16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Intrathecal Consensus Statement:
Applicable to all patients?
Salim Hayek, MD, PhD
Professor, Dept. of Anesthesiology
Case Western Reserve University
Chief, Division of Pain Medicine
University Hospitals Case Medical Center
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Relevant Conflicts of Interest
• Research/Fellowship Support
– Medtronic
2
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Learning Objectives
•
•
•
•
•
Pharmacokinetics of Intrathecal Meds
CSF Flow Dynamics
Catheter Localization
Different Pain Populations
Critique current algorithm (PACC 2012)
3
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Patient Selection is Critical

4
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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
Krames E. Journal of Pain and Symptom Management;1996, Vol 11, No 6: 333-352
Hayek SM, Veizi E, Narouze S, Mekhail N. Pain Med, 2011 Aug;12(8):1179-89
Veizi E, Hayek SM, Narouze S, Mekhail N. Pope, JE. Pain Med, 2011 Oct;12(10):1481-9
Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351
5
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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
6
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Mechanism of Action—IT Meds
Opioids
Clonidine
Bupivacaine
Synapses Ziconotide
• CSF ~ ISF
• Most receptors are in the
substantia gelatinosa 1-2 mm
from surface of dorsal horn
Hydrophilic>Hydrophobic
o
o
o
o
Longer ½ life
Deeper penetration
Smaller volume of distribution
Rostral spread
Kroin JS. Clin.Pharmacokinet. 22:319-326, 1992
Nordberg G. Acta Anaesthesiol.Scand.Suppl 79:1-38, 1984
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Partition Elimination
Lumbar to
coefficient half-life (h) 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
Fentanyl
Citrate
1788
1.5
--
1.5
--
Bupivacaine
2565
2.7
--
Ropivacaine
775
1.6
--
813
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 455-465
Hayek, S. et al., Seminars in Pain Medicine 1(4):238-253
8
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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
Kroin JS et al: The distribution of medication along the spinal canal after chronic
intrathecal administration. Neurosurgery 33:226-230, 1993
9
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Bupivacaine
Opioids
Clonidine
Ziconotide
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Dorsal Rootlets
(sensory)
Bupivacaine
Opioids
Clonidine
Dorsal Rootlets
(sensory)
Ziconotide
Ventral Rootlets
(motor)
Ventral Rootlets
(motor)
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
CSF Oscillatory Flow
•
CSF is a POORLY MIXED system
–
Known concentration gradients exist
•
Homovanillic acid concentrations
– 6 x higher in cisternal CSF vs. lumbar CSF
•
Uric acid concentrations
– 2x higher in lumbar than cisternal CSF
–
–
–
CSF motion propelled in opposite directions cyclically
Areas along the spine with no measurable CSF flow
Limited circumferential flow
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
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal
infusion in Pigs. Anesthesiology 2006;105:169-78.
Degrell I, Nagy E: Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid. Biol
Psychiatry 1990; 27:891–6
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Posterior Catheter
Posterior
Lateral
Anterior
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and
Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Pharmacokinetic Determinants
20 μL/hr rate
1 mL/hr rate
1mL/hr bolused
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and
Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
IT Opioid Adverse Effects
•
•
•
•
•
Pruritus: IT>>oral
Peripheral edema
Hypogonadotrophic hypogonadism
Opioid-induced hyperalgesia
IT granuloma
– Total Dose
– Concentration
Hayek, S. et al., Seminars in Pain Medicine 1(4):238-253
16
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
IT Opioid Dose Escalation
Paice J et al., J Pain Symptom Manage 11, 1996
17
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Cancer vs. Non-Cancer:
Limited by Survival
• Of the 119 patients implanted, 15 made it to 13
months
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16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
IT Opioid Escalation (1 y, non-cancer)
1200%
14
12
145%
43%
10
8
6
IT Morphine
Equivalent
(mg)
333%
200%
4
106%
2
Paice 1996
Roberts 2001
Rainov 2001
Dominguez 2002
Shaladi 2007
Atli 2010
0
S2 12 mo post-Implant
S1 Baseline
Study
19
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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
20
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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 desirable
Atkins 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
21
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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 evidence
Ebell 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.
22
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Limited IT Data 
Consensus Statements
23
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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
24
Line 1
th Annual Meeting
16
Morphine
Hydromorphone
Ziconotide
Fentanyl
December 6-9, 2012, Las Vegas, NV
Line 2
Line 3
Line 4
Line 5
Morphine +
bupivacaine
Ziconotide + opioid
Hydromorphone +
bupivacaine
Opioid (morphine, hydromorphone, or fentanyl) +
clonidine
Opioid + clonidine + bupivacaine
Fentanyl + bupivacaine
Sufentanil
Sufentanil + bupivacaine OR clonidine
Sufentanil + bupivacaine + clonidine
2012 Polyanalgesic Algorithm for Intrathecal Therapies in Nociceptive Pain
Line 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
25
Line 1
Morphine
th
Ziconotide
Morphine + Bupivacaine
16 Annual Meeting
December 6-9, 2012, Las Vegas, NV
Hydromorphone + bupivacaine or
Hydromorphone + clonidine
Line 2
Hydromorphone
Line 3
Clonidine
Line 4
Opioid + clonidine + bupivacaine
Line 5
Ziconotide + opioid
Fentanyl
Morphine + clonidine
Fentanyl + bupivacaine
or Fentanyl + clonidine
Bupivacaine + clonidine
Baclofen
2012 Polyanalgesic Algorithm for Intrathecal Therapies in Neuropathic pain
Line 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.
