16 th Annual Meeting December 6-9, 2012, Las Vegas, NV Intrathecal Consensus Statement: Applicable...

16th Annual Meeting December 6-9, 2012, Las Vegas, NV

Intrathecal Consensus Statement:Applicable to all patients?

Salim Hayek, MD, PhDProfessor, Dept. of AnesthesiologyCase Western Reserve UniversityChief, Division of Pain MedicineUniversity Hospitals Case Medical Center


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Relevant Conflicts of Interest

• Research/Fellowship Support– Medtronic


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Learning Objectives• Pharmacokinetics of Intrathecal Meds• CSF Flow Dynamics• Catheter Localization• Different Pain Populations• Critique current algorithm (PACC 2012)


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Patient Selection is Critical


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Krames E. Journal of Pain and Symptom Management;1996, Vol 11, No 6: 333-352Hayek SM, Veizi E, Narouze S, Mekhail N. Pain Med, 2011 Aug;12(8):1179-89Veizi E, Hayek SM, Narouze S, Mekhail N. Pope, JE. Pain Med, 2011 Oct;12(10):1481-9Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351

Patient Selection--Challenges• Objective evidence of pathology• Failure to achieve adequate results from oral

opioids • Inability to tolerate the side effects of oral opioids • Psychological evaluation• Cancer vs. non-cancer pain• Young vs. old• Localized vs. diffuse pain• Baseline dose of Opioids: High vs. low


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IT Medication--Considerations

• Receptors for the agents have to be at the spinal level• Drug considerations

– Lipid solubility– Density and baricity– Bolus vs. continuous– Location of catheter/receptors


Kroin JS. Clin.Pharmacokinet. 22:319-326, 1992 Nordberg G. Acta Anaesthesiol.Scand.Suppl 79:1-38, 1984

Mechanism of Action—IT Meds• CSF ~ ISF• Most receptors are in the

substantia gelatinosa 1-2 mm from surface of dorsal horn

Synapses

OpioidsClonidineZiconotide

Bupivacaine

Hydrophilic>Hydrophobico Longer ½ lifeo Deeper penetrationo Smaller volume of distributiono Rostral spread


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Partition coefficient

Elimination half-life (h)

Lumbar to cisternal [CSF]

Morphine 1.4 1.2-1.5 4.6-7.0

Clonidine 7.1 1.7-2.1 3.2

Baclofen 0.1 1.5 4.1

Sufentanil Citrate

17881.5 --

Fentanyl Citrate

8131.5 --

Bupivacaine 2565 2.7 --

Ropivacaine 775 1.6 --

Bernards CM et al: Epidural, Cerebrospinal Fluid, and Plasma Pharmacokinetics of Epidural Opioids (Part 1): Differences among Opioids. Anesthesiology:August 2003 - Volume 99 - Issue 2 - pp 455-465Hayek, S. et al., Seminars in Pain Medicine 1(4):238-253


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Kroin JS et al: The distribution of medication along the spinal canal after chronic intrathecal administration. Neurosurgery 33:226-230, 1993

Pharmacokinetics-lipophilicity• Moderately hydrophilic agents

(such as morphine, baclofen or clonidine) concentration gradient in the CNS – cisternal CSF drug concentration is

1/3 to 1/7 that in the lumbar CSF (*I-DPTA)

• Bupivacaine/Fentanyl-lipohilic



Bupivacaine



Bupivacaine

DRGDRG

Dorsal Rootlets(sensory)

Dorsal Rootlets(sensory)

Ventral Rootlets(motor)

Ventral Rootlets(motor)


CSF Oscillatory FlowCSF is a POORLY MIXED system

Known concentration gradients existHomovanillic acid concentrations

6 x higher in cisternal CSF vs. lumbar CSFUric acid concentrations

2x higher in lumbar than cisternal CSF

CSF motion propelled in opposite directions cyclicallyAreas along the spine with no measurable CSF flowLimited circumferential flow

Degrell I, Nagy E: Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid. Biol Psychiatry 1990; 27:891–6

Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.

Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid CerebrospinalFluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging. 2000 (18) 387-395


Posterior Catheter


Posterior

Lateral

Anterior


Pharmacokinetic Determinants20 μL/hr rate 1 mL/hr rate 1mL/hr bolused



Flack SH, Anderson CM, Bernards C., Morphine distribution in the spinal cord after chronic infusion in pigs. Anesth Analg. 2011 Feb;112(2):460-4


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Hayek, S. et al., Seminars in Pain Medicine 1(4):238-253

IT Opioid Adverse Effects• Pruritus: IT>>oral • Peripheral edema• Hypogonadotrophic hypogonadism• Opioid-induced hyperalgesia • IT granuloma

– Total Dose– Concentration

http://www.ajronline.org/content/vol189/issue6/images/large/12_07_2225_01c.jpeg

http://www.ajronline.org/content/vol189/issue6/images/large/12_07_2225_01c.jpeg


17Paice J et al., J Pain Symptom Manage 11, 1996

IT Opioid Dose Escalation


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Cancer vs. Non-Cancer: Limited by Survival

• Of the 119 patients implanted, 15 made it to 13 months


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Atli 2

010

Shal

adi 2

007

Dom

ingu

ez 2

002

Rai

nov

2001

Rob

erts

200

1

Paic

e 19

96

S1S2

0

2

4

6

8

10

12

14

Study

IT Morphine Equivalent

43%145%

200%

1200%

106%

333% (mg)

Baseline12 mo post-Implant

IT Opioid Escalation (1 y, non-cancer)


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Societal Guidelines• Limited robust studies guidelines may be

helpful to physicians in clinical decision making

• Guidelines are often developed with the intent of helping clinicians – assimilate rapidly expanding medical

knowledge– making appropriate decisions about health

care


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Guidelines• Guidelines generally follow strict sequential

processes including– collection of data– preparation of systematic reviews– weighing the strength of the evidence– grading the strength of recommendations

• Assessment of adaptation and implementation of guidelines is highly desirableAtkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh

MC, Henry D et al: Grading quality of evidence and strength of recommendations. BMJ 2004, 328(7454):1490


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Consensus Guidelines• When evidence is significantly

limited, consensus guidelines may be helpful – RCT’s highest level of evidence– Observational studies intermediate– Expert opinion and consensus

guidelines lowest level of evidenceEbell MH, Siwek J, Weiss BD, Woolf SH, Susman JL, Ewigman B, Bowman M: Simplifying the language of evidence to improve patient care: Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in medical literature. The Journal of family practice 2004, 53(2):111-120.


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Limited IT Data Consensus Statements


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2012 PACC Guidelines• Guideline authors have attempted-- using

best available evidence as well as their collective experiences-- to formulate “lines” of therapy

• Invariably, Consensus statements Controversial– Limited outcome data from IT studies– “Infinite” number of IT agent

combinations/rankings– Individual author biases – generalization of algorithms to all patients despite

individual differences


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Line 1 Morphine Hydromorphone Ziconotide Fentanyl

Line 2 Morphine + bupivacaine Ziconotide + opioid Hydromorphone +

bupivacaine Fentanyl + bupivacaine

Line 3 Opioid (morphine, hydromorphone, or fentanyl) + clonidine Sufentanil

Line 4 Opioid + clonidine + bupivacaine Sufentanil + bupivacaine OR clonidine

Line 5 Sufentanil + bupivacaine + clonidine

2012 Polyanalgesic Algorithm for Intrathecal Therapies in Nociceptive PainLine 1: Morphine and ziconotide are approved by the US Food and Drug Administration for IT therapy and are recommended as first-line therapy for nociceptive pain. Hydromorphone is recommended on the basis of widespread clinical use and apparent safety. Fentanyl has been upgraded to first-line use by the consensus conference.Line 2: Bupivacaine in combination with morphine, hydromorphone, or fentanyl is recommended. Alternatively, the combination of ziconotide and an opioid drug can be employed.Line 3: Recommendations include clonidine plus an opioid (ie, morphine, hydromorphone, or fentanyl) or sufentanil monotherapy.Line 4: The triple combination of an opioid, clonidine, and bupivacaine is recommended. An alternate recommendation is sufentanil in combination with either bupivacaine or clonidine.Line 5: The triple combination of sufentanil, bupivacaine, and clonidine is suggested.

