtoxin A 200-500 units/ml 1500 U / limb 2000 U / session

Incobotulinumtoxin A 25-100 units/ml 400 U/ limb 500 U / session

Rimabotulinumtoxin B 5000 units/ml 10,000 U / limb 20.000 U / session

Intrathecal baclofen therapy

• Traditionally, effects of ITB have been related to two factors:– Catheter tip location– Dosage administered

• Emerging data suggests that drug concentration / volume administered / flow rate can play a role in therapeutic effects.

Visual example of volume effects

0.1 mL1 mL test dose 0.048 mL

Concentration effects

• Bernards and colleagues have demonstrated enhanced distribution of ITB away from the catheter tip at lower concentrations in an animal models

• Same group also demonstrated logarimithic relationship between ITB concentration and baricity

Agent

• Chiodo and colleaues reported improved spasticity control in a small case series with lower ITB concentration

• Stokic and Yablon demonstrated enhanced electrophysiological suppression of spasticity at lower ITB concentrations

• van des Plas and colleagues failed to detect a difference in CRPS-dystonia reduction with differential flow rate and fixed ITB dosing

Agents

• Intrathecal Lioresal – FDA approved – Medtronic / Novartis

• Intrathecal Gablofen – FDA approved – CNS therapeutics

• Compounded baclofen – not FDA approved – state regulated, compounding pharmacies

Agent

• 2 published articles (Moberg-Wolff and Farid et al) describe considerable variability in compounded baclofen compared to branded intrathecal Lioresal

• Handful of conference abstracts describing adverse effects with compounded baclofen products