Pain on injection is one of the most notable adverse effects of propofol with 80-90% of patients experiencing pain on propofol injection if a vein on the dorsum of the hand is used [1,2]. A variety of manoeuvres have been tried to minimize the injection pain of propofol including varying the injection speed and the carrier fluid , its dilution [4,5], temperature , the concomitant use of drugs  or modifying the propofol emulsion . One well-accepted technique is the use of a premixture of lidocaine with propofol [9,10]. However, despite this treatment, the pain on injection of propofol is not completely eliminated and continues to be a problem .
Remifentanil is a new, a piperidine-based, potent and selective μ-opioid agonist [11,12]. Its pharmacokinetic profile is unique among the opioids by having a very rapid onset and a very short-term effect. Its biological half-life is 3-10 min . It has been recently reported that a very low dose of remifentanil may prevent the injection pain of propofol [13-15]. Furthermore, a few trials have shown that remifentanil relieves pain as effectively as lidocaine . However, even in those studies, the incidence of injection pain of propofol is still significant. Therefore, combination therapy with two partially effective drugs has been suggested to solve this problem . To date, no studies have been undertaken to assess the effect of combination of pretreatment of remifentanil and premixture of lidocaine with propofol. The purpose of this study was to investigate the analgesic effect of the combination of pretreatment of remifentanil and premixture of lidocaine with propofol, compared with either treatment alone during propofol injection in dorsal hand-veins.
With Institutional Ethics Committee approval and informed written consent, we examined 141 adults, ASA physical status I and II patients. All patients were scheduled for elective surgery under general anaesthesia with propofol as the induction drug. Exclusion criteria were known sensitivity to propofol, neurological and psychiatric disease, concomitant analgesic or sedative medication or the presence of infection on the dorsum of the left hand.
No premedication was administered to any of the patients. An 18-G cannula was placed in a vein on the dorsum of the left hand and a three-way tap was connected directly to the catheter. An infusion system with 1000 mL of Ringer's lactate solution and the syringe pump system for drug application were directly connected to it. Monitoring consisted of pulse oximetry, electrocardiography (lead 2) and non-invasive blood pressure.
A randomized, double-blind trial was conducted with patients allocated randomly to one of three groups (n = 47 each) using sealed envelopes. Patients in Group A received saline 0.9% (0.035 mL kg−1 min−1, same volume as remifentanil in order to obtain blinding) via a syringe pump 30 s before the injection of propofol premixed with lidocaine. Patients in Group B received remifentanil (0.35 μg kg−1 min−1) 30 s before the injection of propofol. Patients in Group C received remifentanil (0.35 μg kg−1 min−1) 30 s before the injection of propofol premixed with lidocaine. The running carrier-fluid was stopped before any study drug or test substances were injected.
All study drugs were prepared freshly prior to injection at room temperature. For propofol premixed with lidocaine, propofol 1% (Diprivan®; AstraZeneca, Italy) and lidocaine 1% were mixed in a 10 : 1 volume ratio. General anaesthesia was induced with propofol 2 mg kg−1. During the induction of anaesthesia, propofol was administered at a rate of 990 mL h−1 in Group A, C and 900 mL h−1 in Group B (equivalent to 2.5 mg s−1) by an infusion pump.
The infusion pump was programmed with the blinded observer absent and the infusion rate display on the pump hidden from view by an opaque cover. A study-blinded investigator evaluated the level of pain on injection of propofol. If there was no spontaneous complaint of pain, patients were asked if they experienced any pain in the arm 20 s after the start of the injection. Pain scores were recorded using a verbal rating scale: 0 = none (negative response to questioning), 1 = mild pain (pain reported in response to questioning only, without any behavioural sign), 2 = moderate pain (pain recorded in response to questioning and accompanied by a behavioural sign, or pain reported simultaneously without questioning), 3 = severe pain (strong vocal response or response accompanied by facial grimacing, arm withdrawal or tears).
From examination of previously published data [10,14,16], we expected an incidence of no pain on injection of propofol of at least 60% in the treatment group. Based on an α-error of 0.05 (two-sided) and the β-error of 0.8, a minimum sample size of 34 patients per group was estimated to detect a 25% difference in the incidence of pain on propofol injection between groups. Assuming the likelihood of patients dropping out, the sample size was increased to 47 patients per group.
Statistical analysis was conducted using SPSS for Windows soft program version 12.0. Data were analysed using ANOVA, Fisher's exact test and U-test, where appropriate. A Bonferroni corrected P value of 0.05/3 (P < 0.017) was considered significant.
A total of 136 patients were successfully examined in the course of the study and five patients had to be excluded for a technical reason such as a defect of the infusion pump or difficulty with venous cannulation. There were no differences between the three groups of patients as regards to sex, age or weight, as shown in Table 1.
The overall incidence and severity of pain during injection of propofol in the three groups is shown in Table 2. The incidence of no-pain on injection of propofol was similar in Groups A and B. Twenty-eight patients (62.2%) in each group did not complain of pain on injection. The incidence of absence of pain on injection of propofol was greater in Group C, 42 (91.3%) compared with either Group A (P < 0.001) or Group B (P < 0.001). On analysing the injection pain scores, we found a significant reduction of the score in Group C compared with Group A (P < 0.001) and Group B (P < 0.001).
