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

Richard K. Osenbach, M.D.

Director of Neuroscience and Neurosurgery

Cape Fear Valley Health System

Fayetteville, NC

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Spinal Opiates for Benign PainSpinal Opiates for Benign Pain

Controversial

Mixed reviews and results

Reporting of outcomes non-uniform

No definitive end-point for therapy

Controversial

Mixed reviews and results

Reporting of outcomes non-uniform

No definitive end-point for therapy

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Rationale of IT Drug InfusionRationale 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

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 AnalgesiaHistory 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

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 LigandsOpioid Receptors and Ligands

Opioid

Receptor

Endogenous

Agonist

Synthetic

AgonistsAntagonists

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

hORL1Nociceptin/OFQ None

Location of Opioid Receptors in the CNS

Dorsal hornLamina ISubstantia gelatinosa

BrainstemNucleus caudalis

SupraspinalPAGThalamic nucleiStriatumHypothalamusLimbic systemCortex

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Mu ReceptorMu ReceptorDefined by affinity for morphine

Less affinity for other receptor subtypes

Most clinically important opioids selective for Mu receptorCross react at higher doses1 - supraspinal 2 – spinal

Most analgesic effects of systemic morphine mediated through 1 effects

70% located pre-synaptically

Defined by affinity for morphineLess affinity for other receptor subtypes

Most clinically important opioids selective for Mu receptorCross react at higher doses1 - supraspinal 2 – spinal

Most analgesic effects of systemic morphine mediated through 1 effects

70% located pre-synaptically

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Opioid Recptor PhysiologyOpioid Recptor Physiology

G-protein-coupled receptor familySynthesized in DRGSecond messenger using cAMPNegative coupling

Inhibit cAMP via Gi-protein

And - opening of K+ channels - Closing of ca2+

G-protein-coupled receptor familySynthesized in DRGSecond messenger using cAMPNegative coupling

Inhibit cAMP via Gi-protein

And - opening of K+ channels - Closing of ca2+

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Opioid ActionsOpioid ActionsAnalgesiaPruritisUrinary retentionAutonomic Effects

Cough suppression, orthostatic hypotension• Nucleus tractus solitarius and ambiguous, locus ceruleus

Respiratory depression• Nucleus tractus solitarius, parabrachial nucleus

Nausea/vomiting• Area postrema

ConstipationMeiosis

• Superior colliculus, pretectal nuclei

Endocrine effectsPosterior pituitary – inhibition of vasopressinHormonal effects – hypothalamic infundibulum

Behavioral effectsAmygdala, hippocampus, nucleus accumbuns, basal ganglia

Motor rigidityStriatum

AnalgesiaPruritisUrinary retentionAutonomic Effects

Cough suppression, orthostatic hypotension• Nucleus tractus solitarius and ambiguous, locus ceruleus

Respiratory depression• Nucleus tractus solitarius, parabrachial nucleus

Nausea/vomiting• Area postrema

ConstipationMeiosis

• Superior colliculus, pretectal nuclei

Endocrine effectsPosterior pituitary – inhibition of vasopressinHormonal effects – hypothalamic infundibulum

Behavioral effectsAmygdala, hippocampus, nucleus accumbuns, basal ganglia

Motor rigidityStriatum

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Intraspinal MorphineConversion Ratios

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

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 SelectionPatient 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

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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Pump anchored with sutures or pouch

Catheter connector which also functions as the primary anchor

V-wing anchor

Dural puncture

Catheter tip

Paramedian Oblique Entry

5 cm of slack in catheter

Loop of excess catheter under pump

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Implantable Drug PumpsImplantable Drug Pumps

Programmable

Constant flow

Programmable

Constant flow

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Constant Flow PumpConstant 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

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

Constant Flow PumpFactors 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

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 capacityflow rate calibrated for 50% capacity;4% variability at extremes of volume

Pump “Dead Space”4ml “dead volume”correction factor for concentration

Drug viscosity Q = K x (P1-P2) u

Reservoir capacityflow 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 PumpsProgrammable PumpsADVANTAGES

Maximum flexibility

Variable rates

Program bolus doses

Alter dose by telemetry

DISADVANTAGES

Finite life expectancy

More expensive (?)

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

General Guidelines for IT Drug Selection

Consider these issues regarding administration of intrathecal drugs: Drug stabilityDrug stability Drug-drug compatibility for co-administrationDrug-drug compatibility for co-administration Drug-pump compatibilityDrug-pump compatibility Effect of diluents on pumpEffect of diluents on pump pHpH

Choose appropriate concentration based on: Desired doseDesired dose Pump capabilitiesPump capabilities Refill interval (no less than 2-4 wks)Refill interval (no less than 2-4 wks)

Consider these issues regarding administration of intrathecal drugs: Drug stabilityDrug stability Drug-drug compatibility for co-administrationDrug-drug compatibility for co-administration Drug-pump compatibilityDrug-pump compatibility Effect of diluents on pumpEffect of diluents on pump pHpH

Choose appropriate concentration based on: Desired doseDesired dose Pump capabilitiesPump capabilities Refill interval (no less than 2-4 wks)Refill interval (no less than 2-4 wks)

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General Guidelines (cont.)General Guidelines (cont.)

DOSING STRATEGYDose 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 integrityInterrogate and empty (refill assess volume)

– Dye study of catheter integrity

Pathophysiology of the pain

DOSING STRATEGYDose 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 integrityInterrogate and empty (refill assess volume)

– Dye study of catheter integrity

Pathophysiology of the pain

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Trialing for IT TherapyTrialing for IT Therapy

Multiple accepted methods

No consensus as to the single best method

Multiple accepted methods

No consensus as to the single best method

What do we know about screening?

