15 annual pain medicine meeting texas pain society... 15th annual pain medicine meeting november...
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15th Annual Pain Medicine Meeting November 17-19, 2016
Hilton San Diego Bayfront Hotel, San Diego, California
American Society of Regional Anesthesia and Pain Medicine Advancing the science and practice of regional anesthesia and pain medicine
www.asra.com
Neuromodulation Technology
Updates
Ricardo Vallejo, M.D., PhD
Director of Research,
Millennium Pain Center
Disclaimer
Director of Research, Millennium Pain Center
Medical Director, Comprehensive Spine Center, UnityPoint, Peoria, Illinois
Co-founder, Millennium Pain Management-Quiron-Teknon, Barcelona, Spain
Secretary Illinois Society of Interventional Pain Physicians
Adjunct Professor, Department of Biological Sciences, Illinois State University
Adjunct Research Professor, Wesleyan University, Illionis
Board of Examiners, American Board of Interventional Pain Physicians (ABIPP)
Board of examiners, World Institute of Pain
Associate Editor “Pain Practice”
Associate Editor, “ Pain Physician”
Chief Editor “Techniques in Regional Anesthesia and Pain Management”
Editorial Board, “Journal of Opioid Management”
Editorial Board “Clinical Journal of Pain”
DISCLOSURES
• Basic Science Research Agreements: Boston Scientific Neuromodulation and Nevro Corporation.
• Clinical trials: Nevro Corporation, Medtronic Spinal and Biologics, and St. Jude Medical.
• Advisory Board/ Consultant: Medtronic, Halyard
Patent application with USPTO (US2016/0256689, US2016/0271392, US2016/0271413
WO2016/154091, Provisional: US62/377,139) for a novel neuromodulation system.
Spinal Cord Stimulation
Spinal Cord Stimulation: Exploration of the Physiological Basis of a Widely Used Therapy
Linderoth, Bengt;, Anesthesiology. 2010.
NE = norepinephrine; STT =
spinothalamic tract.
Current paradigm is focused on
Neuronal Stimulation
SCS MAY suppress enhanced
responsiveness of Wide Dynamic
Range Neurons (WDR)
WDR neurons play a major role on
the development of Chronic
Neuropathic Pain
Many of the mechanisms of action
are still unknown [X].
Neurostimulation
Cathodic stimulation is more effective
Electrical field PULSE to neuron ∆ transmembrane potential
Current density depends on
DELIVERED CURRENT
(key determinant of stimulation)
The Electric Field = current density
I=1/dCSF
Diameter=1/ I Th
Activating Neurons with Single Pulses
• Definition:
• Stimulation Threshold:
• At a given PW, enough mA pulse current to activate neuron = generate an action potential
• Single pulse can depolarize neuron if meets mA & PW requirements
Reilly et al 1985
Low Fc
Stimulu
s
Oakley (2006) Pain Medicine, 7(S1), S58-S63.
11
Modeling suggests that only large (9-12 µm)
dorsal column (DC) fibers will be activated at nominal PW values (e.g., 210 µs) (Wesselink and Holsheimer, 1997).
In the superficial DC, ~85% of fibers are smaller than 7 µm and <1% are larger than 10 µm (Feirabend et al, 2004).
Longer PW values promote the activation of smaller diameter fibers relative to larger diameter fibers, as found in other neurostimulation applications (Gorman and Mortimer, 1983).
In SCS, longer PW may increase the number of fibers activated and thereby increase the likelihood of generating paresthesia in broader dermatomal regions (Meyerson, 1997). Feirabend et al,
Brain 2004
Wide Pulse Width
Strength-duration curve for large and small nerve fibers
Amplitude vs. Pulse Width
Small fiber
Large fiber
At shorter PW: larger differences
in thresholds between large
and small fibers
At longer PW: smaller differences
in thresholds between large and
small fibers
Amplitude
Pulse Width
Ith
PW
Rheobase
Chronaxie
“In neurostimulation applications, the pulse amplitude and width relate directly to the depolarization of the cell membrane and are therefore critical parameters for determining the locus of excited tissue”
Strength Duration Curve Depolarization of the cell membrane which elicits an action potential is mediated by a single stim pulse Charge/pulse = amp x pulse width
Pulse width affects coverage
Change in Paradigm?
