Intrathecal Consensus Statement: Applicable to all patients?

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. Research/Fellowship Support Medtronic Relevant Conflicts of Interest

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

4. Patient Selection is Critical 

5. 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, EtscheidtMA, Pain Physician 2011; 14:343-351 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 Patient Selection--Challenges

6. 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 IT Medication--Considerations

7. Opioids Clonidine Ziconotide Bupivacaine Synapses Mechanism of Action—IT Meds • CSF ~ ISF • Most receptors are in the substantiagelatinosa 1-2 mm from surface of dorsal horn • Hydrophilic>Hydrophobic • Longer ½ life • Deeper penetration • Smaller volume of distribution • Rostral spread Kroin JS. Clin.Pharmacokinet. 22:319-326, 1992 Nordberg G. ActaAnaesthesiol.Scand.Suppl 79:1-38, 1984

8. 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

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

10. Bupivacaine Opioids Clonidine Ziconotide

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

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

13. 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.

14. 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.

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

16. Hayek, S. et al., Seminars in Pain Medicine 1(4):238-253 Pruritus: IT>>oral Peripheral edema Hypogonadotrophichypogonadism Opioid-induced hyperalgesia IT Opioid Adverse Effects • IT granuloma • Total Dose • Concentration

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

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

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 guidelinesmay be helpful • RCT’s  highest level of evidence • Observational studies intermediate • Expert opinion and consensus guidelines lowest level of evidence EbellMH, 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.

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. 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 sufentanilmonotherapy. 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

26. 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

27. 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? 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. Neuropathic Pain 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. 2012 Sep;15(5):436-466

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 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

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 • 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. 2012 Sep;15(5):436-466

33. * p<0.001 * p<0.05 p<0.055 Other Relevant Characteristics? • Patient Age • Older • Younger • Catheter Location • Anterior vs. Posterior • Distance from site of action • Pain Location • Diffuse • Localized 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

34. Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351 Opioid taper over 3-4 weeks Opioid free for 5 weeks  trial 22 patients, retrospective Baseline Opioid Dose: IT Microdosing

35. Grider J Harned ME, Etscheidt MA, Pain Physician 2011; 14:343-351 Average Effective Dose = 140 mcg

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

37. Prospective “Microdosing” Study Hamza Met 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.

38. Age: > 50 y.o.  lesser escalation Starting dose opioids:  better IT bupivacaine Adding bupivacaine to IT opioids may not improve pain scores or QoL StartingIT bupivacaine concomitantly with IT opioids appears to blunt opioid dose escalation Limiting IT Opioid 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

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

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

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. CurrMed Res Opin. 2006 Oct;22(10):1911-20.