Secondary Logo

Journal Logo

Prevention of Pain on Injection with Propofol: A Quantitative Systematic Review

Picard, Pascale, MD*; Tramèr, Martin R., MD, DPhil

doi: 10.1213/00000539-200004000-00035
GENERAL ARTICLES
Free

The best intervention to prevent pain on injection with propofol is unknown. We conducted a systematic literature search (Medline, Embase, Cochrane Library, bibliographies, hand searching, any language, up to September 1999) for full reports of randomized comparisons of analgesic interventions with placebo to prevent that pain. We analyzed data from 6264 patients (mostly adults) of 56 reports. On average, 70% of the patients reported pain on injection. Fifteen drugs, 12 physical measurements, and combinations were tested. With IV lidocaine 40 mg, given with a tourniquet 30 to 120 s before the injection of propofol, the number of patients needed to be treated (NNT) to prevent pain in one who would have had pain had they received placebo was 1.6. The closest to this came meperidine 40 mg with tourniquet (NNT 1.9) and metoclopramide 10 mg with tourniquet (NNT 2.2). With lidocaine mixed with propofol, the best NNT was 2.4; with IV alfentanil or fentanyl, it was 3 to 4. IV lidocaine before the injection of propofol was less analgesic. Temperature had no significant effect. There was a lack of data for all other interventions to allow meaningful conclusions. The diameter of venous catheters and speed of injection had no impact on pain.

Implications: IV lidocaine (0.5 mg/kg) should be given with a rubber tourniquet on the forearm, 30 to 120 s before the injection of propofol; lidocaine will prevent pain in approximately 60% of the patients treated in this manner.

*Consultation de la douleur, Service de pharmacologie clinique, CHU, Clermont-Ferrand Cedex, France; and †Division d’Anesthésiologie, Département APSIC, Hôpitaux Universitaires de Genève, Genève, Switzerland

December 14, 1999.

This work was funded by Prosper grant (No. 3233–051939-97) from the Swiss National Science Foundation (MRT).

Address correspondence and reprint requests to Dr. M. R. Tramèr, Division of Anaesthesiology, Department APSIC, Geneva University Hospitals, CH-1211 Geneva 14, Switzerland. Address e-mail to martin.tramer@hcuge.ch.

Adisadvantage of propofol is pain on injection, which is sometimes very distressing to patients. Among 33 clinical problems, propofol-induced pain has been ranked seventh, when both clinical importance and frequency were considered (1). Many different methods have been proposed to reduce the incidence and severity of this adverse effect of propofol. The aim of this quantitative systematic review was to test, with the best available evidence, the relative efficacy of analgesic interventions that have been used to prevent pain caused by propofol injection.

Back to Top | Article Outline

Methods

We conducted a systematic search for reports of randomized, controlled trials that tested the analgesic effect of prophylactic interventions (active) compared with placebo or “no treatment” (control) on pain on injection with propofol. When physical measurements were tested, the group with propofol (as manufactured) was regarded as a “no treatment” control. For instance, when cold (i.e., 4°C) propofol was tested, propofol at room temperature (i.e., 23°C) was regarded as control. We searched the MEDLINE (Datastar and PubMed, from 1966 to September 1999), COCHRANE Library (1999, issue 3), and EMBASE (from 1982 to February 1999) databases without restriction to the English language and by using different search strategies with the free text key words “propofol,” “pain,” “injection,” and “random,” and a combination of these words. Additional trials were identified from reference lists of retrieved reports and review articles on propofol and pain on injection (2,3), and by manually searching locally available anesthesia journals. We did not contact the manufacturers of propofol. Authors were contacted if there was ambiguity about data. We did not consider data from abstracts. Reports on experimental pain and comparisons without a placebo- or a “no treatment-” arm were not analyzed.

Both authors independently read each report that could possibly meet the inclusion criteria and scored them for inclusion and methodological validity using the three-item, five-point, Oxford scale (4). We then reached a consensus by discussion. The scale takes into account proper randomization, double-blinding, and reporting of withdrawals and drop-outs. The minimum score of an included randomized controlled trial is one, the maximum score is five.

