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Anesth Analg 2004;99:1076-1079 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000130344.17898.CD
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Abstract |
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Propofol is well known for its association with pain on injection. The most frequently used method to reduce this pain is premixture with lidocaine. Recently, a modified lipid emulsion of propofol containing medium-chain triglycerides (MCT) with long-chain triglycerides (LCT), in contrast to the usual LCT formulation, has been advocated to alleviate pain. In a randomized, prospective, controlled, double-blind study on 222 surgical patients, we compared the effect of the two solutions on the incidence and intensity of injection pain. Patients were randomly allocated to receive either propofol MCT/LCT (group M; n = 109) or standard propofol LCT with the addition of 20 mg of lidocaine (2 mL of lidocaine 1%) to 200 mg of propofol (group L; n = 113). Pain scores were assessed using a verbal analog scale (VAS) ranging from 0–10. Group L was found to have significantly less pain on the injection of propofol (mean VAS, 2.5 ± 2.9) (mean ± SD) than group M (mean VAS, 3.8 ± 3.2; P = 0.002). Regarding postoperative recall of pain on injection, patients in group L indicated significantly less pain (mean VAS, 2.2 ± 2.4) than patients in group M (mean VAS, 3.0 ± 2.7; P = 0.02). Premixing of 20 mg of lidocaine (2 mL of lidocaine 1%) to 200 mg of standard propofol LCT causes less pain on injection than propofol MCT/LCT and thus increases patient comfort.
IMPLICATIONS: Premixing of 20 mg of lidocaine (2 mL of lidocaine 1%) to 200 mg of standard propofol containing long-chain triglycerides (LCT) causes less pain on injection than propofol containing both medium-chain triglycerides (MCT) and LCT and thus increases patient comfort.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Pain on propofol injection has been widely investigated and is reported to occur on average in 70% of patients when used without any other treatment (1). Several strategies have been applied to alleviate pain, such as previous administration of opioids or metoclopramide and adaptation of the temperature of the emulsion. The most frequently used method to reduce the incidence and intensity of injection pain is the administration of lidocaine, either before propofol injection, with or without a tourniquet (2), or added to the propofol emulsion as a premixture (1,3,4).
Injection pain has been attributed to the amount of free propofol in the aqueous phase of the emulsion. In 1997, Doenicke et al. (5) advocated a reformulated lipid emulsion of propofol to alleviate injection pain. This reformulation of propofol contains both medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) in equal proportions in contrast to the usual LCT formulation. The amount of free propofol in an MCT/LCT emulsion is assumed to be less compared with propofol LCT thus causing less pain on injection. Interestingly, lidocaine not only works as a local anesthetic on the venous nociceptors, but it also decreases pH value, which decreases the percentage of free propofol in the aqueous phase of the emulsion and thus reduces pain on injection (4).
The aim of this study was to determine whether propofol in a reformulated MCT/LCT lipid emulsion without further addition was more effective in preventing pain on injection compared with the frequently used standard LCT propofol with a premixture of lidocaine.
Several studies have attempted to find the optimal dose of premixed lidocaine. The suggestions range from 10 mg of lidocaine (6) to 30 mg of lidocaine (3,7) in 200 mg of propofol. In two other studies (8,9), 20 mg of lidocaine premixed with 200 mg of propofol was found to appropriately reduce propofol-injection pain, so we decided to use that mixture of lidocaine with propofol in this study.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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With approval of the Local Ethics Committee of the Erasmus Medical Center Rotterdam and after obtaining written informed consent, 237 patients, 18–79 yr old, (ASA physical status I–III), scheduled to undergo minor elective surgery lasting up to 2 h, were included in the study. Exclusion criteria included the presence of neurological or psychiatric diseases, difficulty with communication, history of renal or hepatic insufficiency, suspected or known difficult airway, and hypersensitivity to the study drugs. Patients were allowed to receive 7.5 mg of midazolam, 1000 mg of paracetamol, or both as oral premedication given 1 h before the induction of anesthesia. On arrival in the operating room, patients were asked to indicate their anxiety about the operation and anesthesia on a verbal analog scale (VAS) (0 = no anxiety and 10 = worst anxiety imaginable). An 18-gauge IV cannula (BD VenflonTM Pro, Beckton Dickinson, Helsingborg, Sweden) was inserted into a vein on either the dorsum of the hand or the forearm. Patients were asked to indicate the severity of pain they experienced on insertion again by means of VAS (0 = no pain and 10 = worst pain imaginable) and on a four-point verbal categorical scoring system: none to mild pain to moderate pain to severe pain.
