Opioid Induced Hyperalgesia

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Opioid Induced Hyperalgesia

• Walter Ling MD
• Integrated Substance Abuse Programs
• UCLA
• lwalter_at_ucla.edu
• APA annual meeting
• New York NY
• May 3, 2004

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Opioid Induced Hyperalgesia

• Hyperalgesia Exaggerated response to noxious
  stimuli
• Allodynia Normally innocuous stimuli produce
  pain

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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

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Chronic Opioid Exposure

• Tolerance
• Dependence
• Abstinence
• Addiction
• Hyperalgesia

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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

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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

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Tolerance hyperalgesiacommon mechanisms
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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

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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

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Methadone maintenance patients pain sensitivity
(CPT)
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Morphine in MM patients
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HIGH DOSE MORPHINE CP TEST
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RESPONSE BY STIMULUS INTENSITY
Hyperalgesia methadone maintenance
Hyperalgesia/ Allodynia
Controls
Pain Tolerance
Response
Pain Threshold
Stimulus Intensity
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Opponent Process Theory
Opioid-induced hyperalgesia
Pain tolerance
Opioid-induced analgesia
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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?

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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?
• NMDA receptor antagonists
• NK1 antagonists
• Opioids of different receptor mechanisms
• Combining with ultra low dose antagonists

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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

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Overcoming OIH

• Turning off hyperalgesia
• PKC inhibitors gangliosides
• NMDA Antagonists
• NOS inhibitors
• Calcium channel antagonists
• Orphanin/FQ (nociceptin) receptor modulators
• NK antagonists
• Dynorphin modulators
• Ultra-low dose antagonists

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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

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NMDA receptor antagonist ketamine
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Agonists acting on different receptor mechanisms
oxycodone morphine antinocoception after
selective mu antagonist naloxonazine
administration
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Co-administration of ultra low dose NTX with
morphine
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Clinical Implications

• Analogy with TD?
• Ultra-rapid detoxification?

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Detoxification

• Detoxification is good for a lot of things
  staying off drugs is not one of them.

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Thanks to
National Institute on Drug Abuse You the audience