1. 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

2. Relevant Conflicts of Interest
Research/Fellowship Support
Medtronic

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

4. Patient Selection is Critical

5. 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
When to Consider Intrathecal Pain Therapy
It is generally appropriate to consider intrathecal pain therapy for patients suffering from chronic pain when these factors exist.
Objective evidence of pathology.
If they fail to achieve adequate results from oral opioid therapy or are unable to tolerate the side effects of oral opioids.
If these patients are committed and able to comply with the requirements of intrathecal pain therapy, they must first undergo a psychological evaluation before proceeding to a screening test.
Krames E. Journal of Pain and Symptom Management;1996, Vol 11, No 6:
Hayek SM, Veizi E, Narouze S, Mekhail N. Pain Med, 2011 Aug;12(8):
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:

6. 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

7. Mechanism of Action—IT Meds
Opioids
Clonidine
Ziconotide
CSF ~ ISF
Most receptors are in the substantia gelatinosa 1-2 mm from surface of dorsal horn
Bupivacaine
Synapses
Hydrophilic>Hydrophobic
Longer ½ life
Deeper penetration
Smaller volume of distribution
Rostral spread
Kroin JS. Clin.Pharmacokinet. 22: , Nordberg G. Acta Anaesthesiol.Scand.Suppl 79:1-38, 1984

8. Partition coefficient Elimination half-life (h)
Partition coefficient
Elimination half-life (h)
Lumbar to cisternal [CSF]
Morphine
1.4
Clonidine
7.1
3.2
Baclofen
0.1
1.5
4.1
Sufentanil Citrate
1788 --
Fentanyl Citrate
813
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 Volume 99 - Issue 2 - pp
Hayek, S. et al., Seminars in Pain Medicine 1(4):

9. 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: , 1993

10. Bupivacaine
Opioids
Clonidine
Ziconotide

11. Bupivacaine Dorsal Rootlets (sensory) Dorsal Rootlets (sensory)
Opioids
Clonidine
Ziconotide
DRG
DRG
Ventral Rootlets
(motor)
Ventral Rootlets
(motor)

12. 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
Homovanillic acid concentrations
6 x higher in cisternal CSF as compared to lumbar CSF
Uric acid concentrations
2x higher in lumbar than cisternal CSF
Degrell I, Nagy E: Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid. Biol Psychiatry 1990; 27:891–6
Henry-Feugeas MC, Idy-Peretti I, Baledent O et al. Origin of Subarachnoid CerebrospinalFluid Pulsations: a phase-contrast MR analysis. Magnetic Resonance Imaging (18)
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105:
Degrell I, Nagy E: Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid. Biol Psychiatry 1990; 27:891–6 12

13. Posterior Catheter Posterior Lateral Anterior
Pilot study with methylene blue, infused at 20microliters/hr x 8 hours
A-posterior
B-lateral
C-anterior
Predominance in posterior and lateral locations with limited rostrocaudal spread.
Anterior
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and
Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105: 13

14. Pharmacokinetic Determinants
20 μL/hr rate
1 mL/hr rate
1mL/hr bolused
Clearly distribution along the craniocaudal sampling sites:
1. striking is anterior/posterior difference
2. distance from infusion location
3. None were detected within the cerebral spinal group
Drug concentration differed by both distance from infusion site and posterior>anterior concentration, although anterior concentration was higher in the 1mL and bolus groups as compared to the 20 microliter group
Baclofen was similar in distribution from site of infusion, with greater circumferential spread than bupivacaine
The bolus group did not differ from the 1mL/min group in terms of drug distribution
Bernards, CM. Cerebrospinal Fluid and Spinal Cord Distribution of Baclofen and
Bupivacaine during slow intrathecal infusion in Pigs. Anesthesiology 2006;105: 14

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

16. IT Opioid Adverse Effects
IT granuloma
Total Dose
Concentration
Pruritus: IT>>oral
Peripheral edema
Hypogonadotrophic hypogonadism
Opioid-induced hyperalgesia
Hayek, S. et al., Seminars in Pain Medicine 1(4):

