| Opioids are the most commonly used analgesic drugs in clinical settings, they have long been used for the preoperative medication and the main analgesic drugs in general anesthesia as well as the treatment of acute and chronic pain with good analgesic effects. However, clinical studies have suggested that opioids may induce acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH). AOT is defined as an increase in the dose required maintaining adequate analgesia in patients receiving opioid medication for the treatment with a rightward shift of the dose-response curve. OIH is defined as a state of nociceptive sensitization, which is characterized by a paradoxical response, whereby a patient receiving opioids for pain treatment might have an increased sensitivity to painful stimuli manifested as decrease in pain threshold and more sensitive to pain with stimulus pain curve shifts to the left. In clinic settings, opioid-induced hyperalgesia often is confused with acute opioid tolerance because of the manifestations of similar symptoms. AOT and OIH share similar molecular mechanisms with mutual coordination. In theory, the method of quantitative sensory testing (QST) can be used to distinguish between OIH and AOT in evaluating the patient’s pain sensitivity, because a significant characteristic of hyperalgesia is the reduction in the pain threshold. The most studies have focused on the phenomenon of AOT and OIH by using pain-related clinical outcomes like postoperative pain intensity and opioid analgesics requirements instead of using quantitative sensory testing. However, studies have showed that postoperative hyperalgesia of incision was negatively correlated with the clinical pain severity.Therefore, we introduced the latest automatic advanced electronic pain threshold analyzer to determine the mechanical pain threshold and secondary hyperalgesia around the surgical incision to further explore the development of AOT and OIH. In this study, we used Electronic Von Frey (EVF) as a quantitative sensory testing to observe mechanical hyperalgesia which was more reliable and rapid than traditional VFM in exploring mechanical pain thresholds.Remifentanil is a novel ultra short-acting μ opioid receptor agonist, its unique pharmacokinetic properties afford a fast onset of action and a predictable and rapid recovery independent of the infusion duration. The very short elimination half-life and stable context-sensitive half time of remifentanil reflects the exceptionally high clearance of remifentanil by plasma and tissue esterases. While the advantageous pharmacokinetic properties of remifentanil favor its use, significant concern exist among clinicians that such use may negatively affect postoperative pain. More specifically, severe postoperative pain after high doses of intraoperative use of remifentanil has repeatedly been linked to the development of acute tolerance and/or opioid-induced hyperalgesia (OIH). In addition, postoperative hyperalgesia and pain intensity are considered to be related to postoperative chronic pain. Therefore, prevention of opioid induced hyperalgesia is a positive clinical significance in reduction on the incidence of postsurgical chronic pain.The underlying mechanism of remifentanil induced acute tolerance and/ hyperalgesia has not been elucidated, it may be associated to the change with the opioid receptors, NMDA receptor activation, GABA receptor reduction and increase in the release of opioid peptides, neuropeptides, nociceptin as well as dynorphin A. The inflammatory cytokines (such as prostaglandin, interleukin-1, interleukin-6) may also contributed to the development of remifentanil induced acute tolerance and/ hyperalgesia. The NMDA receptor pathway may play an important role in the underlying mechanism. Clinical work in attenuating or preventing the expression of OIH has primarily focused on manipulation of the glutaminergic system, either through direct or indirect modulation of the NMDA receptor. However, the clinical efficacy and significance of these approaches has not been evaluated in large prospective clinical trials.Some basic and clinical researches showed that propofol and COX inhibitors (such as parecoxib sodium, flurbiprofen axetil) as well as alpha 2 receptor agonists (such as dexmedetomidine) may play important roles in regulating remifentanil induced hyperalgesia by acting on NMDA receptor pathway. But the most clinical observations reflected only postoperative pain scores and analgesic consumption without measuring postoperative pain threshold and hyperalgesia around surgical incision, therefore it