doi: /bja/aew248 Pain

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1 British Journal of Anaesthesia, 117 (4): (216) doi: 1.193/bja/aew248 Pain Preoperative butorphanol and flurbiprofen axetil therapy attenuates remifentanil-induced hyperalgesia after laparoscopic gynaecological surgery: a randomized double-blind controlled trial L. Zhang 1,2, R. Shu 1,2, Q. Zhao 1,2,Y.Li 1,2,Y.Yu 1,2 and G. Wang 1,2, 1 Department of Anaesthesiology, Tianjin Medical University General Hospital, Tianjin 352, PR China, and 2 Tianjin Research Institute of Anaesthesiology, Tianjin 352, PR China Corresponding author. wangguolinghad@hotmail.com Abstract Background: Several studies indicate that remifentanil exposure may engender opioid-induced hyperalgesia. Butorphanol and flurbiprofen axetil are proposed as adjunctive analgesics for postoperative pain control. This randomized double-blind controlled study was designed to investigate the antihyperalgesic effects of butorphanol combined with flurbiprofen axetil on opioid-induced hyperalgesia. Methods: One hundred and twenty patients undergoing elective laparoscopic gynaecological surgery with sevoflurane anaesthesia were randomized to one of four groups, as follows: intraoperative sufentanil.3 µg kg 1 (Group S); remifentanil.3 µg kg 1 min 1 (Group R); intraoperative remifentanil and pre-anaesthesia butorphanol 2 µg kg 1 (Group B); or intraoperative remifentanil and pre-anaesthesia butorphanol 1 µg kg 1 combined with flurbiprofen axetil.5 mg kg 1 (Group BF). Sufentanil was used to control postoperative pain. The threshold and area of postoperative mechanical hyperalgesia were measured with Von Frey filaments. Pain intensity, sufentanil consumption, and side-effects were recorded for 24 h after surgery. Results: Compared with Group S, remifentanil anaesthesia increased the pain score, postoperative sufentanil consumption, and area of hyperalgesia [mean 49.9 (SD 8.6) vs 6.5 (1.) cm 2, P<.1] and reduced the hyperalgesia threshold on the dominant inner forearm [mean 89.5 (SD 23.4) vs 6.6 (22.6) g, P=.4]. Compared with Group R, the pain score, sufentanil consumption, and area of hyperalgesia were reduced and hyperalgesia threshold was elevated likewise in Groups B and BF. However, the efficacy in Group BF was higher than in Group B (P=.21). Conclusions: The preoperative combination of butorphanol and flurbiprofen axetil effectively ameliorated opioid-induced hyperalgesia in patients undergoing laparoscopic gynaecological surgery under sevoflurane remifentanil anaesthesia. Clinical trial registration: NCT Key words: analgesics; opioid; remifentanil; complications; hyperalgesia; cyclo-oxygenase inhibitors; flurbiprofen axetil; opioid mixed agonist-antagonists; butorphanol; pain threshold Remifentanil is commonly used in analgesia during general anaesthesia. 12 However, several studies suggest that intraoperative remifentanil infusion may be responsible for postoperative opioid-induced hyperalgesia (OIH), a paradoxical state of hypersensitivity to nociceptive stimuli. 3 7 Although the specific mechanism and clinical significance of OIH remain controversial, 89 Accepted: June 1, 216 The Author 216. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com 54

2 Opioid-induced hyperalgesia 55 Editor s key points Opioid-induced hyperalgesia (OIH) may be problematic after remifentail anaesthesia, with strategies needed to reduce it. Inhibition of cyclo-oxygenase, combined with a κ agonist, may target some of the underlying mechanisms. This randomized controlled trial found a reduction in mechanical hyperalgesia with flurbiprofen and butorphanol. Further studies are needed on remifentanil-induced OIH and targeted strategies to minimize its clinical impact. the phenomenon has been implicated in chronic postsurgical pain and, possibly, in chronic pain treatment with opioids Therefore, prevention of OIH in surgical patients may improve clinical care and deserves further clinical investigation. Several experimental and clinical reports suggest that cyclooxygenase inhibition ameliorates OIH in animals, human volunteers, and patients However, cyclo-oxygenase inhibitors have potential drawbacks and must be administered