Effect of Dexmedetomidine Combined With Low-dose Nalmefene on Preventing Remifentanil-induced Postoperative Hyperalgesia

Effect of Dexmedetomidine Combined With Low-dose Nalmefene on Preventing Remifentanil-induced Postoperative Hyperalgesia

The Effect of Dexmedetomidine Combined With Low-dose Nalmefene on Preventing Remifentanil-induced Postoperative Hyperalgesia in Patients Undergoing Gynecological Surgery

To explore and compare antihyperalgesic effects of Dexmedetomidine,Nalmefene,and a combination of both received before anesthesia induction. To evaluate and examine the incidence of adverse effects with the purpose of selecting the optimum dose.

There are a dramatically increasing number of evidences that administration of the potent, ultra-short-acting opioid remifentanil seems to cause opioid-induced hyperalgesia (OIH) more frequently and predictably compared with the others, likely due to its rapid onset and offset. Therefore, prophylaxis of remifentanil induced hyperalgesia is indispensable to postoperative comfort and satisfaction. There is no denying the fact that OIH is related to central glutaminergic system and N-methyl-d-aspartate(NMDA)receptor-activation induced central sensitization. Dexmedetomidine is an 2-adrenergic agonist that has been shown to synergize with opioids. Dexmedetomidine inhibits NMDAR excitability by reducing the phosphorylation of N-methyl-D-aspartate receptor 2B subunit phosphorylation of spinal dorsal horn induced by remifentanil, thereby achieving the goal of reducing OIH. Nalmefene is a pure opioid receptor antagonist that antagonizes the Mu receptor, alleviating the central sensitization of NMDA, thereby reducing OIH. At the same time reported in the literature, opioid receptor has a bimode：On the one hand can be mediated by Gs protein-mediated pain, respiratory depression, nausea and vomiting, etc ; on the other hand can be coupled with Gi / Go protein mediated analgesic effect. Low-dose nalmefene (<1.0ug / kg) and other opioid receptor antagonists can antagonize the role of Gs protein-coupled opioid receptors, blocking the pathway of opioid excitatory effects, thereby reducing the incidence of adverse reactions.The following study is carried out to evaluate whether dexmedetomidine combined with nalmefene can be safely and effectively applied to prevent postoperative hyperalgesia induced by remifentanil in patients undergoing Laparoscopic gynecological surgery.

Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil

Normal saline is intravenously admistrated before anesthesia induction and intraoperative pain management was with sufentanil

Dexmedetomidine is intravenously administrated at a dose of 0.5ug/kg 10min before anesthesia induction and intraoperative pain management was with remifentanil

Nalmefene is intravenously administrated at a dose of 0.2ug/kg before anesthesia induction and intraoperative pain management was with remifentanil

A dose of 0.1ug/kg nalmefene and a dose of 0.25ug/kg dexmedetomidine for 10 minutes before anesthesia induction and intraoperative pain management was with remifentanil

The mechanical hyperalgesia threshold was defined as the lowest force (g) necessary to bend a Von Frey filament, which was perceived to be painful by the patient and measured by Von Frey filament at 24 hours postoperatively

The skin around the incision is stimulated in steps of 5 mm at intervals of 1 s starting outside of the hyperalgesic area in the direction of the incision. The distance from the incision to the first point where a 'painful', 'sore' or 'sharper' feeling occurred is measured and noted. This measurement is repeated at predefined radial lines around the incision. To eliminate the variable length of incision, this length is subtracted from the longer diameter leaving four radial distances from the end and from the middle of the incision. The normalized area of hyperalgesia is calculated by summing up the areas of the remaining four triangles measured by and Von Frey filament.

The pain score at rest was evaluated by pain 11-point numerical rating scale : 0 = no pain, 10 = greatest imaginable pain.

Each patient was administered analgesics using a PCA pump containing sufentanil (100μg) in normal saline at a total volume of 100 ml after leaving post-anaesthesia care unit . This 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. Sufentanyl cumulative consumption is recorded 24 hours postoperatively

Occurrence of side effects: nausea, vomiting, dizziness, headache, shivering, pruritus，hypotention/hypertention，bradycardia/tachycardia

Inclusion Criteria: Patients are scheduled to undergo Gynecological surgery under a short general anesthesia of 1-3 hours. American Society of Anesthesiologists physical status is I-II. Written informed consent was obtained from all the subjects. Exclusion Criteria: Subject has a diagnosis of Coronary heart disease, bronchial asthma, cardiac, lung, hepatic and renal insufficiency. Subject has a diagnosis of Severe high blood pressure , diabetes, obesity (BMI>30). Subject has a history of chronic pain, a history of alcohol or opioid abuse, pre-existing therapy with opioids, intake of any analgesic drug within 48 h before surgery. .Subject has Pregnancy, psychiatric disease. Subject has any contraindication for the use of patient-controlled analgesia (PCA). Inability to understand the Study Information Sheet and provide a written consent to take part in the study.