intrathecal consensus statement: applicable to all patients?
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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. Research/Fellowship Support Medtronic. - PowerPoint PPT PresentationTRANSCRIPT
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
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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
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OpioidsClonidineZiconotide
Bupivacaine
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OpioidsClonidineZiconotide
Bupivacaine
DRGDRG
Dorsal Rootlets(sensory) Dorsal Rootlets
(sensory)
Ventral Rootlets(motor)
Ventral Rootlets(motor)
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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 CSFCSF 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
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Posterior Catheter
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:169-78.
Posterior
Lateral
Anterior
16th Annual Meeting December 6-9, 2012, Las Vegas, NV
Pharmacokinetic Determinants20 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.
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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
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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
Sha
ladi
200
7
Dom
ingu
ez 2
002
Rai
nov
2001
Rob
erts
200
1
Pai
ce 1
996
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.
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 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
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
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
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
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
02468
101214161820
Week 1 Week 2 Week 3*
Mea
n %
Cha
nge
in V
ASP
I Sco
re
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.”
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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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
trath
ecal
opi
oid
dose
from
bas
elin
e (a
s a
% in
crea
se fr
om im
plan
t dat
e do
se)
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
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Baseline Opioid Dose: IT Microdosing
• Opioid taper over 3-4 weeks• Opioid free for 5 weeks trial• 22 patients, retrospective
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Average Effective Dose = 140 mcg
16th Annual Meeting December 6-9, 2012, Las Vegas, NV
Grid
er 2
011
Atli
2010
Shala
di 2
007
Domi
ngue
z 20
02
Raino
v 200
1
Robe
rts 2
001
Paice
1996
Baseline
02468
101214IT
Amo
unt
(mg)
Study
I T Morphine Eq. Dose Escalation
Baseline12 months
43% 145%
200%
1200%
106%
333%139%
16th Annual Meeting December 6-9, 2012, Las Vegas, NV
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
16th Annual Meeting December 6-9, 2012, Las Vegas, NV
39PAC2012 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
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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.