Using sealed envelopes, patients were randomly allocated either to group M—Propofol-Lipuro 1%TM (B. Braun Melsungen AG, Melsungen, Germany) containing propofol MCT/LCT—or group L—standard propofol LCT (Propofol 1% FreseniusTM, Fresenius, ‘s-Hertogenbosch, the Netherlands) premixed with lidocaine (Lidocaine HCl, B. Braun Melsungen AG). For preparation of the solutions, 40 mL of propofol was mixed with 4 mL of either normal saline (group M) or lidocaine 1% (group L), resulting in a propofol concentration of 0.909% (400 mg of propofol in a 44-mL total solution). The solutions were drawn into a 50-mL polyethylene syringe, kept at room temperature, and used within 30 min of preparation. The investigator, the anesthesiologist in charge, the anesthesia nurse, and the patient were all blinded to the propofol solution used.
During the induction of anesthesia, an IV infusion of 0.9% sodium chloride was given at a rate of 999 mL/h using a pump. Propofol was administered via a side-drip at the same speed of injection (20 mL/min) in all patients by means of an infusion pump. The induction dosage of propofol was determined by the anesthesiologist in charge. Each patient was asked in the same manner and had sufficient time to respond to the question on how they experienced the injection on the VAS (0 = no pain and 10 = worst pain imaginable). Before the induction of anesthesia, patients did not receive any other drugs. In particular, opioids and other narcotics were not given to exclude any potential influence on the study results. The injection of an opioid was allowed only after the administration of propofol had been completed to attenuate the cardiovascular response to the intubation of the patient’s trachea or insertion of a laryngeal mask. Perioperative physiologic monitoring included lead II and V electrocardiography, noninvasive arterial blood pressure measurement, and pulse oximetry. Postoperatively, using the VAS 0–10 at approximately 1 h after tracheal extubation, patients were asked how they recalled the sensation of injection.
Statistical analysis was conducted using SPSS for Windows release 10.1 (SPSS, Chicago, IL). Values are expressed as mean ± SD. Patient characteristics were compared with Student’s t-test and 
2 test. Statistical significance of differences between groups concerning pain evaluation during injection and recall was evaluated by Mann-Whitney U-test and 2 test. A P value < 0.05 was considered to be statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Of the 237 patients originally enrolled in the study, the pain scores of 15 patients had to be excluded, either for technical reasons (defect of infusion pump) or other violations of the study protocol. The results from 222 patients were evaluated, with 109 patients randomly allocated to group M and 113 patients to group L.
There were no significant differences between the two study groups with regard to age, weight, sex, ASA classification, number of patients receiving premedication, location of venous cannula, propofol induction dosage, and the duration of operation, as shown in Table 1. Nor was there a statistically significant difference in the VAS for the anxiety levels of the patients regarding the operation or anesthesia. Similarly, there was no difference for the VAS on insertion of the IV cannula (3.7 ± 2.1 in group M versus 3.5 ± 2.1 in group L).
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Concerning the VAS of the propofol injection, the mean pain score of patients in group M was 3.8 ± 3.2 compared with 2.5 ± 2.9 in group L, which was a statistically significant difference (P = 0.002). Low VAS scores (0–2) were reported more often in group L compared to group M, and medium and high VAS scores (3–10) were indicated more often in group M compared to group L. The distribution of the VAS values for pain on injection of the two study groups is shown in Figure 1.
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With regard to postoperative recall of pain on injection, both groups gave lower mean VAS scores compared with those recorded at the time of injection, with significantly lower VAS scores in group M but not in group L (Fig. 2). Postoperatively, patients in group L (2.2 ± 2.4) still recalled less pain on propofol injection compared with patients in group M (3.0 ± 2.7; P = 0.02), as displayed in Figure 2.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we have shown that propofol, in a standard lipid emulsion containing LCT with premixture of 20 mg of lidocaine to 200 mg of propofol, causes significantly less pain on injection than propofol in a modified reformulated lipid emulsion containing both MCT and LCT without premixed lidocaine. Also, we found that patients recalled less pain on injection when given propofol LCT with lidocaine compared with propofol MCT/LCT after general anesthesia.
Reformulation of the lipid emulsion using MCT/LCT in contrast to LCT alone was found to cause less pain on injection when compared with the standard propofol LCT emulsion without the addition of lidocaine (5). A study performed by Rau et al. (10) confirmed these findings in the clinical setting.
Premixture of lidocaine with propofol was shown to be more effective in reducing pain than previous separate IV injection of lidocaine (11,12). The pain-reducing effect of lidocaine on propofol injection has not only been attributed to its local anesthetic effect, but also to a decrease in the pH value of the propofol-lidocaine mixture. It is hypothesized that the lower pH value causes propofol to migrate into the lipid phase and to progressively decrease the effective concentration of free propofol in the aqueous phase of the lipid emulsion (4).
However, the addition of lidocaine might lead to destabilization of the propofol solution (4). When applying the emulsion in a 9:1 mixture of propofol-lidocaine within a short time frame (<30 minutes), this effect can be ignored (13). In a recent study published by Tan and Hwang (14), the induction dosages of propofol with and without lidocaine were similar, indicating no relevant clinical destabilization of the emulsion when lidocaine is premixed. Because, in the present study, the mean dosages of propofol for the induction of anesthesia were similar in both groups, any major destabilizing effect of lidocaine on the propofol emulsion cannot be suspected.
