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Dexmedetomidine pretreatment alleviates propofol injection pain

Objective The incidence of propofol injection pain during induction of general anesthesia varies from 28% to 90%. This prospective, randomized, double-blind, placebo-controlled study evaluated the effect of dexmedetomidine (DEX) for reducing the incidence and severity of propofol injection pain. Methods Patients undergoing elective surgical procedures were randomly allocated into seven groups of 30 patients each. Experimental treatments were intravenously administered over 10 min (total volume 10 mL) prior to intravenous propofol injection, as follows: group I, the control group, was given isotonic saline. Patients in groups II, III, and IV received DEX 0.25 µg/kg, 0.5 µg/kg, or 1.0 µg/kg, respectively, mixed with isotonic saline immediately before propofol injection. Patients in groups V, VI, and VII received DEX as above, but 5 minutes before propofol injection. Propofol consisted of 1% long-chain triglyceride propofol (2.5 mg/kg) injected at 1 mL/s. Results Median propofol injection pain score was 0.00 (IQR 0.00–3.00) in patients who received 1.0 µg/kg DEX 5 min before the propofol injection (group VII), and only 1 patient (of 30) in this group received a pain score >2. The median pain score and number of patients with pain scores >2 in group VII were both significantly less than in the control (group I; p = 0.000, both). There were no differences in either mean arterial pressure or heart rate at any time point after DEX injection among the groups. Conclusions Pretreatment with intravenous DEX 1 µg/kg 5 min prior to injection of long-chain triglyceride propofol is effective and safe in reducing the incidence and severity of pain due to propofol injection.


Introduction
Propofol is widely administered during anesthetic induction. However, the pain of injection is undesirable, and may cause hand withdrawal and dislodging of the venous cannula (1,2). The incidence of propofol injection pain varies from 28% to 90% (3). Many methods have been used to relieve the pain of propofol injection, such as pretreatment with lidocaine, ondansetron, and methylene blue, but the effectiveness of these methods remains uncertain (4)(5)(6)(7)(8).
The alpha-2 adrenoceptor agonist clonidine was found to alleviate the pain of injected propofol effectively (9). Dexmedetomidine (DEX; Jiangsu Singch Pharmaceutical, Lianyungang, Jiangsu province, China) is also an alpha-2 adrenoceptor agonist, but is more selective than clonidine and has analgesic and sedative properties (2). DEX has been evaluated for reducing the incidence and intensity of propofol-induced pain, but reported results are inconsistent (1,2).
We hypothesized that DEX injection before propofol would reduce propofol injection pain. We also studied the effectiveness of different doses of DEX and the time interval between DEX and propofol injection.