We noted information about patients (adults or children), size and site of venous cannulation, speed of injection of propofol, and analgesic interventions from each included report. Different scores of pain measurement (for instance, visual analog or verbal rating scales) were used in these trials. Combining these data was impossible. We therefore decided to extract dichotomous data on complete absence of pain. This dichotomous hurdle may be unnecessarily high. An experimental intervention that does not completely prevent pain may alleviate most symptoms. Such an intervention may, of course, be very useful. However, to extract homogeneous data and to minimize the risk of bias caused by different definitions of endpoints, we decided to concentrate on a clearly defined hard endpoint. Complete absence of pain is such an endpoint.

We calculated relative “benefit” as relative risk with 95% confidence interval (CI) (5), using a fixed-effect model to combine data (6). As an estimate of the clinical relevance of the analgesic efficacy, we calculated the number needed to treat (NNT) (7) using the weighted means (weighted by the sample size) of the event rates of active and control interventions. A positive NNT indicated how many patients had to be exposed to an active intervention to prevent pain in one who would have had pain had they all received control (i.e., propofol without the analgesic intervention). A 95% CI around the NNT point estimate was obtained by taking the reciprocals of the values defining the 95% CI for the absolute risk reduction (8). A statistically significant treatment effect was assumed when the 95% CI around the relative benefit excluded 1; the 95% CI around the NNT would then contain positive numbers only.

Back to Top | Article Outline

Results

Seventy potentially relevant reports were retrieved, published between 1981 and 1999. Fifteen reports were subsequently excluded. Four were not randomized trials (9–12). In six, a placebo or “no treatment” group was lacking (13–18). Three reports were excluded for different reasons: pain outcomes were not dichotomous (19), the study was on experimental pain only (20), or the number of patients per group was not reported (21). There was strong suspicion that the same data have been used in three different full reports (22–24); because the original authors were unable to clarify this, we analyzed the data from only one report (23).

We analyzed data from 56 randomized, controlled trials (6264 patients) (17,23,25–78). Average trial size was 111 patients (range, 28 to 368). The median quality score was 2 (range, 1 to 4). Three reports were published as letters (44,63,73); in one a pseudo-randomization method (allocation according to medical record number) was used (27), and in one randomization was unclear (63). These five reports were included in the analysis. Six trials (11%) reported an appropriate method of blinding (identical ampoules, for instance). In 18 trials (33%), there was no attempt for any blinding. Authors of four trials acknowledged support from the manufacturer (35,44,48,56). Three studies were performed in children (31,34,74), two in both adults and children (32,70); all others were in adults only. In all trials, propofol was injected into the upper limb.

Back to Top | Article Outline

Subgroup Analyses

We performed three subgroup analyses to test the propriety of pooling data. This was done with data from control patients only. In seven trials, propofol was injected into an IV catheter “on the forearm” (41,46), in the cephalic vein (45,72,73), or in both a vein on the back of the hand or the forearm (44,49): 261 of 385 controls (68%; range 24% to 80%) reported pain on injection with propofol. In 49 trials, IV catheters were placed exclusively on the back of a hand: 1156 of 1674 controls (69%, range 10% to 100%) reported pain on injection. The difference between these two subgroups was not statistically significant, relative risk 1.02 (95% CI 0.94 to 1.10, P > 0.05). In 43 trials, propofol was injected on the dorsum of a hand, and the diameter of the catheter (median 21-gauge; range 17- to 23-gauge) was reported. In 45 trials, IV catheters were placed on the back of a hand, and the speed of injection of propofol (average 0.6 mL/s; range 0.125 to 2.0 mL/s) was reported. Graphically, there was no evidence of any relationship between the size of the catheter or the speed of injection and the likelihood of pain on injection with propofol (Figure 1). Thus, we pooled efficacy data according to experimental interventions and doses, whenever appropriate.

Figure 1

Figure 1

Back to Top | Article Outline

Analgesic Interventions

IV lidocaine, fentanyl, alfentanil, meperidine, metoclopramide, and temperature were each tested in more than two trials. All results were, except for temperature, statistically significant in favor of the analgesic interventions (Table 1, Figure 2).