is difficult to accurately explore the phenomenon of remifentanil induced hyperalgesia after the surgery. Since the mechanism of remifentanil induced hyperalgesia is complex with a multi-pathway and multi-factor interaction, even in the NMDA receptor pathway, there are many factors affecting the interaction. Based on the above mentioned, our hypothesis is that whether there is a synergistic effect of preoperative intervention medications to prevent postoperative hyperalgesia. In addition, studies have shown that prostaglandin E2 and interleukin-1β as well as interleukin-6 are associated closely to the acute postoperative pain and hyperalgesia.Based on the above analysis and hypothesis, this paper is divided into three parts for clinical research. The first part of the study is to investigate whether propofol-remifentanil anesthesia and sevoflurane-remifentanil anesthesia will impact on the remifentanil induced hyperalgesia at different dosage of remifentanil, to explore if propofol has the function of regulating OIH. The second part is to study the effects of parecoxib on high dose of remifentanil induced hyperalgesia in terms of measurements of postoperative pain threshold and the extent of hyperalgesia as well as serological index (such as prostaglandin E2, interleukin-1β and interleukin-6). The third part of the study is to investigate whether dexmedetomidine alone or combined with flurbiprofen axetil has preventive effect or a synergistic preventive effect on remifentanil induced hyperalgesia.Part 1 Modulation of high dose remifentanil induced hyperalgesia by propofol in humansObjectiveThe aim of the study was to investigate the effects of maintenance with propofol or sevoflurane on postoperative hyperalgesia after different dosage of remifentanil-based anaesthesia.MethodsNinety patients aged between 20 and 60 yr with an ASA physical status of I or II undergoing laparoscopic cholecystectomy were randomly assigned into three groups: sevoflurane with high dose remifentanil group (SH group), sevoflurane with low dose remifentanil group (SL group) and propofol with high dose of remifentanil group (pH group). In the operating theatre, standard monitoring and bispectral index monitoring as well as anesthetic gas concentration were performed and baseline values were recorded. After received midazolam 3 mg, patients in SH group and SL group were induced with sevoflurane and remifentanil (2μg·kg-1); patients in PH group induced with propofol and remifentanil. Anaesthesia was maintained according to the allocated group, SH group with sevoflurane and remifentanil 0.3μ·g·kg-1·min-1, SL group with sevoflurane and remifentanil 0.1μg·kg-1·min-1; PH group with propofol and remifentanil 0.3μg·kg-1·min-1. The BIS value was used to guide administration of propofol and sevoflurane. The target range of BIS during maintenance was 40-50. Mechanical ventilation was adjusted to maintain an end-tidal carbon dioxide concentration of 30-35 mmHg throughout surgery. PCIA pump was applied to all patients when surgery was completed. PCIA pump contained sufentanil (150μg), Granisetron (10mg) and normal saline in a total volume of 150 mL, and was set to initial dose of 5 mL, and deliver a bolus dose of 3 mL with 15 min lockout interval without background infusion. The patients were transferred to the post-anaesthesia care unit (PACU) for further observation. The mechanical pain threshold on the incision site was measured by using electronic von Frey (EVF) device in the preoperative and postoperative 6h and postoperative 24h, respectively. The time to first analgesic requirement, postoperative analgesic consumption, visual analogue scale (VAS) pain score, and incidence of related side effects also recorded.All data were processed by the Statistical Package for Social Sciences (SPSS 20.0). Numeric variables were described as the mean (standard deviation, SD) or median (interquartile range, IQR) while categorical variables expressed as number (percentage,%). The demographic characters, surgical related information, time to first analgesic requirement were analyzed using one-way analysis of variance. Post Hoc multiple comparisons among each time spot in different groups and different time spots in each group were analyzed by using LSD test. As for analgesic related adverse effects, differences between groups were compared with Chi-square or Fisher’s exact test. P<0.05 was considered statistically significant.ResultsThere were no significant differences in age, BMI, duration of anesthesia and surgery, awakening time and extubation time among the three groups. Mechanical pain