Christopher J. Connor, DO Pain Medicine Fellow

Spinal Cord Stimulation: A Review of the Basics and Utilization in Failed Back Surgery Syndrome
Christopher J. Connor, DO Pain Medicine Fellow Dartmouth-Hitchcock Medical Center

Disclosures Specific manufacturers and devices will be briefly reviewed I have no relevant financial relationships with any of the products mentioned throughout

Overview History of Electricity and Pain Neuropathic Pain Cascade
Modulating effects of SCS Basic SCS Technology Review Role of SCS in FBSS Therapeutic efficacy Cost effectiveness New Technology Review

Spinal Cord Stimulation
The application of electrical stimulation to the dorsal columns of the spinal cord for the purpose of modulating or modifying the perception of neuropathic pain Falls under the umbrella term of Neuromodulation Gildenberg, PL

A Practical Treatise on the
Electricity and Pain 1965 Gate-Control Theory 1919 First stimulator designed for therapeutic use: Electreat by Charles Wille Kent Black Torpedo Fish (ancient Greek and romans). - A Transcutaneous Electrical Stimulation - the patient would endure electrical discharges from the fish until the pain was relieved - Scribonius Largus (Roman Physician) & Claudius Galen described shocks to tx: gout and headaches Described stimulating muscles and nerves with a direct current inductorium device - similar devices used by Ben Franklin for pain relief as well as other ailments - interestingly Rockwell is credited for creating the electric chair Electreat – 1st high powered TENS unit. Ran on 2 D-cell batteries and a mechanical inductorium Kent was first individual to be prosecuted under 1938 Food, Drug and Cosmetic Act for making unsubstantiated medical claims for the Electreat  thereafter only allowed to claim treatment for pain relief Shealy – Harvard trained neurosurgeon. Performed operation at Case Western Reserve University - was an external Battery device - **with the help of Thomas Mortimer, a graduate engineer student who designed the implantable electrode AND asked Medtronic engineer, Norm Hagfors to use a cardiac stimulator for the power source 46 CE Ancient Greeks & Romans 1967 C. Norman Shealy implanted the first intrathecal SCS for Cancer pain 1871 Beard and Rockwell A Practical Treatise on the Medical and Surgical Uses of Electricity

First rechargeable IPG,
Electricity and Pain 1977 FDA Approval 1968 First commercially Available SCS system 2004 First rechargeable IPG, Boston Scientific/ Advanced Bionics Medtronic – Mortimer and Shealy collaborated with Medtronic to expand upon their Cardiac stimulators (carotid sinus stim for HTN, carotid sinus stim for angina) - Used Radiofrequency coupled with dorsal-column stimulators (antennas) - NO IPGs yet Advances in cardiac pacemaker technology led to Implantable Pulse Generators (IPG) and dual multipolar leads in mid- 1980s. Boston Scientific – merged with advanced bionics who using cochlear implant technology created first rechargeable IPG - with this came smaller IPG size Once IPGs and Multipolar leads were created – this allowed for growth and more reliably effective systems 2015 Nevro releases high frequency, paresthesia-free stimulation 1981 First implantable pulse generator

Gate Control Theory Melzack and Wall, 1965
Substantia Gelatinosa in the the dorsal horn of spinal cord acts as a Gate Control System that modulates afferent impulses from periphery to central receptors Small myelinated and unmyelinated fibers maintain a tonically active state (subconscious levels)  holds the gate in open position External stimulus activates large myelinated fibers will “close the gate” on small fiber input System will adapt if frequency or intensity remains constant Central Control Trigger- central influences are mediated through the gate control system Perception of pain is a result of balance between peripheral and central input ___________________________________ Ronald Melzack ( ) – Canadian Psychologist, Founding member of International Association for the Study of Pain (IASP). Professor at McGill University Patrick David Wall – ( ) – British neuroscientist, Was the Scientific study officer for IASP and the first editor of its journal: PAIN. Professor at MIT When they proposed this Theory of Pain: there were 2 opposing theories most used: - Specificity Theory: pain is a specific modality such as hearing/vision with its own central and peripheral apparatus - Pattern Theory: nerve impulse pattern for pain is produced via intense stimulation of nonspecific receptors Central Control – how emotions/memories/past experiences can also affect perception of pain Melzack and Wall also described how they believed the interpretation of signals as pain occurred in multiple regions of the brain and cannot be localized to one structure

Peripheral Nerve Spontaneous firing through upregulation of Ca and Na influx and Decreased K influx Collateral sprouting with cross talk between low (Abeta, Adelta) and high (Adelta, C) afferents Dorsal Root Ganglion Altered gene transcription-> Channel Expression (Inc Na+/Ca+) (Dec K+) and activation of glial cells causing spontaneous excitation DRG lies outside of BBB similar BV innervation Post-Ganglionic Sympathetic sprouting on DRG which causes activation when stimulated Dorsal Horn Excitation  through Ca influx leading to phosypholyation of membrane protein channels and eventual gene transcription Fiber Convergence of A-Beta and A-delta/C fibers at Lamina V (Wide Dynamic Range) Loss of Inhibition  change in Cl- channel expression leading to reversal of ion flow and subsequent activation with AB stimulation Activation of astrocytes and microglia cells Supraspinal - Excitation of laminae I activates Bulbospinal pathway which release Serotonin that projects to Laminae V, 2nd order neurons causing excitation  binding to 5HT3 rec (which have been shown to be pro-nociceptive)

