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

2. 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

3. 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

4. Surgery ITB Neurolytic Blockade Oral Medications Physical Measures Removal of Noxious Stimuli Synergistic Model of Spasticity Management

5. Surgery ITB Neurolytic Blockade Oral Medications Physical Measures Removal of Noxious Stimuli Synergistic Model of Spasticity Management

6. Oral Pharmacological Options Baclofen (Lioresal) * Diazepam (Valium) Neurontin (Gabapentin) Clonidine (Catapress) Tizadine (Zanaflex) * Dantrolene (Dantrium) * * FDA approved for spasticity

7. 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

8. 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

9. 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

10. 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

11. Arbaclofen SCI Trial

14. 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

15. 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

16. Mechanism of action

18. Toxin Formulations Available in US Only Onabotulinumtoxin A (Botox) is approved for adult upper extremity spasticity

19. ToxinDilution Reasonable Max Dosing Onabotulinumtoxin A25-100 units/ml 400 U / limb 600 U / session Abobotulinumtoxin A200-500 units/ml 1500 U / limb 2000 U / session Incobotulinumtoxin A25-100 units/ml 400 U/ limb 500 U / session Rimabotulinumtoxin B5000 units/ml 10,000 U / limb 20.000 U / session

20. 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.

21. Visual example of volume effects 0.1 mL 1 mL test dose 0.048 mL

22. 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

23. 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

24. Agents Intrathecal Lioresal – FDA approved – Medtronic / Novartis Intrathecal Gablofen – FDA approved – CNS therapeutics Compounded baclofen – not FDA approved – state regulated, compounding pharmacies

25. 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