novel therapies and technologies richard l. rauck president-elect world institute of pain president,...
TRANSCRIPT
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 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
0 1 2 3 4 5 6 2 40
2 0 0
4 0 0
6 0 0
****
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I n t r a t h e c a l I n t r a v e n o u s
F i g u r e 2 : A r e a s o f a l l o d y n i a b e f o r e a n d a f t e r i n j e c t i o n , a t t i m e 0 , o f i n t r a t h e c a l ( s o l i d c i r c l e s ) o r i n t r a v e n o u s ( o p e n c i r c l e s ) a d e n o s i n e , 2 m g . E a c h s y m b o l r e p r e s e n t s t h e m e a n S E o f 7 s u b j e c t s . O n l y i n t r a t h e c a l i n j e c t i o n r e d u c e d t h e a r e a o f a l l o d y n i a ( * P < 0 . 0 5 c o m p a r e d t o t i m e 0 ) .
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
0
1
2
3
4
5
6
0.5 mg 5.7 5 4.6 4.2 3.6 3.9 2.9 3.4
1.0 mg 3.7 3.9 3.4 2.3 2.6 2.5 2.5 2.6
2 5.4 5.1 3.9 3.1 3.1 2.5 2.5 2.6
baseline 15 minutes 30 minutes 45 minutes 60 minutes 120 minutes 180 minutes 240 minutes
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.
Change in VASPI Score
• 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
12.0
5.0
0
5
10
15
20
PRIALT(n=112)
Placebo(n=108)
Mea
n %
Cha
nge
in V
ASP
I p=0.04
Mean % Change in VASPI Scores from Baseline to Day 21
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
Observed and Fitted Lumbar CSF and Plasma
0 24 48 72 96 120 144 1681
10
100
1000
10000
100000
1000000
CSF Observed
CSF Fitted
Plasma Fitted
Plasma Observed
Time (hr)
Co
ncen
trati
on
(u
g/L
)
• Increasing CSF & plasma levels as infusion rate/dose was escalated• Steady-state levels determined with linear pharmacokinetics
Clinical Study Design
Part 1 Blinded Dosing
Randomization
21 Day Blinded Dosing
Gabapentin Injection 1 mg / day
Pump Rate = 0.4 mL / day
Pump Rate = 0.4 mL / day
Gabapentin Injection 6 mg / day
Pump Rate = 0.4 mL / day
Gabapentin Injection 30 mg / day
Placebo
Pump Rate = 0.4 mL / day
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
Primary Efficacy Objective - Results Mean change from baseline in average daily pain scores
Dose Group NMean 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 40 0.07 0.98 0.879 Not sig
30 mg/day 40 -0.09 1.03 0.904 Not sig
* 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
Change from Baseline to Day 22 in Average Daily Pain Scores
-1
-0.5
0
0.5
1
1.5
2
0 mg/day 1 mg/day 6 mg/day 30 mg/day
Treatment Group
Ch
ang
e in
Pai
n (
Bas
elin
e -
Day
22)
Error bars show ± 2 standard errors
Improvement
Additional Objective: BPI Interference
Better
BPI - Overall Pain Interference Scores
0
2
4
6
8
10
12
0 mg/day 1 mg/day 6 mg/day 30 mg/day
Treatment Group
Me
an
Ov
era
ll In
terf
ere
nc
e S
co
re
Baseline Day 22Error bars show ± 2 standard deviations
Gabapentin Dose Levels Achieved in Part 2 – Open-Label
Maximum Gabapentin Dose Levels in Part 2 - Open-label
19% 19%
13%
49%
0%
10%
20%
30%
40%
50%
60%
6-20 mg/dy 20-40 mg/day 40-50 mg/day 50-60 mg/day
Maximum Dose
Per
cen
t o
f S
ub
ject
s
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
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
85
87.5
90
92.5
95
97.5
100
0.0-0.14 (168) 0.14-0.24 (220) 0.24-0.32 (226) 0.32-0.45 (302) >0.45 (179)
Flow Rate mL/day (Total Refill Visits)
Ac
cu
rac
y M
ea
n %
Data represents 1098 visits over 21 months
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
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