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Questions Regarding TrialingQuestions Regarding Trialing

Screening method

Duration of trial

Drug and dose

Use of placebo

Systemic opioids

Criteria for success

Screening method

Duration of trial

Drug and dose

Use of placebo

Systemic opioids

Criteria for success

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Functional (Continuous) TrialFunctional (Continuous) TrialADVANTAGES

Most accurately replicates permanent pumpAllows for longer trialsControlled dose titrationAssess starting dose for IT therapyReduce risk of drug-related side effectsDissipates placebo effect over timeAssessment of functional outcome

DISADVANTGES

Procedurally more complicatedRequires greater expertiseHigher morbidityMore costly

ADVANTAGES

Most accurately replicates permanent pumpAllows for longer trialsControlled dose titrationAssess starting dose for IT therapyReduce risk of drug-related side effectsDissipates placebo effect over timeAssessment of functional outcome

DISADVANTGES

Procedurally more complicatedRequires greater expertiseHigher morbidityMore costly

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Epidural Vs. IntrathecalEpidural Vs. Intrathecal

CRITERIA EPIDURAL INTRATHECAL

Onset of ActionSlower onset of analgesia Faster onset of analgesia

Systemic EffectsGreater systemic effects Minimal systemic effects

Duration of EffectShorter-lasting Longer-lasting

DoseHigher 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 AdministrationPlacebo 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

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 TrialOral Opioids During TrialNo 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

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)

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

86 patient screened for inclusion28 excluded from inclusion

58 patients approached18 declined inclusion

40 patients randomized ITB (n=18) or CEI (n=19)

27 successful trial - pump implantationITB, 67% (12/18) CEI, 79% (15/19)3 patients lost to follow-upITB (n=10), CEI (n=14

86 patient screened for inclusion28 excluded from inclusion

58 patients approached18 declined inclusion

40 patients randomized ITB (n=18) or CEI (n=19)

27 successful trial - pump implantationITB, 67% (12/18) CEI, 79% (15/19)3 patients lost to follow-upITB (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. CEIIT Bolus Vs. CEINo 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)

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. CEIIT Bolus Vs. CEI

0

20

40

60

80

100

Baseline 6 Months % Change

VAS Pain Scores

IT CEI

0

20

40

60

80

100

Baseline 6 Months % Change

VAS Pain Scores

IT 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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ComplicationsComplicationsBleeding 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

Bleeding problemsSpinal 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

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

PA03 Update of Clinical Guidelines for the use of Intraspinal Drug Infusion in Pain Management

Morphine Hydromorphone

Morphine (or Hydromorphone) + Bupivacaine

Morphine (or Hydromorphone) + Clonidine

Morphine (or Hydromorphone) + Bupivacaine + Clonidine

Neostigmine, Adenosine, Ketorolac

Fentanyl, Sufentanil, Midazolam, Baclofen

For Selected Patients Only

Ropivacaine, Meperidine, Gabapentin, Buprenorphine, Octreotide, other **

* The specific line to be determined after FDA review of NDA** Potential spinal analgesics: Methadone, Oxymorphone, NMDA antagonists

Line 1

Line 5

Line 4

Line 6

Line 3

Line 2

* Ziconotide

Neuropathic Pain

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Recommended Maximum Intrathecal Dosages and Concentrations*

Recommended Maximum Intrathecal Dosages and Concentrations*

* 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.

Drug Dosage (mg/day) Concentration(mg/ml)

Morphine 15 30

Hydromorphone 10 30

Bupivacaine 30 38

Clonidine 1.0 2.0

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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% (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 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% (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

Winkellmuller et al.: J Neurosurgery 85:458-467, 1996

0

20

40

60

80

100

Before 1st FU Last FU

Mean VAS

0

20

40

60

80

100

Before 1st FU Last FU

Mean VAS • 74% benefit

•Avg. pain reduction• 67% at 6 months•58% last follow-up

• 81% improved QOL

•92% “satisfied”

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Mean Daily Morphine Dose

2

2.5

3

3.5

4

4.5

5

Initial exam First FU Last FUMea

n IT

Mor

phin

e D

ose

(mg/

day) LBP Totals

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

Excellent 52.4%

Good 42.9%

Poor 4.8%

52%

43%

5%

Paice: J Pain Symptom Management, 1996

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Changes in ADL

Increased82%

No Change14%

Decreased 4%

82%

14% 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 > 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 ScoresVisual Analog ScoresMean initial VAS

78.5 ± 15.9 (39-100)

Decrease in VAS greatest during the initial 3 months

Reduction in VAS remained relatively constant

Mean initial VAS

78.5 ± 15.9 (39-100)

Decrease in VAS greatest during the initial 3 months

Reduction in VAS remained relatively constant

0

10

20

30

40

50

60

70

80

Initial 3-mo 6-mo 12-mo 18-mo 24-mo0

10

20

30

40

50

60

70

80

Initial 3-mo 6-mo 12-mo 18-mo 24-mo

Anderson V,Burchiel K: Neurosurgery, Feb. 1999

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Medication IntakeMedication 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)

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, 1996Spinal 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

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.

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

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 IssuesUnresolved Issues

How should outcome be measured?

Management of tolerance

Question of neurotoxicity

Development of hyperalgesia

Indefinite requirement for medical care

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 !

8/3/20068/3/2006“What do you mean, ‘It’s a bit muddy’ ?”

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“Men Are From Mars”“Men Are From Mars”