Deer TR et al., Polyanalgesic Consensus Conference 2012: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel. Neuromodulation. 2012 Sep;15(5):436-466


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Line 1 Morphine Ziconotide Morphine + Bupivacaine

Line 2 Hydromorphone Hydromorphone + bupivacaine or Hydromorphone + clonidine

Morphine + clonidine

Line 3 Clonidine Ziconotide + opioid Fentanyl Fentanyl + bupivacaine or Fentanyl + clonidine

Line 4 Opioid + clonidine + bupivacaine Bupivacaine + clonidine

Line 5 Baclofen

2012 Polyanalgesic Algorithm for Intrathecal Therapies in Neuropathic painLine 1: Morphine and ziconotide are approved by the US Food and Drug Administration for IT therapy and are recommended as first-line therapy for neuropathic pain. The combination of morphine and bupivacaine is recommended for neuropathic pain on the basis of clinical use and apparent safety. Line 2: Hydromorphone, alone or in combination with bupivacaine or clonidine is recommended. Alternatively, the combination of morphine and clonidine may be used. Line 3: Third-line recommendations for neuropathic pain include clonidine, ziconotide plus an opioid, and fentanyl alone or in combination with bupivacaine or clonidine.Line 4: The combination of bupivacaine and clonidine (with or without an opioid drug) is recommended. Line 5: Baclofen is recommended on the basis of safety, although reports of efficacy are limited.



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Line 1 Morphine Hydromorphone Ziconotide Fentanyl

Line 2 Morphine + bupivacaine Ziconotide + opioid Hydromorphone +

bupivacaine Fentanyl + bupivacaine

Line 3 Opioid (morphine, hydromorphone, or fentanyl) + clonidine Sufentanil

Line 4 Opioid + clonidine + bupivacaine Sufentanil + bupivacaine OR clonidine

Line 5 Sufentanil + bupivacaine + clonidine


Nociceptive Pain

?• Fentanyl: 1st line based on safety only

– No efficacy data– Why not for Neuropathic Pain (localized)?

• Did authors assume nociceptive pain is localized as in LBP but neuropathic is diffuse as in DPN? What about PHN?


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Line 1 Morphine Ziconotide Morphine + Bupivacaine

Line 2 Hydromorphone Hydromorphone + bupivacaine or Hydromorphone + clonidine

Morphine + clonidine

Line 3 Clonidine Ziconotide + opioid Fentanyl Fentanyl + bupivacaine or Fentanyl + clonidine

Line 4 Opioid + clonidine + bupivacaine Bupivacaine + clonidine

Line 5 Baclofen


Neuropathic Pain

• Where would “bupivacaine + ziconotide” fall into? • Why not ziconotide as third line combination agent along with

opioid + bupivacaine?

Why not?


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Ziconotide Slow Titration Study

VASPI improved from baseline to the end of Week 3 by a mean 14.7% in the ziconotide-treated group and 7.2% in the placebo group (p=0.036; two-sample t-test)*Primary Efficacy Variable

0

24

6

810

12

14

1618

20

Week 1 Week 2 Week 3*

Me

an

% C

ha

ng

e

in V

AS

PI

Sc

ore

ZiconotidePlacebo

p=0.003

p=0.121p=0.036

Rauck RL, Wallace MS, Leong MS, et al. 2006. A Randomized, Double-Blind, Placebo-Controlled Study of Intrathecal Ziconotide in Adults with Severe Chronic Pain. J Pain Symptom Manage, 31:393-406

Start: 2.4 mg/day Mean concentration wk 3 = 6.96 mg/day


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Ziconotide• Though ziconotide is listed as a first line

agent because of FDA approved status, how often in practice is it used as a first line agent, given its weak analgesic efficacy and difficult trialing and titration?


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Types of Pain

Nociceptive NeuropathicMixed

Diabetic NeuropathyPostherpetic Neuralgia

ArthritisAxial Mechanical Neck/Back Pain

FBSS


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PACC 2012• MIXED PAIN

– “In some cases, the managing physician or team member will have trouble identifying the pain type. In these cases, the clinical scenario should drive the decision-making process in choosing the appropriate treatment algorithm.”



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Other Relevant Characteristics?