Table 1

Table 1

Figure 2

Figure 2

Lidocaine. Lidocaine was given before the injection of propofol (Table 1, A) or mixed with propofol (i.e., made up to a total volume of 20 mL) (Table 1, B) or given IV with a tourniquet (i.e., as a Bier’s block in the isolated arm) (Table 1, C). Bier’s blocks were usually described as rubber tourniquets on the forearm; when pressure of the tourniquet was reported, it was between 50 and 70 mm Hg, and it was applied for 30 to 120 s. With this technique, the NNT to prevent any pain compared with placebo was 1.6 to 1.9 (Table 1, C). IV lidocaine given before propofol (i.e., without a tourniquet) and lidocaine mixed with propofol were less effective (Table 1, A and B). In one trial, lidocaine 100 mg was given IV to 22 patients 1 min before the injection of propofol; this was not different from placebo (42).

Opioids. In two trials, some patients received fentanyl or alfentanil immediately before the injection of propofol (32,34). We considered this method a priori as insufficiently analgesic in this context; these data were, therefore, not analyzed further. With alfentanil, fentanyl, or meperidine, given minutes before the injection of propofol, NNTs were between 3 and 4 (Table 1, D). When meperidine 40 mg was given with a tourniquet, the NNT was 1.9. Alfentanil 10 μg/kg, tested in 51 adults (75), had an NNT of 4.3 (95% CI 2.5 to 15); alfentanil 20 μg/kg, tested in 20 children (34), had an NNT of 1.4 (95% CI 1.1 to 2). With fentanyl 100 μg or 150 μg (adults only) (23,28,44,49), the NNT was 4.

Metoclopramide. The NNT of IV metoclopramide 5 or 10 mg, given before the injection of propofol, was 2.7 (Table 1, E). When injected with a tourniquet, the NNT decreased to 2.2.

Back to Top | Article Outline

Temperature

Cooled (i.e., 4°C) propofol and warmed (i.e., 37°C) propofol had no statistically significant analgesic effect (Table 1, E).

Back to Top | Article Outline

Other Interventions

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.

Back to Top | Article Outline

Discussion

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.

We generated comparisons between treatment options (Figure 2). Conclusions derived from such a “league table” of relative efficacy must be interpreted cautiously, because confounding variables cannot be excluded. The data suggested that, for best efficacy, it may not be worthwhile, compared with the lidocaine-tourniquet method, to give lidocaine IV before the injection of propofol or to mix it with propofol. Of 100 the patients treated with lidocaine 20 mg, 53 patients (NNT 1.9) will not have any pain when a tourniquet is used, 42 (NNT 2.4) will be pain-free when the lidocaine is mixed with propofol, and only 25 (NNT 4.0) will profit, when the lidocaine is given before propofol (Table 1, A–C).

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).

Bier’s block with metoclopramide decreased propofol-induced pain (Table 1, E). Metoclopramide has been shown to possess weak local anesthetic properties (81); its chemical structure is an analog of procaine.

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.