Supraspinal Pain Pathways
De Ridder & Vanneste, Neuromodulation. 2016 Network of 2 ascending and 1 descending pathway Lateral Pathway encodes discriminatory/sensory component to pain - Activated by C, Adelta, Abeta VPL of thalamus SS cortex and parietal area Medial Pathways encodes the motivational/affective component of pain - Activated by C-Fibers mediodorsal and VPL Thalamus anterior cingulate and anterior insula Descending Pathway: involves rostral and pregenual anterior cingulate cortex and connects to PAG  somatosensory periphery The exact anatomical and functional connections in pain not completely understood but fMRI shows a complex interaction b/w SS cortex, cingulate cortex, insula, amygdala, thalamus and frontal cortex

Neuromodulation of Pain
Peripheral Nerve Spinal Cord Supraspinal Pathways - Depolarization & hyperpolarization of large diameter fibers -Electrical effect at Lam I,II,V - Activation of GABA/Glycine & other inhibitory substances at Lam V - Decreases extracellular Glutamate - Antidromic Stimulation has been shown to decrease neuroma firing - Dampens DRG sensitivity Activation of lateral & medial ascending pathways - Activation of descending Bulbospinal pathways - Inc NE/5HT *** We now know the therapeutic effects of SCS are far beyond activation of AB fibers blocking Adelta/C fiber signals. It now works through a combination of neurophysiologic changes at spinal and supraspinal levels **neuropathic pain in RAT model ** De Ridder, D. and Vanneste, S. Neuromodulation 2016 – showed activation of different ascending supraspinal pathways in burst vs. tonic stim (burst = more medial pathways) via EEG (5 pts) Suppress enhanced response to peripheral responses at WDN through release of GABA and decrease in Extracellular Glutamate (via- GABA B rec activation) Acetylcholine release in DH with activation of M4 rec Increase release of Adenosine, binding to A1 rec Bulbospinal pathway (NOT SHOWN HERE) Activation of some of the 5HT (2a, 3?, 4) receptors appears to assist in NP relief. NE more effective with inhibitory effect on DH ***AT peripheral level through antidromic activation has been shown to decrease neuroma discharge Activation of anterior pretectal nucleus (junction of midbrain and forebrain = diencephalon. pretectum is located directly anterior to the superior colliculus and posterior to the thalamus. It is situated above the periaqueductal grey and nucleus of the posterior commissure.[) which has descending pain inhibitory influences on lower segments **in both animal and human models- epidural injections of Baclofen and Oxotremorine (muscarinic agonist) have been shown to enhance the pain relieving effects of SCS ** NO relation exists with SCS and endogenous opioid pain relieving mechanism B/C effects not blocked or reversed with Naloxone

SCS Indications Failed Back Surgery Syndrome CRPS Radiculopathy
FDA Approved Non-FDA Approved Failed Back Surgery Syndrome Cervical and Lumbar CRPS Radiculopathy Plexopathy Arachnoiditis Epidural fibrosis Painful peripheral neuropathy Peripheral vascular disease* Refractory angina* Phantom limb pain Post herpetic neuralgia Post-thoracotomy pain Intercostal neuralgia Other visceral pain syndromes Indicated for Neuropathic pain syndromes **Chronic and severe pain

Selection Process Does the patient have a specific diagnosis with objective evidence of painful disorder? Pre-procedure psychological evaluation as part of multidisciplinary treatment program 3. Have all reasonable alternative therapies been exhausted? 4. **Is majority of pain more appendicular vs. axial _______________________________________________ Longer mean duration of pain is associated with reduction in SCS pain relief (2% decrease in effectiveness/12mo of pre-existing pain) Taylor, et al Psychological Evaluation (Beltrutti et al): 1. Identify presence of psychological and/or social characteristics that could limit benefit 2. Identify those in whom treatment would result in uncertainty, failure or medico-legal consequences Such as anxiety, depression, poor coping skills, Somatoform d/o (somatization, conversion, hypochondriasis), factitious d/o, Personality d/o, PTSD, drug/etoh abuse, unreasonable expectations **** Research has not been able to prognosticate differences among personality profiles that might suggest predisposition to chronic pain or poor outcome Taylor et al – multivariate analysis of literature search of SCS in low back and leg pain

Trial Phase Percutaneous placement of 1-2 cylindrical leads with external power source 5-7 days in duration Success measured by at least 50% improvement in pain With functional improvement

Implant Phase Either use cylindrical or paddle lead
Leads anchors to thoracolumbar fascia Tunneled to IPG pocket IPG usually placed in subcutaneous tissue of low back (R or L) above the belt line

Basic Technologic Considerations
Principles of SCS Lead Placement Paddle vs. Cylindrical Stimulation Modes Constant Voltage vs. Current Difficulty with Low Back Coverage The Companies

