Clinical trial NCT03096730
Conditions: Pain Anesthesia
Keywords: Remifentanil Opioid-induced hyperalgesia Postoperative pain pain intensity
Sponsor: Tianjin Medical University General Hospital
Start date: 2017-02-06; Completion date: 2017-12-30
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil arm 2: Normal saline is intravenously admistrated before anesthesia induction and intraoperative pain management was with sufentanil arm 3: Dexmedetomidine is intravenously administrated at a dose of 0.5ug/kg 10min before anesthesia induction and intraoperative pain management was with remifentanil arm 4: Nalmefene is intravenously administrated at a dose of 0.2ug/kg before anesthesia induction and intraoperative pain management was with remifentanil arm 5: 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
Interventions: intervention 1: Normal saline intervention 2: Remifentanil intervention 3: Sufentanil intervention 4: Dexmedetomidine injection intervention 5: Nalmefene
Intervention descriptions: intervention 1: Normal saline is intravenously administrated before anesthesia induction intervention 2: Remifentanil is intravenously administrated intervention 3: Sufentanil is intravenously administrated intervention 4: Dexmedetomidine is intravenously administrated before anesthesia induction intervention 5: Nalmefene is intravenously administrated before anesthesia induction

Protocol documents:
Prot_000.pdf: 
 
Effect of dexmedetomidine combined with low-dose nalmefene on 
preventing remifentanil-induced postoperative hyperalgesia  
 
NCT ID: NCT03096730 
Document date: 2017-2-15 
 
This randomized double-blind controlled study was approved by the 
Tianjin Medical University General Hospital Ethic Committee (Tianjin, 
China; approval number IRB2017-009-01) and written informed consent 
was obtained from all patients.  
Patients undergoing elective laparoscopic gynecological surgery 
were screened and enrolled between March 2017 and October 2017. 
Inclusion criteria were patients aged 20–64 yr; American Society of 
Anesthesiologists physical status I or II; cognitive capacity to use the 
patient-controlled analgesia (PCA).The exclusion criteria were as follows: 
bronchial asthma; coronary heart disease; severe hypertension; diabetes 
mellitus; obesity (BMI >30 kg/m2); 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 
dexmedetomidine or nalmefene; 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. 
    All surgical procedures were performed by senior surgeons. Patients 
fasted preoperatively. 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 
anesthesia. 
   Induction was performed with midazolam 0.05 mg/kg, sufentanil 0.2 
µg /kg, and etomidate 0.3mg/kg, and tracheal intubation was facilitated 
with rocuronium 0.7mg/kg. After intubation, all the patients were 
mechanically ventilated [end-tidal carbon dioxide values of 35–45 mm 
Hg]. Anesthesia was maintained with continuous remifentanil (RenFu Co., 
Hubei, China) infusion (at 0.30 µg /kg /min) as an intraoperative analgesic, 
and desflurane (Baxter Co., Shanghai, China) as an initial 1.0 minimal 
alveolar concentration (MAC) and oxygen–air mixture (fraction of 
oxygen, 50%). The depth of anesthesia was adjusted during surgery by 1% 
stepwise titration of desflurane, based on targeting bispectral index 
(45–60) and hemodynamic changes: HR exceeding pre-induction values 
by 15% and mean arterial blood pressure (MAP) exceeding baseline 
values by 20% or <60 mm Hg for at least 1 min. Rocuronium (0.3 mg/kg) 


