Neuromodulation for Failed Back Surgery Syndrome Part II

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Neuromodulation for Failed Back Surgery
SyndromePart II

• Richard K. Osenbach, M.D.
• Director of Neuroscience and Neurosurgery
• Cape Fear Valley Health System
• Fayetteville, NC

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INTRATHECAL DRUG DELIVERY
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Spinal Opiates for Benign Pain

• Controversial
• Mixed reviews and results
• Reporting of outcomes non-uniform
• No definitive end-point for therapy

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Rationale of IT Drug Infusion

• Provide high concentration of drug at the site of
  interaction with spinal receptors and minimize
  spread to other regions in the brain

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History of Opiate Analgesia

• 1901 - intrathecal injection of morphine
• 1915 - antagonist of morphine discovered
• 1951 - 1st human use of morphine antagonists
• 1976 - 1st use of IT morphine in animals
• 1980 - spinal morphine used for cancer pain

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Opioid Receptors and Ligands
Location of Opioid Receptors in the CNS Dorsal
horn Lamina I Substantia gelatinosa Brainstem N
ucleus caudalis Supraspinal PAG Thalamic
nuclei Striatum Hypothalamus Limbic
system Cortex
Opioid Receptor Endogenous Agonist Synthetic Agonists Antagonists
Mu (70) ß-Endorphin Endomorphins Morphine DAMGO Naloxone ß-FNA
Delta (20-30) Met-Enkephalin Leu-Enkephalin DPDPE SNC-80 DSTBULET Naltrindole Naloxone
Kappa (5-10) Dynorphine A Dynorphine B
hORL1 Nociceptin/OFQ None
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Mu Receptor

• Defined by affinity for morphine
• Less affinity for other receptor subtypes
• Most clinically important opioids selective for
  Mu receptor
• Cross react at higher doses
• ?1 - supraspinal ?2 spinal
• Most analgesic effects of systemic morphine
  mediated through ?1 effects
• 70 located pre-synaptically

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Opioid Recptor Physiology

• G-protein-coupled receptor family
• Synthesized in DRG
• Second messenger using cAMP
• Negative coupling
• Inhibit cAMP via Gi-protein
• ? And ? - opening of K channels
• ? - Closing of ca2

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Opioid Actions

• Analgesia
• Pruritis
• Urinary retention
• Autonomic Effects
• Cough suppression, orthostatic hypotension
• Nucleus tractus solitarius and ambiguous, locus
  ceruleus
• Respiratory depression
• Nucleus tractus solitarius, parabrachial nucleus
• Nausea/vomiting
• Area postrema
• Constipation
• Meiosis
• Superior colliculus, pretectal nuclei
• Endocrine effects
• Posterior pituitary inhibition of vasopressin
• Hormonal effects hypothalamic infundibulum
• Behavioral effects
• Amygdala, hippocampus, nucleus accumbuns, basal
  ganglia
• Motor rigidity

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Intraspinal MorphineConversion Ratios

• 300 mg oral morphine
• 100 mg parenteral morphine
• 10 mg epidural morphine
• 1 mg intrathecal morphine
• May not be accurate at high doses

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Patient Selection

• Inclusion Criteria
• Opioid-responsive pain
• Failure of long-acting oral opioids
• Exclusion Criteria
• Spinal pathology precluding catheter placement
• Allergy to opiates
• Difficulty coming for pump refills

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Catheter tip
Pump anchored with sutures or pouch
Dural puncture
Paramedian Oblique Entry
V-wing anchor
Loop of excess catheter under pump
5 cm of slack in catheter
Catheter connector which also functions as the
primary anchor
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Implantable Drug Pumps

• Programmable
• Constant flow

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Constant Flow Pump

• Drug delivered at constant, pre-programmed rate
• ADVANTAGES
• Unlimited life expectancy
• Less costly (?)
• DISADVANTAGES
• Less versatile than programmable pumps
• Dose changes require pump refill
• Flow rates influenced by physical parameters

