Pain on injection with microemulsion propofol

Abstract

Aims: To evaluate the incidence and severity of injection pain caused by microemulsion propofol and lipid emulsion propofol in relation to plasma bradykinin generation and aqueous free propofol concentrations.

Methods: Injection pain was evaluated in 147 patients. Aqueous free propofol concentrations in each formulation, and in formulation mixtures containing agents that reduce propofol-induced pain, were measured by high-performance liquid chromatography. Plasma bradykinin concentrations in both formulations and in their components mixed with blood sampled from six volunteers were measured by radioimmunoassays. Injection pain caused by 8% polyethylene glycol 660 hydroxystearate (PEG660 HS) was evaluated in another 10 volunteers.

Results: The incidence of injection pain [visual analogue scale (VAS) >30 mm] caused by microemulsion and lipid emulsion propofol was 69.7 and 42.3% (P < 0.001), respectively. The median VAS scores for microemulsion and lipid emulsion propofol were 59 and 24 mm, respectively (95% confidence interval for the difference 12.5, 40.0). The aqueous free propofol concentration of microemulsion propofol was seven times higher than that of lipid emulsion propofol. Agents that reduce injection pain did not affect aqueous free propofol concentrations. Microemulsion propofol and 8% PEG660 HS enhanced plasma bradykinin generation, whereas lipid emulsion propofol and lipid solvent did not. PEG660 HS did not cause injection pain.

Conclusions: Higher aqueous free propofol concentrations of microemulsion propofol produce more frequent and severe pain. The plasma kallikrein-kinin system may not be involved, and the agents that reduce injection pain may not act by decreasing aqueous free propofol concentrations.

Figure 1

An illustration of the dialysis approach used to measure the concentration of free propofol in the aqueous phase of microemulsion and lipid emulsion propofol. Because their molecular sizes are greater than the molecular weight cut-off (MWCO) of the dialysis tubing, microemulsion and lipid emulsion propofol remain inside the membrane bag, whereas free propofol, which is below the MWCO, escapes into the release medium. After reaching saturation, the concentration of free propofol in a solution of 2.25% glycerine was measured by high-performance liquid chromatography. Lipid emulsion or microemulsion propofol (○); Free propofol (∘)

Figure 2

The distribution of visual analogue scale (VAS) scores for pain on injection with an intravenous bolus (30 mg) of microemulsion (•) or lipid emulsion (○) propofol in 147 patients (VAS, 0 mm = no pain, 100 mm = worst pain imaginable). The solid horizontal lines represent median VAS scores for pain on injection with microemulsion and lipid emulsion propofol (59 and 24 mm, respectively, P < 0.001 by Mann–Whitney rank sum test)

Figure 3

The concentration of bradykinin in plasma obtained after mixing 3.5 ml venous blood, sampled from six healthy volunteers, with 1.5 ml normal saline [control, 14.2 ± 1.6, coefficient of variation (CV) 11.5%, 95% confidence interval (CI) 12.5, 15.9], lipid emulsion propofol (13.2 ± 1.3, CV 10.2%, 95% CI 11.8, 14.6), 10% lipid solvent (Intralipid 13.3 ± 1.6, CV 12.1%, 95% CI 11.6, 15.0), microemulsion propofol (20.2 ± 3.2, CV 16.0%, 95% CI 16.8, 23.6), 8% polyethylene glycol 660 hydroxystearate (PEG660 HS, 22.0 ± 3.6, CV 16.4%, 95% CI 18.3, 25.8), 5% tetrahydrofurfuryl alcohol polyethylene glycol ether (THFA PEGE, 13.2 ± 1.4, CV 10.5%, 95% CI 11.7, 14.6) and a mixture of other ingredients in microemulsion propofol minus propofol, polyethylene glycol 660 hydroxystearate and tetrahydrofurfuryl alcohol polyethylene glycol ether (MIX, 12.9 ± 1.8, CV 14.3%, 95% CI 11.0, 14.9). *P < 0.05 vs. normal saline by the Holm–Sidak method. Data are presented as mean ± SD. CV, SD/mean × 100%; CI, confidence interval of population mean