Principles of SCS Cathode (-): produces a positively charged neuron inducing a Action Potential Anode (+): hyperpolarizes a neuron shielding structures from stimulation Variables: Bipolar SCS: + - Tripolar SCS: Contact spacing Number of leads/rows Anatomic vs. Physiologic Midline Ideal contact spacing based on computer modes Ideal contact spacing: 6-8mm Figure B highlights the difference with wide spaced leads: Anode loses effect = less depth of penetration, more circular field of stimulation = unpleasant stimulation With 3 wide lead system= can have transverse tripolar stim Studies have shown single lead is most effective for back coverage due to direct penetration of stim into DC (North 2005 – no difference b/w single vs. 2 lead for LBP) With multiple leads some of the stimulation instead of traveling deep with move transversely = cross talk b/w leads… HOWEVER, Multiple leads offer other advantages, which include: increased programmability (incase of lead migration), with newer configurations/IPG programs can get fractionalization of current at each electrode = current steering, and tripole configurations with narrower spacing allows for more direct/deeper penetration. ** in 40% of patients the spinal cord is not in anatomic midline BUT physiologic midline = 1-2mm left or right of midline

Principles of SCS Ohm’s Law: I= V/R Holsheimer & Buitenweg
Ohm’s Law = current is proportional to voltage and inversely proportional to resistance *I-V/R, resistance is a constant Gray matter = dorsal horn Impedance increases with: Epidural fibrosis that occurs unevenly around leads (26% inc in scar formation by 3mo post implant) Epidural space: C mm vs. upper thoracic 3-4mm vs. L2: 5-6mm Males seem to have 21% higher impedance (? Due to increased epidural fat layer?) Holsheimer & Buitenweg

Lead Placement Must take into account: 1. Dorsal Column Anatomy
2. Focus of Stimulation Moving cephalad along Dorsal Columns, lamina progressively move more medial This guides lead placement LE coverage: T10 Back coverage: T8 Note: Talk about anatomy of dorsal columns Cuneate Fascicle and Gracile Fascicle C T8-S5 Similar anatomic arrangement but no spatial or functional overlap CV may include larger fiber size of up to 15micrometers ***most of models based on cat anatomy??? Transvers section of SC at T11: Current stim via CATHODE will target more medial lamina but if wanting to target more lateral locations (ie: low back) often need to turn stimulus higher approaching discomfort threshold…. - to increase likelihood of capturing more lateral lamina and avoiding Vdt = move rostral by 2-3 vertebral levels thereby shifting target lamina more medial Large diameter fibers (A-beta) and dorsal root sensory nerves have LOW Threshold for stim == preferentially activated Leg coverage – Cathode within T9-T12, b/c DR fibers of LE (L3-S1) enter SC more caudally than L2 and laminae will be situated more medially Note: S5 laminae are located medially at T11 vertebral segment BUT a study by D.D. Law showed recruitment of dermatomes may not be in sequential order?? Placed near physiologic midline, closely spaced longitudinal contacts

Cylindrical vs. Paddle Lead
Circumferential current Farther from Dorsal Column less with 2 leads Placed percutaneously Paddle Ventrally directed current *Consumes 54-60% less energy Requires Laminotomy Paddle – needs less current flow to produce paresthesia due to being closer to dorsal column (size of paddle dictates this) **DC fibers have same diameter ? ~ 12micrometer * Energy consumption now is not a big factor because of rechargeable batteries Recruitment of DC fibers start closest to cathode and extends with increasing depth to maximum mm depth. CC- current configuration Vdt- discomfort threshold Vpt – perception threshold Advantage of 2 perc leads vs. 1 = decreased dorsal distance/thickness of spinal fluid and increased recruited DC are. DISADVANTAGE = reduction in discomfort threshold due to be more laterally placed/ near DR - Ideally should have 4mm distance between center of contacts with guarded cathode on same lead ** NORTH study found that one lead better than 2????????? - reason being- get more transverse current spread and less deep spread into DC? (Holsheimer & Buitenweg)

Rates of lead migration and stimulation loss in spinal cord Stimulation: a retrospective comparison of laminotomy versus percutaneous implantation David D Kim, Rakesh Bakharyia, Henry R. Kroli, Adam Shuster Neuromodulation, 2013 – Analyzed 13,774 patients b/w Complication Rate: overall 2.8% ; Paddles 1.5x as likely to develop post operative complication at 90d postop All cause Reoperation Rates: 16.2% vs. 9.0 % (Perc/Paddle) Cumulative 5 year overall cost (Total Inpatient, Outpatient and Medication) was not statistically significant different (Paddle: $169,768, Percutaneous $186,139) 2. Pain Physician 2011 – 1 institution (paddle lead via 1 NS, perc via 1 pain doc) Loss of capture 23% vs. 24% (perc/paddle) Radiologic evidence of migration 13.63% and 12.67% (Perc/Paddle) with no difference in length of time until loss of coverage/migration 3. Neuromodulation (2014) Retrospective Chart Review of 143 percutaneous implants 3 clinically significant lead migrations (all caudal) – 2.1% surgical revision rate for lead migration VS. pre-2008 data: 13-22% lead migration ***This study does not detect all Lead Migration vs. Clinically significant migration Note: Normal fibrous reaction around the lead can make revision surgery and lead replacement difficult

Stimulation Modes Conventional (low frequency, tonic) Burst
Amp 2-6mA, Pulse Width microsec, Hz Constant current or voltage Paresthesia mapping required Burst 40Hz burst mode with packets of 5 spikes at 500Hz, with 1ms Pulse Width Constant current No paresthesia mapping High Frequency 10kHz, Amp 1-5mA, narrow pulse width (30 microsec) Constant current, tonic Conventional stim = patient feels parenthesis and the goal with placement is to have paresthesias overlap pain *** Downside of traditional stim = paresthesia, postural changes (due to slight movement of spinal cord and/or lead(s), and thickness of spinal fluid), inability to conduct placebo controlled trials **pulse width helps to preferentially select higher threshold afferents - narrow PW = large fiber stim - wider PW (requires lower amplitude) = recruits large and SMALL fibers essential for modulating dendrites or cell bodies - can help capture additional areas of pain (ie: back) Hertz = once cycle/sec

