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

Relevant Conflicts of Interest Research/Fellowship Support Medtronic

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

Patient Selection is Critical 

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: 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

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

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

Partition coefficient Elimination half-life (h)   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 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 2003 - Volume 99 - Issue 2 - pp 455-465 Hayek, S. et al., Seminars in Pain Medicine 1(4):238-253

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

Bupivacaine Opioids Clonidine Ziconotide

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

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. 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 12

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;105:169-78. 13

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;105:169-78. 14

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. 2011 Feb;112(2):460-4

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):238-253

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

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

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

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

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

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.

Limited IT Data  Consensus Statements

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

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. 2012 Sep;15(5):436-466

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. 2012 Sep;15(5):436-466

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

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. 2012 Sep;15(5):436-466

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. 2006. A Randomized, Double-Blind, Placebo-Controlled Study of Intrathecal Ziconotide in Adults with Severe Chronic Pain. J Pain Symptom Manage, 31:393-406

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?

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

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

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):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

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

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

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

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. 

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

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

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

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

Thank You!! PACC 2012

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

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.