Methods
After the approval of the Hospital Ethics Committee of Second Xiangya Hospital of Central South University, 210 patients, aged 18 to 60 years, ASA (American Society of Anesthesiologists) physical classification I to II, and scheduled for minor elective surgery, were included in the study. All patients signed a written informed consent form. Patients were excluded if they had a history of drug abuse, chronic use of any medication, presence of neurological or psychiatric diseases, uncontrolled hypertension, or renal or hepatic insufficiency. Patients were also excluded if they had a known history of hypersensitivity to the study drugs.
Before surgery (24 h) the patients did not receive analgesics or sedatives. Upon arrival to the operating room, a 20-gauge cannula was inserted into the dorsum of the patient's hand and connected to a T-connector for drug administration. Standard ASA monitors were attached, including non-invasive arterial pressure, electrocardiography, and pulse oximetry.
Patients were randomly allocated to seven groups (I-VII; n = 30 each) using a computer-generated table with random numbers (Table I). Patients in group I, the control group, were given 10 mL of isotonic saline intravenously over 10 min via a micro-infusion pump. Patients in groups II, III, and IV received DEX (200 mg/2 mL; Singch Pharm, Lianyungang, China) 0.25 mg/kg, 0.5 mg/kg, or 1.0 mg/kg, respectively, mixed with isotonic saline over 10 min (final volume, 10 mL), and then 1% long-chain triglyceride (LCT) propofol (propofol 1%; Fresenius Kabi, Beijing, Beijing municipality, China) was immediately injected intravenously. Patients in groups V, VI, and VII were given DEX 0.25 mg/kg, 0.5 mg/kg, or 1.0 mg/kg, respectively, mixed with isotonic saline, over 10 min (final volume, 10 mL). Five minutes later, 1% LCT propofol was injected. All groups received 2.5 mg/kg of 1% LCT propofol, injected at a rate of 1 mL/s.
All study medications were prepared in a 10-mL syringe that was covered with black tape by an anesthesiologist who was not involved in the study. All study drugs were maintained at room temperature and were used within 30 min after preparation. Another anesthesiologist, who was unaware of the group assignment, assessed the intensity of pain after propofol injections. The assessing anesthesiologist used a specially designed composite pain scale described by Rochette and colleagues (7) to evaluate the level of propofol injection pain. The pain score is based on assessments of patients' motor and verbal reactions, from the time of propofol injection to loss of consciousness (Table II). Pain is graded on a 0-6 scale, with a score >2 considered unacceptable (8). Mean arterial pressure (MAP) and heart rate (HR) were recorded immediately before injection of the study drug, and then every 5 min until propofol injection. All patients received 1% LCT propofol 2.5 mg/kg (Fresenius Kabi, Beijing, Beijing municipality, France) at a rate of 1 mL/s with different pretreatments.
For the design of this study, an estimation of the required minimum sample size was determined based on a previous report that pain caused by propofol injection was experienced by 70% of adults (8), and an assumption that a pretreatment with DEX would cause a 50% reduction in the injection pain. With a probability of less than 5% of making a type I error, (i.e. significance level a = 0.05) and the probability of less than 10% of making a type II error (accepting a null hypothesis that is false, b = 0.10), we were required to enroll at least 24 patients in each group; we recruited 30 patients in each group.
Statistical analyses were performed using Statistical Product for Social Sciences (SPSS) software v. 18.0. The continuous normally distributed data (age and weight) are described as mean ± standard deviation and compared using one-way ANOVA. Changes in HR and BP over time were tested for normality using the mean ± standard deviation and then compared

Results
All patients completed the study. There were no statistically significant differences among the seven groups with regard to age, weight, gender, or ASA class (p > 0.05) (Table III). There was no difference in median propofol injection pain scores among groups I (3.00 (IQR 2.00-4.00)), II, III, V, and VI. However, the median pain score of group IV (2.00 (IQR 0.00-3.00)) was significantly lower than that of group I (p = 0.003), and the median propofol injection pain score of group VII was 0.00 (IQR 0.00-3.00), which was significantly lower than that of group I (p = 0.000).
The incidence of pain scored >2 was 17/30 in the control group I (Figure 1). There were no differences in this incidence rate among groups I, II, III, IV, V, and VI. However, the incidence of pain scored >2 in group VII was 1/30, which was the lowest among all the groups and was significantly lower than that of group I (p = 0.000).
There were no differences between the groups as regards MAP and HR at any time point after DEX injection (p > 0.05, detailed data not shown).

