Remifentanil exposure produces hyperalgesia but not morphine tolerance in rats

The mu‐opioid receptor agonist remifentanil is infused intravenously (i.v.) during surgery to promote anesthesia and analgesia and has been reported to increase postoperative pain and morphine requirements. The present study investigated the effects of continuous i.v. remifentanil administration to rats on noxious stimuli thresholds and morphine requirements. Rats were implanted with i.v. catheters and infused with remifentanil (0–320 mcg/kg/h) for 1 h followed by one of two noxious stimuli: an intraperitoneal injection of diluted acetic acid or a thermal stimulus. Abdominal stretches and withdrawal latencies, respectively, were measured. Remifentanil exposure produced a dose‐dependent increase in the number and duration of acid‐induced abdominal stretches, but it did not alter tail withdrawal latency. In rats exposed to remifentanil, larger doses of morphine were required to decrease stretches as compared with saline‐infused rats. Injecting higher acid concentrations in saline‐infused rats also required larger doses of morphine to decrease stretching, demonstrating that morphine requirements were relative to noxious stimulus intensity. In conclusion, these data demonstrate that exposure to remifentanil produces hyperalgesic states and higher morphine requirements, which is likely due to elevated pain thresholds rather than opioid tolerance. This study was supported by USPHS grant 04087.