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Constant Flow PumpFactors Affecting Drug Delivery

• Drug viscosity Q K x (P1-P2)
  u
• Reservoir capacity
• flow rate calibrated for 50 capacity4
  variability at extremes of volume
• Pump Dead Space
• 4ml dead volume
• correction factor for concentration

• Body temperature
• 10-13 increase in flow per 1ºC rise
• Geographical elevation
• flow increases at higher altitudes
• Blood pressure
• inversely proportional
• 3 change for every 10mmHg MAP

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Programmable Pumps

• ADVANTAGES
• Maximum flexibility
• Variable rates
• Program bolus doses
• Alter dose by telemetry
• DISADVANTAGES
• Finite life expectancy
• More expensive (?)

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General Guidelines for IT Drug Selection

• Consider these issues regarding administration of
  intrathecal drugs
• Drug stability
• Drug-drug compatibility for co-administration
• Drug-pump compatibility
• Effect of diluents on pump
• pH
• Choose appropriate concentration based on
• Desired dose
• Pump capabilities
• Refill interval (no less than 2-4 wks)

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General Guidelines (cont.)

• DOSING STRATEGY
• Dose escalation with inadequate analgesia
• Cautious dose reduction if adequate analgesia but
  intolerable side effects
• Addition of drug reduction of opioid dose with
  second analgesic
• EVALUATION OF THERAPEUTIC FAILURE
• Comprehensive patient reevaluation
• Assess pump and system integrity
• Interrogate and empty (refill assess volume)
• Dye study of catheter integrity
• Pathophysiology of the pain

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Trialing for IT Therapy
What do we know about screening?

• Multiple accepted methods
• No consensus as to the single best method

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Questions Regarding Trialing

• Screening method
• Duration of trial
• Drug and dose
• Use of placebo
• Systemic opioids
• Criteria for success

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Functional (Continuous) Trial

• ADVANTAGES
• Most accurately replicates permanent pump
• Allows for longer trials
• Controlled dose titration
• Assess starting dose for IT therapy
• Reduce risk of drug-related side effects
• Dissipates placebo effect over time
• Assessment of functional outcome
• DISADVANTGES
• Procedurally more complicated
• Requires greater expertise
• Higher morbidity
• More costly

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Epidural Vs. Intrathecal
CRITERIA EPIDURAL INTRATHECAL
Onset of Action Slower onset of analgesia Faster onset of analgesia
Systemic Effects Greater systemic effects Minimal systemic effects
Duration of Effect Shorter-lasting Longer-lasting
Dose Higher dose to achieve effect Lower dose required (1/10 epidural dose)
Adverse Effects/Risks Higher incidence of systemic side effects Risk of epidural abscess Post-LP headache Respiratory depression Meningitis
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Placebo Administration

• Rationale reduce the likelihood of a false
  positive trial
• Normal individuals may exhibit a placebo response
• Difficulty interpreting placebo response
• A positive placebo response should not
  necessarily mean no pump
• Functional trialing with dose titration
  dissipates the placebo response over time

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Oral Opioids During Trial

• No consensus on alteration of systemic opioids
  during the trial
• Maintaining the patient on a portion of their
  daily dose will lessen the likelihood of
  withdrawal
• Withdrawal from systemic opioids may result in
  reduction in opioid-induced hyperalgesia
• May produce a false positive result
• 50-75 reduction in systemic dose
• Liberal use of breakthrough medication
• Minimal use of breakthough medication can be
  taken as one objective measure of pain relief

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IT Bolus (ITB) Vs. Continuous Epidural Infusion
(CEI)

• 86 patient screened for inclusion
• 28 excluded from inclusion
• 58 patients approached
• 18 declined inclusion
• 40 patients randomized
• ITB (n18) or CEI (n19)
• 27 successful trial - pump implantation
• ITB, 67 (12/18) CEI, 79 (15/19)
• 3 patients lost to follow-up
• ITB (n10), CEI (n14