Back to Top | Article Outline

References

1. Macario A, Weinger M, Truong P, Lee M. Which clinical anesthesia outcomes are both common and important to avoid? The perspective of a panel of expert anesthesiologists. Anesth Analg 1999; 88:1085–91.
2. Banssillon V. Douleur à l’injection du Diprivan. Ann Fr Anesth Réanim 1994; 13:465–70.
3. Tan CH, Onsiong MK. Pain on injection of propofol. Anaesthesia 1998; 53:468–76.
4. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17:1–12.
5. Morris JA, Gardner MJ. Calculating confidence intervals for relative risk, odds ratios, and standardised ratios and rates. Statistics with confidence. In: Gardner MJ, Altman DG, eds. Confidence intervals and statistical guidelines. London: British Medical Journal 1995: 50–63.
6. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985; 27:335–71.
7. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988; 318:1728–33.
8. Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995; 310:452–4.
9. Cameron E, Johnston G, Crofts S, Morton NS. The minimum effective dose of lignocaine to prevent injection pain due to propofol in children. Anaesthesia 1992; 47:604–6.
10. Cangini D, Fusari M, Taddei S, et al. Il propofol ed il dolore all’iniezione. Minerva Anestesiol 1991; 57:568–9.
11. Major E, Verniquet AJW, Waddell TK, et al. A study of three doses of ICI 35868 for induction and maintenance of anaesthesia. Br J Anaesth 1981; 53:267–72.
12. McLeskey CH, Walawander CA, Nahrwold ML, et al. Adverse events in a multicenter phase IV study of propofol: evaluation by anesthesiologists and postanesthesia care unit nurses. Anesth Analg 1993; 77:S3–9.
13. Bosques NG, Rangel AF, Goiz ACM. Dolor a la asdministracion de propofol: comparacion de lidocaina con metoclopramida. Rev Mex Anestesiol 1997; 20:53–6.
14. Dewandre J, Van Bos R, Van Hemelrijck J, Van Aken H. A comparison of the 2% and 1% formulations of propofol during anaesthesia for craniotomy. Anaesthesia 1994; 49:8–12.
15. Goldmann R, Bornscheurer A, Kirchner. Einfluss der applikationsart von lidocain auf die verminderung des injektions- schmerzes durch propofol. Anästhesiol Intensivmed Notfallmed Schmerzther 1997; 32:98–100.
16. Hiller A, Saarnivaara L. Injection pain, cardiovascular changes and recovery following induction of anaesthesia with propofol in combination with alfentanil or lignocaine in children. Acta Anaesth Scand 1992; 36:564–8.
17. Kobayashi Y, Kamada Y, Kumagaia A, et al. Pain-free injection of propofol. Masui 1998; 47:835–8.
18. Mecklem DW. Propofol injection pain: comparing the addition of lignocaine or metoclopramide. Anaesth Intensive Care 1994; 22:568–70.
19. Eriksson M, Englesson S, Niklasson F, Hartvig P. Effect of lignocaine and pH on propofol-induced pain. Br J Anaesth 1997; 78:502–6.
20. Klement W, Arndt J. Pain on injection of propofol: effects of concentration and diluent. Br J Anaesth 1991; 67:281–4.
21. Saarnivaara L, Klemola U. Injection pain, intubating conditions and cardiovascular changes following induction of anaesthesia with propofol alone or in combination with alfentanil. Acta Anaesth Scand 1991; 35:19–23.
22. Pang WW, Huang S, Chung YT, Cang DP, et al. Comparison of intravenous retention of fentanyl and lidocaine of local analgesia in propofol injection pain. Acta Anaesth Sin 1997; 35:217–21.
23. Pang WW, Mok MS, Huang S, Hwang MH. The analgesic effect of fentanyl, morphine, meperidine, and lidocaine in the peripheral veins: a comparative study. Anesth Analg 1998; 86:382–6.
24. Pang WW, Huang PY, Chang DP, Huang MH. The peripheral analgesic effect of tramadol in reducing propofol injection pain: a comparison with lidocaine. Reg Anesth Pain Med 1999; 24:246–9.
25. Alyafi WA, Rangasami J. Reduction of propofol pain: fentanyl vs lidocaine. Middle East J Anesthesiol 1996; 13:613–9.
26. Ambesh SP, Dubey PK, Sinha PK. Ondansetron pretreatment to alleviate pain on propofol injection: a randomized, controlled, double-blinded study. Anesth Analg 1999; 89:197–9.
27. Angst MS, Mackey SC, Zupfer GH, et al. Reduction of propofol injection pain with a double lumen i.v. set. J Clin Anesth 1997; 9:462–6.
