Merja Kokki

Oxycodone for the treatment of postoperative pain

Introduction: Pain is a likely outcome of any surgical procedure. In several countries the use of oxycodone has surpassed that of morphine in postoperative pain management. Areas covered: This review summarizes the recent pharmacological and clinical data on oxycodone use for postoperative pain management. The benefits and the impact oxycodone may have on outcome in different patient groups is addressed. As oxycodone is available on different pharmaceutical formulations and as a new combination product with naloxone, the different approaches that may be used with oxycodone in postoperative pain management are also reviewed. Expert opinion: The recent interest in oxycodone is based on its favorable pharmacokinetics and pharmacodynamics, especially in the central nervous system. Moreover, relatively high enteral bioavailability allows an easy switch from one drug formulation to another during the course of pain management. Oxycodone is highly effective and well tolerated in different types of surgical procedures and patient groups, from preterm to aged patients. In the future, the use of transmucosal administration and enteral oxycodone–naloxone controlled-release tablets is likely to increase, and an appropriate concurrent use of different enteral drug formulations will decrease the need for more complex administration techniques, such as intravenous patient-controlled analgesia.

A prospective study on postoperative pain after cataract surgery.

Purpose To evaluate postoperative pain and early recovery in cataract patients. Patients and methods A total of 201 patients who underwent elective first eye cataract extraction surgery were enrolled, and 196 were included in the final analysis. The study design was a single-center, prospective, follow-up study in a tertiary hospital in eastern Finland. Postoperative pain was evaluated with the Brief Pain Inventory at four time points: at baseline, and at 24 hours, 1 week, and 6 weeks postsurgery. Results Postoperative pain was relatively common during the first hours after surgery, as it was reported by 67 (34%) patients. After hospital discharge, the prevalence decreased; at 24 hours, 1 week, and 6 weeks, 18 (10%), 15 (9%) and 12 (7%) patients reported having ocular pain, respectively. Most patients with eye pain reported significant pain, with a score of ≥4 on a pain scale of 0–10, but few had taken analgesics for eye pain. Those who had used analgesics rated the analgesic efficacy of paracetamol and ibuprofen as good or excellent. Other ocular irritation symptoms were common after surgery; as a new postoperative symptom, foreign-body sensation was reported by 40 patients (22%), light sensitivity by 29 (16%), burning by 15 (8%), and itching by 15 (8%). Conclusion Moderate or severe postoperative pain was relatively common after cataract surgery. Thus, all patients undergoing cataract surgery should be provided appropriate counseling on pain and pain management after surgery.

Analgesic Concentrations of Oxycodone – A Prospective Clinical PK/PD Study in Patients with Laparoscopic Cholecystectomy

The analgesic concentrations of oxycodone in acute post-operative pain management have not been established. Here, we have evaluated the minimum effective concentration (MEC) and the minimum effective analgesic concentration (MEAC) of oxycodone in pain after laparoscopic cholecystectomy (LCC) in 23 adult patients. The patients were provided with 0.1 mg/kg of oxycodone i.v. 10-15 min. before the end of surgery. After surgery, when the wound pain at rest was ≥3/10 and/or ≥5/10 during wound compression, a first blood sample was obtained (MEC). A second blood sample was obtained after titration with 2 mg i.v. of oxycodone to wound pain <3/10 at rest and <5/10 during wound compression (MEAC). A third blood sample was obtained at the recurrence of the wound pain (the second MEC), and the final blood sample when pain relief was obtained a second time (the second MEAC). At the first onset of pain (MEC), mean P-oxycodone was 21 ng/mL (95% CI 13-29 ng/mL). At the first pain relief (MEAC), P-oxycodone was 55 ng/mL (19-91 ng/mL). The second MEC was 34 ng/mL (11-57 ng/mL), and the second MEAC was 47 ng/mL (14-80 ng/mL). In conclusion, the estimated MEC, 20-35 ng/mL, and MEAC, 45-50 ng/mL, values of P-oxycodone in patients after LLC were significantly higher than those proposed previously. Early pain after LCC appeared to be a feasible method to estimate the analgesic efficacy of oxycodone in acute pain management.

Epidural blood patches are effective for postdural puncture headache in pediatrics – a 10‐year experience

Postdural puncture headache (PDPH) is a relatively common complication after lumbar punctures (LP). If conservative treatment is not sufficient within a few days and the symptoms are severe, an epidural blood patch (EBP) may be performed.

Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

AIMS This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n= 27) or by mouth as syrup (n= 37). A single cerebrospinal fluid (CSF) sample (n= 60) was collected at the induction of anaesthesia, and plasma samples (n= 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96l h(-1) 70 kg(-1) . Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (V(ss) ) was 8.1 l 70 kg(-1) . Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6months, while more research is needed in neonates and in younger infants.

