INTRATHECAL MICRODOSING: FACT OR FICTION?

Jay S Grider DO/PhDDivision Chief, Pain Medicine and Regional Anesthesia

Medical Director, UKHealthCare Pain ServicesAssociate Professor, Department of Anesthesiology

University of Kentucky College of MedicineLexington, KY

Disclaimers

• Vertos Medical: Educational Trainer

Myths and Legends

Myths and Legends

Myths and Legends

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

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

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

IDD 2012

IDD efficacy

Patient population

Patient Selection

Patient management

IDD 2004

IDD efficacy

Patient Selection

DosingTrialing

Microdosing Timeline

• 1960’s-70’s– William R Martin MD/PHD

Microdosing Timeline

• 1960’s-80’s– William R Martin MD/PHD

• 1990’s– Scott Hamman MD/PhD– Joe Holtman MD/PhD

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

Original Idea

• Dr William Witt – Director Emeritus

Pain Medicine Program University of Kentucky

Original Idea

• Dr William Witt – Director Emeritus

Pain Medicine Program University of Kentucky

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

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

Opioid Pharmacology

• Dorsal horn effects• Supraspinal effects• Emotional and addiction

centers

Descending Modulation

• Receptors– Opioid

• Mu, Kappa, Delta• Laminea 2 • Pre and post synaptic

– Arachadonic acid metabolites

Central processing

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

Early 2000’s Opioid-induced Hyperalgesia

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

Recent Low-dose Study

• Hamza, Doleys et al Pain Med 2012

* Morphine equivalents

• Nomenclature of low vs microdosing is not well established

Baseline 3 months 3 yearsVAS average 7.47 ---------------- 4.02

Oral opioid dose

128.9 mg/d* 3.8 mg/d* --------------------

IT dose 1.4 mg/d* ----------------- 1.48 mg/d*

Opioid-Induced Hyperalgesia

• Three clinical settings to consider–Maintenance dosing–High dose therapy–Low dose therapy

Opponent Process Theory

Pain tolerance

Opioid-induced analgesia

Opioid-induced hyperalgesia

Concept by Walter Ling PhD

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

Opioid-Induced Hyperalgesia

• Three clinical settings to consider–Maintenance dosing–High dose therapy–Low dose therapy

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

Low Dose Hyperalgesia

Series1

Opioid Plasma Concentration

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

Protocol Outcomes

• Pre opioid taper VAS7.3

• Post opioid taper VAS7.15

Series1

Opioid Plasma Concen-tration

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

Functional Assessment

• MPI Pre-opioid taper60

• MPI 6 weeks opioid free57

• MPI 12 months post implant53

Functional AssessmentVAS 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 +/- 1.0 7.8 +/- 0.7 7.3 +/- 0.6 7.4 +/- 1.2 7.7 +/- 1.4 7.2 +/- 0.8 7.5 +/- 0.9 n=0

25 mcg/day (n=20)

6.1 +/- 1.0 5.8 +/- 0.8 5.9 +/- 2.4 5.8 +/- 0.1 5.9 +/- 1.8 6.9 +/- 2.2 4.8 +/- 2.8 n=0

50 mcg/day(n=19)

3.2+/- 0.2 4.0 +/- 1.2 4.1 +/- 2.2 3.8 +/-2.5 4.6 +/- 1.7 5.2 +/- 1.9 5.1 +/-2.4 n=0

100 mcg/day(n=17)

2.8 +/- 1.9 3.8 +/-0.6 2.8 +/- 0.8 3.2 +/-0.3 2.9 +/-0.6 3.8 +/- 2.6 1.8 +/- 2.6 n=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=82.1 +/- 0.9*

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

Dose-Response

Initial 25 mcg 50 mcg 100 mcg 200 mcg 400 mcg0

1

2

3

4

5

6

7

8

VASVAS

n=20 n=20 n=19 n=17 n=10 n=2

Dose Efficacy

25 mcg 50 mcg 100 mcg 200 mcg 400 mcg0

1

2

3

4

5

6

7

8

9

Subjects at Efficacy

Num

ber o

f sub

ject

s

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

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

Outcomes

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

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