Transcript PAIN IN ADDICTION - StopRxDrugAbuse.org

Opioid Induced Hyperalgesia
Walter Ling MD
Integrated Substance Abuse Programs
UCLA
[email protected]
APA annual meeting
New York NY
May 3, 2004
Opioid Induced Hyperalgesia
• Hyperalgesia: Exaggerated response to
noxious stimuli
• Allodynia: Normally innocuous stimuli
produce pain
Hyperalgesia: Why Bother?
• Common among patients
– More patients taking opioids
• Chronic pain &/or opioid addiction
• Opioid prescription use and abuse
• Universal to opioid use
• Confuses clinical picture
• Complicates pain management
Chronic Opioid Exposure
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Tolerance
Dependence
Abstinence
Addiction
Hyperalgesia
Hyperalgesia
• Opioid administration, in particular
chronic administration, induced
hyperalgesia & tolerance
• Related but distinct from tolerance
• Sensitization vs desensitization
• Shared mechanism with chronic,
neuropathic pain
• Confusing pain assessment and
management
Factors reducing opioid analgesia
• Loss of opioid receptors
• Disrupted synergy between supra-spinal and
spinal opioid systems
• Anti-opioid peptides
• Non-opioid mechanisms (NMDA)
• Tolerance
• A beta-fiber-mediated allodynia
• Opioid induced hyperalgesia
Tolerance &hyperalgesia:
common mechanisms
NMDA Receptor Activation from
Persistent Pain & Opioid
Administration: I
• Ca+ + influx
– PKC mediated phosphorylation
• NMDA receptor
• Mu opioid receptor
– NO & superoxides
• Dark neurons
• Dynorphine A release
– Release of nociceptive neurotransmitters
• Glutamate, substance P, CGRP
NMDA Receptor Activation from
Persistent Pain & Opioid
Administration: II
• Production of anti-opioids
– Vasopressin, oxytocin, nociceptin, NPFF,
CCK
• Mu receptor desensitization
– G protein coupled receptor kinases
•  arrestin,  adrenergic receptor kinases
–  receptor agonists
– / opioid receptor complexes
Methadone maintenance
patients: pain sensitivity (CPT)
COLD PRESSOR TEST
70
Time (seconds)
60
50
Control
MM
40

30
***
20
10
0
***
Detection
Tolerance
0 HOURS
Detection
***p<0.0001
 p<0.0001

*
*p=0.023
Tolerance
3 HOURS
ELECTRICAL STIMULATION
70
*

60
**
50
Volts


40
* p=0.015
** p=0.013
***p<0.0001
 p<0.0001
***
30
20
10
0
Detection
Tolerance
0 HOURS
Detection
Control
MM
Tolerance
3 HOURS
Morphine in MM patients
COLD PRESSOR TEST
140
Tolerance
(seconds)
120
Methadone (trough)
Methadone (peak)
Control
100
80
60
40
20
0
0
10
20
30
40
50
Plasma morphine (ng/ml)
60
HIGH DOSE MORPHINE: CP TEST
RESPONSE BY STIMULUS
INTENSITY
Hyperalgesia: methadone
Hyperalgesia/
Controls
maintenance
Pain
Tolerance
Response
Pain
Threshold
Stimulus Intensity
Allodynia
Opponent Process Theory
Opioid-induced hyperalgesia
Pain
tolerance
Opioid-induced
analgesia
OIH vs Pre-existing Pain
• Increase in pain intensity with further
opioid administration
• Decrease in pain threshold/tolerance
• Changing slope between threshold and
tolerance ?
• Diffused pain extending beyond
distribution of pre-existing pain
• Presence of allodynia?
Lots of Unknown
• More research on hyperalgesia:
– What opioids make a difference, if any?
– Route and manner of administration matter?
– How much and for how long?
• Can we separate hyperalgesia from tolerance?
• Can we prevent or reverse hyperalgesia?
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NMDA receptor antagonists
NK1 antagonists
Opioids of different receptor mechanisms
Combining with ultra low dose antagonists
Morphia:
Hyperalgesia & allodynia
• If any man want to learn sympathetic
charity, let him keep pain subdued for six
months by morphia, and then make the
experiment of giving up the drug. By this
time he will have become irritable, nervous
and cowardly. The nerves, muffled, so to
speak, by narcotics, will have grown to be
not less sensitive, but acutely, abnormally
capable of feeling pain and of feeling as
pain a multitude of things not usually
competent to cause it.
S.W. Mitchell
Overcoming OIH
“Turning off” hyperalgesia
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PKC inhibitors: gangliosides
NMDA Antagonists
NOS inhibitors
Calcium channel antagonists
Orphanin/FQ (nociceptin) receptor modulators
NK antagonists
Dynorphin modulators
Ultra-low dose antagonists
Overcoming Opioid Tolerance &
Hyperalgesia: Promising Examples
• NMDA receptor antagonists
• Opioids with novel receptor mechanisms
• Combining opioid agonists with ultra low
dose antagonists
– Morphine /naltrexone
– Buprenorphine/ORL antagonist
NMDA receptor antagonist:
ketamine
MM (S+)-ket)
Control (S(+)-ket)
Tolerance
(seconds)
110
MM (S(+)-ket + morphine)
Control (S(+)-ket + morphine)
COLD PRESSOR TEST
90
70
50
30
10
0
1
2
3
4
5
Time (hours)
6
7
Agonists acting on different receptor
mechanisms: oxycodone & morphine
antinocoception after selective mu antagonist
naloxonazine administration
Co-administration of ultra low dose
NTX with morphine
Clinical Implications
• Analogy with TD?
• Ultra-rapid detoxification?
Detoxification
Detoxification is good for a lot of things;
staying off drugs is not one of them.
Thanks to
National Institute on Drug Abuse
You the audience