Low Doses Nalmefene Reduces Remifentanil-induced Hyperalgesia And Enhances Analgesia: A Clinical Trial

Objective:Remifentanil is a very potent and ultra-short-acting opioid drug which is widely used in general anesthesia due to its rapid onset of action and continuous accumulation without accumulation.However,in recent years,studies have found that after a large amount of remifentanil infusion over a long period of time,who sensitivity to pain increases and analgesics are required.This phenomenon is known as remifentanil-induced hyperalgesia（RIH）.Nalmefene,as the latest generation of opioid receptor antagonists,has been studied that low dose nalmefene（<1.0μg/kg）can reduce opioid-induced hyperalgesia and enhance analgesia.Therefore,this research focus on the effect of analgesic at different low dose nalmefene combined with remifentanil on patients with general anesthesia,and explores the optimal dose of nalmefene to find a more complete new pattern of analgesia.Methods:90 adult patients scheduled for open rectectomy and colectomy entered the study.Written informed consent was obtained from all patients.Patients with ASA I-III,they were assigned into three groups randomly,with 30 patients in each group.The three groups were Group N₁（nalmefene 0.05μg/kg）,Group N₂（nalmefene 0.15μg/kg）and Group N₃（nalmefene 0.25μg/kg）.Monitoring included HR,MAP,Sp O2,BIS,PETCO2.Induction of anaesthesia was identical in the three groups.The three groups of patients were injected with an initial dose of remifentanil（1μg/kg）（>60S）,propofol（2mg/kg）.Then cisatracurium（0.15mg/kg）was used for neuromuscular blockade before endotracheal intubation.During induction of anaesthesia,all patients received 500 m L of lactated Ringer’s solution.Continuous injected remifentanil（0.30μg/kg/min）,inhalated sevoflurane concentration of 1%to 2%continuously,and cisatracurium was administered intermittently.The patients were injected different low doses of nalmefene described above at the end of surgery.Stop sevoflurane inhalation before skin suture,stop pumping remifentanil after surgery,remove the tracheal tube after the extubation indication,evaluate the patient’s pain NRS score,and connect with PCIA that diluting sufentani（2μg/kg）and tropisetron（10mg）to 100ml with normal saline.The device was set to deliver a basal infusion of 2 ml/h and bolus doses of 0.5 ml with a 15 min lockout period.The pain NRS score remained less than 4.The experiment monitoring indexes in the study including:（1）We recorded patient characteristics:age,BMI,ASA status,current medical history and past history（2）Mainly monitoring indexes:postoperative pain intensity at 30min,1h,6h,12h,24h,the number of self-controlled analgesia compressions and effective compressions sufentanil consumption was recorded 48h after surgery.（3）the other monitoring indexes:operation time and dosage of remifentanil,postoperative eye opening time and extubation time,the residence time of postanesthesia care unit.And recording the postoperative side-effectsResults:（1）There were no significant differences between the three groups with respect to age,ASA status,BMI,current medical history and past history（P>0.05）.（2）Compared with Group N₁,the pain NRS scores were lower in Group N₂ at 1h（P<0.05）;compared with Group N₁ and Group N₃,the pain NRS scores were significantly lower in Group N₂ at 6h（P<0.01）;There was no difference in pain NRS scores between Group N1 and Group N₃ at all time point（P>0.05）.The ues of Group N₂ in sufentanil consumption by PCIA was significantly lower than Group N₁ and Group N₃（P<0.05）.As well as Group N₂,the number of compressions were significantly less than that in Group N₁（P<0.05）.No significant difference in sufentanil consumption by PCIA between Group N₁ and Group N₃（P>0.05）.（3）The time of eye opening and extubation in Group N₁ were longer than Group N₂ and Groups N₃（P<0.05）,the residence time of postanesthesia care unit was similar among all the groups（P>0.05）.The incidence of nausea and respiratory depression were higher in Group N₁（P<0.05）.Furthermore,the incidence of drowsiness was significantly lower in Group N₃（P<0.05）.Duration of surgery,hemodynamics at all time points,duration of anesthesia related drugs infusion and the intraoperative volume during the operation were no significant difference among the three groups（P>0.05）.Conclusions:During anesthesia of patients undergoing open rectum resection and colectomy,pretreatment with nalmefene 0.15μg/kg at the end of the operation relieved postoperative hyperalgesia caused by remifentanil,enhanced the postoperative analgesic,exhibited shorter eye opening time and extubation time,reduced the incidence of nausea and respiratory depression.Pretreatment with nalmefene 0.25μg/kg exhibited shorter eye opening time and extubation time,reduced adverse reactions such as nausea and drowsiness after surgery.