1. Jay S Grider DO/PhD Division Chief, Pain Medicine and Regional Anesthesia Medical Director, UKHealthCare Pain Services Associate Professor, Department of Anesthesiology University of Kentucky College of Medicine Lexington, KY

2. Disclaimers Vertos Medical: Educational Trainer

3. Myths and Legends

6. Microdosing df A concept that attempts to maximize therapeutic and functional benefit for the patient by minimizing the total opioid dose – Patient selection – Psychological mindset – Trialing method – Post-implant patient management scheme

7. Stages of Theory Building Observation- Describing a phenomena and documenting results goal is stimulate discussion and activity Classification- Researchers simplify and organize the phenomena based upon it’s attributes Definition- In depth description of the relationship and categorizing the outcomes. – Carlile and Christensen, Harvard Review, 2010 Criticism- Microdosing as an untried unverified therapeutic approach – Harden RN, Argoff CE, Williams DA, Pain Med 2012

8. IDD 2012 IDD has experienced no growth while oral opioid therapy has exploded – Implant morbidity and mortality – Coffey et al Pain Med 2010 – Inconvenience – Granuloma – Deer et al Neuromodulation 2012 – Ramsey, Witt, Grider et al Pain Physician 2008 – Combo therapy (oral + intrathecal) – Patient satisfaction- lack of control – Expense/Reimbursement

9. IDD 2012 IDD efficacy Patient population Patient Selection Patient management

10. IDD 2004 IDD efficacy Patient Selection DosingTrialing

11. Microdosing Timeline 1960’s-70’s – William R Martin MD/PHD

12. Microdosing Timeline 1960’s-80’s – William R Martin MD/PHD 1990’s – Scott Hamman MD/PhD – Joe Holtman MD/PhD

13. Microdosing Timeline 1960’s-70’s – William R Martin MD/PHD 1990’s – Scott Hamman MD/PhD and Joe Holtman MD/PhD Early 2000’s – William O Witt MD

14. Original Idea Dr William Witt – Director Emeritus Pain Medicine Program University of Kentucky

15. Original Idea Dr William Witt – Director Emeritus Pain Medicine Program University of Kentucky

16. Witt Microdosing Protocol Opioid-free interval for 6 weeks Behavioral evaluation with testing Functional evaluation with PT pre-during trial Inpatient intrathecal trial Starting dose 25 mcg/day morphine Every 12 hours double dose to VAS less than 4 Observe 24 at efficacious dose Implant at efficacious dose

17. Protocol Trial Day 1 6 am 25 mcg/day morphine Trial Day 1 6pm 50 mcg/day morphine Trial Day 2 6am 100 mcg/day morphine Trial Day 2 6pm 200 mcg/day morphine Trial Day 3 6am 400 mcg/day morphine

18. Opioid Pharmacology Dorsal horn effects Supraspinal effects Emotional and addiction centers

19. Descending Modulation Receptors –Opioid Mu, Kappa, Delta Laminea 2 Pre and post synaptic –Arachadonic acid metabolites Central processing

20. Intrathecal Opioid Yaksh et al Reg Anesth Pain Med 2000 – Over 15 studies all retrospective – Several areas of focus Drug Selection Patient Selection Trialing technique Starting dose Efficacy of therapy Continued management IDD efficacy Patient Selection DosingTrialing

23. Early 2000’s Opioid-induced Hyperalgesia

24. 1999-Present Anderson and Burchiel 1999 Starting at 2.5 mg/day progressing to an average of 12 mg/day 30% of subjects continued oral opioids Kumar et al Surg Neur 2001 – 25 patients with best results in deafferentation and mixed pain – Initial dose average 1.1 mg/d increased by 6 months to 3.1 mg/d Thimineur et al Pain 2004 – Prospective observational (38 received pump) – 10.8 mg/d at 3 years Atli et al 2010 6.5 mg/d starting dose 12.2 mg/d yr 3 Higher oral opioid consumption correlated with a lower likelihood of long term relief with IT opioids Duarte et al 2012 – Created a predictive model for dose escalation – 0.8 mg/d starting dose – By year 3 between 2.5-3 mg/d – Dose escalation leveled off after yr3 – stable through year 6 Deer et al Consensus Conference Neuromodulation 2012 – Trialing doses Low (our studies but often in the 1-3 mg range) – Recommendations - 0.1-0.5 mg/d

25. Recent Low-dose Study Hamza, Doleys et al Pain Med 2012 * Morphine equivalents Nomenclature of low vs microdosing is not well established Baseline3 months3 years VAS average7.47----------------4.02 Oral opioid dose 128.9 mg/d*3.8 mg/d*-------------------- IT dose1.4 mg/d*-----------------1.48 mg/d*

