Opioid Induced Hyperalgesia Walter Ling MD Integrated Substance

Opioid Induced Hyperalgesia Walter Ling MD Integrated Substance Abuse Programs UCLA lwalter@ucla. edu 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 • • • 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

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? – – NMDA receptor antagonists NK 1 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

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 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