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



• Effect of high frequency: • Multiple pulses delivered

at high frequencies can activate neurons using less mA


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



• Effect of high frequency: • Multiple pulses delivered

at high frequencies can activate neurons using less mA


enough’ are accumulated by the neural membrane, ultimately depolarizing the neuron to create an AP

Reilly et al 1985



1 ‘pulse’: 0.98mA



• 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%

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

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

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