Propofol (propofol 1%; Fresenius, Fresenius Kabi, Austria GmbH) has the disadvantage of pain on injection and several methods have been used to reduce it  although the most effective intervention is unknown. Remifentanil (Ultiva™; Glaxo Wellcome, The Upjohn Company, Belgium) is a piperidine-based opioid which acts as a μ-receptor agonist. Its pharmacokinetic profile is unique among the opioids having a very rapid plasma clearance and onset time and a very short context-sensitive half-life of 2-10 min . Two previous studies have examined the effects of remifentanil in preventing propofol injection pain [1,3]. We have conducted a double-blind study to investigate the effect of different doses and timing of remifentanil administration and compare it with meperidine and placebo on the incidence and severity of pain during propofol injection.
The study was approved by the medical Ethics Committee of our institution and written consent obtained from each patient before surgery. We included 225 patients, ASA I-II, unpremedicated, aged 19-73 years scheduled for elective gynaecology, otolaryngology, urology or ophthalmic surgery. Exclusion criteria were pregnancy, concomitant analgesic or sedative medication, patients requiring rapid sequence induction, patients in whom difficult intubation was anticipated, a history of reaction to local anaesthetic agents, anticipated difficulty in venous access, difficulty in communication or weighing less than 50 kg. On arrival in the operating theatre, a 20-G intravenous cannula was inserted in the dorsum of the non-dominant hand after attaching the electrocardiogram, noninvasive blood pressure and pulse oximeter. An infusion of saline was commenced. Patients were randomly allocated to one of five groups. Group R1 (n = 45) and Group R2 (n = 45) received remifentanil immediately prior to propofol (2 mg kg−1) injection at a dose of 1 μg kg−1 min−1 and 0.25 μg kg−1 min−1, respectively. Group R3 (n = 45) received remifentanil (0.25 μg kg−1 min−1) commenced 1 min before propofol (2 mg kg−1) injection. Group M (n = 45) received meperidine (Aldolan; Gerot Pharmazeutika, Vien, Austria) (40 mg in 4 mL) and Group P (n = 45) received saline (4 mL) immediately prior to propofol (2 mg kg−1) injection. The propofol was injected over 30 s. An independent anaesthetist prepared the solutions and the investigator did not know the contents of the solutions. Another independent clinician, unaware of the group to which the patients had been allocated, assessed the level of pain on injection of propofol. A preliminary study had shown that 10 mL (100 mg) propofol was sufficient to induce anaesthesia and pain if it was going to occur. For this reason, we chose 10 mL of propofol for this study.
The severity of injection pain was evaluated using a four-point scale. Expression of pain by strong vocal response or response accompanied by facial grimacing or withdrawal of arm was scored as severe pain. Verbal expression of pain without grimacing or withdrawal of arm was scored as moderate pain. If severe or moderate pain was not observed within 30 s the patient was asked whether they had any discomfort in the arms; if they answered ‘yes’ this was scored as mild pain or if the answer was ‘no’, this was scored as no pain. Additional propofol was then administered as required at the anaesthetist's discretion. Tracheal intubation was facilitated with succinylcholine and anaesthesia maintained with sevoflurane 2% and nitrous oxide 50% in oxygen.
Statistical analysis was performed with Instat™ (GraphPad Software, Inc., San Diego, CA, USA). Results were analysed by ANOVA and Fisher's exact test. P < 0.05 was considered as statistically significant.
There were no differences between the different groups regarding gender although the number of female patients were different between the different groups (Table 1). The incidence of injection pain in the different groups and their distribution are given in Table 2. The overall incidence of pain on injection of propofol was 20% (n = 9, P < 0.0001) in Group R1, 60% (n = 27, P = 0.5) in Group R2, 44% (n = 20, P = 0.033) in Group R3, 47% (n = 21, P = 0.054) in Group M and 69% (n = 31) in the placebo group. The incidence of pain was lowest in Group R1. Using Fisher's exact test we found a significant reduction in the incidence of pain on injection of propofol in Groups R1 and R3 compared with placebo (P < 0.05) (Table 2). The incidence of severe pain was 4% (n = 2, P = 0.02) in Group R1, 11% (n = 5, P = 0.2) in Group R2, 7% (n = 3, P = 0.06) in Group R3, 7% (n = 3, P = 0.06) in Group M and 22% (n = 10) in the placebo group.
