Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal
by
Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M.
Department of Anesthesia,
Stanford University School of Medicine,
300 Pasteur Drive, 94305, Stanford, CA, USA
Pain. 2003 Nov;106(1-2):49-57.

ABSTRACT

Numerous animal studies suggest that acute and chronic exposure to opioids can be associated with the development of hyperalgesia, i.e. an increased sensitivity to noxious stimuli. Hyperalgesia has been documented during withdrawal and on occasion while animals were still exposed to opioids. A pivotal role in the genesis of opioid-associated hyperalgesia has been attributed to a pain facilitating system involving the N-methyl-D-aspartate (NMDA)-receptor. In humans little direct evidence documents opioid-associated hyperalgesia, albeit observational data suggest that such hyperalgesia may be relevant in a clinical context. This study used a double blind, randomized, crossover and placebo-controlled design to test in opioid-nai;ve, healthy human volunteers whether hyperalgesia would develop within 30 min of stopping a 90-min infusion with the mu-opioid agonist remifentanil, and whether co-administration of the NMDA-receptor antagonist S-ketamine would prevent such hyperalgesia. We found that a skin area with pre-existing mechanical hyperalgesia was significantly enlarged after stopping the remifentanil infusion. However, the pain response to heat assessed in regular skin was not different before and after the infusion of remifentanil. Co-administration of the NMDA-receptor antagonist S-ketamine abolished observed enlargement of the hyperalgesic skin area. This study provides direct evidence in humans that short-term administration of an opioid can enhance hyperalgesia as observed during withdrawal and points to a potential role of the NMDA-receptor system in mediating such a hyperalgesic response. This study also points to a differential susceptibility of different pain modalities for the expression of hyperalgesia associated with opioid administration.

Pain
Lofexidine
Oxycodone
Endomorphins
Novelty and pain
Fentanyl and ketamine
Signalling mechanisms
The extended amygdala
Withdrawal hyperalgesia
Opioids, mood and cognition
Tolerance, sensitization and dependence
Nucleus accumbens shell/medium spiny neurons
Alpha-2 adrenergic agonists for opioid withdrawal

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