Anesthetic Pharmacology: Brief Report
Pain on injection of propofol is a common clinical problem. Various methods have been used to minimize propofol-induced pain, most commonly premixing with lidocaine. However, the reported percentage of patients experiencing pain ranged from 5% to 48% (1). Recently, propofol has been reformulated as an emulsion containing medium- and long-chain triglycerides (MCT and LCT), but the incidence of pain still ranges from 28% to 38% (2–4).
It has not been determined whether the addition of lidocaine to the propofol-MCT/LCT emulsion further decreases pain on injection. We conducted this prospective, double-blind, randomized controlled study to determine if propofol-MCT/LCT premixed with lidocaine, as well as given alone, is effective in reducing pain on injection.
The study was approved by the institutional ethics committee. Written informed patient consent was obtained from 75 ASA I–II patients between the ages of 18 to 60 yr undergoing elective surgery requiring general anesthesia under spontaneous ventilation. Exclusion criteria were patients with ischemic heart disease and neurological problems, pregnant or lactating patients, those who were taking any analgesics before surgery, or those with known hypersensitivity to propofol or to any of the constituents of the emulsion (soy-bean oil, MCT, glycerol, egg lecithin, sodium oleate, water for injection).
The drugs used were propofol-LCT (Diprivan®, AstraZeneca, United Kingdom), lidocaine 1% (Pharmacia and Upjohn, Australia), and propofol-MCT/LCT (Lipuro®, B. Braun, Germany).
The patients were assigned to 3 groups by computer-generated randomization with 25 patients in each group. Group A received propofol formulated with LCT premixed with lidocaine (i.e., 2 mL of 1% lidocaine in 20 mL of propofol). Group B received propofol-LCT/MCT premixed with 2 mL normal saline, and group C received propofol-LCT/MCT premixed with lidocaine (2 mL of 1% lidocaine in 20 mL of propofol). The drugs were prepared by one of the investigators, with both the patient and an independent observer (a trainee anesthesiologist) blinded.
Patients received no premedication. An 18-gauge cannula was inserted into a vein in the dorsum of the hand and a fast-running drip was started. The temperature of injected propofol was not standardized, as previous studies have indicated that this does not affect pain on injection (5). Propofol was then injected at a rate of 400 mL/h. This was delivered via a syringe pump (ALARIS Medical Systems, United Kingdom) connected to a three-way tap placed immediately distal to the venous cannula. Any spontaneous complaints of pain were noted and patients were asked to rate the pain as none, mild, moderate, or severe. If there were no spontaneous complaints, patients were directly questioned about pain after 30 s. Observations were noted by the independent observer. After loss of the eyelash reflex, IV fentanyl 1 μ/kg was given and a laryngeal mask was inserted.
Statistical analysis was conducted using SPSS version 11.5. Categorical data were analyzed using χ2 and Fisher’s exact tests, and parametric data were analyzed with analysis of variance. Statistical significance was taken as P < 0.05.
No difference was detected among groups with respect to demographic data (Table 1). There was a significant pain reduction in group C where only one patient (incidence of 4%, 95% confidence interval 0.7%–19%) complained of pain. The incidence of pain in groups A and B was similar, with six patients (24%, 95% confidence interval 11.5 to 43%) complaining of pain in both groups. There was a 20% reduction in the proportion of patients with pain in group C as compared with groups A and B that was statistically significant (95% confidence interval 0.1 to 39.7%, P = 0.049). The number of patients that needed to be treated to prevent pain was 5 (95% confidence interval 3–63). There was no difference in the severity of pain between groups A and B (Fig. 1).
In this study, patients who were given a mixture of propofol-MCT/LCT and lidocaine had significantly less pain on injection than those given either propofol-MCT/LCT alone or the conventional propofol-lidocaine mixture.
Since the first clinical trial in 1977 (6), pain on injection of propofol remains a significant problem. Of a list of clinically important difficulties faced by anesthesiologists, propofol pain ranked seventh (7). Propofol is most commonly reformulated in an emulsion with LCT. However, 32% to 67% of patients experience moderate to severe pain on injection of this emulsion (8).
Several mechanisms of pain on injection have been suggested, but investigators have shown that the free concentration of propofol in the aqueous phase may be the most important factor (9–11). Emulsions of MCT/LCT, although maintaining similar pharmacological properties as standard propofol (12), have smaller propofol concentrations in the aqueous phase (11). Rau et al. (4) reported that 37.8% of patients given such a preparation were pain-free and of the patients who did have pain, none graded it as severe. Others have reported an incidence of pain with propofol-MCT/LCT as 28%–37% (2,3).
Of the various methods that have been used to minimize injection pain, the most common is mixing with lidocaine. However, this is still associated with an incidence of pain of up to 38.3% (5).
We found that mixing propofol-MCT/LCT with lidocaine was effective in significantly reducing the incidence of pain. We speculate that the mechanism of pain relief is twofold; first by the reduction of propofol concentrations in the aqueous phase and second by lidocaine acting as a stabilizer of the kinin cascade (13).
The effects of adding lidocaine to propofol are debatable. Eriksson et al. (14) reported a reduction in anesthetic potency, with the dose required to induce hypnosis in rats increasing by 64%–68%. Lilley et al. (15) found that addition of lidocaine to propofol causes a destabilization of the emulsion, although it was unlikely to have clinically significant effects.
In conclusion, the addition of lidocaine to propofol-MCT/LCT significantly reduced the incidence of pain on injection. In contrast, we did not find any advantage of using propofol-MCT/LCT alone as compared with the conventional propofol-lidocaine mixture. We recommend that lidocaine 20 mg should be premixed with propofol-MCT/LCT to ensure maximal patient comfort. However, we acknowledge that a limitation of our study is the small sample size and suggest that larger studies be performed.
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© 2005 International Anesthesia Research Society
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