Constant Voltage vs. Current Stimulation
V = I x R - I affected by R I = V / R - I independent of R Washburn, et al. 6d SCS trial Crossover at D3 No significant difference in pain scores 70% of patients preferred CC CV – current applied by CV depends on impedance that may change over time CC – adjusts output voltage to provide CC irrespective of impedance (in response to impedance) Voltage = is the difference in electric potential energy between two points per unit electric charge Current = amps Resistance = ohms Washburn – single blinded cross over of CC and CV (15 pt started with CC and 15pt with CV then crossed over at D3) Possible Advantages to CC Research has shown different pulse shapes can selectively activate nerves of different diameters Spike shaped (CV) – small Adelta and Cfiber activation NOT A-Beta fibers in Dorsal Column 2. In rat models – CC seems to decrease visceral pain greater than CV 3. Changes in epidural space impedances with time will affect stim - In CV stim = need to increase amplitude to overcome Impedance  which may be uncomfortable and as Current decreases so does efficacy

Difficulties with Low Back Coverage
Laterally located lamina within Fasciculus Gracilis CSF has very low resistivity Compton, et al ~90% current dispersed ~10% reaches dorsal columns 3mm CSF Thickness at T12 level 6mm CSF Thickness at T6 level Spatial distribution of fiber diameters in ea. Laminae Perception threshold inversely related to fiber diameter Holsheimer & Buitenweg 0.5mm increase is SF distance q each level from L1 to T5-6 **this is why we try to capture low back at T8-9-ish Spatial distribution: As afferent fibers enter DREZ and travel up DC  branch into smaller fibers as travel rostrally. (ie: at low thoracic segments = smaller fiber size representing more distal limb vs. low back = larger fiber size)  perception threshold better for smaller fibers Occurs similarly at cervical enlargement area

The Companies 32 contact lead(s) Numerous programming options
Current based stim Whole body Perc-lead MRI compatible Adaptive stim for position changes Whole body 1.5T MRI compatible First SCS Company High frequency stim No stimulation felt by patient Head and Extremity 1.5 & 3T MRI 5 column paddle lead Burst & DRG stim Boston Scientific - formally known as Advanced Bionics, first to have 16contact lead in 2004 *** Perc lead full body MRI -2016 Medtronic- first, commercialized a SCS system in 1972 Nevro – newest, recently gained FDA approval, High Frequency St. Jude Medical – formally known as Advanced Neuromodulation Systems, First to have 8 contact lead in 1986, Recently acquired Spinal Modulation Company (DRG stim) ** Perc and paddle lead full body MRI -2016 St. Jude – Penta Paddle Lead – is 9mm wide (cord at T9 is 4.5 mm wide

SCS in Failed Back Surgery Syndrome
SCS vs. Reoperation SCS vs. CMM Cost Effectiveness Newer Technology Future Studies

Failed Back Surgery Syndrome
Patients with previous lumbosacral spine surgery who have failed to obtain lasting relief despite receiving a variety of therapies, including repeated operations, oral medications, nerve blocks, corticosteroid injections, physical therapy and chiropractic care. North et al. FBSS is characterized by disabling neuropathic radicular leg pain with or without low back pain, which might have mixed neuropathic and nociceptive pain components. FBSS is defined as persistent or recurrent low back and leg pain of at least 6mo duration, following at least one decompression and/or fusion procedure. 10-40% of patients who undergo lumbosacral spine surgery to alleviate pain culminates in recurrent or persistent pain - Quoted in Neurosurgery and Pain journals

% of patients with at least 50% relief (mean):
6mo: 59%, 2yr: 52%, 5yr: 47% ***83% continued using SCS at 5years Pre-SCS: 74% of patients used opioid vs. 12% post Trend toward improved ADLs Both studies published in same Neurosurgery Journal volume in 1991, both by RB North Study 1: surveys of 50 consecutive patients who underwent SCS by Dr. North (avg duration of s/s 3-20yr, 54% M, 2-4 surgeries Primary Outcome: at least 50% pain relief, pt satisfaction with treatment Secondary Outcomes: ADLs and Pain meds Study 2: Retrospective review: for radicular pain Primary Outcome- 50% relief, satisfaction with procedure No real change in ADLs **study found that women >men, radicular >axial and those who had good response to prior surgery for 1-2 years seemed to have better repeat surgical outcomes % of patients with at least 50% relief (mean): 6mo: 47%, 2yr: 38%, 5yr: 36% 37% of patients discontinued opioids, 23% decreased their dose

Opioid usage increased in 42% of surgery vs. 13% of SCS
North, et al. Neurosurgery, 2005 Primary 12mo: 52% success w/ SCS 19% success w/ Surgery Crossover: 43% success w/ SCS 0 success w/ Surgery Secondary Outcomes: Opioid usage increased in 42% of surgery vs. 13% of SCS 2005 study in Neurosurgery 30 pt in ea group (avg. 3 yr post initial surgery)  17/24 implanted, 5 crossed over.  26 reoperation with 14 crossing over after SCS: 15 successes/14 failures and Surgery 3 success/13 failures at long term Crossover allowed within 6mo if patient not satisfied with treatment Primary Outcome of Success defined as: at least 50% improvement in pain and patient satisfaction Secondary Outcomes: ADLS, Medication usage **No workers compensation patients due to some denials of coverage Patients enrolled within 1st 2 years of study only had paddle implants; however perc implants allowed thereafter?? NOTE: This is part of PROCESS Trial  24mo f/u published in Neurosurgery in 2008: The effects of spinal cord stimulation in neuropathic pain are sustained: A 24-month follow up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation. Kumbar, Taylor, Jacques, et al.