with discretion in patients with active peptic ulcer, recent gastrointestinal bleeding, renal dysfunction, pregnancy, or allergy to aspirin. Butorphanol has both spinal analgesic and sedative functions because of predominantly central κ-receptor agonist activation Furthermore, antihyperalgesic activity and potency of κ opioids have been reported in various acute pain models Butorphanol and the cyclo-oxygenase inhibitor flurbiprofen axetil (FA) are proposed as adjunctive pre-anaesthetics and analgesics for postoperative pain control. However, no report has focused on the antihyperalgesic efficacy of butorphanol or butorphanol combined with FA in OIH in the clinical setting. The objective of the study was to verify the hypothesis that butorphanol combined with FA administration can prevent intraoperative remifentanil infusion-induced hyperalgesia in patients undergoing laparoscopic gynaecological surgery with sevoflurane anaesthesia. We selected a modified threshold of the mechanical hyperalgesia on the dominant inner forearm before and 24 h after surgery as the primary outcome. Pain intensity, cumulative sufentanyl consumption, hyperalgesia area and threshold around the incision, and side-effects were the secondary outcomes investigated for 24 h after surgery. Methods Ethical approval and study population The study was approved by the Tianjin Medical University General Hospital Ethic Committee (Tianjin, China; approval number IRB ), and the study protocol was registered ( Identifier: NCT243366; the current manuscript is part of a larger study). We contacted patients aged 2 6 yr, with ASA physical status I II, who were to undergo laparoscopic ovarian cyst resection. Written informed consent was obtained from all the subjects. The exclusion criteria were as follows: bronchial asthma; coronary heart disease; severe hypertension; diabetes mellitus; obesity (BMI >3 kg m 2 ); cardiac, hepatic, and renal dysfunction; psychiatric disease; history of chronic pain;history of alcohol or opioid abuse; chronic use of opioids; intake of any analgesic within 48 h before surgery; pregnancy; allergy and contraindication to butorphanol or nonsteroidal anti-inflammatory drugs; history of gastrointestinal disease (peptic ulcer disease, Crohn s disease, or ulcerative colitis); contraindication for the use of patient-controlled analgesia (PCA); or incapacity to comprehend pain assessment. After randomization and allocation, patients were withdrawn if laparoscopy was converted to open surgery or if they required reinvestigation for postoperative bleeding. Procedures and outcomes Patients were randomly divided into one of four groups, as follows: (i) patients in Group S received intraoperative sufentanil.3 µg kg 1 and placebo (normal saline, similar volume of butorphanol) before induction of anaesthesia; (ii) patients in Group R received intraoperative remifentanil.3 µg kg 1 min 1 and placebo before induction of anaesthesia; (iii) patients in Group B received intraoperative remifentanil.3 µg kg 1 min 1 and butorphanol (Hengrui Medicine Co., Jiangsu, China) 2 µg kg 1 (clinical dosage) before induction of anaesthesia; and (iv) patients in Group BF received intraoperative remifentanil.3 µg kg 1 min 1 and butorphanol 1 µg kg 1 combined with FA (Tide Pharmaceutical Co., Beijing, China).5 mg kg 1 before induction of anaesthesia. Patients were randomly assigned to treatment regimens based on a randomization list provided by the Department of Anaesthesiology, Tianjin Medical University General Hospital according to the relevant Standard Operating Procedure (computer-generated random number system). The allocation sequence was concealed until after consent was obtained. Patients and a treating anaesthetist involved in the perioperative management were blinded to the group assignment. Primary and secondary outcomes were analysed and recorded by another anaesthetist responsible for the data collection but not directly involved in the treatment of the patient and who was blinded to randomization. On the day before surgery, all the patients were instructed to use a PCA device and were evaluated for pain on a 11-point numerical rating scale (NRS): =no pain; and 