Opioid Induced Hyperalgesia

Walter Ling MD

Integrated Substance Abuse Programs

UCLA

lwalter@ucla.edu

APA annual meetingNew 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

• 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)

Morphine in MM patients

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Methadone (trough)Methadone (peak)Control

COLD PRESSOR TEST

Plasma morphine (ng/ml)

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HIGH DOSE MORPHINE: CP TEST

RESPONSE BY STIMULUS INTENSITY

Response

Stimulus Intensity

Pain Threshold

Pain Tolerance

Controls Hyperalgesia: methadone maintenance

Hyperalgesia/ Allodynia

Opponent Process Theory

Pain tolerance

Opioid-induced analgesia

Opioid-induced hyperalgesia

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?

– 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

• 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

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MM (S+)-ket)Control (S(+)-ket)

COLD PRESSOR TEST

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Control (S(+)-ket + morphine)

Time (hours)

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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