The Effect of Dexmedetomidine Combined With Low-dose Nalmefene on Preventing Remifentanil-induced Postoperative Hyperalgesia in Patients Undergoing Gynecological Surgery
Phase: NA
Conditions: Pain, Anesthesia
Sponsor: Tianjin Medical University General Hospital

 
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 After randomization and allocation, patients were withdrawn 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.