propofol is a short - acting intravenous hypnotic agent , which is widely used for sedation and general anesthesia . however , pain during injection of propofol can occur in up to 80% of patients , which can be very stressful to patients . many methods including cooling or diluting the propofol solution or the concomitant use of drugs such as methylene blue , pregabalin , or magnesium sulfate have been used to reduce this pain . however therefore , propofol long - chain triglycerides ( lcts)/medium - chain triglycerides ( mcts ) were introduced to minimize injection pain , which has less concentration of aqueous free propofol than propofol - lct . however , pain on injection still occurs despite use of propofol - lct / mct . pretreatment with small dose of remifentanil has been demonstrated to be effective in reducing pain from propofol injection without side effects . esmolol , a short - acting 1 adrenergic receptor antagonist , is widely used to reduce cardiovascular stress response to layngoscopy and tracheal intubation . it was shown that perioperative infusion of esmolol reduced anesthetic requirement for surgery   and postoperative analgesic consumption . recently , it was reported that pretreatment with esmolol 0.5  mg / kg has analgesic effect on rocuronium injection pain without side effects . the present study was designed to compare the analgesic effect of pretreatment with remifentanil 0.35  g / kg , and esmolol 0.5  mg / kg and 1  mg / kg in minimizing pain during injection of propofol - lct , compared with placebo . in all , 120 patients aged 18 to 70 years , american society of anesthesiologists physical status i and ii , scheduled for elective dental surgery requiring general anesthesia were included . we excluded patients who have cardiac , neurologic or psychiatric problem , patients who had analgesic or sedative agents within 24  hours before surgery , and patients requiring a rapid sequence induction . the present study was approved by the ethics committee of kyungpook national university hospital ( knuh 201305003001 ) and informed written consent was obtained from all patients . on arrival in the operating room , electrocardiogram , noninvasive blood pressure , and pulse oximetry were measured , and a 22-gauge catheter was inserted into a dorsal vein of the patient 's nondominant hand . using a computer - generated table , patients were randomized to 1 of the 4 treatment arms ( n  =  30 each ) receiving normal saline , remifentanil 0.35  g / kg , esmolol 0.5  mg / kg and 1  mg / kg as pretreatment . a study - blinded nurse prepared pretreatment substance using identically coded syringes at room temperature . thirty seconds after injection of pretreatment drug , patients received propofol - lct 0.5  mg / kg at rate of 0.5  ml / sec using syringe pump . a study - blinded anesthesiologist measured score of injection pain of propofol using a 4-point scale ( 0  =  none [ negative response to questioning ] , 1  =  mild pain [ pain reported in response to questioning only , without any behavioral sign ] , 2  =  moderate pain [ pain reported in response to questioning and accompanied by a behavioral sign , or pain reported simultaneously without questioning ] , 3  =  severe pain [ strong vocal response or response accompanied by facial grimacing , arm withdrawal or tears ] ) . thereafter , propofol - lct1.5  mg / kg and rocuronium 0.8  mg / kg were administered for tracheal intubation , and anesthesia was maintained with desflurane 4% to 7% in 50% n2o / o2 . emergence reactions associated with pretreatment substances such as hypotension and bradycardia were recorded . in the present study , the incidence and severity of pain after propofol injection was the primary outcome , and all other variables were secondary outcomes . on the basis of previously published data , we estimated the incidence of pain during propofol injection in the placebo group to be around 80% . a 40% difference ( 80%40% ) between placebo group and treatment groups would be considered of clinical significance . using a 2-tailed test of the proportions with  error of 0.05 and  error of 0.8 , data were analyzed using statistical software ( spss , version 23.0 for windows ; spss , chicago , il ) . fisher exact test or the chi - square test was used for sex , incidence of pain , and incidence of side effects . in all , 120 patients aged 18 to 70 years , american society