was administered intermittently i.v. during anesthesia. If bradycardia (HR 
<45 beats/min) and continuous hypotension (MAP <60 mmHg) persisted, 
additional fluid infusion, atropine (0.5 mg), and phenylephrine (0.1 mg) 
were also administered. During skin suturing, desflurane and remifentanil 
were stopped, and tropisetron (2mg) was injected i.v. Residual 
neuromuscular block was antagonized by neostigmine 0.04 mg /kg and 
atropine 0.01 mg/kg when the tidal volume of spontaneous breathing 
exceeded 200 ml. When the bispectral index value reached 80, response 
to oral command was observed, followed by eye opening and 
spontaneous breathing rate exceeding 10 bpm, the patient was extubated 
and moved to the postanesthetic care unit (PACU) for recovery at least 1 
h. 
    Patients were randomly divided into one of five groups, each of 
which received dexmedetomidine or nalmefene or placebo saline 10 min 
before the induction of anesthesia as follow: (i) Group R received 3ml 
normal saline; (ii) Group N received nalmefene (Tiantaishan Medicine 
Co., Chendu, China) 0.2µg /kg in bolus; (iii) Group D received continuous 
infusion of dexmedetomidine (Enhua Medicine Co., Jiasu, China) at 0.5 
µg /kg/h for10min; (iv) Group DN received both nalmefene 0.1µg /kg and 
dexmedetomidine 0.25µg /kg/h; (v) Group S received 3ml normal saline. 
All patient assignments were guided by a computer-generated random 
number system and individually sealed envelope. Study medication were 


provided by the hospital pharmacy and administrated by an 
anesthesiologist not involved in the intraoperative management and data 
collection. Patients were blinded to the group assignment. Primary and 
secondary outcomes were analyzed and documented by another 
anesthesiologist responsible for the data collection, but not directly 
involved in the treatment of the patients and was blinded to 
randomization. 
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, 10, 15, 30, and 60 min after arrival at the PACU. 
    Pain levels were evaluated on an 11-point numerical rating scale 
(NRS): 0=no pain; and 10=worst pain imaginable. 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 weight 
bearing while escaping any harm.  
The baseline mechanical nociceptive threshold was assessed using 
20 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 method1,17,18. Every position was measured three times at 
intervals of 15 s, then 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 at 24 h preoperation and 
postoperation. The normalized area of hyperalgesia around the incision 
was measured at 24 h after surgery according to the previous published 
method. 17 
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 <4. However, sufentanil titration was discontinued if the 
Ramsay score was >3, peripheral oxygen saturation decreased <92%, or 
breathing rate was <10 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 (100 µg) 
diluted by normal saline to a total volume of 100 ml after discharge from 
the PACU. The device was set to deliver a basal infusion of 2 ml/h and 
bolus doses of 0.5 ml with a 15min lockout period. Sufentanil 
comsumption was recorded at 1, 3, 6, 12 and 24 h after sugery. The 
incidence of postoperative side-effects was monitored during the 24 h 
after surgery. 

SAP_001.pdf: 
 
Effect of dexmedetomidine combined with low-dose nalmefene on 
preventing remifentanil-induced postoperative hyperalgesia  
 
NCT ID: NCT03096730 
Document date :2017-2-15 
Statistical analyses 
The mechanical hyperalgesia threshold of the dominant inner 
forearm was considered the primary outcome. Based on our previous 
results (Zhen. Jia, Yi .Chen, and Guolin. 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 96.0 g, whereas the means of the 
four treatment groups (Group R, Group N, Group D, and Group DN) at 
24 h after surgery were 61.5, 67.2, 73.0, and 74.0g, respectively. We 
determined a difference of at least 30% (error standard deviation=26.0) 
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 27 patients per group was found to be 
sufficient to detect a significant difference (α=5%) with a statistical 
power (β-value) of 0.8. Presuming a 10% failure rate, we considered 
increasing the sample size to 30 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 repeated measures 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 with Dunnett’s post hoc comparisons. Other 
quantitative data, such as age, weight, duration of remifentanil infusion, 
mean concentration of desflurane, recovery time and extubation time 
were also analysed using one-way with Dunnett’s post hoc comparisons. 
Simultaneously, the χ2 test and Fisher’s exact test were used to analyze 
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 <0.05. SPSS 21.0 software (SPSS, Inc., 
Chicago, IL, USA) was used for all statistical analysis.