Secondary Outcome @ 6mo: Sig. change in ODI, SF36 for SCS
PAIN, 2007 Randomized 100 pts with FBSS into Conservative vs. SCS tx. Primary 6mo: 48% vs. 9% achieved 50% relief Secondary 6mo: Sig. change in ODI, SF36 for SCS Trend for dec. opioids in SCS No difference in return to work **this and study before are the only 2 RCT for SCS in FBSS. Many observation, retrospective and case reports in literature. ??? Focus on leg >back pain ***only stat. sig dif. b/w groups  Higher back pain scores in CMM group - both groups: ~45% with >1 surgery, time since last surgery 4.5 years Results: 6mo period b/c b/w 6-12mo there is cross over **At 6mo- intention to treat analysis CMM: 6mo (28 crossed over) 12mo SCS: 6mo (5 crossed over) 12mo ODI (assess functional capacity) and SF 36 (assess QoL) in all categories for SCS group Charts: percent of pt with >50% leg pain relief / ODI **at 12mo = 32% device related complications 13% Hardware related issues: 10% lead migration, 2% lead fracture, 1% IPG migration 19% Biologic issues: 8% infection/wound breakdown (higher than 3.4% previously reported – Cameron, 2004 thought due to including trial + implant infections vs. implant only?), 6% pain at IPG/incision site, 5% Fluid at pocket site **limitations = high cross over  increases risk of expectation bias, cannot blind patients = don’t specifically discuss what CMM was

SCS Cost Effectiveness in FBSS
North, RB., et al performed a Randomized, Controlled Cross-Over study comparing Cost Effectiveness of SCS vs. Reoperation for FBSS with 3 year f/u $31k for SCS vs. $38k (not stat. sig) 48k for SCS vs. 106k Reoperation in patients who achieved long term success (3 yr) $117k for SCS crossover vs. $260k Reop. Crossover 62% crossed over to SCS vs. 26% to reoperation Journal of Neurosurgery, 2007. 19 scs pt, 5 failure and crossovers 21 reop pt with 13 failure and crossovers ***small N ** cost was reported in US dollars **intention to treat analysis and as treated analysis performed. Numbers above = intention to treat Primary outcomes: No cross over to reoperation had successful outcome * Cross over occurred at 6mo Secondary outcomes: 50% pain relief and patient satisfaction: ~ 50% SCS vs. 15% Reop. ** looked at hospitalization costs/labs, admissions, etc as well as professional fees. ** used SPINE guidelines for evaluated cost effectiveness and cost utility analysis ** study likely underpowered but seems to echo other studies results

SCS Cost Effectiveness in FBSS
Bell et al (1997) compared 5-yr cost of SCS to medical management in FBSS $50k (SCS) vs. $76k (CMM) with break even point for SCS at 3.5 years Kumar et al (2004) examined SCS vs. non-interventional care for FBSS over 5-yr period $29k/SCS vs. $38k/CMM (Canadian dollars) at 5yr with break even point for SCS at 2.5 years Blond et al (2004, French Study) reported a SCS reduced the cost of pain treatment by 64% #3: 43 patients in 9 hospitals over 2 years

SCS Cost Effectiveness in Workers Compensation Population with FBSS
Hollingworth, et al (2011) compared SCS vs. Pain clinic vs. Usual care in Worker’s compensation FBSS patients At 2 yr follow up SCS was NOT cost-effective $20-30k more compared to treatment groups Limitations: SCS group had longer duration of pain, out of work longer and 2x as likely to have legal representation #1: SPINE, observational study **SCS group had longer duration of pain ~12mo, out of work longer ~9-14mo and legal representation 2x as likely **Also, study only 2 years BUT pain score improvements not as high as what has been reproduced in many studies leading me to think patient selection may have biased the results

- 16,060 undergoing reoperation (97.6%)
SPINE, 2014 Retrospective analysis of Medicare database b/w for patients who underwent reoperation vs. SCS implant and associated costs patient met inclusion - 16,060 undergoing reoperation (97.6%) - 395 undergoing SCS implantation (2.4%) - Had stat. sig. higher Medicaid population and stat. sig higher co-morbidities vs. reoperation group Results: - No statistically sig. difference in overall cost at 1 or 2 years - SCS group had higher ED and medication costs - Stat. sig. increase in wound complications in Surgery vs. SCS **no outcomes measured ** overall cost = hospitalization, ED (higher in SCS population and is where more cost came from for this group), medications (no difference), etc **20 deaths in surgical group, 0 in SCS but not stat. sig **SCS group had stat. sig more co-morbidities Based on Charlson Comorbidity Index scale **only 2 year f/u  break even point for SCS b/w years  also more females, Medicaid and sicker individuals in SCS group