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
26
Nociceptive
16th Annual
Meeting Pain
Line 1
December 6-9,
2012, Las Vegas, NV Ziconotide
Morphine
Hydromorphone
Line 2
Morphine +
bupivacaine
Line 3
Line 4
Line 5
?
Ziconotide + opioid
Hydromorphone +
bupivacaine
Opioid (morphine, hydromorphone, or fentanyl) +
clonidine
Opioid + clonidine + bupivacaine
Fentanyl
Fentanyl + bupivacaine
Sufentanil
Sufentanil + bupivacaine OR clonidine
Sufentanil + bupivacaine + clonidine
• 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?
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
27
Neuropathic
16th Annual
Meeting Pain
Line 1
Line 2
December
NV
Morphine6-9, 2012, Las Vegas,
Ziconotide
Hydromorphone
Morphine + Bupivacaine
Hydromorphone + bupivacaine or
Hydromorphone + clonidine
Morphine + clonidine
Why not?
Line 3
Clonidine
Line 4
Opioid + clonidine + bupivacaine
Line 5
Ziconotide + opioid
Fentanyl
Fentanyl + bupivacaine
or Fentanyl + clonidine
Bupivacaine + clonidine
Baclofen
• Where would “bupivacaine + ziconotide” fall into?
• Why not ziconotide as third line combination agent along with
opioid + bupivacaine?
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
28
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Mean % Change
in VASPI Score
Ziconotide Slow Titration Study
20
18
16
14
12
10
8
6
4
2
0
p=0.003
p=0.121
Week 1
Week 2
p=0.036
Ziconotide
Placebo
Start: 2.4 mg/day Mean
concentration wk 3 =
6.96 mg/day
Week 3*
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
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
29
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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?
30
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Types of Pain
Nociceptive Mixed Neuropathic
Arthritis
Axial Mechanical
Neck/Back Pain
FBSS
Diabetic Neuropathy
Postherpetic Neuralgia
31
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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.”
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
32
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Other Relevant Characteristics?
– Older
– Younger
• Pain Location
– Diffuse
– Localized
• Catheter Location
– Anterior vs. Posterior
– Distance from site of action
Change in intrathecal opioid dose from baseline
(as a % increase from implant date dose)
• Patient Age
IT Morphine equivalent dose increase
(% of baseline)
* p<0.001
1200
800
Morphine group
Morphine+Bupivacaine group
* p<0.05
<50 yrs old
>50 yrs old
600
p<0.055
1000
800
400
600
400
200
200
0
0
3m
6m
12 m
Treatment
(from
implant)
implant date)
from
(months
time time
Treatment
Hayek SM, Veizi E, Narouze S, Mekhail N. Pain Med, 2011 Aug;12(8):1179-89
Veizi E, Hayek SM, Narouze S, Mekhail N. Pope, JE. Pain Med, 2011 Oct;12(10):1481-9
Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351
33
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Baseline Opioid Dose:
IT Microdosing
• Opioid taper over 3-4 weeks
• Opioid free for 5 weeks  trial
• 22 patients, retrospective
Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351
34
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Average Effective Dose = 140 mcg
Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351
35
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
1200%
43%
145%
333%
200%
Baseline
12 months
Paice 1996
Baseline
Roberts 2001
Rainov 2001
Dominguez 2002
106%
Shaladi 2007
Atli 2010
14
12
10
8 139%
6
4
2
0
Grider 2011
IT Amount (mg)
IT Morphine Eq. Dose Escalation
Study
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
Prospective “Microdosing” Study
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.
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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):1179-89
Veizi E, Hayek SM, Narouze S, Mekhail N. Pope, JE. Pain Med, 2011 Oct;12(10):1481-9
Bernards CM. Current Opinion in Anaesthesiology 2004, 17:441–447
38
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
PAC2012 Figure 1. Algorithm for behavioral evaluation of patients considered for intrathecal
therapy for management of pain. (Prepared by Marilyn S. Jacobs, PhD).
39
16th Annual Meeting
Pain Patient
December 6-9, 2012, Las Vegas,forChronic
NV
IDDS Consideration
Cancer vs.
Non-Cancer
Algorithm
Cancer Pain or
Other Painful
Condition with
Limited
Survival
Non-Cancer
Related Pain
Failed Less
Invasive
Modalities
Failed Less
Invasive
Modalities and
Opioid Rotation
No
Yes
Opiod Rotation,
Blocks, Palliative
Care Referral
Effective
Pain Relief
No
Attempt Other
Treatments
Obtain a 2nd
Opinon
Consider
Chronic Pain
Rehabilitation
Programs
Yes
Age >50
No
Yes
No
Yes
No
Pain relief
Expected Survival > 3 months
Continue
Yes
No
Hospice
Yes
Patient Appropriate for IDDS Trial
Repeat as
Needed
No
Favorable Psych Profile
Yes
Patient Appropriate for IDDS Trial
Hayek, SM, ASRA Newsletter, November 2012, 4-6 http://www.asra.com/Newsletters/november-2012.pdf
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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
41
Thank You!!
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
42
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
IT Meds
• FDA Approved
– Morphine
– Ziconotide
– Baclofen (spasticity)
• Standard of care
–
–
–
–
Hydromorphone
Bupivacaine
Clonidine
Fentanyl
43
16th Annual Meeting
December 6-9, 2012, Las Vegas, NV
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 NePcomponent
Freynhagen 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.
44