1. Opioid Induced Hyperalgesia Walter Ling MD Integrated Substance Abuse Programs UCLA lwalter@ucla.edu APA annual meeting New York NY May 3, 2004

2. Opioid Induced Hyperalgesia Hyperalgesia: Exaggerated response to noxious stimuli Allodynia: Normally innocuous stimuli produce pain

3. 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

4. Chronic Opioid Exposure Tolerance Dependence Abstinence Addiction Hyperalgesia

5. 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

6. 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

7. Tolerance &hyperalgesia: common mechanisms

8. 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

9. 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

10. Methadone maintenance patients: pain sensitivity (CPT)

12. Morphine in MM patients

13. HIGH DOSE MORPHINE: CP TEST

14. RESPONSE BY STIMULUS INTENSITY Response Stimulus Intensity Pain Threshold Pain Tolerance Controls Hyperalgesia: methadone maintenance Hyperalgesia/ Allodynia

15. Opponent Process Theory Pain tolerance Opioid-induced analgesia Opioid-induced hyperalgesia

16. 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?

17. 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

20. 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

21. 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

22. 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

23. NMDA receptor antagonist: ketamine

24. Agonists acting on different receptor mechanisms: oxycodone & morphine antinocoception after selective mu antagonist naloxonazine administration

25. Co-administration of ultra low dose NTX with morphine

26. Clinical Implications Analogy with TD? Ultra-rapid detoxification?

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

28. Thanks to National Institute on Drug Abuse You the audience