Short-term infusion of the μ-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal

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-naïve, 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.