Pain after injection of propofol occurs in 28%-90% of patients and may be severe [1,2]. The addition of lidocaine to propofol (premixing) reduces the incidence of pain on injection [3-6]. However, mixtures of propofol and lidocaine are not stable and must be used within 30 min of preparation. Alfentanil administered up to 2 min before the injection of propofol (pretreatment) also significantly reduces pain on injection [7-9]. The use of a potent opioid drug may not always appropriate, for example, if the planned technique requires the patient to maintain spontaneous respiration. The aim of this study was to compare the use of premixed lidocaine (40 mg) and propofol with pretreatment with alfentanil (1 mg) for the reduction of pain during the injection of propofol in adult patients.
With the approval of our institution's ethical committee and informed, written consent, 89 patients scheduled to undergo elective surgery were recruited into a randomized, placebo-controlled, double-blind study. Exclusion criteria were a history of chronic pain syndromes, thrombophlebitis, neurological disease, and analgesic administration at the time of the study. Patients were either unpremedicated or lightly premedicated with a benzodiazepine, at the discretion of the anesthesiologist, 1 h prior to induction of anesthesia. A 22-gauge cannula was inserted into a vein on the dorsum of the nondominant hand. All study drugs were kept at room temperature and used within 30 min of preparation.
Patients were randomly allocated to one of three groups. Patients in Group L (lidocaine) received 2 mL of normal saline followed 30 s later by premixed propofol 180 mg (18 mL) and lidocaine 40 mg (2 mL of lidocaine 2%); Group A (alfentanil) received pretreatment with alfentanil 1 mg followed 30 s later by propofol and normal saline (propofol 180 mg mixed with 2 mL normal saline), and patients in Group P (placebo) receive 2 mL normal saline followed 30 s later by propofol and normal saline (as for Group A).
The propofol mixture was injected at a rate of 2.5 mL every 5 s and continued until loss of consciousness as assessed by standard clinical criteria (no verbal response, loss of eyelash reflex). Every 5-10 s during the propofol injection, the patient was questioned regarding the presence of pain or discomfort and, if present, was asked to grade it as mild, moderate, or severe. After induction of anesthesia, the choice of anesthetic technique was left to the discretion of the attending anesthesiologist. After recovery from anesthesia, patients were asked if they had any recollection of discomfort or pain during the induction period.
From previous studies, the expected incidence of pain was 0% in Group L, 36% in Group A, and 73% in Group P [7,10]. A power analysis indicated that a sample size of 75 was sufficient to have an 80% chance (Type II error = 0.2) of detecting a difference in incidence of pain between the three groups at the 95% (Type I error = 0.05) significance level. The results were analyzed by analysis of variance and the chi squared test using Instat (GraphPAD Software, San Diego, CA) statistical software.
There were no significant demographic differences between the groups or significant differences in the use of premedication Table 1. The mean (SD) dose of lidocaine in Group L patients was 0.48 (0.07) mg/kg, and that of alfentanil in Group A patients was 14.6 (2.6) micro gram/kg. There was no significant difference in the amount of propofol administered to patients in the three groups: Group L, 2.17 (0.31) mg/kg; Group A, 2.06 (0.48) mg/kg; and Group P, 2.09 (0.42) mg/kg (mean (SD)). The mean time from start of injection to loss of consciousness was similar for all three groups. The incidence of reported pain Table 2 was significantly less in both Group L (13%) and Group A (24%) than in Group P (67%). The incidence of pain in the two treatment groups was not significantly different. Three patients reported severe pain; all were in the placebo group. Fifty-two percent of patients who reported pain were able to recall it in the recovery room, and there was no difference in the recall rate between the three groups. The incidence of recall of pain was similar in patients who did and did not receive benzodiazepine premedication.
We have confirmed that the incidence of pain on injection of propofol is high but is significantly reduced by either addition of lidocaine or pretreatment with alfentanil. However, we were unable to demonstrate a significant difference between these two treatment strategies.
The mean dose of lidocaine in Group L patients was 0.48 mg/kg, and the maximum dose was 0.73 mg/kg. This is below the toxic dose for lidocaine. Rather than inject the lidocaine prior to the propofol (pretreatment), we chose to add the lidocaine to the propofol, as this has been shown to be more effective [10,11]. Helbo-Hansen et al.  gave premixed lidocaine (0.125 mg/kg) and propofol and found that the incidence of pain was 25%. The efficacy of premixed lidocaine is dose related [5,12]. Johnson et al.  found lidocaine 40 mg premixed with propofol highly effective (pain was abolished). It is unclear why we found the same dose of lidocaine less effective than did Johnson et al. . However, mixtures of propofol and lidocaine are unstable and the effect of such mixtures on the incidence of pain may therefore be unpredictable. The mixture must be freshly prepared and used within 30 min, because after this time the lidocaine enters the lipid phase of the propofol emulsion and is no longer effective. The manufacturer of propofol (Diprivan Registered Trademark; Zeneca Ltd., Macclesfield, Cheshire, UK) does not recommend that propofol and lidocaine be mixed.
Helmers et al.  found pretreatment with fentanyl 100 micro gram or alfentanil 1 mg to be equally effective in reducing pain on injection of propofol. Alfentanil 1 mg 15 s prior to propofol (compared with placebo) reduces the incidence of pain from 84% to 36% . Saarnivaara and Klemola  found that alfentanil 30 micro gram/kg given 30 s before propofol abolished pain on injection. However, all patients in this study received oxycodone as a premedicant. Hiller and Saarnivaara , studying children, compared three doses of alfentanil administered 1 min prior to propofol with 10 mg lidocaine premixed with propofol. The incidence of moderate or severe pain was 4% in the lidocaine group and 40%, 16%, and 20% in the groups receiving 10, 15, and 20 micro gram/kg of alfentanil, respectively. The mean dose of alfentanil in Group A patients was 14.6 micro gram/kg, and the incidence of pain was 24%. The site of action of alfentanil in reducing pain on injection of propofol may be either central or peripheral. We did not observe any significant differences of the induction dose of propofol between the three groups, possibly because of the relatively short time (30 s) between administration of the alfentanil and the propofol. This suggests that a central mechanism for the reduction in pain from propofol is less likely. A similar dose of alfentanil, 1-2 min before propofol, results in a 17%-20% reduction of the induction dose of propofol [7,14]. Alfentanil may not be a suitable drug to reduce pain on injection of propofol if the use of a potent opioid drug leading to possible respiratory depression is to be avoided.
We chose to use only benzodiazepine premedication, as opioid premedication may reduce the incidence of pain on injection of propofol . Benzodiazepine premedication reduces recall of procedures such as insertion of the intravenous cannula  and may therefore reduce recall of unpleasant or painful injection during induction. Recall of pain from propofol has been described in 81%-96% of unpremedicated patients [5,9] and in 68% of patients receiving diazepam 10 mg 1 h prior to induction . Forty-eight percent of our patients received benzodiazepine premedication, and the incidence of recall was 52%.
In conclusion, we have shown that alfentanil 1 mg and lidocaine 40 mg are effective in reducing the incidence of pain during injection of propofol. The use of alfentanil is an acceptable alternative to lidocaine when an opioid is to be administered as part of the anesthetic technique.
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