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 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:

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: 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:

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 ug/day
Intrathecal doses range from 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., 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: mg
Prochazka, J et al., Pain Med 2011; 12:

13. 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.

14. 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

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 ( 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
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.

20. Demographics Age at implant Gender Pain Type
Average 49.6 years (range 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

21. 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.

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

23. 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.

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

25. 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

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. 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

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