Analgesic efficacy and pharmacokinetics of epidural oxycodone in pain management after gynaecological laparoscopy-A randomised, double blind, active control, double-dummy clinical comparison with intravenous administration

Abstract

Aims: Early pain after laparoscopy is often severe. Oxycodone is a feasible analgesic option after laparoscopy, but there are sparse data on epidural administration. The aim was to evaluate the analgesic efficacy and pharmacokinetics of a single dose of epidural oxycodone as a part of multimodal analgesia after gynaecological laparoscopy.

Methods: Women (n = 60), aged 23-71 years, undergoing elective gynaecological laparoscopy, were administrated either epidural oxycodone 0.1 mg kg^-1 and intravenous (i.v.) saline (EPI-group n = 31), or epidural saline and i.v. oxycodone 0.1 mg kg^-1 (IV-group = 29) in a randomised, double blind, active control, double dummy clinical trial. A pharmacokinetic model was developed using population modelling of plasma and cerebrospinal fluid (CSF) concentrations obtained in these patients and data of 2 published studies. The primary outcome was the amount of i.v. fentanyl for rescue analgesia during the first 4 hours.

Results: Twenty of the 31 patients in the EPI-group and 26 of the 29 patients in the IV-group needed i.v. fentanyl for rescue analgesia, P = .021. The median (interquartile range) number of fentanyl doses were 1.0 (1.0-3.0) in the EPI-group and 2.5 (1.0-4.0) doses in the IV-group, P = .008. Plasma concentrations were similar, but CSF concentrations were 100-fold higher in the EPI-group. The population model indicated that 60% of oxycodone injected into the epidural space enters into CSF and 40% is absorbed into the systemic circulation.

Conclusions: The data support superiority of epidural administration of oxycodone compared to i.v. administration during the first hours after laparoscopic surgery. This is likely to be based on enhanced permeation into the central nervous system after epidural administration.

Keywords: analgesia; epidural; oxycodone; pharmacokinetics.

Figure 1

Flow chart

Figure 2

Pharmacokinetic schematic model. A 2‐compartment (central V1 and peripheral V2) linear disposition model was used to fit oxycodone plasma concentration (Cp, ng mL⁻¹) data. Drug is cleared (CL, clearance) from the central compartment (V1, Cp). A third compartment was used to model cerebrospinal fluid (CSF) concentration (C_CSF, ng mL⁻¹). Input from the epidural space to the central compartment (Ka_EPI, L⁻¹) or CSF (Ka_CSF, L⁻¹) was characterised using rate constants (Ka). The CSF compartment was given a volume of 150 mL and was linked to the central compartment using an intercompartment clearance (Q_CSF, L h⁻¹). A partition coefficient (PC) was used to describe the ratio between CSF and plasma concentration at steady‐state

Figure 3

Fentanyl doses during the first 4 hours

Figure 4

Plasma and cerebrospinal fluid (CSF) oxycodone concentrations in the EPI‐group (n = 17) and in the IV‐group (n = 25)

Figure 5

Visual predictive check for the pharmacokinetic models for plasma oxycodone showing median (solid) and 90% intervals (dashed lines). All plots show median (solid) and 90% intervals (dashed lines). Left hand plot shows all prediction corrected observed plasma concentrations. Right hand plot shows prediction corrected percentiles (10%, 50%, and 90%) for observations (black dashed lines) and predictions (pink dashed lines) with 95% confidence intervals for prediction percentiles (median, pink shading; 5^th and 95^th blue shading)

Figure 6

Visual predictive check for the pharmacokinetic models for cerebrospinal fluid oxycodone showing median (solid) and 90% intervals (dashed lines). All plots show median (solid) and 90% intervals (dashed lines). Left hand plot shows all prediction corrected observed CSF concentrations. Right hand plot shows prediction corrected percentiles (10%, 50%, and 90%) for observations (black dashed lines) and predictions (pink dashed lines) with 95% confidence intervals for prediction percentiles (median, pink shading; 5^th and 95^th blue shading)