Anderson V, Burchiel K, Cooke B A Prospective
Randomized Trial of Intrathecal Injection vs.
Epidural Infusion in the Selection of Patients
for Continuous Intrathecal Opioid Therapy.
Neuromodulation, 2003
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IT Bolus Vs. CEI

• No significant difference in 6 month outcomes
  between ITB and CEI
• ITB 60 successful response
• CEI 64 successful response
• Drug-related complications more common in ITB
  group (88) vs. CEI group (70)
• CEI 2.5 times more costly (4,762 vs. 1,862)

CONCLUSION Differences in pain and functional
response to long-term IT opioids among patients
selected by either trial method are not large
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IT Bolus Vs. CEI
Anderson V, Burchiel K, Cooke B A Prospective
Randomized Trial of Intrathecal Injection vs.
Epidural Infusion in the Selection of Patients
for Continuous Intrathecal Opioid Therapy.
Neuromodulation, 2003
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Complications

• Bleeding problems
• Spinal epidural hematoma
• Pump pocket hematoma/seroma
• Infection
• most often occurs at pump pocket
• REMOVE the system
• Post-dural puncture headache
• CSF leak
• Drug-related side effects
• Catheter complications

• 20-25 incidence
• 20,000 implants annually
• 5,000 catheter revisions annually
• Estimated revision cost 10,000
• 50,000,000 yearly revision cost

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PA03 Update of Clinical Guidelines for the use of
Intraspinal Drug Infusion in Pain Management
Neuropathic Pain
Morphine
Hydromorphone
Line 1
Z i c o n o t i d e
Morphine (or Hydromorphone) Bupivacaine Morphine
(or Hydromorphone) Clonidine
Line 2
Morphine (or Hydromorphone) Bupivacaine
Clonidine
Line 3
Fentanyl, Sufentanil, Midazolam, Baclofen
Line 4
For Selected Patients Only
Neostigmine, Adenosine, Ketorolac
Line 5
Ropivacaine, Meperidine, Gabapentin,
Buprenorphine, Octreotide, other
Line 6
The specific line to be determined after FDA
review of NDA Potential spinal analgesics
Methadone, Oxymorphone, NMDA antagonists
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Recommended Maximum Intrathecal Dosages and
Concentrations
Drug Dosage (mg/day) Concentration(mg/ml)
Morphine 15 30
Hydromorphone 10 30
Bupivacaine 30 38
Clonidine 1.0 2.0
These represent general recommendations and are
dependent upon the specific patient and the
clinical experience of the physician and thus,
maximum dosage and/or concentrations may vary
from these.
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Spinal OpiatesNon-malignant Pain

• Mean morphine dose
• initial 2.7 mg/day (0.3-12 mg/day)
• after 3.4 years 4.7 mg/day (0.3-12 mg/day)
• 28 patients followed more than 4 years
• 64 (n18) constant dosage history
• 36 (n10) increase in morphine dose gt 6mg/day
  after 1 year

Winkellmuller et al. J Neurosurgery 85458-467,
1996
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Spinal OpiatesNon-Malignant Pain

• U.S. experience, 1981-1992
• 14 authors, 156 patients
• 69 (107) good-excellent pain relief
• 75 with cancer pain good/excellent pain relief

Krames E Spinal Administration of Opioids for
Nonmalignant Pain Syndromes A U.S. Experience
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Spinal Opiates Non-Malignant Pain

• 120 patients
• 63 (n76) with FBSS or LBP
• Mean age 54.0 11.2 years (28-79)
• Follow-up period
• mean 3.4 1.3 years (0.5 - 5.7 years)

Winkellmuller et al. J Neurosurgery 85458-467,
1996
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Mean Pain Scores

• 74 benefit
• Avg. pain reduction
• 67 at 6 months
• 58 last follow-up
• 81 improved QOL
• 92 satisfied

Winkellmuller et al. J Neurosurgery 85458-467,
1996
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Mean Daily Morphine Dose
Winkellmuller et al. J Neurosurgery 85458-467,
1996
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Multicenter Review of Spinal Opiates

