Influence of high-dose intraoperative remifentanil with or without amantadine on postoperative pain intensity and morphine consumption in major abdominal surgery patients: A randomised trial

BACKGROUND Human volunteer studies demonstrate ketamine-reversible opioid-induced hyperalgesia, consistent with reports of increased postoperative pain and analgesic consumption. However, recent clinical trials showed controversial results after intraoperative administration of high-dose remifentanil. OBJECTIVE To investigate in lower abdominal surgery patients whether postoperative pain intensity and analgesic consumption are increased following intraoperative high-dose vs. low-dose remifentanil, and whether this could be prevented by preoperative administration of the NMDA antagonist amantadine. DESIGN Randomised, placebo-controlled, clinical study. SETTING University hospital. PATIENTS Sixty patients scheduled for elective major lower abdominal surgery. INTERVENTIONS Patients were randomly assigned to one of three anaesthetic regimens. First, in the group ‘low-dose remifentanil and preoperative isotonic saline’ (n = 15), a remifentanil infusion was maintained at a rate of 0.1 &mgr;g kg−1 min−1 throughout anaesthesia, and the end-tidal concentration of sevoflurane started at 0.5 minimum alveolar concentration (MAC) and was increased by 0.2% increments according to clinical demand. Preoperatively, 500 ml NaCl 0.9% were infused as study solution. Second, in the group ‘high-dose remifentanil and preoperative saline’ (n = 17), the end-tidal concentration of sevoflurane was maintained at 0.5 MAC throughout anaesthesia. A remifentanil infusion was started at a rate of 0.2 &mgr;g kg−1 min−1 and subsequently increased by 0.05 &mgr;g kg−1 min−1 increments to clinical demand. Preoperatively, these patients also received a solution of 500 ml NaCl 0.9% as study solution. Third, the group ‘high-dose remifentanil and preoperative amantadine’ (n = 16) received the same anaesthetic protocol as the second group, but the preoperative study solution was substituted by amantadine (200 mg/500 ml). MAIN OUTCOME MEASURES Pain intensity measured by the numerical rating scale and cumulative morphine consumption. RESULTS The remifentanil dose in both high-dose groups was significantly higher compared with the low-dose remifentanil group (0.20 ± 0.04 and 0.23 ± 0.02 vs. 0.08 ± 0.04 &mgr;g kg−1 min−1; P <0.001). Pain intensity gradually increased up to 45 min postoperatively in all groups, and then decreased again towards low levels in parallel with a linear increase in morphine consumption. Postoperative pain intensity and morphine consumption did not significantly differ between groups. Moreover, preoperative amantadine revealed no additional benefit. CONCLUSION We were not able to demonstrate any influence on routine clinical outcome parameters of pain after high-dose remifentanil. Although not without limitations, these findings are in line with other clinical trials that could not detect an opioid-induced impact on postoperative pain parameters, which might be less sensitive to detect opioid-induced hyperalgesia compared with quantitative sensory testing. TRIAL REGISTRATION DRKS00004626.