Newer Technology Burst Stimulation Dorsal Root Ganglion Stimulation
High Frequency Stimulation Exact mechanisms not entirely known with Burst and High Frequency Speculation that: Burst – has an affect on medial thalamic pathways (projections to)  dorsal anterior cingulate and right dorsolateral prefrontal cortex EEG data seems to show burst stim affecting “medial pain pathways”/ dorsal anterior cingulate and right dorsolateral prefrontal cortex more than tonic stim unlike tonic stim and may be reason get improved pain response? BASED ON Deep Brain Stimulation while using Burst stim High Frequency – induces a frequency-dependent conduction block of voltage-driven ion channels

Burst Stimulation Schu, S. et al. Neuromodulation 2014
Intermittent packets of closely spaced High-frequency stimuli: 40Hz burst mode with 5 spikes at 500Hz per burst, PW 1ms and 1ms interspike interval delivered with constant current and amplitude at 90% subthreshold level. Place at T8-9 anatomic midline 500-Hz spike mode was based on maximal post synaptic inhibition obtained by 500hz burst firing in basic neuroscientific studies Small study in Neuromodulation, 2015: did not show a different between 2 week trial of 500hz vs. 1000hz burst stim in VAS scores or SF36 (measures overall health related QOL experienced by the patient). Schu, S. et al. Neuromodulation 2014

Mean Change in Pain Scores* Mean Change in ODI
Neuromodulation 2014 Mean Change in Pain Scores* Mean Change in ODI Neuromodulation 2014 20 pts who had been stable on St. Jude Traditional Stim for Failed back with Leg>back symptoms (avg years) Randomized and blinded to 3- 1 wk long stim periods with no washout time 500hz tonic, 500hz burst, placebo Outcome: NRS= stat. sig ODI = trend but no stat. sig difference Limitations: Short trial No washout Small # of patients 80% of patients preferred bust stimulation setting

De Ridder, D. et al, Clin J Pain 2015
Retrospective analysis of patients who used tonic stim for at least 6mo and then underwent 2 wk Burst Stim trial 2 Centers, total of 92 pt with FBSS/DPN Results: Flawed study: Very limited in data that is reported  don’t actually give pain scores, don’t show population data, etc I would argue the results were NOT Reproducible as Belgium site had much more robust response ***Other Trials: Clin J. Pain 2015, retrospective chart review of 102 patients showed that patients who lost their response to tonic stim had statistically significant response to switching to burst for both back and leg pain/ On avg pain improved from 50.6% to 73.6% (tonic to burst) 2014 Neuromodulation article showed that pt with DPN and FBSS who had tonic stim for at least 6mo had statistically sig improvements in pain with 2 week Burst stim trial (an extra 44% (DPN) and 28% (FBSS) pain relief ** Does appear there is a subset of poorly responding tonic stim patients who may benefit from Burst. ** Patients who respond to tonic stim seem to have even a more robust response to Burst

DRG Stimulation Liem, L. et al Deer, T. et al
DRG has been implicated in a host of electrophysiological and gene expression changes that may contribute to chronic pain. Proposed Benefit to DRG Stim Allow us to capture distal foot pain more easily compared to Dorsal Column stimulation: More specific site of neuromodulation Less migration Decreased distance from lead to DRG with less CSF between thus requiring less energy  possible longer battery life? Narrow bipole or tripole configurations = DC Wide bipole or monopole favors DR Covers a max spinal length of 10-20mm with parenthesis in 2 adjacent dermatomes at most Holsheimer and Buitenweg With DC stim – ideal dSF layer is 2-2.5mm thick DR fiber are excited at transition from well conducting spinal fluid to the gray matter in the DH having 7.4x higher resistivity Liem, L. et al Deer, T. et al

Other Observations: Coverage of discrete areas (foot)
Neuromodulation 2013 Patient population: 36patients: CRPS and FBSS most common Device specifics: Quadripolar, Constant Voltage: (avg settings) PW 362msec, Amp 907microvolt, Freq 46hz Limitations: Small N No control, Cant blind due to paresthesias 6mo only This study used “as treated analysis”  can overemphasize results… Constant voltage – long term? Other Observations: Coverage of discrete areas (foot) 3% lead migration No change in paresthesia intensity with positional changes At least 50% pain reduction in back (57%), leg (70%) and foot (89%)

High Frequency Russo and Van Buyten

60% of patients experienced at least 50% relief in back pain
Pain Medicine European study looking at efficacy of HF10 therapy in FBSS (n57), previously failed SCS (n11) and no back surgery (n15) At 24mo 60% of patients reported at least 50% relief in back pain At 24mo 71% of patients reported at least 50% relief in leg pain Mean ODI decrease of 15pts Mead subjective sleep disturbances/night decreased from 3.7 to 1.4 BIG DIFFERENCES B/W THIS AND PROCESS TRIAL: Difficult to treat primary back pain excluded in process Process had 40 of 42 pts with at least 50% leg pain relief at 24mo Note: Perruchoud, C. et al. Neuromodulation 2013 performed Randomized, DBPCT study looking at efficacy of 5kHz vs. sham in 33 pts  not difference - 2 wk blocks of conventional/HF/Sham in predetermined 4 blocks= 8 weeks (conventional stim occurred twice) - Medtronic device Results: 60% of patients experienced at least 50% relief in back pain 71% of patients reported at least 50% relief in leg pain Mean ODI decrease of 15pts Mean dosage of oral morphine equivalents decrease by 57mg 88% would recommend or highly recommend it to others

