Transcript Neuromodulation for Failed Back Surgery Syndrome Part II

Neuromodulation for Failed
Back Surgery Syndrome
Part II
Richard K. Osenbach, M.D.
Director of Neuroscience and Neurosurgery
Cape Fear Valley Health System
Fayetteville, NC
8/3/2006
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
Opioid
Endogenous
Dorsal
horn
Receptor
Agonist
Lamina I
ß-Endorphin
Substantia
gelatinosa
Mu (70%)
Endomorphins
Brainstem
NucleusMet-Enkephalin
caudalis
Leu-Enkephalin
Supraspinal
Delta (20-30%)
PAG
Thalamic
nuclei A
Dynorphine
StriatumDynorphine B
Kappa (5-10%)
Hypothalamus
Limbic Nociceptin/OFQ
system
hORL1
Cortex
Synthetic
Agonists
Antagonists
Morphine
DAMGO
Naloxone
ß-FNA
DPDPE
SNC-80
DSTBULET
Naltrindole
Naloxone
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 Giprotein
 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
Striatum
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Intraspinal Morphine
Conversion 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
Dural
puncture
Pump anchored
with sutures or
pouch
Paramedian
Oblique Entry
V-wing anchor
5 cm of slack in
catheter
Loop of excess
catheter under
pump
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 Pump
Factors Affecting Drug Delivery
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
Drug viscosity
Q = K x (P1-P2)
u
Reservoir capacity
flow rate calibrated for 50%
capacity;4% variability at
extremes of volume
Pump “Dead Space”
4ml “dead volume”
correction factor for concentration
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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
Slower onset of analgesia
Faster onset of analgesia
Greater systemic effects
Minimal systemic effects
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
Onset of Action
Systemic Effects
Duration of Effect
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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 (n=18) or CEI (n=19)
27 successful trial - pump implantation
ITB, 67% (12/18)
CEI, 79% (15/19)
3 patients lost to follow-up
ITB (n=10), CEI (n=14
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
VAS Pain Scores
100
80
60
40
20
0
Baseline
6 Months
IT
% Change
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
8/3/2006
Complications
Bleeding problems
Spinal epidural hematoma
Pump pocket hematoma/seroma
Infection
most often occurs at pump pocket
REMOVE the system
Post-dural puncture headache
20-25% incidence
CSF leak
20,000 implants annually
Drug-related side effects
5,000 catheter revisions annually
Catheter complications
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
Line 1
Morphine
Hydromorphone
Neuropathic
Pain
Morphine (or Hydromorphone) + Bupivacaine
Line 2
Line 3
Morphine (or Hydromorphone) + Clonidine
Morphine (or Hydromorphone) + Bupivacaine + Clonidine
Fentanyl, Sufentanil, Midazolam, Baclofen
Line 4
*
Z
i
c
o
n
o
t
i
d
e
For Selected Patients Only
Line 5
Line 6
Neostigmine, Adenosine, Ketorolac
Ropivacaine, Meperidine, Gabapentin, Buprenorphine, Octreotide, other **
* 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 Opiates
Non-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% (n=18) constant dosage history
36% (n=10) increase in morphine dose > 6mg/day
after 1 year
Winkellmuller et al.: J Neurosurgery 85:458-467, 1996
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Spinal Opiates
Non-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
8/3/2006
Spinal Opiates
Non-Malignant Pain
120 patients
63% (n=76) 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 85:458-467, 1996
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Mean Pain Scores
100
Mean VAS • 74%
80
benefit
•Avg. pain reduction
• 67% at 6 months
•58% last follow-up
60
40
20
• 81% improved QOL
0
Before
1st FU
Last FU
•92% “satisfied”
Winkellmuller et al.: J Neurosurgery 85:458-467, 1996
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Mean IT Morphine Dose (mg/day)
Mean Daily Morphine Dose
5
LBP
Totals
4.5
4
3.5
3
2.5
2
Initial exam
First FU
Last FU
Winkellmuller et al.: J Neurosurgery 85:458-467, 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
43%
5%
Excellent
52.4%
Good
42.9%
Poor
4.8%
52%
Paice: J Pain Symptom Management, 1996
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Changes in ADL
14%
4%
82%
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 nonmalignant 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 > 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
80
70
78.5 ± 15.9 (39-100)
60
Decrease in VAS
greatest during the
initial 3 months
50
40
30
Reduction in VAS
remained relatively
constant
20
10
0
Initial
3-mo
6-mo
12-mo 18-mo 24-mo
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 Pain
Maron 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 FBSS
Doleys, 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, ‘It’s a bit muddy’ ?”
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“Men Are From Mars”
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