Traditional SCS
• Paresthesia coverage of pain is considered a necessary (though not sufficient) requirement for efficacy
• Low back coverage is known to be particularly challenging to achieve and maintain • Deeper penetration via
midline placement
North et al 1991
100%
Coverage
No
Coverag
e
No
Relief
100%
Relief
Traditional SCS Thinking: More paresthesia = more pain
relief
Paresthesia Induced Uncomfortable
Stimulation
• 71% of patients find paresthesia to lead to uncomfortable
stimulation (Kuechmann et al. 2009)
Source: restoresensor.eu
"There are three kinds of lies: lies,
damned lies, and statistics."
Burst
17
Single center, Prospective, Observational
12 pts: 7 LBP, 4 UE pain, 1 PNP
Pts were programmed for tonic and Burst
Mean f/u=20.5 months
Improvement in VAS and McGill at +/- 12 months
17% of pts felt paresthesias = THEY DID NOT
LIKE IT
DeRidder et al 2010
DeRidder 2013
DBRC trial
1 week per treatment group
15 pts
Pts programmed for paresthesias
No significant difference vs. tonic
for back and limb pain
Only difference observed: generalized pain
21
EEG show activation of the DLPFC and dACC
“Burst stimulation… patients experienced a
frontal lobectomies”
LATERAL PATHWAY
sensory/discriminative portion of pain
“Where/How hard I being pinched?”
MEDIAL PATHWAY
Affective/emotional portion of pain
“How do I feel about being pinched?”
DeVos 2013
48 pts with >6 months of tonic SCS
24 FBSS, 12 PDN, 12 poor responders
14 days Burst
Pt preference:
Overall: 54% prefer burst
PDN: 43% prefer burst
FBSS: 29% prefer burst
PR: No preference
SUNBURST
23
PET Scan & fMRI in Traditional SCS
Kishima H, Neuroimage 2010
Deogaonkar M, Neuromodulation 2016
Effects of HF on Impedance
• One field applied at a given region of the neural tissue and at adequate amplitude and frequency would:
Reduce tissue impedance
Reduce threshold
Wei and Grill , 2009, J
Neural Eng (Brain tissue)
Sankar et al, 2014,
Frontier Neuroeng
(somatosensory cortex)
High Frequency Effects on Neurons
Membrane Integration
• Effect of high frequency: • Multiple pulses delivered at
high frequencies can activate neurons using less mA
• Neural Membrane Integration • Pulses delivered ‘fast
enough’ are accumulated by the neural membrane, ultimately depolarizing the neuron to create an AP
1 ‘pulse’: 0.98mA
Reilly et al 1985
High Frequency Effects on Neurons
Membrane Integration
• Effect of high frequency: • Multiple pulses delivered
at high frequencies can activate neurons using less mA
• Neural Membrane Integration • Pulses delivered ‘fast
enough’ are accumulated by the neural membrane, ultimately depolarizing the neuron to create an AP 1 ‘pulse’: 0.98mA
2 ‘pulses’: 0.90mA
Reilly et al 1985
High Frequency Effects on Neurons
Membrane Integration
• Effect of high frequency: • Multiple pulses delivered
at high frequencies can activate neurons using less mA
• Neural Membrane Integration • Pulses delivered ‘fast
enough’ are accumulated by the neural membrane, ultimately depolarizing the neuron to create an AP
Reilly et al 1985
3 ‘pulses’: 0.87mA
2 ‘pulses’: 0.90mA
1 ‘pulse’: 0.98mA
High Frequency Effects on Neurons
Membrane Integration
• Higher frequencies may have even lower thresholds
• “Trade rate for mA”
mA
th
resh
old
fo
r a s
ing
le p
uls
e
Reilly et al 1985
High Frequency Effects on Neurons:
Desynchronization
• Low Frequency: • All neurons follow in
“lock-step” with stimulus
• Non-varying
• High Frequency: • Each neuron fires at its
own rate, pattern
• Average rate for each neuron different from neighboring neurons
Adapted from Rubinstein et al 1999
Low f
Stimulus
High f
Stimulus
31
High Frequency Effects on Neurons:
Desynchronization
Overall nerve population response to high frequency:
• Mean neuron firing rate ~ 100s of Hz
• Individual neuron firing rate variable
Believed to be more ‘natural’ neuron pattern (“pseudospontaneous”)