28. Bahar M, McAteer E, Dundee J, Briggs L. Aspirin in the prevention of painful intravenous injection of disoprofol (ICI 35,868) and diazepam (Valium). Anaesthesia 1982; 37:847–8.
29. Barker P, Langton JA, Murphy P, Rowbotham DJ. Effect of prior administration of cold saline on pain during propofol injection: a comparison with cold propofol and propofol with lignocaine. Anaesthesia 1991; 46:1069–70.
30. Basar H, Sayin M, Ketene A, Okten F. Propofol ve etomidate enjeksiyon agrisini lignokain ve metoklopramid ile onlenmesi. Turk Anest Rean 1995; 23:87–90.
31. Chessa D, Cossu F, Serra G. Il fentanyl previene il dolore nella sede di iniezione del propofol. Minerva Anestesiol 1992; 58:1319–21.
32. Croston J, Espinosa V, de Henriquez L, de Jimenez L. Changes in the pain produced by the peripheral venous injection of propofol when it is combined with lidocaine or fentanyl. Rev Med Panama 1992; 17:199–202.
33. Doenicke A, Roizen M, Rau J, et al. Reducing pain during propofol injection: the role of the solvent. Anesth Analg 1996; 82:472–4.
34. Dru M, Lory C, Journois D, Playe E. Influence de l’alfentanil sur la douleur à l’injection de propofol, lors de l’induction anesthésique pediatrique. Cah Anesth 1991; 39:383–6.
35. Eriksson M. Prilocaine reduces injection pain caused by propofol. Acta Anaesth Scand 1995; 39:210–3.
36. Fletcher JE, Seavell CR, Bowen DJ. Pretreatment with alfentanil reduces pain caused by propofol. Br J Anaesth 1994; 72:342–4.
37. Fletcher G, Gillespie J, Davidson J. The effect of temperature upon pain during injection of propofol. Anaesthesia 1996; 51:498–99.
38. Fragen RJ, De Grood PM, Robertson EN, et al. Effects of premedication on diprivan induction. Br J Anaesth 1982; 54:913–6.
39. Gajraj NM, Nathanson MH. Preventing pain during injection of propofol: the optimal dose of lidocaine. J Clin Anesth 1996; 8:575–7.
40. Ganta R, Fee JP. Pain on injection of propofol: comparison of lignocaine with metoclopramide. Br J Anaesth 1992; 69:316–7.
41. Gehan G, Karoubi P, Quinet F, et al. Optimal dose of lignocaine for preventing pain on injection of propofol. Br J Anaesth 1991; 66:324–6.
42. Haugen R, Vaghadia H, Waters T, Merrick P. Thiopentone pretreatment for propofol injection pain in ambulatory patients. Can J Anaesth 1995; 42:1108–12.
43. Helbo-Hansen S, Westergaard V, Krogh BL, Svendsen HP. The reduction of pain on injection of propofol: the effect of addition of lignocaine. Acta Anaesth Scand 1988; 32:502–4.
44. Helmers HHJH, Kraaijenhaagen RJ, Leeuwen LV, Zuurmond VWA. Reduction of pain on injection caused by propofol [letter]. Can J Anaesth 1990; 37:267–8.
45. Huang C, Wang Y, Cheng Y, et al. The effect of carrier intravenous fluid speed on the injection pain of propofol. Anesth Analg 1995; 81:1087–8.
46. Iwama H, Nakane M, Ohmori S, et al. Nafamostat mesilate, a kallikrein inhibitor, prevents pain on injection with propofol. Br J Anaesth 1998; 81:963–4.
47. Johnson R, Harper N, Chadwick S, Vohra A. Pain on injection of propofol: methods of alleviation. Anaesthesia 1990; 45:439–42.
48. King SY, Davis FM, Wells JE, et al. Lidocaine for the prevention of pain due to injection of propofol. Anesth Analg 1992; 74:246–9.
49. Kobayashi Y, Naganuma R, Seki S, et al. Reduction of pain on injection of propofol: a comparison of fentanyl with lidocaine. Masui 1998; 47:963–7.
50. Lee T, Loewenthal A, Strachan J, Todd B. Pain during injection of propofol: the effect of prior administration of thiopentone. Anaesthesia 1994; 49:817–8.
51. Liaw WJ, Pang WW, Chang DP, Hwang MH. Pain on injection of propofol: the mitigating influence of metoclopramide using different techniques. Acta Anaesth Scand 1999; 43:24–7.
52. Lin SS, Chen GT, Lin JC, et al. Pain on injection of propofol. Acta Anaesth Sin 1994; 32:73–6.
53. Lyons B, Lohan D, Flynn C, McCarroll M. Modification of pain on injection of propofol: a comparison of pethidine and lignocaine. Anaesthesia 1996; 51:394–5.