of anesthesiologists physical status i and ii , scheduled for elective dental surgery requiring general anesthesia were included . we excluded patients who have cardiac , neurologic or psychiatric problem , patients who had analgesic or sedative agents within 24  hours before surgery , and patients requiring a rapid sequence induction . the present study was approved by the ethics committee of kyungpook national university hospital ( knuh 201305003001 ) and informed written consent was obtained from all patients . on arrival in the operating room , electrocardiogram , noninvasive blood pressure , and pulse oximetry were measured , and a 22-gauge catheter was inserted into a dorsal vein of the patient 's nondominant hand . using a computer - generated table , patients were randomized to 1 of the 4 treatment arms ( n  =  30 each ) receiving normal saline , remifentanil 0.35  g / kg , esmolol 0.5  mg / kg and 1  mg / kg as pretreatment . a study - blinded nurse prepared pretreatment substance using identically coded syringes at room temperature . thirty seconds after injection of pretreatment drug , patients received propofol - lct 0.5  mg / kg at rate of 0.5  ml / sec using syringe pump . a study - blinded anesthesiologist measured score of injection pain of propofol using a 4-point scale ( 0  =  none [ negative response to questioning ] , 1  =  mild pain [ pain reported in response to questioning only , without any behavioral sign ] , 2  =  moderate pain [ pain reported in response to questioning and accompanied by a behavioral sign , or pain reported simultaneously without questioning ] , 3  =  severe pain [ strong vocal response or response accompanied by facial grimacing , arm withdrawal or tears ] ) . thereafter , propofol - lct1.5  mg / kg and rocuronium 0.8  mg / kg were administered for tracheal intubation , and anesthesia was maintained with desflurane 4% to 7% in 50% n2o / o2 . emergence reactions associated with pretreatment substances such as hypotension and bradycardia were recorded . in the present study , the incidence and severity of pain after propofol injection was the primary outcome , and all other variables were secondary outcomes . on the basis of previously published data , we estimated the incidence of pain during propofol injection in the placebo group to be around 80% . a 40% difference ( 80%40% ) between placebo group and treatment groups would be considered of clinical significance . using a 2-tailed test of the proportions with  error of 0.05 and  error of 0.8 , data were analyzed using statistical software ( spss , version 23.0 for windows ; spss , chicago , il ) . fisher exact test or the chi - square test was used for sex , incidence of pain , and incidence of side effects . 1 ) . there was no difference in demographic data between groups ( table 1 ) . the incidence of pain during propofol injection was significantly reduced with remifentanil 0.35  g / kg ( 36.7% ) , esmolol 0.5  mg / kg ( 40% ) and 1  mg / kg ( 36.7% ) , compared with placebo group ( 83.3% ) ( respectively , p  <  0.05 ) . in addition , pretreatment with remifentanil ( 3.3% ) , and esmolol 0.5  mg / kg ( 3.3% ) and 1  mg / kg ( 3.3% ) significantly decreased the incidence of severe injection pain , compared with placebo ( 26.7% ) ( respectively , p  <  0.05 ) . there were no emergence reactions associated with pretreatment substances such as hypotension and bradycardia in all groups . . demographic characteristics of the study population ( n  =  120 ) . incidence and pain severity during injection of propofol . this study showed that pretreatment with remifentanil 0.35  g / kg , and esmolol 0.5  mg / kg and 1  mg / kg , was equally effective to reduce pain during propofol injection , compared with placebo . but propofol is associated with high incidence of pain at injection site , which is often very stressful to patients . the direct exposure of nociceptive receptors or free nerve ending in the vein by free propofol can increase the pain on injection . varghese et al reported that when added with lidocaine , both propofol - lct / mct and propofol - lct had similar incidence of injection pain . by a systemic review and meta - analysis in 2011 , pretreatment with a small dose of opioids halved the incidence of pain after propofol injection , which can generally be recommended . the previous study demonstrated that pretreatment with remifentanil 0.35  