Aronson, Jeffrey K.
Propofol is a short-acting intravenous induction agent, given by bolus injection in general anesthesia and by infusion in ICUs. Its rapid onset of action, short half-life, and favorable recovery characteristics make it suitable for day procedures, such as gastrointestinal endoscopy.
The most common adverse reaction to propofol is pain on injection. The incidence can be as high as 70% or more.1
The mechanism of propofol-induced pain is not known. It may involve the generation of bradykinin, although there are conflicting results.2,3 The pH of the injected solution may be relevant, as the addition of lidocaine is effective and reduces the pH of propofol solutions, thereby reducing the concentration of propofol in the aqueous phase4; however, in one study when the lidocaine was alkalinized with sodium bicarbonate there was an additional benefit.5 Alternatively, the mechanism may be related to the lipid solvent in which propofol in dissolved.2
There have been many studies on the ways of reducing the pain, with varying success rates.6 Most of these have involved the use of lidocaine, either alone or with other drugs, and often with venous occlusion. Some drugs that have been used for this purpose are analgesics (e.g., paracetamol, opioids, nitrous oxide, NSAIDs), but the mechanisms by which drugs that are not analgesics (e.g., 5HT3 receptor antagonists, glyceryl trinitrate, methylthioninium chloride, metoclopramide) appear to reduce the frequency and/or intensity of pain during injection of propofol are not clear. The amnesiac effects of nitrous oxide may contribute to its efficacy.
Site of injection
The incidence of pain is lower when large veins are used rather than the small veins in the back of the hand.7,8
Speed of injection
Propofol-induced pain may be reduced by rapid injection.9–11
Varying the formulation
Propofol was originally formulated in polyoxylated castor oil (Cremophor EL), which caused non-immunoglobulin E-mediated anaphylactic (anaphylactoid) reactions and was replaced by 10% soybean oil. However, such formulations can cause injection pain, sepsis, and hyperlipidemia, and other formulations were developed, including emulsions, non-emulsion formulations containing cyclodextrin, and polymeric micelle formulations.
The effect of altering the lipid emulsion carrier has been analyzed in prospective randomized comparisons of a modified lipid emulsion of propofol containing a mixture of medium-chain and long-chain triglycerides (MCTs/LCTs) and a formulation containing long-chain triglycerides (LCTs) only.12–17 In general, MCT/LCT propofol was associated with less pain than LCT propofol. Lidocaine pretreatment improved the outcomes in both cases. In a comparison between a propofol emulsion containing MCTs and a lipid-free formulation, the latter caused more pain on injection.18
In a double-blind, randomized comparison of propofol in a lipid formulation with propofol in a modified cyclodextrin formulation, the former was associated with lower pain scores.19
In double-blind, randomized studies of formulations containing propofol in different particle sizes, those that contained smaller particles were associated with less pain.20,21
Propofol is generally formulated in solutions of 0.5, 1, and 2%. Dilution of propofol to 0.33% was associated with a significant reduction in pain.22
Warming propofol to 37°C had no effect on the incidence of pain.23–25
Lidocaine is the most extensively studied treatment for propofol-induced pain and is usually used as a comparator for other compounds. It reduces the incidence and severity of pain26–41 and was ineffective in only a few studies.42–45 The size of effect was highly variable in different studies, but in some studies the incidence of pain was reduced to a few percentage. Lidocaine is efficacious whether given shortly before the propofol or mixed with the propofol immediately before administration.46–48 However, venous occlusion for up to 2 min before injecting the propofol improves the effect.49–53
Studies of the most effective dose of lidocaine have given varying results. Doses used have varied from 5 to 100 mg, in strengths varying from 0.5 to 2%. Although no dose relation has been shown in some studies,54,55 there is evidence, as would be expected, of dose-relatedness,56,57 a dose of around 60 mg in adults having maximum efficacy.58
Route of administration
Lidocaine is usually given intravenously for this purpose, although epidural administration may be equally effective.59 Topical anaesthesia using 60% lidocaine tape reduced the incidence of propofol-induced pain.60,61, as did local iontophoresis,62 but not as effectively as intravenous administration.63
Topical 5% lidocaine and prilocaine cream (Emla) may be effective, if it is applied several hours in advance of propofol64; it was ineffective when applied 1 h in advance.65
In a placebo-controlled study in 180 adults, intravenous preinjection of diphenhydramine 20 mg or lidocaine 40 mg reduced the incidence of propofol-induced pain from 42 to 5.0% and 3.3%, respectively.66
In a placebo-controlled study in 90 patients, intravenous metoprolol and lidocaine reduced propofol-induced pain from 57 to 17% and 10%, respectively.67 This was attributed to vasodilatation by metoprolol, but it may have been to the result of a membrane stabilizing action.68 Other β-blockers have not been studied. However, esmolol reduced the frequency of pain associated with injection of rocuronium.69
The α2-adrenoceptor agonist dexmedetomidine 0.25 μg/kg reduced the frequency of pain from propofol to nearly the same extent as lidocaine; the intensity of pain, when it occurred, was also reduced.70
In randomized, placebo-controlled, double-blind studies intravenous dexamethasone 0.15 mg/kg up to a maximum of 8 mg reduced the incidence of propofol injection pain significantly when it was given 1 min before propofol, in some cases with venous occlusion.71–73 However, in some cases it was associated with perineal itching and pain.
