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
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. Disclaimers. - PowerPoint PPT Presentation
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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
• 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
• 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