Novel Therapies and Technologies

1. Novel Therapies and Technologies Richard L. Rauck President-elect World Institute of Pain President, Carolinas Pain Institute Pain Fellowship Director Wake Forest University Health Sciences Winston Salem, North Carolina

2. Disclosures • Medtronic: research funding, advisory board, DSMB • Alfred Mann Foundation: research funding, DSMB • Flowonix: research funding, advisory board • Jazz Pharmaceutical: advisory board, speaker’s bureau • CNS therapeutics: consultant, research funding

3. Learning Objectives • Understand novel therapies for intrathecal drug delivery • Describe new technology applicable in intrathecal drug delivery • Present new data on IT gabapentin

4. Mortality Associated with Implantation and Management of Intrathecal Opioid Drug Infusion Systems to Treat Noncancer Pain • Through register Medtronic has data on >90% of patients implanted with IT pumps • Mortality rate with IT therapy: • 0.088% at 3 days • 0.39% at 1 month • 3.89% at 1 year • Higher than death rates with SCS or laminectomies • Respiratory arrest is a significant or contributory factor in large majority of deaths Coffee RJ, et al. Anesthesiology 2009; 111: 881-91

5. Indications for Intrathecal Drug Delivery • Intractable cancer pain • Refractory to systemic opioids • Intractable side effects to opioid analgesics • Shortened life expectancy is a determinant in pump selection • Non-cancer pain • Failed conservative measures • Cleared psychological screening • Successful trial periods

6. Opioids for Intrathecal Analgesia • Morphine sulfate • Large clinical experience • Limited randomized clinical trials for long-term infusions • Must be preservative free • Possible problems with granulomas • Concentration dependent vs total daily dose (?) • Daily doses: 0.2-15 mg; concentrations <20-30 mg/ml • Hydromorphone • Similar in efficacy to morphine • Potency is 4-5 times that of morphine • Granulomas have been reported with long-term use

7. Prospective study of 3 year follow up of low dose intrathecal opioids in the management of chronic nonmalignant pain • n=61 patients; 6.2 year duration of pain • Worst and average VAS: 8.9 and 7.5 decreased to 4.0 and 3.4 at 36 months (p=0.012 and p<0.001) • Reduction in oral opioid consumption 128.9 meq MSO4/day to 3.8 meq/day at 3 months • IT dose remained low: 1.4 mg/day at 6 months and 1.48 mg/day at 36 months • Improvement in physical and behavioral function Hamza, et al. Pain Med 2012; 13: 1304-13

8. Clinical Use of Intrathecal Clonidine • Commonly used in combination with opioids or local anesthetics • Useful as sole agent in patients with CRPS • Tolerance does not seem to be a problem • Does occur in animals • Safe to initiate as an outpatient at 25-50 ug/day • Intrathecal doses range from 25-500 ug/day • Side effects include hypotension, dry mouth, sedation • Significant rebound hypertension can occur with acute cessation of the drug • May protect against granuloma formation seen with opioids

9. Intrathecal Adenosine in Chronic Pain • May be useful in patients with allodynia • Most likely an adjuvant drug • Can be used in combination with opioids, local anesthetics, and/or clonidine • Daily dose: 2 mg as infusion or bolus Eisenach and Rauck, 2003

10. Intrathecal Ketorolac in Chronic Pain • Animal studies and human volunteer studies have been positive • Parris, 1996; Yaksh, 2004 • Eisenach, 2002, 2003, 2005 • Phase I study in chronic pain patients with existing IT pumps showed significant analgesic effect at 0.5, 1.0 and 2.0 mg • Phase II, RCT showed no benefit as single dose trial Rauck ,et al. in press

11. Pilot Studies Identifying PGE2 as a Possible Biomarker for Ketorolac Responsiveness • Pilot study involving existing pump patients and measuring differences in intrathecal PGE2 • Pilot study measuring intrathecal PGE2 in patients receiving epidural steroid injections

12. Intrathecal Midazolam in Chronic Pain • Conflicting animal toxicity studies amid early clinical studies • Johansen, 2004; Yaksh, 2004 • RCT in perianal postoperative study favored IT midazolam w/ bupivacaine over B alone (p<0.05) • Yegin, et al., Eur J Anaesthesiol 2004 • RCT: Combination of IT midazolam (2 mg) with fentanyl (10 mcg) in laboring patients • Tucker, et al., AnesthAnalg 2004 • Clinical studies to date have been short term (acute pain) or observational in nature • Bolus dose of 2 mg common • Review of 15 year experience of single boluses: 2-15 mg • Prochazka, J et al., Pain Med 2011; 12: 1309-15

13. A.P. Ziconotide Mechanism of Action (MOA) • Calcium entering through presynaptic calcium channels trigger calcium-dependent transmitter release • Results in animals suggest that PRIALT binding to N-type calcium channels blocks excitatory neurotransmitter release; the MOA has not been established in humans