1=worst pain imaginable. The baseline mechanical nociceptive threshold was assessed using 2 hand-held Von Frey filaments (North Coast Medical Inc., Gilroy, CA, USA) in an area 2 5 cm around the incision at 12 predefined positions in all four directions and on the dominant inner forearm according to the published method Every position was measured three times at intervals of 15 s, and a mean value was calculated for statistical analysis The mechanical hyperalgesia threshold was defined as the smallest force (in grams) necessary to bend a Von Frey filament that was detected as painful by the patient. The test was performed again at 24 h after surgery. Upon arrival at the operating room, the patients were generally monitored by non-invasive blood pressure, ECG, heart rate (HR), pulse oximetry, and bispectral index. A peripheral i.v. line in the left arm and urinary catheter were attached before induction of anaesthesia. General anaesthesia was induced with midazolam.5 mg kg 1, sufentanil.2 µg kg 1, and propofol 2 mg kg 1, and tracheal intubation was facilitated with rocuronium.7 mg kg 1. After intubation, all the patients were mechanically ventilated [end-tidal carbon dioxide values of mm Hg (1 mm Hg=.133 kpa)]. Anaesthesia was maintained with sufentanil injection before skin incision or continuous remifentanil infusion (RenFu Co., Hubei, China) as an intraoperative analgesic, and administration of sevoflurane (Maruishi Pharmaceutical Co., Osaka, Japan) as an initial 1.3 minimal alveolar concentration (MAC) and oxygen air mixture (fraction of oxygen, 5%). The depth of anaesthesia was adjusted during surgery by 1% stepwise titration of sevoflurane, based on targeting bispectral index (4 6) and haemodynamic changes: HR exceeding pre-induction values by 15% and mean arterial blood pressure (MAP) exceeding baseline

3 56 Zhang et al. values by 2% or <6 mm Hg for at least 1 min. Rocuronium (.3 mg kg 1 ) was administered intermittently i.v. during anaesthesia. If bradycardia (HR <45 beats min 1 ) and continuous hypotension (MAP <6 mm Hg) persisted, additional fluid infusion, atropine (.5 mg), and phenylephrine (.1 mg) were also administered. During skin suturing, sevoflurane and remifentanil were stopped, and tropisetron (2 mg) was injected i.v. Residual neuromuscular block was antagonized by neostigmine.4 mg kg 1 and atropine.1 mg kg 1 when the tidal volume of spontaneous breathing exceeded 2 ml. When the bispectral index value reached 8, response to oral command was observed, followed by eye opening and spontaneous breathing rate exceeding 1 bpm, the patient was extubated and moved to the postanaesthetic care unit (PACU) for at least 1 h. Sedation scores were documented using the Ramsay scale (1=anxious and agitated or restless, or both; 2=cooperative, oriented, and tranquil; 3=responds to command only; 4=asleep, but has a brisk response to light tactile stimulus or a simple verbal command; 5=asleep, but arousable only by strong physical stimulus; and 6=asleep, unarousable) at 5, 1, 15, 3, and 6 min after arrival at the PACU. The NRS score for pain at rest and after movement was assessed at 1, 3, 6, 12, and 24 h after surgery. Movement was specified as active mobilization and weightbearing while escaping any harm. First postoperative pain (NRS>4) was primarily managed by sufentanil titration, which was administered in 3 µg doses at intervals of 3 min until NRS <3. However, sufentanil titration was discontinued if the Ramsay score was >3, peripheral oxygen saturation decreased <92%, or breathing rate was <1 bpm. The time and total dose of first postoperative sufentanil were documented in the PACU. Furthermore, each patient was administered analgesics using a PCA pump containing sufentanil (1 µg) in normal saline in a total volume of 1 ml after discharge from the PACU. The device was set to deliver a basal infusion of 2 ml h 1 and bolus doses of.5 ml with a 15 min lockout period. Sufentanil comsumption was recorded at intervals of 6 h: 6, 12, 18, and 24 h after leaving the PACU. The normalized area of hyperalgesia around the incision was also measured by Von Frey filament at 24 h after surgery as described previously The incidence of