Oxycodone for pain management in the latent phase of labour - A pragmatic trial.

BACKGROUND: Parenteral opioids are used for pain relief in labour but there are little data for oxycodone in this context. The aim of this study was to evaluate the efficacy, foetal exposure and safety of subcutaneous oxycodone in the latent phase of labour. METHODS: This pragmatic trial included 76 parturients, who received subcutaneous oxycodone for pain relief in the latent phase of labour according to the hospital protocol: an initial dose 0.1 mg/kg, and a second dose, 0.05 mg/kg, could be administered four hours later. Pain intensity and pain relief were assessed using a numerical rating scale of 0-10. After delivery, blood samples from the maternal and umbilical veins were collected, and plasma concentrations of oxycodone and its main metabolites were quantified using UPLC-MS/MS. The Apgar scores and maternal and neonatal adverse effects were recorded. RESULTS: The foetal exposure at birth was low, the median oxycodone and oxymorphone umbilical vein plasma concentrations were 1.2 ng/mL (range 0.21-7.8) and 0.14 ng/mL (0-0.26), respectively. Pain scores decreased substantially, from a median pain score of 7/10 before oxycodone to median scores of 5/10 at 30 minutes after administration, 5/10 at 60 minutes and 6/10 at 120 minutes. The median Apgar score was 9 (range 2-10) at 1 minute and 9 (6-10) at 5 minutes. Maternal adverse effects were mild, and there were no oxycodone-related neonatal adverse effects. CONCLUSION: Subcutaneous oxycodone provided effective analgesia during the latent phase of labour. Newborn exposure at birth was low, and oxycodone was well-tolerated.

Oxycodone pharmacokinetics and fetal exposure after intravenous or epidural administration to the ewe.

INTRODUCTION: There are limited data on oxycodone pharmacokinetics during pregnancy and on fetal exposure after maternal administration. The present study describes the pharmacokinetics of intravenous (i.v.) oxycodone in pregnant sheep and fetal exposure after intravenous and epidural administration. MATERIAL AND METHODS: Ten pregnant sheep received 0.1 mg·kg-1 oxycodone intravenously, and blood samples were collected up to 24 hours. Seven days later, the ewes were randomized to receive 0.5 mg·kg-1 oxycodone intravenously (n = 5) or epidurally (n = 5) as a single bolus, before laparotomy for placement of catheters into the fetal superior vena cava and carotid artery. Paired maternal and fetal blood samples were taken when the fetal arterial catheter was in place and at the end of surgery. Maternal blood samples were taken up to 24 hours. RESULTS: After 0.1 mg·kg-1 oxycodone intravenously, the median clearance was 5.2 L·h-1 ·kg-1 (range 4.6-6.2), but the volume of distribution varied between 1.5 and 4.7 L·kg-1 . The area under the curve was 17 h·ng·mL-1 (range 14-19) and the plasma concentration at 2 minutes 60 ng·mL-1 (range 50-74). Following administration of 0.5 mg·kg-1 intravenously or epidurally, oxycodone concentrations were similar in the maternal and the fetal plasma. Accumulation of oxymorphone in the fetus occurred; fetal-to-maternal ratios were 1.3-3.5 (median 2.1) in the i.v.-group and 0.9-3.0 (1.3) in the Epidural-group. CONCLUSIONS: We determined the pharmacokinetics of oxycodone in pregnant sheep. We showed accumulation of oxymorphone, which an active metabolite of oxycodone, in the fetus. Further studies in human pregnancies are required to evaluate the safety of oxycodone.

A randomized multicenter study of minilaparotomy cholecystectomy versus laparoscopic cholecystectomy with ultrasonic dissection in both groups.

OBJECTIVE: Ultrasonic dissection (UsD) has been used in laparoscopic cholecystectomy (LC), though it is not the golden standard technique. Applying UsD to cholecystectomy by minilaparotomy (MC) is less common and there are no prospective randomized trials comparing these two techniques. Therefore, we conducted the present study to investigate the use of the UsD in the MC versus the LC procedure. MATERIAL AND METHODS: Initially 104 patients with non-complicated symptomatic gallstone disease were randomized into MC (n = 53) or LC (n = 51) groups, both groups using UsD, over a period of 2 years (2013-2015). The study groups were similar in terms of age and American Society of Anesthesiologists (ASA) physical status score. RESULTS: The demographic variables and the surgical data were similar in the study groups. Similar low postoperative pain scores were reported in the two study groups during the first four hours after surgery. The incidence of nausea/vomiting was similar between the two study groups, 47% in the MC group versus 42% in the LC group. However, the patients in the MC group were treated more frequently with antiemetics, the incidence being 39% in the MC group versus 21% in the LC group (p = 0.02). The pain at rest at 24h after the surgery was similar in the two study groups, but the LC patients reported less pain at the normal activity, the mean of numerical rating scale (NRS) of 0-10 score being 3.9 in the MC group versus 2.9 in the LC group (p = 0.05), and the pain at the quick movement/coughing, the mean NRS being 4.9 in the MC group versus 3.2 in the LC group (p = 0.005). The length of sick leave was 17.4 days in the MC group and 14.4 days in the LC group (p = 0.05). CONCLUSION: Our results suggest that both MC and LC are feasible and safe options for mini-invasive cholecystectomy. A new finding with clinical relevance in the present work is a relatively similar short-term outcome in the MC and LC although the LC patients reported significantly lower pain score 24 hours postoperatively and a shorter convalescence.

