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Pain on Injection: A Double-Blind Comparison of Propofol with Lidocaine Pretreatment Versus Propofol Formulated with Long- and Medium-Chain Triglycerides

Schaub, E; Kern, C; Landau, R

doi: 10.1213/01.ANE.0000136848.54207.97
Anesthetic Pharmacology: Research Report
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The incidence of pain on injection of propofol has been reported to be 70%. A new propofol formulation with a 10% emulsion of long- and medium-chain triglycerides (LCT/MCT) is associated with less pain on injection. Our goal was to compare the effect of propofol-LCT/MCT on the incidence of pain versus propofol with lidocaine 40 mg IV pretreatment injected as a Bier’s block. Two hundred healthy women scheduled for ambulatory gynecological procedures were allocated to 1 of 2 groups in a randomized double-blind fashion. Group LIDO received lidocaine 2% 2 mL injected with a tourniquet 1 min before propofol 1% 2 mg/kg IV; group LCT/MCT received NaCl 0.9% 2 mL with tourniquet 1 min before propofol-LCT/MCT 1% 2 mg/kg IV. Spontaneous verbal expressions of pain, movement of hand, frowning, and moaning during the injection were recorded. The incidence and severity of pain were assessed 30 min and 6 h after surgery. Recall of pain was considered with a visual analog scale (VAS) score >1, and pain was graded as VAS 0–10. More women reported spontaneous verbal expression of pain with propofol-LCT/MCT (47% versus 24%; P = 0.0014; relative risk 1.61 [95% confidence interval, 1.22–2.13]). Among women with a painful injection, there was no difference after surgery regarding the intensity of pain or recall of pain. In contrast to previous reports, we found that propofol-LCT/MCT resulted in a more frequent incidence of pain than propofol 1% with IV lidocaine pretreatment. This may be due to the diversity of pain definitions used in studies or to the lack of premedication in our study.

IMPLICATIONS: Propofol–long- and medium-chain triglycerides resulted in a more frequent incidence of pain upon injection than propofol with 40 mg IV of lidocaine pretreatment as a Bier’s block (47% versus 24%, respectively).

Service d’Anesthésiologie, Département d’Anesthésiologie, Pharmacologie et Soins Intensifs de Chirurgie (APSIC), Hôpitaux Universitaires de Genève, Switzerland

Presented at the European Society of Anaesthesiology meeting, Lisbon 2004.

Accepted for publication June 11, 2004.

Address correspondence and reprint requests to Dr. Ruth Landau, Service d’Anesthésiologie, Hôpitaux Universitaires de Genève, Rue Micheli du Crest 24, 1211 Genève 14, Switzerland. Address e-mail to ruth.landau@hcuge.ch.

Propofol is widely used as an IV anesthetic induction drug. However, pain on injection is a major disadvantage with a reported incidence of approximately 70% when a standard formulation of propofol is administrated with no intervention to reduce pain (1). The most effective technique in reducing pain has been shown to be lidocaine 40 mg IV given with a tourniquet as a Bier’s block 30–120 s before the injection of propofol, which decreases the incidence of pain to approximately 30% (number needed to treat, 1.6) (1,2).

It has been suggested that increasing the lipid content of the solvent to decrease the concentration of free propofol in the aqueous phase may reduce the pain on injection of propofol (3). Propofol-®Lipuro 1% (BBraun, Melsungen, Germany) is a new formulation of propofol with a 10% fat emulsion consisting of long-chain triglycerides (LCT) and medium-chain triglycerides (MCT), with similar pharmacokinetics and efficacy as propofol (4). Propofol-LCT/MCT formulations have been associated with less pain on injection (5–8).

The purpose of this study was to compare the incidence of pain on injection of propofol-LCT/MCT versus standard propofol formulation with IV lidocaine pretreatment injected as a Bier’s block.

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Methods

With IRB approval and informed written consent, we recruited 200 healthy women (ASA physical status I–II), aged 16–44 yr, scheduled for ambulatory gynecological procedures (voluntary termination of pregnancy or dilation and curettage for first trimester spontaneous abortions), requiring general anesthesia without orotracheal intubation. Women taking sedatives or analgesics within 24 h preceding surgery or requesting anxiolysis were excluded.

