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.

Eur J Anaesthesiol 2014 Jan;31(1):41-9

From the Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Virchow-Klinikum (ST, SAM, MS) and Department of Anesthesiology and Intensive Care Medicine, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany (MK, AK).

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 μg kg min 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 μg kg min and subsequently increased by 0.05 μg kg min 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 μg kg min; 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.

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