• Retrospective review of 429 patients
• 66 non-malignant pain
• Physician assessment
• global pain relief scores
• percent pain relief
• VAS scores for pain intensity
• ADL, overall activity level
• Employment

Paice J Pain Symptom Management, 1996
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Is it time for a nap?
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Global Pain Relief

• Excellent 52.4
• Good 42.9
• Poor 4.8

Paice J Pain Symptom Management, 1996
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Changes in ADL

• Increased 82
• No Change 14
• Decreased 4

Paice J Pain Symptom Management, 1996
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Daily Opiate Dosage

• Mean daily dose, 9.2 mg/day
• Initial dose higher for non-malignant pain
• Gradual linear dose escalation in non-malignant
  pain
• At 24 months, dosages similar in patients with
  non-malignant and cancer pain

Paice J Pain Symptom Management, 1996
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Conclusions of Multicenter Review

• Nociceptive pain responds best to spinal opiates
• Neuropathic pain responds to spinal opiates but
  may require higher dosages
• Addition of local anesthetics may by synergistic
  in neuropathic pain

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Prospective Study - Spinal Opiates

• 40 patients with non-malignant pain
• mostly FBSS with gt 3 operations
• Mean duration of pain, 8 9 years (6mos-40yrs)
• 30 (75) had successful screening trial
• minimum of 50 pain reduction by VAS
• Follow-up 6, 12, 18, 24 months
• complete data for 20 patients followed for 2
  years
• Outcome by VAS, CIPI, BDI, MPQ

Anderson V,Burchiel K Neurosurgery, Feb. 1999
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Results

• VAS for pain and pain coping scores remained
  improved
• CIPI and MPQ scores improved and persisted
• Initial morphine dose 1.96 1.8 mg/day, inc. to
  6.0 7.0 at 3 months, 9.43 8.8 at 15 months
• Device complications, 20

Anderson V,Burchiel K Neurosurgery, Feb. 1999
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Visual Analog Scores

• Mean initial VAS
• 78.5 15.9 (39-100)
• Decrease in VAS greatest during the initial 3
  months
• Reduction in VAS remained relatively constant

Anderson V,Burchiel K Neurosurgery, Feb. 1999
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Medication Intake

• Daily IT morphine dose ? 25mg
• Mean equianalgesic opioid dose increased
  significantly over time
• initial 1.96 1.75 mg/day
• 24 months 14.59 20.52 mg/day
• Dose escalation most rapid during initial 3
  months
• Oral narcotic intake
• initial 90 (28/30)
• 24 months 30 (6/30)

Anderson V,Burchiel K Neurosurgery, Feb. 1999
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Spinal Opiates for Benign PainMaron J, Loeser J
The Clinical Journal Pain, 1996

• Data insufficient to permit formal analysis
• The proper role of intraspinal opioids in the
  treatment of non-malignant pain cannot be
  determined from the existing literature
• Spinal opiates for benign pain should be
  considered experimental
• All patients who receive such therapy should be
  part of a clinical protocol

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Intrathecal Therapy vs. Oral Opioids, vs.
Functional Restoration Program for FBSSDoleys,
et. al.

• Interpretation as to the most effective treatment
  depends on the outcome measure emphasized. There
  is a disconnect between ratings of pain,
  disability, mood, and quality of life. The use
  of a multi-dimensional outcomes approach revealed
  a number of inconsistencies in the data which
  could have been overlooked using only pain
  ratings and patient satisfaction data. No one
  treatment emerged as the most effective across
  all of the disease specific and generic measures.
  Although generally satisfied with treatment,
  patients continued to report significant levels
  of pain, disability, and impaired quality of life

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Unresolved Issues

• How should outcome be measured?
• Management of tolerance
• Question of neurotoxicity
• Development of hyperalgesia
• Indefinite requirement for medical care

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The Bottom Line

• There can be no substitute for sound clinical
  judgement based on a detailed assessment of each
  patient !

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What do you mean, Its a bit muddy ?
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Men Are From Mars