86.6% had previous back surgery 88.3% taking opioids
198 patients randomized 13.6yr since diagnosis 86.6% had previous back surgery 88.3% taking opioids Anesthesiology, 2015 Mean Back / Leg Pain VAS Decrease: HF10 = 67% / 70% Boston Scientific = 44% / 49% Avg. 12mo morphine equivalent dosage decrease HF10 = 18.8% Boston Scientific = 1% 55.4% vs. 32.3% satisfaction with HF10 vs. Boston Scientific ** lead migration rate resulting in revision = 3% (HF10) and 5.2% (BS) **2, 8 electrode perc leads implanted **US Study Note: Kinfe, T, et al. Neuromodulation 2015 – evaluated 16pt (8/8) with predominant LBP in FBSS with HF or Burst - NO DIFFERENCE B/W GROUPS, Both had similar improvements (8/102/10). 3 MONTHS

Future Studies PROMISE study
International multicenter randomized controlled study looking at SCS vs. optimal medical treatment for predominant LBP patients with FBSS Recruitment underway, initial results expected in 2017 Using Medtronic lead First study looking at axial lbp predominant Primary outcome – pain scores at 6mo, ODI, SF health survey **following for 2 years

Limitations Long-term efficacy data limited
No placebo-controlled trials Manufacturer sponsored research Due to technological advances, difficult to extrapolate outcome data from older studies (~ before 2008) No prospective head to head comparison of paddle vs. percutaneous electrodes Most studies look only to 2 years, very few go out to 5 or beyond With Burst and HF can now begin to have placebo controlled trials BUT still cant compare blindly to conventional stim Advancements in programming, leads/contacts and anchoring

Questions

References Kreis, PG. Rishman, SM. (2009). Spinal Cord Stimulation: Percutaneous Implantation Techniques. New York, NY: Oxford University Press, Inc. Kumar, K. Rizvi, S. (2014). Historical and Present State of Neuromodulation in Chronic Pain. Curr Pain Headache Rep. 18: Melzack, R. Wall, PD. (1965) Pain Mechanisms: A New Theory. Science. 150(3699): Benzon, HT. et al. (2014). Practical Management of Pain. 5th Edition. Philadelphia, PA: Elsevier-Mosby Taylor, RS. Et al (2014). Predictors of Pain Relief Following Spinal Cord Stimulation in Chronic Back and Leg Pain and Failed Back Surgery Syndrome: A Systematic Review and Meta-Regression Analysis. Pain Practice. 14(6): Washburn S., et al. (2014). Patient-Perceived Differences Between Constant Current and Constant Voltage Spinal Cord Stimulation Systems. Neuromodulation. 17:28-36 Holsheimer J., Buitenweg J.R. (2015) Review: Bioelectrical Mechanisms in Spinal Cord Stimulation. Neuromodulation. 18: Beltrutti, D. et al. (2004) The Psychological Assessment of Candidates for Spinal Cord Stimulation for Chronic Pain Management. Pain Practice. 4(3): Schu S. et al. (2014). A Prospective, Randomised, Double-blind, Placebo-controlled Study to Examine the Effectiveness of Burst Spinal Cord Stimulation Patterns for the Treatment of Failed Back Surgery Syndrome. Neuromodulation. 17: Liem L. et al. (2013). A Multicenter, Prospective Trial to Assess the Safety and Performance of the Spinal Modulation Dorsal Root Ganglion Neurostimulator System in the Treatment of Chronic Pain. Neuromodulation. 16: Markman, JD. Et al. (2015). Screening for Neuropathic Characteristics in Failed Back Surgery Syndromes: Challenges for Guided Treatment. Pain Medicine. 16:

References Babu R., et al. (2013) Outcomes of Percutaneous and paddle Lead Implantation for Spinal Cord Stimulation: A Comparative Analysis of Complications, Reoperation Rates, and Health-Care Costs. Neuromodulation. 16: Compton, AK., et al. (2012) Spinal Cord Stimulation: A Review. Curr Pain Headaches Rep. 16:35-42. Holsheimer, J. (2002). Which Neuronal Elements are Activated Directly by Spinal Cord Stimulation. Neuromodulation. 5(1):25-31. Kim, DD. Et al. (2011)Rates of lead migration and stimulation loss in spinal cord stimulation: a retrospective comparison of laminotomy versus percutaneous implantation. Pain Physician. 14: Linderoth, B. Meyerson, BA. (2010). Spinal Cord Stimulation: Exploration of the Physiological Basis of a Widely Used Therapy. Anesthesiology. 113: Song, Z. Meyerson, BA. Linderoth, B. (2011). Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy. PAIN. 152:

