Pain on injection with propofol is a well-known problem. A systematic review analysed data from 56 randomized trials, involving a total of 6264 patients and found that up to 70% of patients reported a degree of pain or discomfort on propofol injection . Diprivan propofol (Diprivan 1%; AstraZeneca, Cheshire, UK) is formulated as an emulsion in a solution of 10% soybean oil containing only long-chain triglycerides. This formulation has been shown to have a large amount of free propofol in the aqueous phase, and it is this substance that is thought to be responsible for injection pain [2,3].
Since 1982, numerous randomized control trials have looked at reducing both incidence and severity of propofol injection pain . The strategies to tackle this problem have included pre-administration or co-administration of lidocaine and various opioids, alteration of speed of injection and temperature of injectate and various sites and sizes of venous cannula . Lidocaine in a dose of 0.5 mg kg−1 administered, while a tourniquet was inflated for 90 s prior to administration of generic propofol, was found to be the most effective method to reduce the injection pain. However, this strategy is not generally adopted in practice because of practicalities involved and time restraints. The most common method adopted in clinical practice is to mix lidocaine in a range of 10–40 mg to propofol immediately prior to administration.
In 2002, Lipuro propofol 1% (B Braun, Melsungen, Germany) was licensed for use in the UK. It is formulated as a 10% lipid emulsion containing equal proportions (50 : 50) medium- and long-chain triglycerides. This emulsion has been shown to have a decreased concentration of free propofol by 30–45% in the aqueous phase compared to generic propofol , and this has been claimed to be responsible for potential reduction of injection pain. To date, there have been many randomized trials comparing both propofol formulations. Some of these trials have shown reduced pain intensity with Lipuro propofol [4–9]. Based on this evidence, Lipuro propofol is increasingly replacing Diprivan in clinical practice. Trials that compared Lipuro propofol to generic propofol with the addition of lidocaine have not shown superiority of Lipuro propofol in terms of reduction in injection pain [10–13]. However, the amount of lidocaine added to generic propofol in these trials varied from 10 to 40 mg, with the most effective dose being 40 mg . Many of these trials have other limitations in terms of speed of administration, pain scoring system and patient variability. In addition, it is not known whether the addition of lidocaine to Lipuro propofol will further reduce the incidence and severity of injection pain and provide painless induction of anaesthesia.
The aim of this prospective randomized double-blind trial was to compare the incidence of injection pain between two formulations of propofol, premixed with or without lidocaine, to answer the question whether painless induction of anaesthesia is possible when lidocaine is premixed with Lipuro propofol.
Following local hospital Ethics Committee approval and written informed consent, 328 ASA I–II patients aged ≥18 yr scheduled for elective surgery under general anaesthesia were enrolled into this prospective randomized double-blind trial. Patients were randomly allocated, using the ‘sealed envelope method', to one of four groups: Group DP received Diprivan propofol 1%, Group LP Lipuro propofol 1%, Group DL Diprivan 1% with lidocaine 2% 2 mL (40 mg) and Group LL Lipuro propofol 1% with lidocaine 2% 2 mL (40 mg). All drugs were drawn up independently and out of view, so that anaesthetic staff and the operator performing the assessments were blinded to group allocation. When group allocation dictated the addition of 2 mL lidocaine or normal saline, this was first added to a syringe containing 20 mL propofol, and then the additional 2 mL volume was discarded to ensure that the syringe volume totalled 20 mL for all groups. Lidocaine was added as near to the time of induction in Groups DL and LL. If administration was delayed for a period of more than 5 min, a new preparation was made.
A 10-point visual analogue scale (VAS) pain scoring system (0 being no pain and 10 being the worst imaginable pain) was explained to patients at the time of consent and again in the anaesthetic room. No patients received pre-medication or intravenous opioids prior to propofol induction. In the anaesthetic room, venous access was established using 20-G cannula onto a suitable vein on the dorsum of the hand. Study drug was then infused at a rate of 400 mL h−1 by an infusion pump (Graseby 3500; Graseby Medical Ltd., Watford, Herts, UK) until the patient lost consciousness. Patients were asked to score injection pain on the VAS 15 s from start of infusion until loss of consciousness. At any time during the study, drug infusion patients were encouraged to indicate any increase in pain experienced by selecting a point on the VAS. Once the assessment of injection pain was made, anaesthesia was continued according to the anaesthetist's routine practice. Upon recovery, the patient was asked to recollect if they had experienced injection pain, and a second VAS score was obtained.
From a power calculation performed, based on the figure of 50% injection pain with Lipuro propofol from analysis of the existing literature, 50% of patients would have a successful treatment (no pain on injection). Considering a 90% increase in success with the new treatment, 95% of patients would not experience any pain. Using the calculation ‘comparing proportion of success' at the 95% significance level and with a statistical power of 80%, 82 patients per group would be required (a total of 328 in four groups) to demonstrate this 90% improvement with the new treatment.
The data collected were entered onto a spreadsheet using Statistical Package for Social Sciences (SPSS 13 for Windows). Patient characteristics data were compared between the groups using t-test. The incidence of pain on injection was analysed using χ2-test. The pain score is expressed as median ±interquartile ranges and analysed using Wilcoxan rank test, with P < 0.05 being considered significant.
A total of 328 patients were enrolled: 82 patients were randomly assigned to Group DP, 81 to Group LP, 82 to Group DL and 81 to Group LL. Two patients were randomized but excluded from analysis owing to cannulation problems. All four groups were comparable with respect to age, weight, gender, ASA physical status and amount of propofol received during induction of anaesthesia (Table 1). No correlation between the occurrence of injection pain and patient characteristics (e.g. age, gender, weight) could be identified.
