Pronociceptive Effects of Remifentanil in a Mouse Model of Postsurgical Pain

Background: Remifentanil anesthesia enhances postopera- tive pain in animals and humans. The authors evaluated the impact of the dose (gkg 1 � min 1 ) and duration of remifen- tanil infusion, and the effects of a second surgery on postoper- ative pain sensitization. Methods: Mice received different doses of remifentanil over 30 or 60 min. The authors assessed thermal (Hargreaves) and me- chanical hyperalgesia (von Frey) at 2, 4, 7, and 10 days. In other experiments, mice had a plantar incision during sevoflurane with or without remifentanil anesthesia that was repeated 27 days later, when nociceptive thresholds returned to baseline. Linear mixed models were used for statistical analysis. Results: Remifentanil induced dose-dependent pronocicep- tive effects with calculated ED50s of 1.7 (95% confidence interval, 1.3-2.1) and 1.26 (1.0-1.6) gkg 1 � min 1 for thermal and mechanical hyperalgesia, respectively, which lasted longer with higher doses (P < 0.001). The duration of infusion did not alter the pronociceptive effects of remifen- tanil when administered at a constant dose of infusion. When given during surgery, high (2.66 gkg 1 � min 1 )o r low (0.66 gkg 1 � min 1 ) remifentanil increased the extent (P < 0.05) and duration (P < 0.01) of thermal and mechanical hyperalgesia. The latter was further enhanced after a second surgery performed in the same experimental conditions (P < 0.05). Surgery or remifentanil infusion, each one individu- ally, induced significant mechanical hyperalgesia, which was greater when repeated (P < 0.05). Conclusions: In this model of incisional pain, remifentanil induces pronociceptive effects, which are dose dependent but unaltered by the duration of administration. A second surgery performed on the same site and experimental conditions in- duces greater postoperative hyperalgesia that is enhanced when remifentanil is used as an anesthetic. REMIFENTANIL is a potent short-acting -opioid recep- tor agonist widely used as anesthetic in humans. Its main advantage over other 4-anilidopiperidine derivatives (fentanyl, alfentanil, sufentanil) relates to its rapid inac- tivation by plasma and tissue esterases. When used as anesthetic, remifentanil has a fast and predictable onset and offset that is independent of the duration of infusion, and its metabolism is not affected by organ failure. 1 Many reports show that intraoperative remifentanil ad- ministration paradoxically enhances pain sensitization and increases analgesic requirements in the postopera- tive period. 2-5 Such opioid-induced hyperalgesia has been described in animal models and humans after sev- eral -opioid receptor agonists administered by different routes. 3,6 Animal studies also show that the magnitude of the pronociceptive effects of morphine, heroin, and methadone (among others) is influenced by the admin- istration schedule. 7-9 In humans, it has been suggested that remifentanil-induced pain sensitization is greater with higher doses. 10 -13 However, the design of such studies does not allow establishing whether the pronociceptive effects of remifentanil are related to the dose of infusion, its duration, or the total dose administered over time. This information could be useful when attempting to prevent or reduce the pronociceptive effects of remifentanil when used as the main anesthetic in humans. Another relevant aspect of the use of remifentanil during surgery is its possible contribution to the devel- opment of long-term changes in pain sensitivity, leading to chronic postsurgical pain. 14 In a previous study using the same mouse model of incisional pain, we demon- strated an increase in postoperative pain in animals re- ceiving intraoperative remifentanil. 4 However, the effect of a second surgery performed with or without remifen- tanil anesthesia was not evaluated. Therefore, the cur- rent experimental study was designed to assess the im- pact of the dose and duration of remifentanil infusion on nociceptive thresholds and to determine whether the intraoperative use of remifentanil may affect the magni- tude of the postoperative pain after a second surgery (performed after full recovery from the first one).