References Oakley, JC. Prager, JP. (2002). Spinal Cord Stimulation: Mechanism of Action. SPINE. 27(22): North, RB., et al. (2007). Spinal Cord Stimulation versus Reoperation for Failed Back Surgery Syndrome: A Cost Effectiveness and Cost Utility Analysis Based on a Randomized, Controlled Trial. Neurosurgery. 61(2): Hollingworth, W. et al. (2011). Cost and Cost-Effectiveness of Spinal Cord Stimulation (SCS) for Failed Back Surgery Syndrome: An Observational Study in a Workers’ Compensation Population. SPINE. 36(24): North, RB. Et al (2005). Spinal Cord Stimulation for Axial Low Back Pain. A Prospective, Controlled Trial Comparing Dual with Single Percutaneous Electrodes. SPINE. 30(12): North, RB. Et al. (2005). Spinal Cord Stimulation versus Repeated Lumbosacral Spine Surgery for Chronic Pain: A Randomized, Controlled Trial. Neurosurgery. 56(1): North, RB, et al. (1991). Failed Back Surgery Syndrome: 5-&ear Follow-Up in 102 Patients Undergoing Repeated Operation. Neurosurgery. 28(5): North, RB. Et al. (1991( Failed Back Surgery Syndrome: 5-Year Follow-Up after Spinal Cord Stimulator Implantation. Neurosurgery. 28(5): North, RB. Et al (2005). Spinal Cord Stimulation Electrode Design: A Prospective, Randomized, Controlled Trial Comparing Percutaneous with Laminectomy Electrodes: Part I: Technical Outcomes. Neurosurgery. 51(2): De Ridder, D. Vanneste, S. (2016). Burst and Tonic Spinal Cord Stimulation: Different and Common Brain Mechanisms. Neuromodulation. 19:47-59.

References North, RB. Et al (2005). Spinal Cord Stimulation Electrode Design: A Prospective, Randomized, Controlled Trial Comparing Percutaneous with Laminectomy Electrodes: Part II-Clinical Outcomes. Neurosurgery. 57(5): Lad, SP. Et al (2014). Utilization of Spinal Cord Stimulation in Patients with Failed Back Surgery Syndrome. SPINE. 39(12): Kumar, K. et al. (2007). Spinal cord stimulation versus conventional medical management for neuropathic pain: A multicentre randomised controlled trial in patients with failed back surgery syndrome. PAIN. 132: Rigoard, P. et al (2013). Spinal cord stimulation for predominant low back pain in failed back surgery syndrome: study protocol for an international mulitcenter randomized controlled trial (PROMISE study). Trials. 14: Kapural, L. et al (2015). Novel 10-kHz High-frequency Therapy (HF10 Therapy) Is Superior to Traditional Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain. The SENZA-RCT Randomized Controlled Trial. Anes. 123: Al-Kaisy, A. et al. (2014). Sustained Effectiveness of 10 kHz High-Frequency Spinal Cord Stimulation for Patients with Chronic, Low Back Pain: 24-Month Results of a Prospective Mulitcenter Study. Pain Medicine. 15: Russo, M. Van Buyten, J-P. (2014). Review Article: 10-kHz High-Frequency SCS Therapy: A Clinical Summary. Pain Medicine. 16: Van Havenbergh T. et al. (2015). Spinal Cord Stimulation for the Treatment of Chronic Back Pain Patients: 500-Hz vs Hz Burst Stimulation. Neuromodulation. 18:9-12. Gildenberg, PL. (2006). History of Electrical Neuromodulation for Chronic Pain. Pain Medicine. 7(S1): S7-13. Deer, T.R., et al. (2012) A Prospective Study of Dorsal Root Ganglion Stimulation for the Relief of Chronic Pain. Neuromodulation. 16:67-72.

Reliable Screening tools for Neuropathic Pain?
LANSS Questionnaire Validated in neuropathic pain syndromes such as DM (Score >12) DN4 Pain Scale Validated in low back pain patients (Score >4) 80% sen, 92% spec Markman, et al found these assessment tools less reliable in patients with persistent pain post lumbar spine surgery *But those >12 or >4 = Higher pain intensity and greater pain related functional impairments * No correlation with radicular vs. axial pain only HUGE LIMITATION in these Assessment tools = NO GOLD STANDARD WAY TO DX NEUROPATHIC LBP Leeds assessment of neuropathic symptoms and signs Douler Neuropathique en 4 Both questionnaires ask about classic “neuropathic” pain qualities and give points for YES DN4 also evaluates sensation to LT/PP Markman study is a clinical observational study **remember can have neuropathic axial pain How do we assess? – nociceptive pain should ease up with certain activity/positions vs. neuropathic it wont?

North et al showed paddle lead results in better pain relief (2005, observational study) ***12 pt in each group At mean 1.9 year f/u: stat. sig difference b/w Paddle (83%) vs. Perc (42%) At mean 2.9 year f/u: NO stat. sig difference b/w Paddle (42%) vs. Perc (25%) ** Caution with interpreting b/c outcomes seem poor compared to other trials.. ? 2/2 small number in trial? Perc lead diameter ~ 1.1mm ***other technical considerations: 4 lead only, 50 programming options, bipole only. 9mm inter-contact spacing (computer models have proven 6-8mm most efficacious). Constant voltage which may not be best in a post surgical spine due to epidural fibrosis *Technology A LOT Better NOW

polyurethane catheters
Platinum alloy contacts Rechargeable lithium ion battery Impedance increases with: Epidural fibrosis that occurs unevenly around leads (26% inc in scar formation by 3mo post implant) Epidural space: C mm vs. upper thoracic 3-4mm vs. L2: 5-6mm Males seem to have 21% higher impedance (? Due to increased epidural fat layer?)

Technology behind SCS

Christopher J. Connor, DO Pain Medicine Fellow

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