Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

University of Louisville, Louisville, Kentucky, United States
Anesthesiology (Impact Factor: 5.88). 07/2005; 103(1):147-55. DOI: 10.1097/00000542-200507000-00022
Source: PubMed


Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia.
Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 microg x kg(-1) x min(-1) (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 microg x kg(-1) x min(-1) until skin closure and then 2 microg x kg(-1) x min(-1) for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h.
Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects.
A relatively large dose of intraoperative remifentanil triggers postoperative secondary hyperalgesia. Remifentanil-induced hyperalgesia was prevented by small-dose ketamine, implicating an N-methyl-d-aspartate pain-facilitator process.

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    • "Punctuate hyperalgesia and extent of hyperalgesia were measured prior to surgery on days 1, 2 and 4 and at 3 months using the von Frey filament technique as previously described.[12] The threshold for punctuate hyperalgesia was measured with calibrated von Frey filaments. "
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    ABSTRACT: Background and Aims: Intravenous (I.V.) lidocaine has analgesic, antihyperalgesic and anti-inflammatory properties and is known to accelerate the return of bowel function after surgery. We evaluated the effects of I.V. lidocaine on pain management and acute rehabilitation protocol after laparoscopic nephrectomy. Materials and Methods: A total of 47 patients scheduled to undergo laparoscopic nephrectomy were included in a two-phase observational study where I.V. lidocaine (1.5 mg/kg/h) was introduced, in the second phase, during surgery and for 24 h post-operatively. All patients underwent the same post-operative rehabilitation program. Post-operative pain scores, opioid consumption and extent of hyperalgesia were measured. Time to first flatus and 6 min walking test (6MWT) were recorded. Results: Patient demographics were similar in the two phases (n = 22 in each group). Lidocaine significantly reduced morphine consumption (median [25-75% interquartile range]; 8.5 mg[4567891011121314151617] vs. 25 mg[1920212223242526272829303132]; P < 0.0001), post-operative pain scores (P < 0.05) and hyperalgesia extent on post-operative day 1-day 2-day 4 (mean ± standard deviation (SD); 1.5 ± 0.9 vs. 4.3 ± 1.2 cm (P < 0.001), 0.6 ± 0.5 vs. 2.8 ± 1.2 cm (P < 0.001) and 0.13 ± 0.3 vs. 1.2 ± 1 cm (P < 0.001), respectively). Time to first flatus (mean ± SD; 29 ± 7 h vs. 48 ± 15 h; P < 0.001) and 6MWT at day 4 (189 ± 50 m vs. 151 ± 53 m; P < 0.001) were significantly enhanced in patients with i.v. lidocaine. Conclusion: Intravenous (I.V.) lidocaine could reduce post-operative morphine consumption and improve post-operative pain management and post-operative recovery after laparoscopic nephrectomy. I.V. lidocaine could contribute to better post-operative rehabilitation.
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    • "Without direct measures to assess hyperalgesia such as QST, the results are not easy to distinguish from acute tolerance (Vinik and Kissin, 1998). Clinical studies examining remifentanil-induced hyperalgesia by QST showed that, at a relatively high dose, remifentanil decreased the pain threshold (Gustorff et al., 2002; Joly et al., 2005; Schmidt et al., 2007; Song et al., 2011; Yalcin et al., 2012). These studies used remifentanil infusions at clinically standard rates, and all of them showed clear hyperalgesia either shortly after discontinuing infusion or 1 and 2 days postoperatively. "
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