A major disadvantage of propofol administration is pain on injection. Pre-treatment with lidocaine, opioids, metoclopramide, ephedrine, magnesium sulphate, neostigmine, ketorolac and injection into a large vein have all been reported to reduce the incidence and severity of pain. In principle, the speed of injection might influence pain since a slow rate will prolong the contact time with the endothelium, but rapid injection allows the propofol to be cleared from the vein and replaced with blood. There are conflicting data about the influence of speed of injection on pain with one study  showing no difference and another showing slow injection increased pain . In the following randomized, double-blind placebocontrolled trial, we compared pain during fast administration of propofol to that during slow administration with and without lidocaine pre-treatment.
We studied 120 unpremedicated females (ASA I-II, aged 18-70 yr) undergoing elective surgery. Ethics committee approval from the University of Tsukuba and written informed consent were obtained. Patients were excluded if they were allergic to propofol, had communication difficulties, a history of cardiovascular or neurological disease, a body mass index >30 kg m−2 or were unsuitable for intravenous (i.v.) induction.
Patients were randomized into four equal-sized groups and the treatment group determined by opening an opaque envelope. In Group A, patients were pre-treated with normal saline 5 mL and then given propofol 2 mg kg−1 at a rate of 3.3 mg s−1. In Group B, patients were pre-treated with preservative-free lidocaine 0.5 mg kg−1 adjusted to a volume of 5 mL and then given propofol 2 mg kg−1 at a rate of 3.3 mg s−1. In Group C, patients were pre-treated with preservative-free lidocaine 1.0 mg kg−1 adjusted to a volume of 5 mL and then given propofol 2 mg kg−1 at a rate of 3.3 mg s−1. In Group D, patients were pre-treated with normal saline 5 ml then given propofol 2 mg kg−1 at a rate of 50 mg s−1.
An 18-G cannula (BD Insyte Autoguard, BD Medical Systems Inc., Utah, USA) was inserted into the largest visible vein on the radial side of the non-dominant forearm, attached to a three-way tap and flushed with Ringer's lactate solution. A 5 mL syringe containing the randomized pre-treatment drug at room temperature was attached to one limb of the tap and a propofol infusion at 5°C attached to the other limb of the tap. A venous tourniquet was applied just above the elbow and the pre-treatment drug was given. The tourniquet was released after 3 min and the propofol infusion commenced. The infusion was prepared immediately before use by drawing unmodified propofol (Diprivan 1%; AstraZeneca, Milano, Italy) without the use of a filter into a 60 mL syringe from three 20 mL glass vials. An i.v. infusion was not commenced during induction and co-induction agents were not administered.
Patients were asked by the anaesthetist, ‘does it hurt’ at 10 s intervals until unresponsive. Any spontaneous movements of the wrist, elbow or shoulder were noted. A second anaesthesiologist, blinded to the type of pre-treatment and rate of propofol infusion, evaluated the response as follows: 0: no verbal pain or movement; 1: verbal pain, but no movement; 2: verbal pain and movement of wrist; and 3: verbal pain and movement of elbow or shoulder. The pain score for the patient was taken as the most severe pain documented.
Following induction of anaesthesia, the laryngeal mask airway was inserted and anaesthesia maintained with 67% nitrous oxide and 1-2% sevoflurane in oxygen. Systolic blood pressure was measured every minute after the completion of propofol infusion and ephedrine 5 mg administered, if it was 30% lower than pre-induction baseline values.
Sample size was selected to detect a projected difference of 50% in the mean pain score between the groups for a Type I error of 0.05 and a power of 0.8. Patient characteristics data was tested by analysis of variance (ANOVA) (Scheffé as a post hoc test), pain intensity by Kruskal-Wallis test and the intensity of pain by χ2-test with P < 0.05 taken as significant.
None of the patients were excluded from the analysis. Patient characteristics data were similar among groups (Table 1). Pain scores are given in Table 2. Rapid injection was less painful than slow injection (P < 0.00001). Rapid injection was similarly painful to slow injection after pre-treatment with lidocaine 1.0%, but less painful than after pre-treatment with lidocaine 0.5% (P < 0.00001). Pre-treatment with lidocaine 0.5% and 1.0% reduced pain during slow injection (both, P < 0.00002). During slow injection, pre-treatment with lidocaine 1.0% was more effective at reducing pain than lidocaine 0.5% (P < 0.00001). No patient required ephedrine.
We found that pain was reduced by rapid injection of propofol. Scott and colleagues , in a study of 30 patients using an induction dose of propofol at room temperature, reported that pain was more severe with slow injection. However, Grauers and colleagues , in a study of 30 patients using a sub-induction dose of propofol at room temperature, reported that infusion rate did not affect local pain on injection when comparing 2 mg s−1 with 10 mg s−1. The differences in study findings may be related to differences in the infusion rates or the total dose of propofol, but are probably not related to injection temperature, since this has no impact on pain .
We found that during slow injection, lidocaine pre-treatment reduced pain and that the effect was dose related, with 1.0% being more effective than 0.5%. The efficacy of lidocaine pre-treatment is well established. A recent meta-analysis found that the best prevention of pain with propofol is lidocaine 0.5 mg kg−1 given with a rubber tourniquet before propofol injection and this will prevent pain in approximately 60% of patients . Our study suggests that 0.5 mg kg−1 will prevent pain in 7%, but 1 mg kg−1 will prevent pain in 63%. The lower dose of lidocaine may have been less effective due to the slowness of the propofol injection.
Our study has four limitations. First, we did not compare haemodynamic responses between fast and slow injection. A potential hazard of rapid injection is a more marked fall in blood pressure than after slow injection ; however, no patient given rapid propofol had a fall in systolic blood pressure >30%, suggesting that rapid injection is probably safe in healthy patients. Second, we did not collect data about apnoea; however, we encountered no problems with ventilation using the laryngeal mask airway in the event of apnoea. Third, we did not collect data about whether patients remembered the pain they experienced; however, we recall that some patients did remember mild pain while others failed to remember severe pain. Fourth, our findings may not be applicable where pre-anaesthesia drugs, such as fentanyl and/or midazolam, are given.
We conclude that fast administration of propofol reduces pain and is comparable to slow administration with lidocaine 1.0% pre-treatment.
J. R. Brimacombe
1Department of Anesthesiology, University of Tsukuba, Tsukuba, Ibaraki, Japan
2Cairns Base Hospital, James Cook University, The Esplanade, Cairns, Australia
1. Grauers A, Liljeroth E, Akeson J. Propofol infusion rate does not affect local pain on injection. Acta Anaesthesiol Scand
2. Scott RP, Saunders DA, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia
3. Picard P, Tramèr MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg
4. Ludbrook GL, Upton RN, Grant C, Martinez A. The effect of rate of administration on brain concentrations of propofol in sheep. Anesth Analg