There was a significant reduction in the overall incidence of pain from propofol injection in Groups R1 and R3, and a significant reduction in the severity of pain in Group R1 compared with placebo. Remifentanil injection 1 μg kg−1 min−1 provided the most effective pain relief.
Administration of meperidine before propofol has previously been shown to reduce pain in the arm [4,5]. Some drugs with opioid activity have a local anaesthetic action and this includes the synthetic opioids of the phenylpiperidine series, meperidine, fentanyl and sufentanil. Remifentanil is also a member of the phenylpiperidine group and could have local anaesthetic effects on nerves.
It was reported that the incidence of pain was declined from 84 to 36% when 1 mg alfentanil was administered followed 15 s later by propofol . It was also shown that alfentanil 30 μg kg−1 given 30 s before propofol abolished pain on injection. Roehm and colleagues showed that the slow administration of remifentanil over 60 s before propofol injection is as effective as lidocaine 40 mg 1 min prior to propofol in reducing the incidence of injection pain . We included a remifentanil 0.25 μg kg−1 min−1 group as a comparator with Roehm's study. Roehm and colleagues found that the incidence of pain was 30.2%. In this study, we used the same doses of remifentanil in Groups R2 and R3 but Group R3 differed by having a time interval of 1 min between administration of remifentanil and administration of propofol. Our suggestion is that the statistical difference between these two groups may depend on the time interval.
Mencke and colleagues used rocuronium for investigating local reactions and pain, and found that the incidence and the degree of withdrawal reactions in response to the injection of rocuronium were significantly higher in female than in male . On the contrary, we showed that the local reactions and pain on injection are the same between female and male patients.
Opioid receptors are found both in the dorsal root ganglia, the central terminals of primary afferent nerves and in peripheral sensory nerve fibres and their terminals. The reduction in injection pain might be the interaction of remifentanil with peripheral μ-opioid receptors. The site of action of remifentanil in reducing pain on injection of propofol may be either central or peripheral. A central mechanism may be responsible in the results of Group R3. The increased dose in Group R1 would markedly increase the concentration of remifentanil and at this concentration, compared with placebo, remifentanil showed some analgesic effects in ameliorating propofol injection pain. In our previous study we administered 1 μg kg−1 min−1 remifentanil to unpremedicated patients before propofol and the incidence of pain was reduced from 64 to 32% . In this study, the incidence of pain was 69% in the placebo group. In conclusion, an increased dosage or time interval of remifentanil might be the cause of the decreased injection pain of propofol.
1Department of Anesthesiology, Vakif Gureba Hospital, Istanbul, Turkey
1. Basaranoglu G, Erden V, Delatioglu H. Reduction of pain on injection of propofol: a comparison of fentanyl with remifentanil. Anesth Analg
2. Calderon E, Pernia A, De Antonia P, Calderon-Pla E, Torres LM. A comparison of two constant - dose continuous infusions of remifentanil for severe postoperative pain. Anesth Analg
3. Roehm KD, Piper SN, Maleck WH, Boldt J. Prevention of propofol-induced injection pain by remifentanil: a placebo-controlled comparison with lidocaine. Anaesthesia
4. Pang WW, Mok MS, Huang S, Hwang MH. The analgesic effect of fentanyl, morphine, pethidine, and lidocaine in the peripheral veins: a comparative study. Anesth Analg
5. Lyons B, Lohan D, Flynn C, McCarroll M. Modification of pain on injection of propofol: a comparison of pethidine and lignocaine. Anaesthesia
6. Fletcher JE, Seavell CR, Bowen DJ. Pretreatment with alfentanil reduces pain caused by propofol. Br J Anaesth
7. Mencke T, Beerhalter U, Fuchs-Buder T. Spontaneous movements, local reactions and pain on injection of rocuronium. A comparison between female and male patients. Acta Anaesthesiol Scand