threshold at the incision site was significantly lower at 6 hours and 24 hours postoperative time points and the VAS scores at postoperative 30 min,2hours,6 hours were higher in SH group when compared with SL group; Mechanical pain threshold at the incision site was significantly higher at 6 hours and 24 hours postoperative time points and the VAS scores at postoperative 30 min,2hours,6 hours were lower in PH group when compared with SH group (all P<0.05); But mechanical pain threshold and VAS scores were not significantly different in PH group when compared with SL group(all P>0.05); The correlation coefficients(r) between the mechanical pain threshold and the static VAS score at 6 hours and 24 hours postoperative time points were-0.236.0.187 respectively (all P>0.05). The time to first analgesic requirement was significantly shorter in Group SH compared with other two groups (both P<0.05). The total amounts of sufentanil consumption were significantly higher in Group SH at postoperative 24h than those in other two groups (all P<0.05); the incidence of bradycardia and postoperative shivering were significantly higher in pH group and SH group than that in the SL group (all P<0.05).ConclusionsIntra-operative use of high dose of remifentanil (0.3μg·kg-1·min-1) with sevoflurane anesthesia would induce postoperative hyperalgesia and the maintenance of general anaesthesia by propofol may reduce remifentanil-induced hyperalgesia induced by high dose of remifentanil usage.Part 2 Inhibition of parecoxib on remifentanil induced hyperalgesia with remifentanil-sevoflurane anaesthesiaObjectiveThe aim was to evaluate analgesic and antihyperalgesic properties of parecoxib on remifentanil-induced hyperalgesia in humans. This study is to investigate the measurements of mechanical pain threshold, the extent of secondary hyperalgesia, VAS scores, postoperative sufentanil consumption as well as serum prostaglandin E2, IL-1β and IL-6 values.MethodsSixty women aged between 35 and 59 yr with an ASA physical status of Ⅰ or Ⅱ undergoing total abdominal hysterectomy were randomized into Group C (control group) and Group P (parecoxib group). Group P received 40mg parecoxib at thirty minutes before anesthetic induction and Group C received normal saline. Anesthesia was induced with midazolam followed by sevoflurane, remifentanil 2μg·kg-1 and Proseal LMA was inserted after cisatracurium given. Anaesthesia was maintained with remifentanil 0.3μg·kg-1·min-1 and sevoflurane. The BIS value was used to guide administration of sevoflurane, and target range of BIS during maintenance was 40-50 and keeping hemodynamic stability. PCIA pump was applied to all patients when surgery was completed. PCIA pump contained sufentanil (300μg), granisetron (15mg), and normal saline in a total volume of 150 mL, and was set to deliver a bolus dose of 2 ml with 15 min lockout interval with background infusion of 2mL. The mechanical pain threshold and the extent of hyperalgesia on the incision site were measured by using EVF device in the preoperative and postoperative periods. The time to first analgesic requirement, postoperative analgesic consumption, visual analogue scale (VAS) pain score, and serum concentration of prostaglandin E2, plasma IL-1β and IL-6 also recorded.All data were processed by the Statistical Package for Social Sciences (SPSS 20.0). Numeric variables were described as the mean (standard deviation, SD) or median (interquartile range, IQR) while categorical variables expressed as number (percentage,%). The Student’s t-test was used to compare parameters between the two groups. For comparisons of other parameters at different time points within the same group, two-way analysis of variance on rank test with time and group as factors was used. For categorical variables, the Chi-square test or Fisher’s exact test was used. P<0.05 was considered statistically significant.ResultsCompared to Group C, the mechanical pain threshold on the incision site in Group P were significantly higher at postoperative 2h,24h and 48h time points; the extent of hyperalgesia on the incision site were significantly lower at postoperative 24h and 48h time points; the VAS scores at postoperative 30 min,2h,6 h,24h and 48h were lower (all P<0.05) both at rest and on movement; the total amounts of sufentanil consumption were significantly lower when compared with Group C (all P<0.05). The mechanical pain threshold on the forearm site at postoperative 2h was significantly decreased in Group C when compared with Group P. Plasma PE2 and IL-6 concentration were significantly increased at postoperative 6h,24h