In addition to its use for induction and maintenance of general anaesthesia, propofol is frequently used for sedation in patients undergoing regional anaesthesia . However the clinical problem of pain after injection with propofol remains unresolved [2,3]. In their analysis of data from 56 reports comprising 6264 patients Picard and Tramer  found a 70% incidence of pain on injection of propofol LCT (long-chain triglyceride). Attempts have been made to minimize this side-effect which include pretreatment or mixing propofol with lidocaine , the co-administration of opioids [5-7], ketamine [8,9], magnesium sulphate , or the kallikrein inhibitor, nafamostat . The effects of temperature , and dilution  as well as varying the infusion rate [14,15] have already been studied.
Since the concentration of free propofol in the aqueous phase has been identified as a possible cause of injection pain, a formulation containing a mixture of medium-chain triglyceride MCT/LCT has been developed . This reduces the free propofol proportion by 25% . Two clinical studies [18,19] reported an incidence of pain on injection with propofol MCT/LCT of 37–38% which was significantly lower than with propofol LCT (64% and 61% respectively). In contrast two following clinical trials [20,21] found that propofol MCT/LCT did not significantly reduce the incidence of pain compared to propofol LCT. Only in one of these studies  was the severity of injection pain reduced due to the propofol application. In both studies the addition of lidocaine to the propofol formulation was tested for the incidence of pain. While the use of lidocaine in the study by Röhm and colleagues  resulted in a significant reduction of pain incidence, the study of Kunitz and colleagues  reported only a slight reduction in pain incidence with lidocaine-supplemented propofol MCT/LCT compared to lidocaine-supplemented propofol LCT.
Our study addressed the primary question of whether lidocaine addition to propofol MCT/LCT reduces the incidence of injection pain compared to the combination of lidocaine and propofol LCT. A secondary question was the role of the pure fat emulsion on pain incidence and severity. This influence has not yet been conclusively studied. A randomized double-blind study of patients undergoing sedation during regional anaesthesia was conducted with four treatment arms: propofol MCT/LCT and propofol LCT, each with and without lidocaine addition.
The study was conducted at Klinikum Minden, a teaching hospital of the University of Hannover, Germany. Approval was obtained from the local Ethics Committee. All patients were required to give informed written consent. The study was conducted according to the principles of Good Clinical Practice (GCP).
Four hundred and sixty four patients scheduled for elective surgery under regional anaesthesia were randomized. Exclusion criteria were emergency, pregnancy, renal, hepatic, cardiac disease, ASA Grade III, age under 18 yr, alcohol or drug abuse, chronic pain, cancer patients with previous radiation therapy, neuroleptic, antidepressant or pain medication and insufficient command of the German language. Patients where no venous access could be obtained were also excluded. The flow chart shows the distribution of the study population (Fig. 1).
Patients were randomly assigned to one of four injection regimens. Group 1 received propofol MCT/LCT (Propofol-®Lipuro 1%; B. Braun, Melsungen, Germany) with lidocaine (B. Braun, Melsungen, Germany) (MCT/LCT +lidocaine), Group 2 received propofol LCT (Disoprivan®; Astra Zeneca, Wedel, Germany) with lidocaine (LCT +lidocaine), Group 3 was treated with propofol MCT/LCT (MCT/LCT) and Group 4 received propofol LCT (LCT). For Groups 1 and 2 propofol MCT/LCT or propofol LCT and lidocaine 1% at a ratio of 20: 1 was mixed, whereas for Groups 3 and 4 only pure propofol MCT/LCT or propofol LCT was used. The medication was prepared immediately before injection by a study nurse who did not participate in the outcome assessment. Patients and the attending anaesthesiologist remained blind to the randomization.
All patients received oral midazolam (7.5 mg) as premedication in accordance with our standard clinical practice and to comply with the Ethics Committee. Routine standard monitoring consisted of electrocardiography, pulse oximetry and non-invasive blood pressure measurements. An intravenous (i.v.) cannula (15-G) was inserted into a dorsal hand vein and an infusion of 1000 mL Ringer’s solution started. The regional anaesthetic technique (spinal anaesthesia (SPA), epidural anaesthesia (EDA), combined spinal-epidural (CSE) anaesthesia, or axillary plexus block (APB)) was then performed. Oxygen (3L min−1) was administered via a face mask. After the block was complete the sedation was initiated.