g / kg reduced injection pain of propofol by 38.8% without any side effects . in the present study , the incidence of pain from propofol injection was 33.3% in the patients who received remifentanil 0.35  g / kg , which is consistent with the previous study . esmolol , antagonist of 1 adrenergic receptor , is often used to blunt adrenergic response to perioperative stimuli . it was demonstrated that a single injection of esmolol 1 to 2  mg / kg is effective to attenuate the increase of heart rate after intubation without adverse effects . in the previous studies , intraoperative infusion of esmolol decreased the requirement of opioid and inhalation anesthetic without causing hemodynamic change , and reduced postoperative analgesic consumption . up to date , the exact analgesic mechanism of  adrenergic receptor antagonist remains unclear . adrenal hormone , commonly known as stress hormone , increases during emotional distress and anxiety , which are associated with activation of hypocampal neurons . adrenergic receptors are involved in learning - facilitated plasticity in the mammalian hippocampus , which requires activation of n - methyl - d - aspartate ( nmda ) receptor . the activation of nmda receptor in the hippocampus is involved in nociceptive processing , at least , in part . in addition , it was found that esmolol can facilitate inhibitory transmitter release in spinal trigeminal nucleus , which produces analgesic effects . in the present study , pretreatment with esmolol 0.5  mg / kg and 1  mg / kg and remifentanil 0.35  g / kg equally decreased pain during propofol injection . the incidence of pain when propofol was injected into vein of the dorsum of hand can reach as high as 80% . pretreatment substances such as remifentanil and esmolol can cause dose - dependent decrease in blood pressure and heart rate . therefore , a placebo group was included to investigate the adverse effect of the pretreatment substances . in the present study , there were no emergence reactions associated with pretreatment with remifentanil 0.35  g / kg , and esmolol 0.5  mg / kg and 1  mg / kg . these results were compatible with the previous studies . the present study had some limitations . in the present study , premedication , such as sedatives , the previous study showed that 87% of patients who did not receive anxiolytic premedication reported the recall about injection pain after propofol injection . therefore , another study is needed to examine the patient 's satisfaction about anesthetic care and the incidence of recall for pain during propofol injection . in conclusion , pretreatment with esmolol 0.5  mg / kg and 1  mg / kg , and remifentanil 0.35  g / kg were equally effective in reducing pain during injection of propofol without adverse effects .
abstractbackground : propofol is associated with pain during injection , which is stressful to patients . the present study was designed to investigate the analgesic effect of pretreatment with remifentanil and esmolol in minimizing propofol injection pain , compared with placebo.methods:in a randomized , double - blind , prospective trial , 120 patients , scheduled for elective dental surgery under general anesthesia , were randomized to 1 of the 4 treatment arms ( n  =  30 each ) receiving normal saline , remifentanil 0.35  g / kg , esmolol 0.5  mg / kg , and 1  mg / kg before administration of propofol . during injection of 1% propofol 0.5  mg / kg , pain was evaluated by a 4-point score ( 0  =  none , 1  =  mild , 2  =  moderate , 3  =  severe ) . 
 any adverse effects such as hypotension and bradycardia were recorded during the perioperative periods.results:in all , 120 patients completed this study . 
 there were no significant differences in terms of demographic data . 
 the incidence of pain on injection of propofol was 11 ( 36.7% ) with remifentanil 0.35  g / kg , 12 ( 40% ) with esmolol 0.5  mg / kg , and 11 ( 36.7% ) with esmolol 1  mg / kg , compared with 25 ( 83.3% ) with normal saline ( respectively , p  <  0.05 ) . 
 there were no significant differences in the incidence of pain between groups with remifentanil 0.35  g / kg , and esmolol 0.5  mg / kg and 1  mg / kg . there were no emergence reactions such as hypotension and bradycardia in all groups.conclusions:pretreatment with esmolol 0.5  mg / kg and 1  mg / kg and remifentanil 0.35  g / kg equally decreased pain during propofol injection .