There have been conflicting results with ephedrine. In some double-blind, randomized studies ephedrine significantly reduced pain after propofol,74,75 although the higher doses used (110 and 150 μg/kg) were associated with increased arterial blood pressure. However, in other studies ephedrine was ineffective.76–78 In one double-blind randomized study the addition of clonidine to ephedrine reduced pain scores.79
In double-blind, randomized, placebo-controlled studies, intravenous granisetron 2 mg was as effective as intravenous lidocaine80–82 and more effective than glyceryl trinitrate, magnesium sulfate, and paracetamol.83,84 Palonosetron is also effective,85 as is ramosetron.86,87 However, ondansetron, although effective,88,89 may be less so.90 In a randomized, double-blind study ondansetron and tramadol were equally effective, but there was significantly less nausea and vomiting with ondansetron.91,92
Intravenous glyceryl trinitrate was effective in two studies,89,93 and topical glyceryl trinitrate ointment was effective in one study94 but not in another.95
In placebo-controlled studies pretreatment with intravenous ketamine in adults in doses up to 0.4 mg/kg reduced the incidence of propofol-induced injection pain.96–100 The combination of lidocaine and ketamine is even more effective.101 Ketamine is also effective in children.102
In a double-blind, randomized study in 90 adults intravenous pretreatment with methylthioninium chloride was effective but less so than lidocaine.103
In double-blind, randomized, placebo-controlled studies metoclopramide, given immediately before propofol, was effective104,105 and in most cases as effective as lidocaine;106–110 the combination was more effective than either alone.111
In a double-blind, randomized, placebo-controlled study in 213 patients, nafamostat mesilate 0.02 mg/kg, an inhibitor of bradykinin generation from kallikrein, significantly reduced propofol-induced pain.112
In double-blind, randomized studies in children and adults nitrous oxide in combination with oxygen was as effective as lidocaine113,114 and the combination was more effective.115–118
NSAIDs are effective in reducing propofol-associated pain, including intravenous parecoxib,119 intravenous flurbiprofen,120 and intravenous ketorolac.121,122 However, in one small study, ketorolac 3 mg given before propofol had no effect.123
Various opioid analgesics are effective, to different extents, in reducing propofol-associated pain, including alfentanil,89,124–127 dezocine,128 fentanyl,129–132 pethidine (meperidine),133 remifentanil,134,135 and tramadol.136,137 Of these, remifentanil was the most effective.
In double-blind, randomized studies paracetamol had similar overall efficacy to lidocaine, albeit with variable results.138–140
There have been many reports that thiopental can reduce the frequency of pain during propofol injection.141–149 In most cases thiopental was as efficacious as lidocaine or more so.
In a double-blind, randomized placebo-controlled study, premedication of 209 patients with oral midazolam 7.5 mg, diclofenac 50 mg, and paracetamol 1000 mg and intravenous fentanyl 1 h before surgery, followed by lidocaine given during propofol injection, was associated with significantly reduced frequency and intensity of pain.150
Propofol-induced pain has been reviewed.151 The authors reached the following conclusions:
- guaranteed pain-free propofol injection is not possible;
- single preventive interventions are not as effective as combinations of different measures;
- the application of a venous tourniquet improves the pain-reducing effect of intravenous drugs such as lidocaine;
- a propofol MCT/LCT emulsion should be used;
- for general anesthesia opioids or ketamine can be used and for sedation a subanesthetic dose of thiopental;
- for children Emla cream (lidocaine and prilocaine) is suitable, because it reduces the pain of both propofol injection and venous cannulation (but it should be applied for several hours before the administration of propofol).
Finally, strategies to reduce the incidence of pain on injection of propofol have been reviewed in meta-analyses.
In one meta-analysis of data from 56 studies in 6264 patients, of whom 70% reported pain on injection, 15 drugs, 12 physical interventions, and combinations were tested.152 The values of NNTB for the prevention of pain in one patient who would have had pain had placebo been used were as follows:
- intravenous lidocaine 40 mg, given with venous compression for 30–120 s before the injection of propofol – 1.6;
- pethidine 40 mg with venous compression – 1.9;
- metoclopramide 10 mg with venous compression – 2.2;
- lidocaine mixed with propofol – 2.4;
- lidocaine mixed with intravenous alfentanil or fentanyl – 3 to 4.
The authors recommended the use of intravenous lidocaine 0.5 mg/kg, with venous compression for 30–120 s before the injection of propofol.
In a later meta-analysis, the most effective single interventions were injection into an antecubital fossa vein and pretreatment with lidocaine using venous occlusion.153 A mixture of lidocaine and propofol, pretreatment with lidocaine without venous occlusion, and pretreatment with opioids or ketamine or NSAIDs were also effective.
Injection with propofol frequently causes pain. There are strategies to lessen the pain with lidocaine being the most commonly used drug.
Conflicts of interest
There are no conflicts of interest.
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