14. Change in VASPI Score Mean % Change in VASPI Scores from Baseline to Day 21 • Primary efficacy variable was mean % change in VASPI score from baseline to day 21 • Patients who did not have a VASPI score recorded days 17-23, inclusive, were assigned 0% improvement p=0.04 Rauck, et al, JPSM, 2005

15. Intrathecal combination of ziconotide and morphine for refractory cancer pain: A rapidly acting and effective choice • n=20 pts with disseminated cancer with bone mets to spine refractory to high dose oral opioids • Mean VAS at entry: 90/100 • 28 day trial: measured at day 2,7,14,21,28 • Ziconotide initiated at 2.4 ug/day and increased by 1.2 ug/day each week as needed • IT MSO4 dependent on oral dose • VAS change from baseline: p<0.001 at all times • Alcino, I, et al., Pain 2012: 153: 245-9

16. Current Topics with Ziconotide • Narrow therapeutic window • Start low (.5-1.2 mcg/day) and titrate slowly • Increase by 1.2 mcg/day no more than 1 time/week • Peptide that is unstable in combination with morphine secondary to oxidative degradation • Appears stable with clonidine, bupivicaine, baclofen and hydromorphone and off-label combinations in use • Tolerance has not been reported • Respiratory depression not a problem • No withdrawal problems with acute cessation

17. Status of Intrathecal Gabapentin • Drug is currently in early investigational stage of human development • No human administration to date via implantable device • Spinal neurotoxicity trials are ongoing • Use outside an investigational trial design could be potentially very dangerous • Medico-legal risk to physician • Drug development if complication occurred

18. CSF & Plasma Pharmacokinetics • Increasing CSF & plasma levels as infusion rate/dose was escalated • Steady-state levels determined with linear pharmacokinetics

19. Clinical Study Design

20. Demographics • Age at implant • Average 49.6 years (range 22-72 years) • Gender • Female: 98 (57%) Male: 73 (43%) • Pain Type • 68 (40%) Neuropathic pain (persistent pain without apparent injury) • 23 (13%) Nociceptive pain (normal pain in response to injury) • 80 (47%) Mixed pain

21. Primary Efficacy Objective - Results Mean change from baseline in average daily pain scores * Baseline – Day 22 Conclusion: None of the dose groups showed statistically significant improvement over placebo in reducing average daily pain. No minimum effective dose was determined.

22. Part 1 – Changes in Average Daily Pain Scores Improvement

23. Better Additional Objective: BPI Interference

24. Gabapentin Dose Levels Achieved in Part 2 – Open-Label

25. Failed Study or Failed Drug • Failed drug • Animal studies failed to predict the lack of efficacy seen in the human trial • No double-blind efficacy trials in animals • Animal studies hinted at mechanism of action that was activated by supra-spinal sites (locus coeruleus and descending inhibition) • Failed trial • Inclusion criteria allowed for broad array of patients placed into study • Short-term trial (22 day) • End result: commercial development of drug is dead

26. New Programmable Intrathecal Infusion System • Non-compliant dosing chamber that provides precise, controlled measurement and drug flow (no motors or rollers) • An isolated, electronic valve system immune to temperature and pressure changes • Energy efficient with durable parts made to last • Significant longevity improvement • Ability to completely shut down (zero flow)

27. Dose Control System Provides High Accuracy and Durability Inlet Valve Dose Measurement Chamber Outlet Valve

28. Accuracy Results Data represents 1098 visits over 21 months Rauck, et al., Neuromodulation, December, 2009

29. Safety Results • No unanticipated adverse device effects or deaths attributed to the Prometra System occurred • Adverse events and device complications reported are consistent with what has been previously reported in other studies • No pump failures occurred during the study • To date, no Granulomas have been observed Rauck, et al., Neuromodulation, December, 2009

30. Pump Refills: Why Worry? • No fool proof way to avoid subcutaneous refill • Some drugs are worse than others: • Clonidine: blood pressure changes, somnolence • High concentration opioids: seizures • Local anesthetics: total spinal • Baclofen overdose: sedation, bradycardia

31. Effective Use of Fluoroscopy

32. The Changing Landscape of IT drug delivery Non-painful conditions • Pulmonary arterial hypertension • Remodulin: Revomid • Refractory hypertension • Intrathecal clonidine • Other possibilities • Parkinson’s disease • Dementia • Autism

33. Summary New advances in intrathecal drug delivery will proceed in the following ways: • pharmacology/physiology based: understanding new analgesic pathways and mechanisms in the dorsal horn • polyanalgesia: using multiple drugs and receptor systems to enhance analgesia and decrease side effects • hardware based: new devices and innovations of current devices and therapies to deliver better analgesia • genetic manipulation: alter painful disease states and enhance internal analgesic mechanisms