postoperative side-effects was monitored during the 24 h after surgery. In addition, postoperative comfort and satisfaction scale (=pretty dissatisfied; 3=highly satisfactory) was documented through assessment of pain, relevant side-effects, and movement limitations for 24 h after surgery. Statistical analyses The mechanical hyperalgesia threshold of the dominant inner forearm was considered the primary outcome. Based on our previous results (L. Zhang, R. Shu, Y, Li and G. Wang, unpublished raw data), a power analysis was implemented to calculate the sample size. The mean mechanical hyperalgesia threshold of the dominant inner forearm at baseline (the day before surgery) was 95.5 g, whereas the means of the four treatment groups (Group S, Group R, Group B, and Group BF) at 24 h after surgery were 84.6, 61.8, 74.6, and 78 g, respectively. We determined a difference of at least 3% (error standard deviation=25.) among the treatment groups. An a priori algorithm was used to estimate the required sample size for analysis of variance (ANOVA) with repeated measures. A sample size of 26 patients per group was found to be sufficient to detect a significant difference (α=5%) with a statistical power (β-value) of.8. Presuming a 15% failure rate, we considered increasing the sample size to 3 patients per group. The Shapiro Wilk test was used to determine the normality of distribution of the data, and parametric statistics were applied. Homogeneity of variance was verified by the Levene test. Data from the Ramsay scores, NRS scores, and mechanical hyperalgesia threshold were analysed by two-way repeatedmeasures ANOVA with Bonferroni post hoc comparisons. Data from time and total dose of first postoperative sufentanil titration, sufentanil consumption by PCA, and normalized area were analysed by one-way ANOVA with Dunnett s post hoc comparisons. Other quantitative data, such as age, height, weight, duration of remifentanil infusion, mean concentration of sevoflurane, intraoperative MAP and HR, recovery time, and comfort and satisfaction scale, were also analysed using one-way ANOVA with Dunnett s post hoc comparisons. Simultaneously, the χ 2 test and Fisher s exact test were used to analyse categorical variables, such as phenylephrine administration, somnolence, dizziness, nausea, and vomiting. Data were expressed as the mean (SD) or number of patients (percentage). A statistically significant difference was interpreted as a P-value of <.5. SPSS 18. software (SPSS, Inc., Chicago, IL, USA) was used for all statistical analysis. Results We recruited 124 patients between February 214 and June 215 and found 12 patients eligible for inclusion. Eight patients were withdrawn after conversion to open surgery or reoperation for postoperative bleeding. One hundred and twelve patients completed the study (Fig. 1). The four groups were comparable with respect to patient characteristics (Table 1). Intraoperative and postoperative clinical variables in anaesthesia Groups were balanced in terms of duration of surgery, duration of remifentanil infusion, mean concentration of sevoflurane, intraoperative MAP, and HR. The proportion of patients administered phenylephrine and atropine was similar among all the groups (Table 1 and Supplementary data, S1). Group S exhibited delayed eye opening [6.4 (1.9) vs 5.4 (1.6) min, P=.1] and extubation [7.5 (1.6) vs 6.2 (1.7) min, P=.2] compared with Group R. Concurrently, the Ramsay score at 5 min after arrival at the PACU was higher in Group S than in Group R (P=.1). However, no differences in eye opening time, extubation time, and Ramsay score were observed among Groups R, B, and BF (P>.5), as shown in Fig. 2A. Postoperative pain intensity Compared with Group S, Group R showed higher NRS scores at rest (Fig. 2B) at 3 (P<.1), 6 (P<.1), 12 (P<.1), and 24 h (P=.3). Furthermore, NRS scores at rest (Fig. 2B) were significantly lower in Group B than in Group R at 3 (P=.4), 6 (P=.1), 12 (P=.3), and 24 h (P=.5). The NRS scores at rest were also lower in Group BF than in Group R at 3 (P=.1), 6 (P=.1), 12 (P<.1), and 24 h (P<.1). However, the NRS scores at rest were similar between Group B and Group BF (P>.5). The NRS score after movement paralleled trends involving the NRS score at rest (Fig. 2C). Postoperative sufentanil consumption The time to first postoperative sufentanil requirement was shorter in Group R than in Group S [22.9 (5.1) vs 27.7 (5.5) min, P=.1], and it was longer in Groups B and BF than in Group R [26.4 (5.5) vs 22.9 (5.1) min, P=.2 and 29.2 (5.9) vs 22.9 (5.1) min, P<.1, respectively], with no differences between Groups B and BF (P=.6). The amount of sufentanil titrated in the PACU was significantlygreateringrouprthaningroups(p<.1). When