17. IT Opioid Dose Escalation
Paice J et al., J Pain Symptom Manage 11, 1996

18. Cancer vs. Non-Cancer: Limited by Survival
Of the 119 patients implanted, 15 made it to 13 months

19. IT Opioid Escalation (1 y, non-cancer)
1200%
145%
43%
(mg)
333%
200%
106%
12 mo post-Implant
Baseline

20. 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

21. 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

22. 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):

23. Limited IT Data  Consensus Statements

24. 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

25. Morphine Hydromorphone Ziconotide Fentanyl
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 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 Sep;15(5):

26. Morphine + Bupivacaine
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 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 Sep;15(5):

27. ? Nociceptive Pain Fentanyl: 1st line based on safety only
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
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 Sep;15(5):

28. Morphine + Bupivacaine
Neuropathic Pain
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
Why not?
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 Sep;15(5):

29. Ziconotide Slow Titration Study
p=0.003
p=0.036
p=0.121
Start: 2.4 mg/day Mean concentration wk 3 = 6.96 mg/day
Additionally, the FDA conducted analysis of the primary endpoint, using the intent-to-treat population. There results are recorded in the US PI. There was also a statistically significant difference in this analysis. The mean percent change in VASPI score from baseline with the ziconotide group having a 12% mean improvement at Week 3 compared to a 5% mean improvement in the placebo group (p=0.04). The 95% CI for the treatment difference (ziconotide – placebo) was 0.4%, 13%.
1. Webster L. Efficacy of intrathecal ziconotide for the treatment of severe chronic pain in adults. Pain Medicine. 2005;6(2):195.
ELAN APPROVED: November 2005
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 A Randomized, Double-Blind, Placebo-Controlled Study of Intrathecal Ziconotide in Adults with Severe Chronic Pain. J Pain Symptom Manage, 31:

30. 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?

31. Types of Pain Nociceptive Mixed Neuropathic FBSS Arthritis
Axial Mechanical Neck/Back Pain
FBSS
Diabetic Neuropathy
Postherpetic Neuralgia

32. 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 Sep;15(5):

33. Other Relevant Characteristics?
p<0.055
* p<0.001
* p<0.05
Patient Age
Older
Younger
Pain Location
Diffuse
Localized
Catheter Location
Anterior vs. Posterior
Distance from site of action
Hayek SM, Veizi E, Narouze S, Mekhail N. Pain Med, 2011 Aug;12(8):
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:

34. 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:

35. Average Effective Dose = 140 mcg
Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:

36. 43%
145%
200%
1200%
106%
333%
139%

37. 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 Jul 30. 

38. 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):
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

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

40. Cancer vs. Non-Cancer Algorithm
Chronic Pain Patient for IDDS Consideration
Cancer vs. Non-Cancer Algorithm
Cancer Pain or Other Painful Condition with Limited Survival
Failed Less Invasive Modalities and Opioid Rotation
Non-Cancer Related Pain
Failed Less Invasive Modalities No
Attempt Other Treatments
Obtain a 2nd Opinon
Consider Chronic Pain Rehabilitation Programs
Repeat as Needed
Yes
Pain relief No
Age >50
Yes
Favorable Psych Profile
Patient Appropriate for IDDS Trial
Yes
Opiod Rotation, Blocks, Palliative Care Referral
Continue
Effective Pain Relief No No
Expected Survival > 3 months
Yes No
Hospice No
Patient Appropriate for IDDS Trial
Yes
Hayek, SM, ASRA Newsletter, November 2012, 4-6

41. 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

42. Thank You!!
PACC 2012

43. IT Meds FDA Approved Standard of care Morphine Ziconotide
Baclofen (spasticity)
Standard of care
Hydromorphone
Bupivacaine
Clonidine
Fentanyl

44. 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 Oct;22(10):