A total dose of 0.5–1 mg kg−1 body weight propofol was calculated and administered over 1–5 min in 2 mL boluses every 20 s for induction, taking into account our experience that local pain can be felt mostly within 10–20 s after i.v. injection of propofol. Injection pain was assessed and the severity was evaluated using a four-point scale according to Ambesh and colleagues . Expression of pain by strong vocal response or response accompanied by facial grimacing, arm withdrawal or tears was scored as severe. Pain reported in response to questioning and accompanied by a behavioural sign or pain reported spontaneously without questioning was scored as moderate. Patients who did not express pain spontaneously within the first 30 s were asked whether they had any discomfort. If they answered ‘yes’ and were without any behavioural signs this was scored as mild. A negative response to questioning was scored as no pain. Where the patient reported varying grades of pain the maximum score was recorded. Bolus injections were continued until the patient had reached grade 3 of the Observer’s Assessment of Alertness/Sedation (OAA/S) scale, i.e. response obtained after loud repetition of name . Then propofol MCT/LCT was infused continuously in Groups 1 and 3 and propofol LCT in Groups 2 and 4 at an infusion rate of 1.5–4.5 mg−1 kg−1 h−1 to maintain an adequate level of sedation, i.e. grade 3 of the OAA/S scale. When necessary, additional bolus injections of 10–20 mL propofol 1% were allowed. At the end of anaesthesia patients were transferred to the post-anaesthesia care unit.
The main object of this study was to ascertain whether the combination of propofol MCT/LCT and lidocaine reduces the incidence of injection pain compared to propofol LCT and lidocaine. Incidence of pain on injection was the primary outcome parameter. This was defined as spontaneously expressed physical pain within the first 30 s after injection or pain reported on questioning. The severity of pain on injection was also evaluated in each group (U -test). The necessary sample size was estimated under the assumptions of a clinically relevant difference of ΔP = PMCT/LCT propofol and lidocaine – PLCT propofol and lidocaine =0.15 (this corresponds here to an odds-ratio of about 0.4), a significance level of α=0.05 and a power of (1− β) =80%. Before closing the data base and unblinding, the analysis sets were defined. Data analysis was performed using Statistical Analysis Software (SAS) version 8.2. Since there is evidence  that females have a higher incidence of injection pain after propofol, gender was used as a stratification variable. The Mantel-Haenzel test was used to analyse the observed frequency of pain. In addition the relative risk (RR), the associated 95% confidence interval (95% CI) and the number needed to treat (NNT) were calculated. Two factorial analysis of variance was used for exploratory data analysis of the other parameters, one factor was the grouping factor and the other factor was gender. Prior to analysis of the primary outcome parameter the groups were examined regarding homogeneity of the major impact factors (Table 1). The same statistical analysis was applied to the secondary question.
A total of 464 patients over a period of 15 months were included in the study. Patient data and clinical data of the four treatment arms are given in Table 1. There were no differences regarding the required propofol induction doses (P =0.60 Group 1 vs. Group 2, P =0.61 Group 3 vs. Group 4). Nineteen (4%) patients were excluded from the data analysis for various reasons, including withdrawal of informed consent before starting anaesthesia (n =10), failure of the regional anaesthetic technique (n =3), change of the operative procedure (n =3), or failure to get venous access on the dorsum of the hand (n =3) (see Fig. 1).
The incidence of pain in the four treatment arms is given in Figure 2. The overall incidence of pain on injection was 18% in Group 1 (MCT/LCT +lidocaine), 31% in Group 2 (LCT +lidocaine), 47% in Group 3 (MCT/LCT) and 60% in Group 4 (LCT). In the primary question the adjusted RR for injection pain was 0.58 (95% CI 0.36–0.94) for patients treated with MCT/LCT +lidocaine compared to LCT + lidocaine, P =0.024. The NNT was 7.7. In the secondary question patients receiving MCT/LCT had an adjusted RR of 0.79 (95% CI 0.62–1.01), P =0.055, in comparison to patients treated with LCT.
The severity of injection pain is given in Table 2. The MCT/LCT +lidocaine Group showed a significantly lower pain score than the LCT +lidocaine Group (P =0.041). The other two treatment groups show a similar trend although statistically insignificant (P =0.082). The percentage of patients experiencing severe injection pain was highest in the LCT Group (12%) compared to <5% in all other Groups.
Pain on i.v. administration of propofol has been ranked seventh among 33 clinical problems in anaesthesiology in both importance and frequency . In a recent case report  profound pain after propofol injection was suggested to have triggered myocardial ischaemia in a patient with a suspected phaeochromocytoma. Nevertheless, due to its excellent pharmacokinetic properties (e.g. rapid onset of action and rapid emergence from sedation, good haemodynamic stability, etc.) the clinical use of propofol has expanded greatly over the past 10 yr, including ambulatory procedures, children, monitored anaesthesia care, intensive care sedation and adequate sedation during regional anaesthesia [1,26,27].
