Early antinociception delays edema but does not reduce the magnitude of persistent pain in the formalin test

Intraplantar formalin injection produces early (Phase 1, 0- to 5-minute) and late (Phase 2, 15-plus minutes after injection) nociceptive responses, including painlike behavior and activation of primary afferents and dorsal horn neurons. Although we and others have reported that opioid analgesia or local anesthesia during Phase 1 does not reduce the overall magnitude of behavioral and/or neuronal responses during Phase 2, recent studies concluded that spinal sensitization during Phase 1 significantly contributes to the magnitude of painlike behavior during Phase 2. In this article, we provide additional evidence that Phase 1 and Phase 2 behaviors are independent. We found that remifentanil analgesia during Phase 1 does not reduce Phase 2, regardless of route of administration, duration of analgesia, types of behavior assessed, formalin concentration, concomitant use of general anesthesia, or concomitant administration of an N-methyl-D-aspartate (NMDA) antagonist. We suggest that Phase 1 behaviors compared with Phase 2 behaviors in the formalin test are not an appropriate model of spinal sensitization or preemptive opioid analgesia. Instead, early opioid administration delayed the onset of edema produced by formalin. Because the antiedema effect of remifentanil was reversed with a peripherally acting opioid receptor antagonist, we suggest that opioids interact with peripheral receptors to temporarily delay the onset and offset of formalin-induced edema.