Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information

Pain. 2012 Jun;153(6):1232-1243. doi: 10.1016/j.pain.2012.02.035. Epub 2012 Apr 13.


The mechanisms supporting temporal processing of pain remain poorly understood. To determine the involvement of opioid mechanisms in temporal processing of pain, responses to dynamic noxious thermal stimuli and offset analgesia were assessed after administration of naloxone, a μ-opioid antagonist, and on a separate day, during and after intravenous administration of remifentanil, a μ-opioid agonist, in 19 healthy human volunteers. Multiple end points were sampled from real-time computerized visual analog scale ratings (VAS, 1 to 10) to assess thermal sensitivity, magnitude and duration of offset analgesia, and painful after sensations. It was hypothesized that the magnitude of offset analgesia would be reduced by direct opioid antagonism and during states of acute opioid-induced hypersensitivity (OIH), as well as diminished by the presence of exogenous opioids. Surprisingly, the magnitude of offset analgesia was not altered after naloxone administration, during remifentanil infusion, or after the termination of remifentanil infusion. Because thermal hyperalgesia was observed after both drugs, 8 of the original 19 subjects returned for an additional session without drug administration. Thermal hyperalgesia and increased magnitude of offset analgesia were observed across conditions of remifentanil, naloxone, and no drug within this subset analysis, indicating that repeated heat testing induced thermal hyperalgesia, which potentiated the magnitude of offset analgesia. Thus, it is concluded that the mechanisms subserving temporal processing of nociceptive information are largely opioid-independent, but that offset analgesia may be potentiated by heat-induced thermal hyperalgesia in a proportion of individuals.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Analgesics, Opioid / administration & dosage
  • Female
  • Humans
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / physiopathology*
  • Hyperalgesia / psychology
  • Male
  • Naloxone / administration & dosage*
  • Narcotic Antagonists / administration & dosage
  • Nociceptors / drug effects*
  • Nociceptors / physiology
  • Opioid Peptides / physiology*
  • Piperidines / administration & dosage*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / physiology
  • Remifentanil
  • Young Adult


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Opioid Peptides
  • Piperidines
  • Receptors, Opioid, mu
  • Naloxone
  • Remifentanil