Efficacy and safety of flurbiprofen‑axetil combined with nalbuphine pretreatment on remifentanil‑induced postoperative hyperalgesia: A randomized clinical trial

Abstract

Remifentanil-induced hyperalgesia (RIH) is a common and complicated issue in patients undergoing laparoscopic cholecystectomy (LC), which significantly reduces patient satisfaction. The present trial was designed to clarify the individual and combined effects of flurbiprofen-axetil and nalbuphine on remifentanil-induced hyperalgesia. This randomized double-blind clinical trial included 120 adult patients who underwent LC at The Second People's Hospital of Wuhu. The individuals were randomized into a flurbiprofen-axetil group (F group), nalbuphine group (N group), flurbiprofen-axetil combined with nalbuphine group (FN group) and saline group (S group). The four groups were given flurbiprofen-axetil (50 mg, iv.), nalbuphine (0.1 mg/kg, iv.), flurbiprofen-axetil (50 mg, iv.) combined with nalbuphine (0.1 mg/kg, iv.) or normal saline respectively prior to skin incision. The primary outcome was the postoperative mechanical pain thresholds at the inner forearm and peri-incisional area. The secondary outcomes were the visual analog scale (VAS) and Ramsay sedation scale at 0.5, 1, 4 and 24 h after surgery, and any other adverse events. The pain threshold of the medial forearm in the FN group did not differ from that in the F and N groups at 24 h after surgery (P=0.310 and P=0.910, respectively). However, the pain threshold around the incision in FN group was significantly lower than that in F and N groups 24 h after surgery (P=0.001). The VAS of the F group, N group and FN group were all significantly lower than that in the S group at 0.5, 1 and 24 h after surgery (P<0.001). No significant differences were observed in the incidence of adverse events between the four groups. Single flurbiprofen-axetil and single nalbuphine effectively prevented RIH 24 h after surgery in LC. The combination of the two analgesic drugs, with different mechanisms of action, was not superior to single therapy. The present study was registered with the Chinese Clinical Trial Registry (registration no. ChiCTR2100045347).

Keywords: Hyperalgesia; flurbiprofen-axetil; laparoscopic cholecystectomy; nalbuphine.

Figure 1

Flow diagram for the present study. Flow diagram of this single-center, double-blind, randomized trial performed on adult patients who underwent LC from April 28, 2021-January 25, 2022. LC, laparoscopic cholecystectomy; S group, 0.3 µg kg^-1 min^-1 of remifentanil with saline group; F group, 0.3 µg kg^-1 min^-1 of remifentanil with 50 mg of flurbiprofen-axetil group; N group, 0.3 µg kg^-1 min^-1 of remifentanil with 0.1 mg kg^-1 of nalbuphine group; FN group, 0.3 µg kg^-1 min^-1 of remifentanil with flurbiprofen-axetil combined with nalbuphine pretreatment.

Figure 2

MAP and MAP were assessed during surgery. (A) MAP and (B) HR at different time points during surgery. Data are presented as mean ± standard deviation. MAP, mean arterial pressure; HR, heart rate; S group, 0.3 ug kg^-1 min^-1 of remifentanil with saline group; F group, 0.3 ug kg^-1 min^-1 of remifentanil with 50 mg of flurbiprofen-axetil group; N group, 0.3 ug kg^-1 min^-1 of remifentanil with 0.1 mg kg^-1 of nalbuphine group; FN group, 0.3 ug kg^-1 min^-1 of remifentanil with flurbiprofen-axetil combined with nalbuphine pretreatment; T1, before induction of anesthesia; T2, immediately after induction; T3, immediately after tracheal intubation; T4, immediately after pneumoperitoneum inflation; T5, at gallbladder removal; T6, incision closure; T7, after tracheal extubation.

Figure 3

Postoperative mechanical pain thresholds. Pain thresholds were assessed postoperatively at the (A) inner forearm and (B) on the peri-incisional area. The bar charts present mean mechanical pain threshold determined with von Frey wires on the inner forearm and the surgical incision area. S group, 0.3 ug kg^-1 min^-1 of remifentanil with saline group; F group, 0.3 ug kg^-1 min^-1 of remifentanil with 50 mg of flurbiprofen-axetil group; N group, 0.3 ug kg^-1 min^-1 of remifentanil with 0.1 mg kg^-1 of nalbuphine group; FN group, 0.3 ug kg^-1 min^-1 of remifentanil with flurbiprofen-axetil combined with nalbuphine pretreatment.

Figure 4

VAS and RSS. (A) VAS and (B) RSS were recorded at 0.5, 1, 4 and 24 h postoperatively. Data are presented as medians (inter-quartile range) or mean ± standard deviation. VAS, visual analog scale; RSS, Ramsay sedation scale; S group, 0.3 ug kg^-1 min^-1 of remifentanil with saline group; F group, 0.3 ug kg^-1 min^-1 of remifentanil with 50 mg of flurbiprofen-axetil group; N group, 0.3 ug kg^-1 min^-1 of remifentanil with 0.1 mg kg^-1 of nalbuphine group; FN group, 0.3 ug kg^-1 min^-1 of remifentanil with flurbiprofen-axetil combined with nalbuphine pretreatment. ^*P<0.001 vs. F group, N group and FN group. ^♦P<0.001 vs. S group.