Sixty percent of patients complained of pain with Lipuro propofol with a median (25th–75th percentile) VAS score of 1.5 (0–4) compared to 72% of patients with Diprivan VAS induction score 4 (0–6). Both the severity and incidence of pain were significantly (P < 0.0001) less with Lipuro propofol (Fig. 1). The incidence and severity of pain were found to be less in Group DL compared to those in Group LP (incidence 27% vs. 60%, P < 0.001, median VAS induction 0.5 (0–1) vs. 1.5 (0–4), (P < 0.0001).
Only 10% patients complained of pain at induction with Lipuro propofol premixed with lidocaine in Group LL. This was significantly lower when compared to Lipuro propofol alone (P < 0.0002) (Fig. 2). The intensity of pain experienced in this group was milder in nature compared to the other three groups. No significant difference was found between VAS scores (median, interquartile range) reported during induction and those reported postoperatively (Table 2).
The main finding of our study is that Lipuro propofol with added lidocaine, in a dose of 40 mg, significantly reduced the incidence and severity of pain on injection. This is in agreement with a recently published study that used a lower dose of lidocaine . Unfortunately, the addition of lidocaine to propofol involves extra work and introduces associated drug-mixing risks e.g. bacterial contamination and drug errors. It has also been shown that addition of lidocaine to Lipuro propofol reduces free propofol concentration in the aqueous phase by 9%, whereas addition of lidocaine to Diprivan does not change the concentration of free propofol in the aqueous phase . This could be partly responsible for the extremely low incidence of pain when lidocaine is added to Lipuro propofol. A previous study reported only 10% incidence of pain with propofol in a lipid emulsion of MCT–LCT . With the introduction of Lipuro propofol, it was initially thought that there might not be any need for lidocaine premixing with propofol. The four group comparisons in our study suggest that Lipuro propofol alone is unable to provide a painless induction of anaesthesia and that, with the addition of lidocaine under aseptic precautions and immediately prior to induction of anaesthesia, pain on injection was significantly reduced to only 10%, and pain was milder (VAS 0–1).
The results of our study are in agreement with the findings of previous randomized trials demonstrating that Lipuro propofol is less painful than Diprivan (Fig. 1). In some studies, the overall incidence of pain was not different between the propofol formulations, although the severity of pain was shown to be less with Lipuro propofol. The incidence of pain with Lipuro propofol has been reported as ranging from 10% to 53% [8–13]. A recent large trial of 600 patients reported an incidence of 27% injection pain with Lipuro propofol, but patients received pre-medication, which may have influenced pain reporting . In contrast, our study reports a slightly higher incidence (60%) of injection pain with Lipuro propofol, similar to the 61% incidence in children aged 2–18 yr, reported by a group of investigators . We attribute this to the constant rate infusion of propofol at 400 mL h−1, which allowed a slow induction of anaesthesia, so that patients had 1 or 2 min to report the pain on VAS. We believe that the literature discrepancies in findings of pain on injection could be explained by different modes of evaluation of pain score used by the investigators, different rates of administration of propofol during induction and the effects of pre-medication used.
Our study confirms that Lipuro propofol is inferior to Diprivan with the addition of 40 mg lidocaine (standard practice), in terms of injection pain (60% vs. 27%). This is consistent with the incidence of pain (47%) with Lipuro propofol compared to generic propofol administered 60 s following lidocaine 40 mg pre-administration with Bier's block tourniquet (24%) reported in another recently published study . In children, Lipuro propofol was associated with pain on injection in 61% of patients whereas generic propofol with premixed lidocaine 0.3 mg kg−1 in 33.3% . The literature reports variability in the incidence of injection pain associated with premixture of 20 and 10 mg of lidocaine. One study reported the incidence of pain to be 52% with addition of 20 mg of lidocaine  while another reported an incidence of 36% with a lower dose of 10 mg lidocaine . A possible explanation for this variability is that a premixture of lidocaine to generic propofol at doses less than 40 mg may be suboptimal.
The dose of lidocaine chosen in our study was 40 mg (2 mL of 2% lidocaine). This was based on the findings of previous studies demonstrating that this is the optimal amount needed to have good efficacy in terms of pain reduction . Maximum efficacy of lidocaine (40 mg or 0.5 mg kg−1) is achieved when pre-administered as a Bier's block 30–120 s prior to propofol injection. This technique is cumbersome and time-consuming. Therefore, the easy and widely adopted technique is to mix lidocaine to propofol prior to injection.
Patients in our study had a thorough explanation about the visual analogue score at the time of consent and again in the anaesthetic room prior to the start of the study. No patients received any anxiolytic or sedative pre-medication, including midazolam or temazepam, as these are known for their anterograde amnesic properties. Alfentanil and fentanyl were not administered before propofol, as usually performed during the induction of general anaesthesia, because these have been suggested to reduce pain on injection and would have biased pain scoring. We found no difference in VAS during induction and in the postoperative period, although some investigators have shown that a significant proportion of patients had no recall of pain postoperatively . In contrast, a recent study reported a significant increase in pain, reporting at 1 h after recovery, in comparison to the pain reporting at induction . Lorazepam used as pre-medication in the study could have made the patients too sedated to answer when actively asked to rate the pain during induction of anaesthesia.
In conclusion, premixing 40 mg of lidocaine to Lipuro propofol almost abolishes the pain on injection, making induction of anaesthesia much less painful compared to Lipuro propofol alone or Diprivan with lidocaine in un-premedicated ASA I–II patients.
B Braun Medical Ltd., Sheffield supplied Lipuro propofol for this trial.
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