The concentration of propofol in the aqueous phase is thought to be the major trigger of this injection pain and it has been shown that the free propofol proportion is 25% lower in the MCT/LCT formulation than in the traditional LCT formulation [13,16,17]. Initial experimental studies provided promising results showing a reduction of severe and moderate propofol injection pain from 59% with the LCT formulation to 9% when the MCT/LCT formulation was used . However in two following reports comprising fewer than 200 patients an overall pain incidence of 37% and 38% respectively was observed with propofol MCT/LCT [18,19].
Although the new propofol MCT/LCT formulation reduced significantly the incidence and severity of injection pain compared to standard propofol in the above mentioned studies and in a more recent one , it is evident that even this innovative reformulation does not ensure complete pain reduction . So far the most widely used method to reduce the incidence and intensity of injection pain due to propofol LCT is the pretreatment with lidocaine either before propofol injection, with or without a tourniquet, or added to the propofol emulsion as a premixture [1,2,29,30]. Eriksson and colleagues  showed that the pain reducing effect of lidocaine on propofol injection has not only been attributed to its local anaesthetic effect, but also to a decrease in the pH value of the propofol– lidocaine mixture. They assumed that the lower pH value produced after mixing lidocaine with propofol causes propofol to migrate into the lipid phase and thereby decreases the effective concentration of free propofol in the aqueous phase of the emulsion .
As a major result of our study we found that lidocaine-supplemented propofol MCT/LCT caused a significantly lower incidence of injection pain (18%) compared to propofol LCT with lidocaine (31%). The NNT was 7.7, i.e. 7.7 patients have to be treated with lidocaine-supplemented propofol MCT/LCT to achieve one patient who would have experienced injection pain if treated with the other regimen. These results are in accordance with the findings of Röhm and colleagues  as well as more recently with those of Yew and colleagues  which used the same pain assessment score. The percentages of patients experiencing pain in their studies were 16% and 31% (4% and 24% respectively) in the lidocaine-supplemented MCT/LCT and the lidocaine-supplemented LCT group, also representing a significant difference. However it must be pointed out that some differences exist in the study designs. Röhm and colleagues  injected a dose of 40 mg lidocaine 1 min prior to the propofol solutions while in our study a premixture of lidocaine and propofol (1: 20) was used. Also the total dosage of 2 mg kg−1 propofol was injected within 30 s in Röhm’s study  which was a more rapid speed of injection than our practice. As yet there is no consensus in the literature on the influence of injection speed [14,15,33,34]. Another point of interest is the different dosage of lidocaine applied in the studies. We used a dilution ratio of 20: 1 (propofol: lidocaine) as recommended in the summary of product characteristics. This lidocaine dose was over 25% lower than that given in the trial by Röhm and colleagues . But our results seemed to show that the lower dose was sufficient. In contrast to the reports by Röhm , Yew  and our findings, Kunitz and colleagues  did not observe a significant difference between lidocaine-supplemented MCT/LCT and lidocaine-supplemented LCT, with percentages of 20% and 40% respectively, of patients suffering from pain in the different treatment arms. This finding could be due to the small number of patients (20 per group) which was considerably lower than in the other studies.
In our study the incidence of pain did not differ significantly between MCT/LCT vs. LCT treated patients. However it has already been pointed out that this was a secondary question and therefore the data has been analysed and interpreted in a exploratory manner. Our study was not powered to detect differences between these two groups. The observed results and the P -value of 0.055 are an indication that a higher sample size may show not only clinical relevance but also statistically significant results.
Our study demonstrated that not only supplemented lidocaine but also the drug carrier used, MCT/LCT or LCT, had an impact on the severity of propofol injection pain. The incidence of severe pain was 12% in the propofol LCT Group, 4% in the propofol MCT/LCT Group, 3% in the propofol LCT plus lidocaine Group and only 1% in the propofol MCT/LCT plus lidocaine Group.
In conclusion, lidocaine addition to propofol is easy to perform and frequently used worldwide [1,20,32]. Our data suggest that both the incidence and severity of injection pain are lowest when the lidocaine-supplemented MCT/LCT formulation is applied. This regimen is associated with a significantly lower RR of injection pain in comparison with the lidocaine-supplemented LCT formulation. Pure propofol LCT is associated with a higher RR of injection pain compared to pure propofol MCT/LCT, even though statistical significance was not quite achieved (P =0.055).
This study was supported by a grant from B. Braun Melsungen, Germany and in part by departmental funds. We give warm thanks to Hilary Sharp for her text editing.
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