Intravenous Oxycodone for Pain Relief in the First Stage of Labour – Maternal Pharmacokinetics and Neonatal Exposure

Physiological changes during pregnancy may change pharmacokinetics of compounds. Oxycodone is an increasingly used opioid agonist in acute pain management but its pharmacokinetics in labouring women has not been established. We studied the maternal pharmacokinetics and neonatal exposure of intravenous oxycodone for pain relief in the first stage of labour. The study was prospective, open‐labelled and with a control group. After informed consent, 15 nulliparous parturients and newborns, and newborns in a control group were studied. In the study group, oxycodone boluses of 1 mg i.v., up to a cumulative dose of 5 mg, was administered when labour pain score was 5/10 or higher. As the control group, 30 other newborns after uncomplicated deliveries with no systemic opioids were assessed for the neonatal outcome. In the study group, maternal pharmacokinetics of oxycodone was measured from plasma concentrations during labour, and neonatal exposure was assessed from umbilical plasma samples using population pharmacokinetic methods. Maternal plasma oxycodone concentration decreased with a median half‐life of 2.6 hr (range, 1.8–2.8). Oxycodone concentrations in the umbilical plasma 2.7 μg/l (0.3–14.5) were similar as in maternal plasma 2.4 (0.1–14.8) μg/l at the time of birth. No severe or unexpected adverse effects were noted. To conclude, firstly, maternal elimination half‐life of i.v. oxycodone was significantly shorter than that reported in non‐pregnant women, and secondly, maternal plasma oxycodone at the birth correlated well with neonatal umbilical concentrations and may, thus, be used as an estimate of neonatal exposure.

The Analgesic Concentration of Oxycodone with Co-administration of Paracetamol - A Dose-Finding Study in Adult Patients Undergoing Laparoscopic Cholecystectomy

We have previously shown that paracetamol has an opioid‐sparing effect in tonsillectomy, and now, we evaluated the analgesic efficacy of paracetamol i.v. in early post‐operative pain after laparoscopic cholecystectomy (LCC). Twenty‐four patients with LCC were randomized to receive paracetamol i.v. 1 g (group 1) or 2 g (group 2) at the end of surgery. All patients were provided 0.1 mg/kg of oxycodone i.v. 15 min. before the end of surgery. At the recovery room when the wound pain at rest was ≥3/10 and/or ≥5/10 during the wound compression, plasma sample was taken for the determination of oxycodone (minimum effective concentration, MEC), its metabolites and paracetamol. After that the patients were titrated with further doses of oxycodone i.v. to wound pain < 3/10 at rest and < 5/10 during wound compression, plasma sample was taken for the determination of minimum effective analgesic concentration (MEAC) of oxycodone. The total oxycodone dose needed for pain relief was similar, about 0.3 mg/kg (range 0.2–0.5), in both groups (p = 0.80). At the onset of pain, P‐oxycodone (MEC) was similar in both groups, 25 ng/ml (19–32) in group 1 and 24 ng/ml (16–34) in group 2. The pain relief (MEAC) was achieved in group 1 with P‐oxycodone 70 ng/ml (30–131) and in group 2 with 62 ng/ml (36–100) (p = 0.48). In conclusion, in the early‐phase after LCC, there was no significant difference between the effect of paracetamol doses of 1 g and 2 g i.v. on the need of i.v. oxycodone.

Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach

ABSTRACT Knowledge of drug concentration‐time profiles at the central nervous system (CNS) target‐site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically‐based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration‐time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin). Values of the system‐specific parameters in the rat CNS PBPK model were replaced by corresponding human values. The contribution of active transporters for the four selected drugs was scaled based on differences in expression of the pertinent transporters in both species. Model predictions were evaluated with available pharmacokinetic (PK) data in human brain extracellular fluid and/or cerebrospinal fluid, obtained under physiologically healthy CNS conditions (acetaminophen, oxycodone, and morphine) and under pathophysiological CNS conditions where CNS physiology could be affected (acetaminophen, morphine and phenytoin). The human CNS PBPK model could successfully predict their concentration‐time profiles in multiple human CNS compartments in physiological CNS conditions within a 1.6‐fold error. Furthermore, the model allowed investigation of the potential underlying mechanisms that can explain differences in CNS PK associated with pathophysiological changes. This analysis supports the relevance of the developed model to allow more effective selection of CNS drug candidates since it enables the prediction of CNS target‐site concentrations in humans, which are essential for drug development and patient treatment. Graphical abstract Figure. No Caption available.

Intravenous dexketoprofen induces less injection pain than racemic ketoprofen

Ketoprofen has high analgesic efficacy against inflammatory and nociceptive pain. Additionally, when ketoprofen is administered in conjunction with an opioid during pain management, it prevents the development of opioid‐induced hyperalgesia. The main limitation for racemic ketoprofen IV administration is venous irritation. Dexketoprofen is the active enantiomer of racemic ketoprofen and has a similar analgesic efficacy in a dose proportion of 1 : 2, but it causes fewer adverse effects than racemic ketoprofen. It has been claimed that dexketoprofen may cause less frequent and less severe injection pain than racemic ketoprofen. In this study, we compared the injection pain of IV administered racemic ketoprofen and dexketoprofen in elective surgical patients.

Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe

Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non‐pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5–2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118–127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 μg/kg/hr were applied to antebrachium, and ewes were then given a 2 μg/kg intravenous bolus followed by an intra‐operative 2.5 μg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra‐ and post‐operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep.