Download Opioid-induced hyperalgesia and tolerance

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
• 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
Trialing
Dosing
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
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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
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•
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Trial Day 1
Trial Day 1
Trial Day 2
Trial Day 2
Trial Day 3
6 am
6pm
6am
6pm
6am
25 mcg/day morphine
50 mcg/day morphine
100 mcg/day morphine
200 mcg/day morphine
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
IDD
efficacy
Patient
Selection
Trialing
Dosing
• Yaksh et al Reg Anesth
Pain Med 2000
– Over 15 studies all
retrospective
– Several areas of focus
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Drug Selection
Patient Selection
Trialing technique
Starting dose
Efficacy of therapy
Continued management
Early 2000’s Opioid-induced Hyperalgesia
1999-Present
•
Anderson and Burchiel 1999
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Kumar et al Surg Neur 2001
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–
•
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
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–
•
Prospective observational (38 received pump)
10.8 mg/d at 3 years
Atli et al 2010
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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
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•
Starting at 2.5 mg/day progressing to an average of 12 mg/day
30% of subjects continued oral opioids
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
Baseline
3 months
3 years
VAS 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*
• Nomenclature of low vs microdosing is not well established
Opioid-Induced Hyperalgesia
• Three clinical settings to consider
–Maintenance dosing
–High dose therapy
–Low dose therapy
Opponent Process Theory
Opioid-induced hyperalgesia
Pain
tolerance
Opioid-induced analgesia
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
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 VAS
7.3
• Post opioid taper VAS
7.15
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
Functional Assessment
• MPI Pre-opioid taper
• MPI 6 weeks opioid free
• MPI 12 months post implant
60
57
53
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 +/- 1.0
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=8
2.1 +/- 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
8
n=20
n=20
n=19
n=17
n=10
n=2
7
6
VAS
5
4
VAS
3
2
1
0
Initial
25 mcg
50 mcg
100 mcg
200 mcg
400 mcg
Dose Efficacy
9
8
Number of subjects
7
6
5
Subjects at Efficacy
4
3
2
1
0
25 mcg
50 mcg
100 mcg
200 mcg
400 mcg
Post Implant
• One week post implant VAS
3.1 +/- 2.4
– Dose 140 mcg/day
• 12 month follow up VAS
– Dose 335 mcg/day
• Grider et al 2010 Pain Physician
3.9 +/- 2.6
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
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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