4 Opioid-induced hyperalgesia 57 Assessed for eligibility (n=124) Excluded (n=4) Not meeting inclusion criteria (n=3) Refused to participate (n=1) Randomization (n=12) Allocation Group S (n=3) placebo and sufentanil Group R (n=3) placebo and remifentanil Group B (n=3) butorphanol and remifentanil Group BF (n=3) butorphanol combined with flurbiprofen axetil and remifentanil Follow-up Loss to follow-up (n=2) Loss to follow-up (n=2) Loss to follow-up (n=2) Loss to follow-up (n=2) Withdrawn because of conversion to open surgery and re-exploration for postoperative bleeding Analysis Analysed Analysed Analysed Analysed Fig 1 Consolidated Standards of Reporting Trials (CONSORT) flow diagram. Table 1 Patient characteristics and anaesthetic data. Group S, normal saline administered i.v. before anaesthesia induction and intraoperative sufentanil therapy.3 µg kg 1 ; Group R, normal saline administered i.v. before induction and intraoperative remifentanil.3 µg kg 1 min 1 ; Group B, intraoperative remifentanil and butorphanol 2 µg kg 1 before induction; and Group BF, intraoperative remifentanil and butorphanol 1 µg kg 1 combined with flurbiprofen axetil.5 mg kg 1 before induction. All patients underwent laparoscopic gynaecological surgery under sevoflurane anaesthesia. Values are presented as mean (SD), mean (range), or the number of patients/% Characteristic Group S Group R Group B Group BF Age (yr) 44 (25 59) 46 (22 58) 48 (21 59) 44 (24 57) Height (cm) 162 (4) 162 (3) 161 (4) 162 (4) Weight (kg) 6 (8) 61 (6) 62 (6) 6 (8) ASA status (I) 22/79 24/86 22/79 21/75 Duration of surgery (min) 59 (11) 57 (11) 54 (11) 59 (11) Duration of remifentanil infusion (min) 62 (12) 6 (11) 65 (12) Mean concentration of sevoflurane (%) 2.7 (.5) 2.6 (.5) 2.5 (.3) 2.7 (.4) Intraoperative administration Atropine 4/14 2/7 1/4 2/7 Phenylephrine 5/18 2/7 2/7 3/11 compared with Group R, the dose of sufentanil titrated was lower in Groups B (P=.1) and BF (P=.1). Furthermore, there was no difference between Groups B and BF (P=.46; Table 2). Sufentanil consumption (Table 2) in Group R was significantly greater than in Group S during the second 6 h (P=.6), the third 6h(P<.1), and the fourth 6 h (P<.1) after PCA, whereas it was lower in Group B during the second 6 h (P=.1), the third 6h(P=.3), and the fourth 6 h (P<.1) after PCA and in Group BF during the first 6 h (P=.1), the second 6 h (P=.7), thethird6h(p<.1), and the fourth 6 h (P<.1) after PCA than in Group R. However, no difference was found between Group B and Group BF (P>.5; Table 2). Mechanical hyperalgesia threshold and area As shown in Fig. 3A, the baseline mechanical pain threshold on the dominant inner forearm and around the incision was similar among all the groups (P>.5). Compared with baseline, remifentanil anaesthesia resulted in a dramatic decrease in pain threshold on the forearm (P<.1) and around the incision (P<.1). The hyperalgesia threshold on the forearm (P=.4) and around the incision (P=.7) was lower in Group R than in Group S at 24 h after surgery. Furthermore, compared with Group R, higher levels of threshold on the forearm (P=.1) and around the incision (P=.3) were recorded in Group B, and on the forearm (P=.5) and around the incision (P=.8) in Group BF. However, similar threshold levels were observed on the forearm (P=.58) and around the incision (P=.62) in Groups B and BF. AsshowninFig.3B, the normalized area of hyperalgesia around the incision was remarkably increased in Group R compared with Group S (P<.1), whereas it was reduced in Group B(P=.9) and Group BF (P=.2) compared with Group S. However, no significant difference was detected in Groups B and BF (P=.56).