Litvak et al 2003
32
Mean firing freq ~
Characteristics Test
(HF10 Therapy)
Control
(Traditional SCS) P-value
Gender ‒ n (%)
Female 57 (62.0%) 51 (58.6%) 0.760
Male 35 (38.0%) 36 (41.4%)
Age (years) at Enrollment
Mean ± SD 54.6 ± 12.4 55.2 ± 13.4 0.717
Range 32.8 to 82.2 19.2 to 82.3
Years Since Diagnosis
Mean ± SD 13.0 ± 10.4 14.2 ± 12.2 0.659
Range 1.0 to 52.0 1.0 to 62.0
Previous Back Surgery ‒ n (%) 80 (87.0%) 75 (86.2%) 1.000
Baseline Use of Opioids ‒ n (%) 83 (90.2%) 75 (86.2%) 0.488
SENZA-RCT Subject
Characteristics
34
Back Pain
Superiority p-value: <0.001 (post-hoc analysis) at all endpoints
SENZA-RCT Responder Rates
Test (HF10) Control (Traditional SCS)
Month
0%
20%
60%
80%
Bac
k P
ain
Re
spo
nd
er
Rat
e 100%
40%
3 6 12
43.8%
51.9%
84.3%
76.4% 78.7%
51.3%
83.1% 80.9% 78.7%
Leg Pain
Month
Leg
Pai
n R
esp
on
der
Rat
e
0%
20%
60%
80%
100%
40%
3 6 12
55.0% 54.4% 51.3%
Analysis of permanent implant population
At 24 months, mean back pain VAS decreased 67% with HF10 therapy compared to a decrease of 41%
for traditional SCS therapy
Test (HF10 therapy) Control (Traditional SCS)
Back Pain at 24 Months
0
1
2
3
4
5
6
7
8
9
10
0 3 6 9 12 15 18 21 24
Bac
k P
ain
VA
S (c
m)
Assessment (mo)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 3 6 9 12 15 18 21 24
Bac
k P
ain
Re
lief
Assessment (mo)
4.5
2.4
41.1%
66.9%
P<0.001 P<0.001
Superior back pain relief by HF10 therapy
At 24mo: n=71 for control, n=85 for test
4.3
2.5
44.7%
66.4%
37
30μs Tai et al
2005
Food for Thought
Tai et al 2005
At longer PW: smaller
differences
in thresholds between
large and
small fibers
Other innovations
• Closed Loop SCS –
Evoked Compound
Action Potentials
(ECAPs) used to
adjust therapy based
on posture and lead
placement.
• Ev
• DRG Stimulation for CRPS (FDA
approved)
• Accurate Study (sponsor:
Spinal Modulation/St Jude
Medical)
• DRG Stimulation provides
better outcome (≥50% pain
relief) than SCS
WDR neurons are not the only class if
neuron in the DH
LT neurons responsive to light touch
NS neurons Respond ONLY to
mechanical and thermal stimulation
“MICROCIRCUIT”
WDR, LT and NS wired differently
May respond differently to SCS
After Peripheral injury:
Aberrant sprouting of myelinated fibers into laminae1
Unmasking excitatory connections onto superficial DH2
Sensitization of NS3
Prescott and Ratte, 2012
1. Woolf, 1992
2. Kohno, 2003
3. Kawamata 2005
Just a Thought, Where is the lead?
Assuming that SCS functions
What am I stimulating?
Synthesis of neuronal Glutamate and GABA is mediated by
glial cells
NEURON NEURON
GLIAL
CELL
Post-Synaptic
Glutamatergic Post-
Synaptic
GABA-ergic
Glutamine Glutamine
Glutamine
Glutamate
ATP + NH4+
Glutamine
synthetase
GABA
GABA
GABA + CO2
Glutamine Glutamine
Glutamate + NH4+
Glutamate + NH4+
Glutaminase Glutaminase
Glutamate
decarboxylase
Glutamate Succinate
semialdehyde
Krebs Cycle
Mitochondria
Mitochondria Mitochondria
Reproduced from Palmada and Centelles, 1998, Front. Biosci.
OX-42
GFAP MCP1
SNI
6 hours
90% MT
Sato, et al A&A 2014
Tawfik VL, Neurosurgery, 2010
47
Genomics of the SCS on SNI
Gene Name Regulation level Role
Calcium Binding Protein (cabp1)
1.45-fold Regulates calcium-dependent activity of inositol 1,4,5-triphosphate (ITP) receptors. This receptors are involved in the signaling between astrocytes via calcium waves, which play a key role in the intercellular communication that propagates astrocyte activation.
Toll-like receptor 2 (tlr2)
2.41-fold Expressed by activated glial cells. Associated to cascades that may lead to the secretion of anti-inflammatory cytokines, such as IL-10.
Chemokine cxcl16 (cxcl16)
2.18-fold Drives the interplay between glial cells and neurons as a result of stimulus. Expressed by glial cells as a neuroprotective agent.
Related to Glial Activation Processes
49 r value>7
Thank You