There was a significant reduction in the overall incidence of pain and severity from propofol injection in Group C compared with Groups A and B.
The results of this study have demonstrated that the combination of pretreatment of remifentanil and premixture of lidocaine with propofol was more effective in decreasing the incidence and severity of pain on injection of propofol than either treatment alone. In this study, known factors to influence pain on propofol injection, such as the site of the intravenous cannula, speed of injection , temperature of propofol  and premedication with analgesics  were controlled. Therefore, the incidence of pain on propofol injection can be attributed to the study drugs
The mechanism of pain on propofol injection remains unclear, although a number of mechanisms have been proposed [4,10,19]. Pain may be immediate or delayed within a latency of 10-20 s. Immediate pain probably results from a direct irritant effect, whereas delayed pain may result from an indirect effect via the kinin cascade . A high concentration of free propofol in the aqueous phase of an emulsion activates the kallikrein-kinin system in plasma, liberating bradykinin. Bradykinin acts on the local vein to make it dilate and become permeable. In this bradykinin-modified vein, the aqueous phase of propofol contacts more free nerve endings outside the endothelial layer of the vessel and causes pain on injection .
Lidocaine, which has been commonly used for pain on propofol injection, may act by stabilizing the kinin cascade . The pain-reducing effect of lidocaine on propofol injection is not only based on its local anaesthetic effect, but also on a decrease in pH of the propofol-lidocaine mixture. Eriksson and colleagues  revealed that lidocaine mixed with propofol decreased its pH, resulting in a lower concentration of propofol in the aqueous phase and less pain. However, the addition of lidocaine might lead to destabilization of the propofol solution in a dose- and time-dependent manner . Therefore, the mixture should be made up and used fresh (e.g. within 30 min of preparation) . The suggested dose of premixed lidocaine for stabilization ranges from 10  to 30 mg [24,25] in 200 mg of propofol. King and colleagues  found that 20 mg of lidocaine premixed with 200 mg of propofol significantly reduced the incidence of injection pain from 73% to 32%. Tan and colleagues  also reported that the incidence of propofol injection pain could be reduced to 25.7% using mixture of propofol 1% and lidocaine 1% in a 10 : 1 ratio. According to previous studies [16,26,27], the dose of lidocaine premixed with propofol in this study was determined. The incidence of no pain on propofol injection in Group B was approximately 62% of patients, which was consistent with previous studies [16,26,27].
There have been only a few studies investigating the effects of remifentanil in preventing propofol injection pain. Remifentanil is an opioid of the phenylpiperidine group and could have a local-anaesthetic effect on nerves. Opioid receptors are found in the dorsal root ganglia, the central terminals of primary afferent nerves and peripheral sensory nerve fibres and their terminals. The reduction in injection pain might be from the interaction of remifentanil with peripheral μ-opioid receptors . Regarding the dose of remifentanil, Roehm and colleagues  showed that remifentanil 0.25 μg kg−1 min−1 before propofol injection is as effective as lidocaine 40 mg prior to propofol injection in reducing the incidence of injection pain (30.2 vs. 62% for placebo). Basaranoglu and colleagues  used remifentanil 1 μg kg−1 min−1 before propofol, and the incidence of propofol injection pain decreased from 32% to 44%. Iyilikci and colleagues  demonstrated that remifentanil should be a dose of at least 0.02 mg for this purpose in patients with a mean weight of 68.3 kg. In our study, remifentanil 0.35 μg kg−1 min−1 was administered to patients.
The time interval from application of the test substances and propofol varies within previous studies from 15 s  to 2 min  when testing opioids against injection pain. Pang and colleagues  did not even find a significant reduction of the incidence of pain when propofol was injected immediately after fentanyl. Basaranoglu and colleagues  showed that the infusion of remifentanil (0.25 μg kg−1 min−1) 60 s prior to propofol injection significantly reduced pain, compared with the infusion of remifentanil 0.25 μg kg−1 min−1 immediately before propofol injection and suggested that the time interval of the administration of remifentanil and propofol might be the cause of the decreased injection pain of propofol. Iyilikci and colleagues  reported this period for alfentanil or remifentanil as 30 s. Using a time interval of 30 s, we revealed that the administration of remifentanil 0.35 μg kg−1 min−1 provided analgesic effects similar to lidocaine premixture. However, although 38% of patient in both remifentanil and lidocaine groups still suffered from injection pain of propofol, the injection pain was reduced to 8.7% of patients who received pretreatment of remifentanil plus premixture of lidocaine with propofol. From our results, we suggest that remifentanil enhances the analgesic efficacy of lidocaine premixture for reducing pain during propofol injection. The likely mechanism of the enhanced analgesic efficacy of the combination of pretreatment of remifentanil and lidocaine premixture may be synergic interactions of the prevention of the local-irritant effect of propofol by the remifentanil and the stabilization of the kinin cascade and decrease in the pH of propofol by the lidocaine.
We did not see any emergence reactions with remifentanil and complications, such as pain, oedema and wheal or flare response at the injection site within the first 24 h.
In conclusion, a combination of pretreatment of remifentanil and premixture of lidocaine with propofol was found to be more effective in decreasing the incidence of pain on injection of propofol than either treatment alone, without any serious adverse reactions.
This research was supported by Kyungpook National University Research Team fund, 2002.
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