Women were allocated to 1 of 2 groups in a randomized double-blind fashion. Randomization was performed using a computer generated list of numbers. All study drugs were prepared and labeled by the institutional pharmacy, ensuring appropriate blinding to study-drug solutions. Two separate vials per study case were provided: 20-mL vials of propofol (Propofol 1% Fresenius or Propofol-®Lipuro) and 2-mL vials containing, respectively, lidocaine 2% or NaCl 0.9%. All vials were stored at room temperature.

Upon arrival into the operating room, an IV cannula (20-gauge) was inserted into a dorsal hand vein, and an infusion of 1000 mL of Ringer’s lactate solution, running via standard tubing with a three-way stopcock, was connected. Women did not receive any sedatives or analgesics before entering the operating room. Standard monitoring was placed (noninvasive arterial blood pressure, electrocardiogram, and pulse oximetry), and administration of oxygen was performed. The induction of anesthesia proceeded according to group allocation, with all members of the anesthesia team blinded to the study drugs. With a tourniquet in place on the forearm, women in the LIDO group received lidocaine 2% 2 mL (40 mg) 1 min before the injection of standard propofol 2 mg/kg IV, whereas women in the LCT/MCT group received NaCl 0.9% 2 mL before the injection of propofol-LCT/MCT 2 mg/kg IV. Study drugs were injected at 1 mL/s. After loss of eyelash reflex, 1000 μg of alfentanil IV was administrated before starting the gynecological procedure and anesthesia continued with sevoflurane, and additional alfentanil was given up to a maximum of 2000 μg.

Women were informed upon consent that during the injection, pain was possible and that they would be evaluated by the anesthesia team at different time points. During anesthetic induction, they were not actively asked whether they felt any discomfort or pain, and evaluation of pain was solely observational. Verbal expression of pain and movement of the hand in an attempt to withdraw the hand on injection were considered as major criteria of pain. Moaning and frowning were considered as minor criteria of pain. Thirty minutes and 4–6 h after the end of the procedure, women were asked for recall of pain, defined as visual analog scale (VAS) score >1, during injection of the study drug by a member of the anesthesia team blinded to study solutions. Severity of pain was determined on a 0- to 10-cm VAS. The injection of the study drug was considered to have been painful if women presented with one or both major criteria of pain or with at least one minor criteria associated with recall of pain (VAS >1) after surgery.

Appropriate sample size was estimated assuming that we were interested in a reduction from 30% of pain on injection with the standard propofol formulation with IV lidocaine pretreatment to 10% with propofol-LCT/MCT (reported incidence at the time of design of the study (9)). This yielded a sample size of 92 subjects per group with a power of 0.9 and an α of 0.05. We planned to include 100 subjects per group, taking into account 5% exclusions. χ2 tests were used for comparison of categorical variables, and Student’s t-tests were used for comparison of continuous variables between groups. A value of P < 0.05 was considered statistically significant.

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Results

One-hundred-eighty-seven women completed the study; eight women in the LCT/MCT group and five women in the LIDO group were excluded because of protocol violation (midazolam given before or during the induction or missing data). Groups were similar with respect to age, weight, and height of patients.

There was a significant difference in pain incidence on injection (Fig. 1). The incidence of spontaneous verbal expression of pain was more frequent in the LCT/MCT group compared with the LIDO group (47% versus 24%, respectively; P = 0.0014; relative risk 1.61 [95% confidence interval, 1.22–2.13]). There was no significant difference regarding the intensity of pain (Table 1). The incidence of recall of pain among women having had a painful injection was similar in both groups (52% in the LCT/MCT group versus 50% in the LIDO group).

