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
Synergistic Model of Spasticity Management
Removal of
Noxious
Stimuli
Physical
Measures
Surgery
ITB
Oral
Medications
Neurolytic
Blockade
Synergistic Model of Spasticity Management
Removal of
Noxious
Stimuli
Physical
Measures
Surgery
ITB
Oral
Medications
Neurolytic
Blockade
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 intestine
Saturable active transport mechanism
Short half life (3-4 hrs)
Requires frequent administrations for effectiveness
Sustained 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
Arbaclofen
Initial 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
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
Onabotulinumtoxin A
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
1 mL test dose
0.1 mL
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