5 58 Zhang et al. A B C S R B BF 6 S R B BF 6 S R B BF Ramsay score min 1 min 15 min 3 min 6 min 1 h 3 h 6h 12h 24h 1h 3h NRS at rest 5 Time from arrival at PACU Time after surgery Time after surgery NRS after movement 5 6h 12h 24h Fig 2 Postoperative sedation levels and pain scores. Sedation levels (A) were assessed using Ramsay scores at 5, 1, 15, 3, and 6 min after arrival at the PACU. The NRS score for pain at rest (B) and after movement (C) was documented at 1, 3, 6, 12, and 24 h after surgery. Group S, normal saline administered i.v. before anaesthesia induction and intraoperative sufentanil therapy.3 µg kg 1 ; Group R, normal saline administered i.v. before induction and intraoperative remifentanil.3 µg kg 1 min 1 ; Group B, intraoperative remifentanil and butorphanol 2 µg kg 1 before induction; and Group BF, intraoperative remifentanil and butorphanol 1 µg kg 1 combined with flurbiprofen axetil.5 mg kg 1 before induction. All the patients underwent laparoscopic gynaecological surgery under sevoflurane anaesthesia. Values are presented as the mean (SD). P<.5 and P<.1 vs Group R. NRS, numerical rating scale; PACU, postanaesthetic care unit. Table 2 Postoperative sufentanil consumption. Postoperative pain was managed by sufentanil titration in the PACU, followed by sufentanil infusion via PCA. Group S, normal saline administered i.v. before anaesthesia induction and intraoperative sufentanil therapy.3 µg kg 1 ; Group R, normal saline administered i.v. before induction and intraoperative remifentanil.3 µg kg 1 min 1 ; Group B, intraoperative remifentanil and butorphanol 2 µg kg 1 before induction; and Group BF, intraoperative remifentanil and butorphanol 1 µg kg 1 combined with flurbiprofen axetil.5 mg kg 1 before induction. All patients underwent laparoscopic gynaecological surgery under sevoflurane anaesthesia. Values are presented as mean (SD). P<.5 and P<.1 vs Group R. P 1, Group R vs Group S; P 2, Group R vs Group B; P 3, Group R vs Group BF; P 4, Group B vs Group BF; P, comparing groups; PACU, postanaesthetic care unit; PCA, patient-controlled analgesia Method of administration of sufentanil Group S Group R Group B Group BF P-value P 1 P 2 P 3 P 4 P By titration in PACU (µg) 14.8 (4.6) 21.1 (5.4) 17.4 (5.3) 16.3 (6.3) < <.1 By PCA (µg) 6 h 16.6 (3.2) 17.9 (2.9) 16.4 (3.2) 15.9 (2.9) h 16. (3.) 18.3 (3.4) 16.2 (3.3) 16. (2.9) h 15.3 (3.3) 18.6 (3.5) 16. (3.5) 15.3 (3.) <.1.3 <.1.46 < h 14.8 (2.4) 18.4 (3.1) 15.3 (3.) 15.1 (2.6) <.1 <.1 <.1.74 <.1 Postoperative comfort and satisfaction Table 3 displays the incidence of significant postoperative sideeffects. The incidence of nausea in Group S was higher than in Group R (P=.4), whereas no differences were found among Groups R, B, and BF (P>.5). Moreover, compared with Group R, Group B presented a higher incidence of somnolence (P=.3) and dizziness (P=.4). However, no difference was found in Groups R and BF (P>.5). In addition, with respect to comfort and satisfaction score (Fig. 3C), patients reported greater satisfaction during the first 24 h after surgery in Group BF than in Group S (P=.4), Group R (P<.1), or Group B (P=.2). Discussion The central findings of the present investigation were as follows: (i) intraoperative analgesia using remifentanil.3 µg kg 1 min 1 reduced mechanical nociceptive threshold, increased hyperalgesia area around the wound, up-regulated pain scores and cumulative sufentanil consumption, and triggered OIH after laparoscopic gynaecological surgery under sevoflurane remifentanil anaesthesia; (ii) pretreatment with butorphanol 2 µg kg 1 effectively prevented the exacerbation of postsurgical OIH but increased the incidence of postoperative somnolence and dizziness; and (iii) the preoperative combination of butorphanol 1 µg kg 1 and FA.5 mg kg 1 showed significant antihyperalgesic properties and might reduce butorphanol-related side-effects. In order to estimate remifentanil-related postoperative hyperalgesia clinically, intraoperative sufentanil injection was controlled, and the surgical procedure selected was laparoscopic ovarian cyst resection using a small surgical incision, resulting in the mild postoperative pain, to minimize the combined influ- ence of surgery-caused central nociceptive sensitization. Sevoflurane was preferred for anaesthesia because it does not affect pro-nociceptive thresholds. 32 We administered consecutive remifentanil infusion at a rate of.3 µg kg 1 min 1 on the basis of previous studies Hyperalgesia was verified by assessing the mechanical hypernociceptive threshold and area using Von Frey filaments As expected, compared with intraoperative sufentanil exposure, remifentanil infusion downregulated the nociceptive threshold both on the forearm and close to the surgical incision. It increased postoperative hyperalgesia, pain