• Catheter Location– Anterior vs. Posterior– Distance from site of action

Hayek SM, Veizi E, Narouze S, Mekhail N. Pain Med, 2011 Aug;12(8):1179-89Veizi E, Hayek SM, Narouze S, Mekhail N. Pope, JE. Pain Med, 2011 Oct;12(10):1481-9Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351

Treatment time (months from implant date)

3 m 6 m 12 mCha

nge

in in

trat

hec

al o

pio

id d

ose

from

bas

elin

e (a

s a

% in

cre

ase

fro

m im

pla

nt d

ate

dose

)

0

200

400

600

800

1000

1200

<50 yrs old>50 yrs old

p<0.055

* p<0.001

* p<0.05

• Pain Location– Diffuse– Localized

• Patient Age– Older– Younger

Treatment time (from implant)

IT M

orph

ine

equi

vale

nt d

ose

incr

ease

(%

of b

asel

ine)

0

200

400

600

800 Morphine groupMorphine+Bupivacaine group

http://www.ccjm.org/content/76/5/297/F1.large.jpg


34Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351

Baseline Opioid Dose: IT Microdosing

• Opioid taper over 3-4 weeks• Opioid free for 5 weeks trial• 22 patients, retrospective


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Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351

Average Effective Dose = 140 mcg


Grid

er 2

011

Atl

i 201

0

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007

Dom

ingu

ez 2

002

Rain

ov 2

001

Robe

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2001

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e 19

96

Baseline

02468

101214

IT A

mou

nt (

mg)

Study

I T Morphine Eq. Dose Escalation

Baseline12 months

43% 145%

200%

1200%

106%

333%

139%


Hamza M et al., Prospective Study of 3-Year Follow-Up of Low-Dose Intrathecal Opioids in the Management of Chronic Nonmalignant Pain. Pain Med. 2012 Jul 30.

Prospective “Microdosing” Study


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Limiting IT Opioid Escalation• Age: > 50 y.o. lesser escalation

• Starting dose opioids: better• IT bupivacaine

– Adding bupivacaine to IT opioids may not improve pain scores or QoL

– Starting IT bupivacaine concomitantly with IT opioids appears to blunt opioid dose escalation

Hayek SM, Veizi E, Narouze S, Mekhail N. Pain Med, 2011 Aug;12(8):1179-89Veizi E, Hayek SM, Narouze S, Mekhail N. Pope, JE. Pain Med, 2011 Oct;12(10):1481-9Bernards CM. Current Opinion in Anaesthesiology 2004, 17:441–447


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PAC2012 Figure 1. Algorithm for behavioral evaluation of patients considered for intrathecal therapy for management of pain. (Prepared by Marilyn S. Jacobs, PhD).

16th Annual Meeting December 6-9, 2012, Las Vegas, NVChronic Pain Patient

for IDDS Consideration

Yes

Opiod Rotation, Blocks, Palliative

Care Referral

Continue

Effective Pain Relief

No

Hospice

No

No

Expected Survival > 3 months

Yes

Non-Cancer Related Pain

Failed Less Invasive

Modalities

No

Attempt Other

TreatmentsObtain a 2nd

OpinonConsider

Chronic Pain Rehabilitation

Programs

Repeat as Needed

Yes

Pain relief

No

No

No

Age >50

Yes

Yes

Favorable Psych Profile

Patient Appropriate for IDDS Trial

Yes

Cancer Pain or Other Painful

Condition with Limited Survival

Failed Less Invasive

Modalities and Opioid Rotation

Patient Appropriate for IDDS Trial

Yes

Hayek, SM, ASRA Newsletter, November 2012, 4-6 http://www.asra.com/Newsletters/november-2012.pdf

Cancer vs. Non-Cancer Algorithm

http://www.asra.com/Newsletters/november-2012.pdf


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PACC 2016• Better Evidence/Newer Agents• Algorithms address other clinical variables

besides rankings of IT agents– Cancer vs. Non-Cancer Chronic Pain– Non-Cancer Pain

• Age• Microdosing• Localized vs. Diffuse Pain/Catheter Location Drug

Choice


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Thank You!!

PACC 2012


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IT Meds • FDA Approved

– Morphine– Ziconotide– Baclofen (spasticity)

• Standard of care– Hydromorphone– Bupivacaine– Clonidine– Fentanyl


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PainDETECT

• Prospective, multicenter study and subsequently applied to approximately 8000 LBP patients– high sensitivity, specificity and positive predictive

accuracy– Patients with NeP showed higher ratings of pain

intensity, with more (and more severe) co-morbidities such as depression, panic/anxiety and sleep disorders

– 14.5% of all female and 11.4% of all male Germans suffer from LBP with a predominant NePcomponentFreynhagen R, Baron R, Gockel U, Tölle TR. painDETECT: a new screening questionnaire to

identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006 Oct;22(10):1911-20.

16 th Annual Meeting December 6-9, 2012, Las Vegas, NV Intrathecal Consensus Statement: Applicable...

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