Discussion
This prospective, randomized, double-blind, placebo-controlled study was carried out in order to evaluate the effect of DEX for reducing the incidence and severity of propofol injection pain. Besides the control group (given isotonic saline vehicle),  treatments consisted of 0.25, 0.5, or 1.0 mg/kg DEX, each delivered either immediately before or 5 minutes prior to LCT propofol injection. We found that pretreatment with 1 mg/kg DEX 5 min before propofol reduced the incidence and severity of pain due to propofol injection. Various other pretreatments have also been evaluated, such as parecoxib with venous occlusion (10), tourniquet-controlled lidocaine (4), ondansetron (5), intravenous methylene blue (6), alfentanil and lidocaine (11), and a small dose of ketamine (12). A recent systematic review and meta-analysis showed that propofol infusion via the antecubital vein and pretreatment with lidocaine in conjunction with venous occlusion were the two most efficient interventions to reduce pain on injection of propofol (13). However, some unexpected adverse side effects have been associated with the two methods. For some patients undergoing short-time surgery with general anesthesia, propofol infusion via a hand vein is more convenient than via an antecubital vein. Tourniquets are the most common compressive devices for venous occlusion, but can cause tourniquet-induced hypertension or even ischemia-reperfusion injury (14)(15)(16)(17). Therefore, venous occlusion before propofol injection may be contraindicated in patients with moderate to severe hypertension.
DEX has been demonstrated to have significant analgesic effects (18)(19)(20)(21)(22)(23). Although the mechanisms of the analgesic effect of DEX have not been fully elucidated, many studies have shown that DEX acted by inhibiting the release of substance P from the dorsal horn of the spinal cord (24,25). A recent study reported that DEX effected strong analgesia through inhibition of the spinal ERK1/2 signaling pathway (26). These studies suggest that DEX has an important role in nociceptive transmission at the spinal level. Boehm et al. (27) demonstrated in rats that when DEX was administered intraperitoneally, the onset of profound analgesia was not reached until 5-10 min after the injection. So, when an infusion of DEX was administered, a time interval was allowed for equilibrium of DEX concentrations between the plasma and effect sites.
So far, there have been only a few studies investigating the inhibiting effect of DEX on the pain of propofol injection, and the question of its efficacy remains controversial. Ayo glu et al. (1) demonstrated that pretreatment with 0.25 mg/kg DEX was not effective in reducing propofol injection pain (1). Yet the research done by Turan and his colleagues (2) contradicted this, showing that pretreatment with 0.25 mg/kg DEX decreased propofol injection pain as effectively as pretreatment with lidocaine 0.50 mg/kg (2).
Our study demonstrated that the reduction of propofol injection pain through pretreatment with DEX depended on the DEX dose, and 0.25 or 0.5 mg/kg DEX could not reduce the intensity and incidence of propofol injection pain. However, when the pretreatment dose of DEX was increased to 1.0 mg/kg, the incidence rate of pain scores >2 decreased from 17/30 to 1/30. Results of other studies demonstrating analgesic effects of DEX are in accord with ours. For example, Park et al. (28) demonstrated that DEX had a dose-dependent analgesic effect in rat models, and Ebert and colleagues (29) showed that increasing concentrations of DEX in humans resulted in a progressive increase in analgesic effect.
Another finding in our study was that the interval between DEX and propofol infusion influenced the analgesic effect of DEX on propofol injection pain. DEX was most effective when 1 mg/kg was injected 5 min before propofol injection. It is possible that, given this time interval, DEX concentrations at the spinal level increased enough to result in an analgesic effect.
Pretreatment with DEX has been reported to cause significant hemodynamic adverse side effects (30). However, a recent study showed that DEX at doses of 0.5 mg/kg or 1 mg/kg can be safely used preoperatively, with stable hemodynamics (31). Koroglu et al. (32) found that administration with a high dose of DEX (a bolus of 2-3 mg/kg over 10 min, or infusion of 1.5-3.0 mgÁkg -1 Áh -1 ) provided adequate sedation in most of the children aged 1-7 years, without hemodynamic changes or adverse sequelae, and no specific treatment required. In our study, none of the patients who received DEX 0.25, 0.5, or 1 mg/kg infusion developed bradycardia or hypotension. Therefore, we believe 1 mg/kg DEX is safe for the general population.
In conclusion, 1 mg/kg DEX given intravenously 5 min before administration of intravenous LCT propofol (2.5 mg/kg) is an effective and safe way to reduce the intensity and incidence of propofol injection pain.

Declaration of interest:
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.