Intrathecal Microdosing: Fact or fiction?

1. Intrathecal Microdosing: Fact or fiction? 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

4. Myths and Legends

5. 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

10. IDD 2004

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

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

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

27. Opponent Process Theory Opioid-induced hyperalgesia Pain tolerance Opioid-induced analgesia 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 taper 60 • MPI 6 weeks opioid free 57 • MPI 12 months post implant 53

36. Functional Assessment

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 VAS 3.1 +/- 2.4 • Dose 140 mcg/day • 12 month follow up VAS 3.9 +/- 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