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

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

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

Mortality rate with IT therapy: 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

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

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

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

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

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

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

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

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., Anesth Analg 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

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 Ziconotide A.P. Although the mechanism of action has not been established in humans, results in animals suggest that its binding blocks calcium entry into the presynaptic nerve terminal, thereby reducing the release of excitatory neurotransmitters from the primary afferent nerve terminals into the synapse. PRIALT has no affinity for other ion channels, nor does it bind to opioid receptors.

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 The primary efficacy variable was the mean percent change in VASPI score from baseline to day 21. There was a statistically significant improvement in VASPI score from baseline (p=0.04) in the PRIALT group compared to placebo. Patients exhibited various degrees of improvement in pain after three weeks of treatment compared to baseline. Patients who did not have a VASPI score recorded at Week 3 (days 17-23, inclusive) were assigned 0% improvement. 34 patients (17 PRIALT, 17 placebo) were assigned 0% as their last VASPI scores were not recorded days 17-23, inclusive. Rauck, et al, JPSM, 2005

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

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

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

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

Clinical Study Design On Day 1, subjects were randomized to receive either placebo (0 mg/day), 1, 6, or 30 mg/day. To maintain the study blind, the drug was prepared in the pharmacy at the appropriate concentrations so that all subjects could have their pumps programmed to deliver 0.4 ml/day.

Demographics Age at implant Gender Pain Type 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 Age Gender Pain type

Primary Efficacy Objective - Results Mean change from baseline in average daily pain scores Dose Group N Mean Change from Baseline* Standard Deviation P-value William’s Test Result 0 mg/day 41 0.46 1.56 1 mg/day 40 0.42 1.36 0.806 Not sig 6 mg/day 0.07 0.98 0.879 30 mg/day -0.09 1.03 0.904 This table shows the mean change from baseline for each treatment group. The Day 22 scores were subtracted from the baseline scores so that “large” positive changes indicate improvement and negative values indicate worsening pain. Placebo and low dose improved by 0.4 points, 30 mg/day was slightly worse at Day 22. None of the dose groups showed statistically significant improvement over placebo in reducing average daily pain. No MED. * 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.

Part 1 – Changes in Average Daily Pain Scores Improvement Placebo group is nearly statistically significant in change from baseline with only 41 subjects.

Additional Objective: BPI Interference Better The Brief Pain Inventory was completed at study visits during the blinded phase using the subject’s electronic diary. Subjects were asked to rate how their pain interfered with various activities of daily living including walking, working sleep mood, relationships with others. The BPI is on a 0 to 10 scale with 0 being no interference and 10 being complete interference. There were small changes from baseline in each of the dose groups.

Gabapentin Dose Levels Achieved in Part 2 – Open-Label This slide shows the maximum gabapentin dose levels subjects received. Almost half received 50-60 mg/day at their highest level.

Failed Study or 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

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)

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

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

Rauck, et al., Neuromodulation, December, 2009 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

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

Effective Use of Fluoroscopy

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

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