6 Opioid-induced hyperalgesia 59 A B C Mechanical hyperalgesia threshold (g) S R B Inner arm baseline Incision baseline ## Inner arm 24 th h BF ## Incision 24 th h Normalized area of hyperalgesia (cm 2 ) 8 P<.1 P= P=.9 Comfort and satisfaction score P=.4 P<.1 P=.21 S R B BF S R B BF Fig 3 Postoperative mechanical pain threshold, normalized area of hyperalgesia, and comfort and satisfaction score. The mechanical pain threshold (A) and normalized area of hyperalgesia (B) were tested before and 24 h after surgery with Von Frey filaments. The postoperative comfort and satisfaction scale (C) was used to record the scores for 24 h after surgery. Group S, normal saline administered i.v. before anaesthesia induction and intraoperative sufentanil therapy.3 µg kg 1 ; Group R, normal saline administered i.v. before induction and intraoperative remifentanil.3 µg kg 1 min 1 ; Group B, intraoperative remifentanil and butorphanol 2 µg kg 1 before induction; and Group BF, intraoperative remifentanil and butorphanol 1 µg kg 1 combined with flurbiprofen axetil.5 mg kg 1 before induction. All patients underwent laparoscopic gynaecological surgery under sevoflurane anaesthesia. Values are presented as the mean (SD). P<.5 and P<.1 vs Group R; ## P<.1 vs baseline threshold. Table 3 Postoperative side-effects. The incidence of the main adverse effects was evaluated during the first 24 h after surgery. Group S, normal saline administered i.v. before anaesthesia induction and intraoperative sufentanil therapy.3 µg kg 1 ; Group R, normal saline administered i.v. before induction and intraoperative remifentanil.3 µg kg 1 min 1 ; Group B, intraoperative remifentanil and butorphanol 2 µg kg 1 before induction; and Group BF, intraoperative remifentanil and butorphanol 1 µg kg 1 combined with flurbiprofen axetil.5 mg kg 1 before induction. All patients underwent laparoscopic gynaecological surgery under sevoflurane anaesthesia. Values are presented as the number of patients/%. P<.5 vs Group R Side-effect Group S Group R Group B Group BF Somnolence 3/11 1/4 7/25 2/7 Headache 2/7 / 2/7 1/4 Dizziness 4/14 2/7 8/29 3/11 Nausea 8/29 2/7 2/7 4/14 Vomiting 3/11 / 1/4 1/4 Respiratory depression 2/7 / 1/4 / Shivering 1/4 4/14 2/7 1/4 Pruritus / 2/7 1//4 2/7 intensity, and the need for analgesics, suggesting the development of OIH in patients undergoing laparoscopic gynaecological surgery with sevoflurane remifentanil anaesthesia. We also observed an increase in postoperative eye opening time, extubation time, Ramsay score, and incidence of nausea after sevoflurane sufentanil anaesthesia, exemplifying the role of sufentanil in postanaesthesia recovery and comfort. Thus, remifentanil exhibits a distinct superiority in minor surgery if remifentanilinduced hypernociception is successfully controlled. The N-methyl-D-aspartate (NMDA) receptor is a pivotal hyperalgesic modulator in OIH Ketamine, pregabalin, and dexmedetomidine have also been found to attenuate OIH by targeting the NMDA receptor, although several side-effects limit their practical use Butorphanol is a synthetic opioid agonist antagonist. 2 Activation of the κ-receptor might be beneficial for mitigating neuropathic pain and inflammatory mechanical hyperalgesia The µ-receptor partial antagonistic action limits the interaction between opioid receptors and NMDA receptor function. 35 Subsequently, butorphanol might be used to manage OIH. In the present study, for the first time, we found that butorphanol mediated clinical OIH after surgery. Furthermore, we discovered that preoperative butorphanol 2 µg kg 1 clearly prevented OIH, by reversing the decrease in mechanical nociceptive threshold, reducing the area of mechanical hyperalgesia and the sufentanil titrated in the PACU, prolonging the time until first administration of postsurgical analgesics, and alleviating pain intensity and cumulative sufentanil consumption for 24 h after remifentanil exposure. Interestingly, the duration of antihyperalgesic efficacy remarkably exceeded the duration of action of butorphanol (3 4 h). 