Cooled (i.e., 4°C) propofol and warmed (i.e., 37°C) propofol had no statistically significant analgesic effect (Table 1, E).
IV thiopentone, lidocaine 60% tape, and nitroglycerine ointment were each tested in two trials. For thiopentone (42,50) and nitroglycerin (61,76), the respective trials produced contradictory results. With lidocaine tape (72,78), pain of both insertion of IV lines and of injection of propofol was decreased. All other pharmacological or physical interventions were each tested in one trial: IV ondansetron, droperidol, nafamostat mesilate, ketamine, aspirin, ketorolac, prilocaine, or morphine; premedication with oral diazepam or IM ketorolac; iontophoresis with lidocaine; dilution of propofol with homologous blood or dextrose; speed of injection of propofol or of carrier; long chain triglycerides; tourniquet; double or single lumen IV sets; and site of injection. No meaningful conclusions could be drawn. In one trial, pretreatment with IV fentanyl was used concomitantly with a propofol-lidocaine mixture (49); this was more analgesic than either treatment alone. In another trial, none of 40 patients receiving pretreatment with fentanyl plus cold propofol mixed with lidocaine reported any pain (17). Reports on adverse effects were sparse. No data on costs were retrieved.
In these systematically searched randomized, controlled trials, approximately 70% of all control patients reported some degree of pain or discomfort on injection with propofol alone. In some trials, all controls reported pain. The most effective analgesic method was IV lidocaine, given as a Bier’s block before the injection of propofol. Of 100 the patients treated with lidocaine 40 mg with a rubber tourniquet at the forearm for 30 to 120 s before the injection of propofol, approximately 60 (NNT 1.6) will not have any pain who would have had pain had they not received lidocaine. A dose-response, with a dose range of 20 to 100 mg, was not obvious. This applies to the injection of propofol into the upper limb in adult patients. No trial tested the effect of an analgesic intervention when propofol was to be injected into the lower limb. Also, only limited data were from children. We have to assume that the most effective analgesic method in adults may be extrapolated to children. Thus, the pediatric lidocaine dose for an effective tourniquet method is approximately 0.5 mg per kg of body weight.
IV opioids showed less efficacy compared with the lidocaine-tourniquet technique. Meperidine looked promising, when given as a Bier’s block (23,64). This may be regarded as further evidence of meperidine’s local-anesthetic properties (79). In one trial, the concomitant use of naloxone did not reduce meperidine’s efficacy, suggesting that its peripheral analgesic effect is not mediated by opioid receptors (23). Fentanyl and alfentanil were also given as Bier’s blocks (64,77), although with less success compared with meperidine. Systematic review was unable to confirm any relevant peripheral analgesic efficacy with Bier’s block with opioids other than meperidine (80).
Early trials reported significant analgesic efficacy when propofol was cooled to 4°C immediately before injection (29,55) or, oppositely, when it was warmed to 37°C (37). These results could not be confirmed in subsequent studies (52,63,65,73). The combined analysis suggested that temperature has no relevant effect on propofol-injection pain. There was a lack of data for all the other analgesic interventions to allow meaningful conclusions.
There were two further interesting findings. First, there was no evidence of any relationship between catheter size and the incidence of pain on injection (Figure 1). Thus, as expected, catheter size per se is of no importance. No relationship could be established between injection pain and size of veins, because original reports did not provide relevant data. There was evidence from two randomized trials that the incidence and severity of pain with propofol can be reduced when the drug is injected into a vein in the antecubital fossa (56,67). It is, however, unlikely that anesthetists will choose the antecubital fossa vein routinely to avoid propofol-injection pain. The second additional finding was unexpected. There is a widely held view that slow injection of propofol may increase the likelihood of pain. This assumption refers to an early publication in which 15 patients had been randomized to slow injection of propofol (67). In these trials, a wide range of injection speeds were tested (i.e., 0.125 to 2 mL/s); there was no evidence of any impact of speed of injection on the incidence of pain (Figure 1).
Several combination therapies were tested. However, it may be overoptimistic to try to further improve the degree of analgesic efficacy as seen with the lidocaine-tourniquet method; incidences of pain were very low (Table 1, C). The best NNT which can be achieved for efficacy is 1. All control patients would have to report pain on injection with propofol, and none who receives the active intervention; this is unlikely with any analgesic intervention. Also, combination therapies may increase cost and the risk of adverse drug reactions, and they may be circumstantial in daily clinical practice.
Some doubt remains concerning the scientific validity of some of these trials. Surely, almost 20 years after the advent of propofol, it is difficult to accept that the injection of this innovative and widely used IV anesthetic still causes pain, and that the mechanisms of that pain are still obscure. The lack of sponsorship from the manufacturer for most of these trials may be a result of a lack of interest. Perhaps as a consequence, a research program was not obvious, although some trials were designed to study peripheral pain mechanisms. More than 6200 patients have been randomized in 56 trials during the past 18 years. According to the instrument of critical appraisal we used (4), most trials were of rather poor quality. Blinding, for instance, was often inadequate, leaving the trials open to the risk of observer bias. Numerous pharmacological treatments, different doses and combinations, alternative methods of administration, and physical interventions were tested, often without a clear biological basis. Propofol has been warmed or cooled, injected faster or more slowly, with or without a tourniquet, diluted or not. Local anesthetics, opioids, nonsteroidal antiinflammatory drugs, ketamine, metoclopramide, droperidol, and other chemical substances have been tested. The lidocaine-tourniquet method is undeniably effective and simple to perform. This begs the question as to the necessity of clinical studies that may identify yet another intervention with some analgesic efficacy to prevent pain on injection with propofol.
In conclusion, for best prevention of pain on injection with propofol, lidocaine 0.5 mg/kg should be given with a rubber tourniquet before the propofol injection; of 100 treated patients, approximately 60 have no pain.
We thank Dr. Y. Kobayashi who responded to our enquiry. We thank Mr. Daniel Haake from the documentation service of the Swiss Academy of Medical Science (DOKDI) for his help in searching electronic databases.
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