With respect to the two preparations used in this study, we compared the pain-inducing effects of two fundamentally different preparations yet with similar underlying mechanisms. Whereas premixing lidocaine to propofol is a widely used method in clinical practice, the reformulated propofol emulsion using MCT/LCT is an innovative technique, which was already shown to have other beneficial effects concerning lipid metabolism in long-term use (15).
After reading the recommendations from the studies by King et al. (8) and Ho et al. (9), we decided to administer lidocaine in a concentration of 0.1% of the propofol emulsion. There was already evidence that MCT/LCT propofol was superior to LCT propofol without the addition of any lidocaine (10). Besides, we did not find it ethically justified using LCT propofol without any method of pain prevention to only confirm already known results. Thus, we accepted the disadvantage of being without a point of reference.
There were no significant differences between the groups with regard to anxiety scores for surgery or anesthesia, respectively, or the scores for pain on insertion of the IV cannula. Because the experience of pain is a highly subjective matter, we standardized the procedure as much as possible and questioned all patients about their pain in a nonsuggestive manner. The VAS with a range from 0 to 10 seems to be more distinctive and more sensitive to smaller changes than are categorical measures such as the four-point verbal categorical scoring system. However, for comparative purposes, we used both scales.
Postoperatively, patients in both groups had the tendency to recall lower pain scores compared to the scores recorded during injection. This may be attributed to premedication with benzodiazepines and to the general anesthesia. The difference in pain scores between the time of injection and recall was significant in group M but not in group L, a finding that is difficult to explain. Still, similarly to the time of the actual injection, patients receiving propofol LCT with premixed lidocaine (group L) recalled a significantly lower mean VAS than patients who were given propofol MCT/LCT (group M).
In conclusion, our study shows that the common practice of mixing lidocaine with the standard propofol LCT emulsion before injection causes less pain on injection than a more expensive reformulation of propofol containing MCT/LCT. However, it remains speculative whether the addition of lidocaine to the reformulated MCT/LCT propofol emulsion will be of benefit to further reduce pain on injection compared with standard LCT propofol premixed with lidocaine. Further studies need to be conducted to determine this.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- Picard P, Tramer M. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg 2000; 90: 963–9.
[Abstract/Free Full Text] - Pang W, Mok M, Huang S, Hwang M. The analgesic effect of fentanyl, morphine, meperidine, and lidocaine in the peripheral veins: a comparative study. Anesth Analg 1998; 86: 382–6.[Abstract]
- Nathanson M, Gajraj N, Russell J. Prevention of pain on injection of propofol: a comparison of lidocaine with alfentanil. Anesth Analg 1996; 82: 469–71.[Abstract]
- Eriksson M, Englesson S, Niklasson F, Hartvig P. Effect of lignocaine and pH on propofol-induced pain. Br J Anaesth 1997; 78: 502–6.
[Abstract/Free Full Text] - Doenicke A, Roizen M, Rau J, et al. Pharmacokinetics and pharmacodynamics of propofol in a new solvent. Anesth Analg 1997; 85: 1399–403.[Abstract]
- Tham C, Khoo S. Modulating effects of lignocaine on propofol. Anaesth Intensive Care 1995; 23: 154–7.[Web of Science][Medline]
- Gajraj N, Nathanson M. Preventing pain during injection of propofol: the optimal dose of lidocaine. J Clin Anesth 1996; 8: 575–7.[Web of Science][Medline]
- King S, Davis F, Wells J, et al. Lidocaine for the prevention of pain due to injection of propofol. Anesth Analg 1992; 74: 246–9.[Abstract]
- Ho C, Tsou M, Sun M, et al. The optimal effective concentration of lidocaine to reduce pain on injection of propofol. J Clin Anesth 1999; 11: 296–300.[Web of Science][Medline]
- Rau J, Roizen M, Doenicke A, et al. Propofol in an emulsion of long-and medium-chain triglycerides: the effect on pain. Anesth Analg 2001; 93: 382–4.
[Abstract/Free Full Text] - Scott R, Saunders D, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia 1988; 43: 492–4.[Web of Science][Medline]
- Tan C, Onsiong M. Pain on injection of propofol. Anaesthesia 1998; 53: 468–76.[Web of Science][Medline]
- Masaki Y, Tanaka M, Nishikawa T. Changes in propofol concentration in a propofol-lidocaine 9:1 volume mixture. Anesth Analg 2000; 90: 989–92.
[Free Full Text] - Tan LH, Hwang NC. The effect of mixing lidocaine with propofol on the dose of propofol required for induction of anesthesia. Anesth Analg 2003; 97: 461–4.
[Abstract/Free Full Text] - Theilen HJ, Adam S, Albrecht MD, Ragaller M. Propofol in a medium- and long-chain triglyceride emulsion: pharmacological characteristics and potential beneficial effects. Anesth Analg 2002; 95: 923–9.
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