54. Mangar D, Holak EJ. Tourniquet at 50 mm Hg followed by intravenous lidocaine diminishes hand pain associated with propofol injection. Anesth Analg 1992; 74:250–2.
55. McCrirrick A, Hunter S. Pain on injection of propofol: the effect of injectate temperature. Anaesthesia 1990; 45:443–4.
56. McCulloch M, Lees N. Assessment and modification of pain on induction with propofol (Diprivan). Anaesthesia 1985; 40:1117–20.
57. McDonald D, Jameson P. Injection pain with propofol: reduction with aspiration of blood. Anaesthesia 1996; 51:878–80.
58. Nathanson MH, Gajraj NM, Russell JA. Prevention of pain on injection of propofol: a comparison of lidocaine with alfentanil. Anesth Analg 1996; 82:469–71.
59. Newcombe GN. The effect, on injection pain, of adding lignocaine to propofol. Anaesth Intensive Care 1990; 18:105–7.
60. Nicol M, Moriarty J, Edwards J, et al. Modification of pain on injection of propofol: a comparison between lignocaine and procaine. Anaesthesia 1991; 46:67–9.
61. O’Hara JF Jr, Sprung J, Laseter JT, et al. Effects of topical nitroglycerin and intravenous lidocaine on propofol-induced pain on injection. Anesth Analg 1997; 84:865–9.
62. Ozkocak I, Gumus T, Gogus N, et al. Propofolun enjeksiyon agrisini onlemede metoklopramid ve dehydrobenzperidol. Turk Anest Reanim 1995; 23:395–7.
63. Ozturk E, Izdes S, Babacan A, Kaya K. Temperature of propofol does not reduce the incidence of injection pain [letter]. Anesthesiology 1998; 89:1041.
64. Pang WW, Mok MS, Huang S, et al. The peripheral analgesic effect of meperidine in reducing propofol injection pain is not naloxone-reversible. Reg Anesth Pain Med 1998; 23:197–200.
65. Parmar AK, Koay CK. Pain on injection of propofol: a comparison of cold propofol with propofol premixed with lignocaine. Anaesthesia 1998; 53:79–88.
66. Sadler PJ, Thompson HM, Maslowski P, et al. Iontophoretically applied lidocaine reduces pain on propofol injection. Br J Anaesth 1999; 82:432–4.
67. Scott R, Saunders D, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia 1988; 43:492–4.
68. Smith A, Power I. The effect of pretreatment with ketorolac on pain during intravenous injection of propofol. Anaesthesia 1996; 51:883–5.
69. Stokes D, Robson N, Hutton P. Effect of diluting propofol on the incidence of pain on injection and venous sequelae. Br J Anaesth 1989; 62:202–3.
70. Tan CH, Onsiong MK, Kua SW. The effect of ketamine pretreatment on propofol injection pain in 100 women. Anaesthesia 1998; 53:302–5.
71. Tham C, Khoo S. Modulating effects of lignocaine on propofol. Anaesth Intensive Care 1995; 23:154–7.
72. Uda R, Otsuka M, Doi Y, et al. Sixty percent lidocaine tape alleviates pain on injection of propofol after diminishing venipuncture pain. Masui 1998; 47:843–7.
73. Uda R, Kadono N, Otsuka M, et al. Strict temperature control has no effect on injection pain with propofol [letter]. Anesthesiology 1999; 91:591
74. Valtonen M, Isalo E, Kanto J, Rosenberg P. Propofol as an induction agent in children: pain on injection and pharmacokinetics. Acta Anaesth Scand 1989; 33:152–5.
75. Wall R, Zacharias M. Effects of alfentanil on induction and recovery from propofol anaesthesia in day surgery. Anaesth Intensive Care 1990; 18:214–8.
76. Wilkinson D, Anderson M, Gauntlett I. Pain on injection of propofol: modification by nitroglycerin. Anesth Analg 1993; 77:1139–42.
77. Wrench I, Girling K, Hobbs G. Alfentanil-mediated analgesia during propofol injection: no evidence for a peripheral action. Br J Anaesth 1996; 77:162–4.
78. Yokota S, Komatsu T, Komura Y, et al. Pretreatment with topical 60% lidocaine tape reduces pain on injection of propofol. Anesth Analg 1997; 85:672–4.
79. Armstrong PJ, Morton CPJ, Nimmo AF. Pethidine has a local anaesthetic action on peripheral nerves in vivo. Anaesthesia 1993; 48:382–6.
80. Picard PR, Tramèr MR, McQuay HJ, Moore RA. Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain 1997; 72:309–18.
81. Pang WW, Mok MS, Chang DP, Huang MH. Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection. Reg Anesth Pain Med 1998; 23:580–3.
© 2000 International Anesthesia Research Society