postoperative time points in both groups; but the values of PE2 at postoperative 6 and 24 hours, the values of IL-6 at postoperative 6h were significantly lower in group P than that in group C (all P<0.05). The plasma IL-1β concentrations were below detection limit (5pg/ml) at baseline and at the postoperative 6 h and 24h time points.ConclusionsParecoxib intravenously prior to anesthetic induction may inhibit remifentanil induced hyperalgesia and the possible mechanism may be associated with reduction on postoperative prostaglandin E2 synthesis and Pro-inflammatory cytokines IL-6 release, so as to achieve the postoperative analgesia and antihyperalgic effect.Part 3 Protective effects of dexmedetomidine combined with flurbiprofen axetil on remifentanil induced hyperalgesiaObjectiveThe aim of this study was to investigate whether dexmedetomidine alone or combined with flurbiprofen axetil has preventive effect or a synergistic preventive effect on remifentanil induced hyperalgesia.MethodsEighty-six aged between 37 and 59 yr with an ASA physical status of I or II patients diagnosed with hysteromyoma and scheduled for laparoscopic assisted vaginal hysterectomy (LAVH) were randomly divided into Group hyperalgesia (Group H, n=29), Group hyperalgesia and dexmedetomidine (Group HD, n=28) and Group hyperalgesia, dexmedetomidine and flurbiprofen axetil (Group HDF, n=29). At 15 min before the anesthesia induction, Group HD were administered with continuous infusion of dexmedetomidine (an initial dose of 0.5μg·kg-1 within 10 min, followed by a continuous infusion of 0.6μg·kg-1·h-1) and Group HDF received flurbiprofen axetil (1.5mg·kg-1) 10 min before induction in combination with dexmedetomidine. As control group, Group H was not given medication before anesthesia induction. Anesthesia was maintained with intravenous remifentanil infusion at 0.3μg·kg-1 min-1 and sevoflurane inhalation among three groups. The concentration of sevoflurane was adjusted (0.3% stepwise titration) according to the target bispectral index between 40 and 60. PCIA pump contained sufentanil (150μg), granisetron (10mg), and normal saline in a total volume of 150 mL, and was set to deliver a bolus dose of 3 ml with 15 min lockout interval with background infusion of 1.5 mL/h. Mechanical pain threshold was measured during the preoperative visit and postoperatively at 1,6 and 24-hours time points. The area of secondary hyperalgesia around incision site at 24 hours after surgery was measured. The visual analogue scale (VAS), time to analgesic requirement, total sufentanil consumption and side effects were assessed postoperatively.All data were processed by the Statistical Package for Social Sciences (SPSS 20.0). Numeric variables were described as the mean (standard deviation, SD) or median (interquartile range, IQR) while categorical variables expressed as number (percentage,%). The demographic characters, surgical related information, time to first analgesic requirement were analyzed using one-way analysis of variance. Two-way repeated measures analysis of variance followed by post-hoc Bonferroni corrections was used in analyzing the difference between the treatments at different time point. As for analgesic related adverse effects, differences between groups were compared with Chi-square or Fisher’s exact test. P<0.05 was considered statistically significant.ResultsMechanical pain threshold at the incision site was significantly lower at 1 hour,6 hours and 24 hours postoperative time points in Group H than those in other two Groups (all.P<0.05). Besides, mechanical pain threshold in Group HDF at above time points were all significantly higher compared with those of Group HD (all P<0.05). The area of secondary hyperalgesia around incision site at 24 hours after surgery was greater in group H than those in the other two groups (both P<0.05), and it was significantly smaller at 24 hour after the surgery in Group HDF than that of the Group HD (P<0.05).The VAS scores at 30 min, lhour,6 hours,12hours and 24 hours were higher in Group H than that in other two groups (all P<0.05). In addition, VAS scores at above time points were significantly lower in Group HDF than those in Group HD (all P<0.05).ConclusionsIntra-operative of high doses remifentanil are associated with postoperative hyperalgesia, which efficiently alleviated by dexmedetomidine. Dexmedetomidine combined with flurbiprofen axetil has a synergistic preventive effect on remifentanil induced hyperalgesia, especially on reduction of the area of hyperalgesia at the incision site. |
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