26. Opioid-Induced Hyperalgesia Three clinical settings to consider – Maintenance dosing – High dose therapy – Low dose therapy

27. Opponent Process Theory Pain tolerance Opioid-induced analgesia Opioid-induced hyperalgesia Concept by Walter Ling PhD

28. OIH/Tolerance Reversibility Opioid addicts in detox – At four weeks no reversibility Pud et al Drug Alcohol Dependence 2006 – At 6 months however reversibility was demonstrated Compton J Pain Symptom Mgt 1994 Hay Proceedings Aust Soc Clin Exp Pharm 2003

29. Opioid-Induced Hyperalgesia Three clinical settings to consider – Maintenance dosing – High dose therapy – Low dose therapy

30. OIH Low Dose Opioid Systemically Opioid agonist systemically in mcg concentrations can ->OIH like picture Opioid antagonist in mcg-pcg range can result in profound analgesia Hamman et al 2005 Mediated by the opioid receptor Clinical significance of this is lies in the opioid taper

31. Low Dose Hyperalgesia

32. Witt Microdosing Protocol Opioid-free interval for 6 weeks Behavioral evaluation with testing Functional evaluation with PT pre-during trial Inpatient intrathecal trial Starting dose 25 mcg/day morphine Every 12 hours double dose to VAS less than 4 Observe 24 at efficacious dose Implant at efficacious dose

33. Protocol Outcomes Pre opioid taper VAS 7.3 Post opioid taper VAS 7.15

34. Witt Microdosing Protocol Opioid-free interval for 6 weeks Behavioral evaluation with testing Functional evaluation with PT pre-during trial Inpatient intrathecal trial Starting dose 25 mcg/day morphine Every 12 hours double dose to VAS less than 4 Observe 24 at efficacious dose Implant at efficacious dose

35. Functional Assessment MPI Pre-opioid taper60 MPI 6 weeks opioid free57 MPI 12 months post implant53

36. Functional Assessment VAS reported by PT/OT during trial At rest Supine to sitting Sitting to standing Gait Lower body dressing Picking up object from floor Overhead reaching Overall VAS at efficacy Initial 7.3 +/- 1.07.8 +/- 0.77.3 +/- 0.67.4 +/- 1.27.7 +/- 1.47.2 +/- 0.87.5 +/- 0.9n=0 25 mcg/day (n=20) 6.1 +/- 1.05.8 +/- 0.85.9 +/- 2.45.8 +/- 0.15.9 +/- 1.86.9 +/- 2.24.8 +/- 2.8n=0 50 mcg/day (n=19) 3.2+/- 0.24.0 +/- 1.24.1 +/- 2.23.8 +/-2.54.6 +/- 1.75.2 +/- 1.95.1 +/-2.4n=0 100 mcg/day (n=17) 2.8 +/- 1.93.8 +/-0.62.8 +/- 0.83.2 +/-0.32.9 +/-0.63.8 +/- 2.61.8 +/- 2.6n=7 200 mcg/day (n=10) 1.1 +/- 1.2*1.9 +/- 1.5*2.5 +/- 1.1*2.2 +/- 0.9*1.8 +/- 1.3*3.8 +/- 2.6*1.4 +/- 1.2*n=8 2.1 +/- 0.9*

37. Witt Microdosing Protocol Opioid-free interval for 6 weeks Behavioral evaluation with testing Functional evaluation with PT pre-during trial Inpatient intrathecal trial Starting dose 25 mcg/day morphine Every 12 hours double dose to VAS less than 4 Observe 24 at efficacious dose Implant at efficacious dose

38. Dose-Response

39. Dose Efficacy

40. Post Implant One week post implant VAS3.1 +/- 2.4 – Dose 140 mcg/day 12 month follow up VAS3.9 +/- 2.6 – Dose 335 mcg/day Grider et al 2010 Pain Physician

41. Recent Data 30 months Retrospective – VAS 4.7 +/- 2.4 – 356 mcg/day daily dose UK IRB # 08-0921- P6H 12 month Observational Prospective – VAS implant 3-4 range: Dosing 211 mcg/d – VAS 12 months3-4 range: Dosing 256 mcg/d – MPI Severity 57 to 50 – MPI Interference 53 to 48 UK IRB # 08-0921-P6H

42. Outcomes No patients on oral opioids Minimal dose titration No dose-related side effects Excellent patient satisfaction Improved functional status

43. Future Studies Possible gender effect – Females may benefit from intrathecal opioids more than males Holtman and Walla, Anesthesiology 2009 Hamman et al Receptors and Channels, 2004 Different pain states Effect of flow rate Better monitoring of functional improvement using SF-12v2 Prospective intrathecal vs oral opioids