Spasticity Update Michael Saulino, MD PhD Physiatrist MossRehab Assistant Professor Physical...
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Spasticity Update
Michael Saulino, MD PhD Physiatrist MossRehab Assistant Professor Physical Medicine and Rehabilitation Thomas Jefferson University Hospital
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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
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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
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Surgery
ITB
NeurolyticBlockade
OralMedications
PhysicalMeasures
Removal ofNoxious Stimuli
Synergistic Model of Spasticity Management
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Surgery
ITB
NeurolyticBlockade
OralMedications
PhysicalMeasures
Removal ofNoxious Stimuli
Synergistic Model of Spasticity Management
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Oral Pharmacological Options • Baclofen (Lioresal) *• Diazepam (Valium)• Neurontin (Gabapentin)• Clonidine (Catapress)• Tizadine (Zanaflex) *• Dantrolene (Dantrium) *
* FDA approved for spasticity
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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
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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
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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
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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
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Arbaclofen SCI Trial
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Arbaclofen SCI Trial
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Arbaclofen SCI Trial
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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
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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
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Mechanism of action
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Mechanism of action
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Toxin Formulations Available in US
• Only Onabotulinumtoxin A (Botox) is approved for adult upper extremity spasticity
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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
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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.
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Visual example of volume effects
0.1 mL1 mL test dose 0.048 mL
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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
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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
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Agents
• Intrathecal Lioresal – FDA approved – Medtronic / Novartis
• Intrathecal Gablofen – FDA approved – CNS therapeutics
• Compounded baclofen – not FDA approved – state regulated, compounding pharmacies
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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