38 This phenomenon might be attributed to pre-emptive analgesia, defined as administration of analgesics before nociceptive transmission processing and central hypersensitivity, to relieve pain and induced antinociception effectively Unfortunately, in the present study it is not possible to distinguish the pre-emptive effect from a clear analgesic activity. A control group treated with butorphanol after surgery is needed. Nonetheless, these results confirm that preoperative butorphanol therapy might provide a new clinical approach for preventing OIH after surgery. Antihyperalgesia associated with cyclo-oxygenase inhibitors has been demonstrated in several experimental studies Lenz and colleagues 15 reported that remifentanil-related hyperalgesia in electrical pain and cold pain models in human volunteers was acutely diminished by parecoxib and ketorolac administration before remifentanil infusion. It was also suggested that parecoxib prophylaxis significantly inhibited remifentanil-induced postinfusion hyperalgesia after transcutaneous electrical stimulation in volunteers. 16 These results suggested that the antihyperalgesic efficacy of the cyclo-oxygenase inhibitor might depend on adequate treatment duration, which also explains why Eisenach and colleagues 41 reported that ketorolac application during remifentanil infusion did not reverse post-remifentanil hyperalgesia evoked by capsaicin in volunteers. Likewise, preoperative FA

7 51 Zhang et al. treatment alleviated OIH after surgery in clinics Nonetheless, FA should still be administered cautiously in patients with gastrointestinal disease or an allergy to aspirin. In parallel, our study also found that butorphanol administration increased the incidence of somnolence and dizziness during the first 24 h after surgery under sevoflurane remifentanil anaesthesia. Therefore, we concluded that a low dose of butorphanol combined with FA effectively attenuated remifentanil-induced hypernociception and did not significantly exacerbate the side-effects after surgery. This is the first report to demonstrate that the preoperative combination of butorphanol 1 µg kg 1 and FA.5 mg kg 1 successfully ameliorate OIH, alleviate pain intensity, and obviate the need for analgesics after remifentanil anaesthesia. Furthermore, patients treated with this combination experienced greater postoperative comfort and satisfaction than those injected with butorphanol 2 µg kg 1 alone, although the antihypernociceptive efficacy was similar. The results suggest that the low-dose combination decreased butorphanol-related side-effects after surgery. In addition, no significant increase in cyclo-oxygenase inhibitor-induced nausea and vomiting was seen in patients receiving the combination after surgery, which might be attributed to tropisetron treatment before the completion of surgery and the low dose of FA injected. The foregoing results suggest that the preoperative combination of butorphanol and FA in low doses reduced OIH and drug-related side-effects after surgery. However, the underlying mechanisms associated with the prophylactic effect on OIH warrant further investigation. A possible weakness of the present study is related to the lack of investigation using the optimal combination of dosages. Another limitation relates to the absence of post-discharge patient outcomes. In summary, the present data suggest that preoperative application of butorphanol 2 µg kg 1 successfully attenuated OIH after surgery. The preoperative combination of butorphanol 1 µg kg 1 and FA.5 mg kg 1 resulted in similar antihyperalgesic efficacy and generated greater patient satisfaction without an increase in drug-related side-effects after surgery. Thus, the combination strategies may be more beneficial in mitigating OIH clinically. However, caution must be exercised in extrapolating the findings of the clinical trial to routine clinical practice. Authors contributions Conceived and designed the experiment: L.Z., G.W. Performed the experiment and collected the data: L.Z., R.S., Q.Z., Y.L. Analysed the data: L.Z., Y.Y. Wrote the paper: L.Z., Y.Y., G.W. Revised the paper: R.S., Q.Z., Y.L. Supplementary material Supplementary material is available at British Journal of Anaesthesia online. 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