Propofol is well established as an induction drug in clinical anesthesia. However, pain on injection continues to be a problem, with an incidence of 32%–67% when injected into small hand veins (1). A clear solution of propofol (Cleofol™; Themis Medicare, Mumbai, India) has been introduced in the Indian market. It has the advantage of having a lower lipid load and less risk of bacterial contamination as compared with the emulsion. The product information suggests that it causes only mild pain on injection. Propofol-Lipuro (B Braun, Melsungen AG, Germany) contains medium-chain triglyceride as lipid carrier and is associated with a decreased incidence of pain on injection (2). We compared the incidence and severity of pain on injection using the two formulations of propofol.
After obtaining informed consent and approval from the institutional ethics committee, we examined 130 adult ASA physical status I and II patients. All were scheduled for surgery under general anesthesia with propofol as the induction drug. Exclusion criteria were known sensitivity to propofol, concomitant analgesic or sedative medication, and presence of infection on the dorsum of the left hand. A randomized, double-blind method of evaluation was used.
No premedication was administered to any of the patients. Routine monitors (lead II electrocardiogram, noninvasive arterial blood pressure, and pulse oximeter) were placed before the induction of anesthesia. A 20-gauge cannula was placed in the largest vein on the dorsum of the left hand. The patients were allocated randomly to one of two groups by use of sealed envelopes.
An independent anesthesiologist loaded one fourth of the total calculated induction dose of propofol (2 mg/kg) at room temperature in a 10-mL syringe. Sticking plaster was used to carefully cover the outer surface of the syringe barrel so that it was not possible to see whether it contained clear propofol or propofol emulsion. No analgesic or sedative was administered before propofol injection. The propofol (0.5 mg/kg) was administered in 5 s. Another independent clinician, unaware of the group to which the patient had been allocated and unaware of the contents of the syringe, assessed the pain on injection of propofol. The patients were asked a standard question, “Is the injection comfortable?” The verbal response and behavioral signs, such as facial grimacing, arm withdrawal, or tears, were noted (3). A score of 0 to 3, corresponding to no, mild, moderate, or severe pain, respectively, was recorded. Adverse effects, if any were noted.
The data were analyzed statistically using χ2 test and large sample test for demographic data. Pain on injection of propofol was analyzed using the Mann-Whitney U-test. EPI Info (version 6.2; Centers for Disease Control and Prevention, Atlanta, GA) and SPSS (version 10.0; SPSS, Chicago, IL) were used for analysis. A value of P < 0.05 was considered as statistically significant.
Both groups were comparable with respect to age (41 ± 13 yr; 38 ± 13 yr) and weight (51 ± 12 kg; 51 ± 10 kg). Assessment of pain is shown in Table 1.
The overall incidence of pain was 89% in the lipid-free propofol group and 40% in the propofol emulsion group. Pain intensity was significantly less in the group receiving propofol emulsion. No significant adverse effects were recorded in this group. Two patients who received lipid-free propofol developed swelling on the dorsum of the left hand, which was noticed in the immediate postoperative period. Both of them were kept under observation for signs of ischemia and responded to conservative management in the form of elevation of the limb.
Pain on injection of propofol has been significant enough to continue looking for better formulations. A large concentration of free propofol in the aqueous phase of an emulsion (4) and the lipid carrier (5–7) are associated with pain on injection. They activate 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 propofol contacts more free nerve endings outside the endothelial layer of the vessel and causes pain on injection.
Various pharmacological and nonpharmacological interventions have been tried in search of elimination of propofol-induced pain (1). Decreasing the concentration of free propofol in the aqueous phase of propofol emulsion by diluting with additional solvent or changing the lipid carrier have also reduced the pain on injection. Propofol-Lipuro, used in our study, contains medium-chain triglycerides and is associated with fewer incidences and severity of pain on injection as compared with the traditional emulsion used (2). It has been suggested that dilution with medium-chain triglyceride reduces the concentration of free propofol in the aqueous phase by 39.9% and decreases pain on injection(8).
The product information of Cleofol™, however, does not disclose the composition of the excipients, which have been added to 10 mg of propofol to prepare 1 mL of the solution. In a phase III multicenter trial involving 418 patients quoted in the product information, 76% experienced mild pain at the site of injection. However, in our study the overall incidence of pain was 89%, and 93% of patients experienced severe pain.
It seems that more propofol is available in the aqueous phase in the lipid-free propofol formulation, causing the frequent and severe pain on injection. Another factor may be the composition of the excipients, which is not known.
In conclusion, the clear propofol solution produces very frequent and severe pain on injection as compared with the emulsion containing medium-chain triglyceride used in clinical practice. The lipid-free preparation is beneficial in clinical conditions where lipid load is unwanted but at the cost of an unacceptably frequent and severe pain on injection.
1. Picard P, Tramer MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg 2000;90:963–9.
2. Rau J, Roizen MF, Doenicke AW, et al. Propofol in an emulsion of long- and medium-chain triglycerides: the effect on pain. Anesth Analg 2001;93:382–4.
3. McCrirrick A, Hunter S. Pain on injection of propofol: the effect of injectate temperature. Anaesthesia 1990;45:443–4.
4. Doenicke AW, Roizen MF, Rau J, et al. Reducing pain during propofol injection: the role of the solvent. Anesth Analg 1996;82:472–4.
5. Doenicke AW, Roizen MF, Rau J, et al. Pharmacokinetics and pharmacodynamics of propofol in a new solvent. Anesth Analg 1997;85:1399–1403.
6. Scott RPF, Saunders DA, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia 1988;43:492–4.
7. Nakane M, Iwama H. A potential mechanism of propofol-induced pain on injection based on studies using nafamostat mesylate. Br J Anaesth 1999;83:397–404.
8. Babl J, Doenicke A, Moench V. New propofol LCT/MCT fat emulsions as solvent: approach to reducing pain on injection of propofol? Eur Hosp Pharm 1995;1:15–21.