Figure 1

Figure 1

Table 1

Table 1

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Discussion

Contrary to our expectations, we found a significantly more frequent incidence of pain among women receiving a propofol-LCT/MCT formulation in comparison to those pretreated with IV lidocaine as Bier’s block receiving standard propofol, suggesting that lidocaine is more effective in reducing pain on injection than LCT/MCT formulations of propofol. The 24% incidence of pain with standard propofol pretreated with lidocaine in our study was in accordance with the reported incidence in other studies (1). However, the incidence of pain with propofol-LCT/MCT (46%) was slightly more frequent than that reported by other investigators using this formulation (3,4,7,9).

In the first large study evaluating the effect of propofol-LCT/MCT formulations on pain during injection, the authors concluded that the use of Lipofundin® MCT10% (BBraun, Melsungen, Germany) was associated with less pain during injection than with standard propofol without lidocaine pretreatment (9). In that study, pain at the time of injection was reported by only 2 patients (3%) receiving the LCT/MCT formulation versus 11 patients (15%) receiving standard propofol (P < 0.05). However, when asked for pain ratings one hour after recovery, 38% of patients with the LCT/MCT formulation versus 61% with standard propofol recalled pain (P < 0.01). It is possible that patients were too sedated to answer when actively asked about pain during the induction of anesthesia because they had also been premedicated with lorazepam. In other studies comparing propofol-LCT/MCT with standard propofol, the incidence of pain was also significantly less with propofol-LCT/MCT (7,8,10). A recent publication (6) examining four groups of patients randomized to receive either propofol-LCT/MCT or standard propofol, each with and without lidocaine pretreatment, reported that propofol-LCT/MCT reduced the intensity but not the incidence of pain (53% versus 64%, respectively) in comparison to standard propofol formulations. Interestingly, pretreatment with lidocaine 40 mg IV achieved a better effect in reducing pain incidence with propofol-LCT/MCT (16% versus 31%, respectively; P < 0.05).

Several mechanisms could explain the discrepancy in findings of pain incidence on injection of propofol. One is the variety of definitions and modes of evaluation of pain used by investigators. In all studies reporting the use of propofol-LCT/MCT, patients were actively asked to grade pain severity while propofol was administrated, and recall of pain was assessed after surgery. We opted to observe women’s reactions to propofol injection after being informed that pain could occur during injection of the study drug. We assessed spontaneous verbal expression of pain, movement of the hand, frowning, and moaning, which were all recorded by a blinded investigator. We considered that movement of the hand on injection or spontaneous verbal indication that the injection was painful were reliable indicators of pain on injection. Therefore, these two variables were considered as major criteria. With one or both of these criteria, women were considered to have had a painful injection, even when no recall of pain was reported during the two postoperative evaluations. Because frowning and moaning could be misinterpreted by the observer and not necessarily related to the occurrence of pain, we decided to consider those as minor criteria. We opted to include in the painful injection group three women who were found to have two minor criteria but did report pain in the postoperative period.

In our study, women did not receive any anxiolytic or sedative premedication. In particular, midazolam, which is known for its anterograde amnesic properties, was not given. Despite the lack of premedication, we noticed that a significant percent of women demonstrating obvious signs of pain during injection had no recall of pain after surgery. It has been suggested that propofol possesses amnesic properties (11,12).

Furthermore, for the purpose of the study, we did not administer alfentanil before propofol, as is usually performed during the induction of general anesthesia, because alfentanil has been suggested to reduce pain on injection of propofol (13). Postponing the injection of alfentanil until loss of eyelash reflex may have affected the incidence of pain on injection in comparison to that found by other investigators.

The fact that all patients included in our study were women studied during the first trimester of pregnancy could be another explanation for the difference in incidence of pain. Influence of pregnancy on pain on injection via factors such as hormonal changes, volume of distribution and protein binding of the drug, and alteration of pain perception has not been studied.

Finally, with a relatively small incidence of pain on injection with standard propofol (26%), of which only 50% of women recall the painful injection, the relevance of this issue could be questioned. However, in a recent case report (14), profound pain after propofol injection was suggested to have triggered myocardial ischemia in a patient with a suspected pheochromocytoma.

In conclusion, administration of a standard propofol formulation with IV lidocaine pretreatment was associated with less pain on injection than propofol-LCT/MCT formulation in nonpremedicated healthy women undergoing ambulatory gynecological procedures.

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