Inflammatory response to surgical trauma in patients with minilaparotomy cholecystectomy versus laparoscopic cholecystectomy: a randomised multicentre study.

OBJECTIVE: The aim of the study was to evaluate the inflammatory response to surgical trauma in minilaparotomy cholecystectomy (MC) compared to laparoscopic cholecystectomy (LC). Assessment of inflammatory response to surgical trauma in MC has not been addressed properly. Therefore, we investigated five interleukins (IL) and C-reactive protein (CRP) in MC versus LC group in a prospective randomised trial. METHODS: Initially, 106 patients with non-complicated symptomatic gallstone disease were randomised into MC (n = 56) or LC (n = 50) groups. Plasma levels of five interleukins (IL-1ß, IL-1ra, IL-6, IL-8, IL-10) and hs-CRP were measured at three time points; before operation (PRE), immediately after operation (POP1) and six hours after operation (POP2). The primary end-point of the study was to compare the plasma levels of five interleukins and CRP in LC versus MC group. RESULTS: The demographic variables and the surgical data were similar in the study groups. The patients in the MC group had higher elevation of the CRP mean values post-operatively (p = 0.01). However, the patients in the MC group had higher elevation of the IL-1ra mean values post-operatively, the mean pre-/post-operative IL-1ra values being 299/614 pg/ml in the MC group versus 379/439 pg/ml in the LC group (p = 0.003). There was no statistical significance in IL-6 mean values between the MC and LC groups pre- and post-operatively (POP1). However, the patients in the MC group had higher IL-6 mean values six hours post-operatively (POP2), the mean IL-6 values being 27.6 pg/ml in the MC group versus 14.8 pg/ml in the LC group (p = 0.037). In addition, the patients in the MC group had higher elevation of the IL-6 mean values post-operatively, the mean pre-/post-operative IL-6 values being 4.1/27.6 pg/ml in the MC group versus 3.8/14.8 pg/ml in the LC group (p = 0.04). There was no statistical significance in IL-8, IL-10, and IL-1ß mean values between the MC and LC groups pre- and post-operatively. CONCLUSION: Our results suggest that the inflammatory response in MC versus LC groups was similar based on the IL-8, IL-10, and IL-1ß values. A new finding with possible clinical relevance in the present work is higher relative elevation of the IL-1ra and IL-6 mean values post-operatively in the MC group.

Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing.

PURPOSE: Low-dose ketamine is a lucrative therapeutic approach in cancer pain, perioperative treatment of pain, and management of treatment-resistant depression. The analgesic potency of its main metabolite norketamine is thought to be one third that of ketamine. However, few studies exist on the pharmacokinetics of orally administered S-ketamine. METHODS: In our study, 11 healthy volunteers received S-ketamine 0.25 mg/kg orally and 0.125 mg/kg intravenously. S-ketamine and norketamine concentrations were measured up to 23.5 h post-dose. A population pharmacokinetic model was built to describe S-ketamine and norketamine pharmacokinetics. RESULTS: A three-compartment model for both S-ketamine and norketamine best described the data. To accommodate for the extensive formation of norketamine after oral S-ketamine, a separate presystemic absorption-phase component was included in addition to its systemic formation. The oral bioavailability of S-ketamine was low, 8% (11% interindividual variability), and its clearance was high, 95 L/h/70 kg (13% interindividual variability). Simulations suggested that after oral dosing, norketamine AUC at steady state is 16.5 times higher than that of S-ketamine. CONCLUSIONS: Given that the analgesic effect of S-ketamine is due to both S-ketamine and norketamine, relatively small oral doses of S-ketamine can be assumed to be a feasible alternative to repeated intravenous dosing, for example in the setting of chronic pain.

Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone.

Global oxycodone consumption has increased sharply during the last two decades, and, in 2008, oxycodone consumption surpassed that of morphine. As oxycodone was synthesized in 1916 and taken to clinical use a year later, it has not undergone the same approval process required by today's standards. Most of the basic oxycodone pharmacokinetic (PK) data are from the 1990s and from academic research; however, a lot of additional data have been published over the last 10 years. In this review, we describe the latest oxycodone data on special populations, including neonates, children, pregnant and lactating women, and the elderly. A lot of important drug interaction data have been published that must also be taken into account when oxycodone is used concomitantly with cytochrome P450 (CYP) 3A inducers and inhibitors and/or CYP2D6 inhibitors. In addition, we gathered data on abuse-deterrent oxycodone formulations, and the PK of alternate administration routes, i.e. transmucosal and epidural, are also described.

Oxycodone concentrations in the central nervous system and cerebrospinal fluid after epidural administration to the pregnant ewe.

The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomized into two groups to receive epidural oxycodone: infusion group (n = 10, 0.1 mg·kg-1 bolus followed by continuous infusion of 0.05 mg·kg-1 ·h-1 for five days) or repeated boluses group (n = 10, 0.2 + 2x0.1 mg·kg-1 bolus followed by a 0.2 mg·kg-1 bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were killed, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentrations of oxycodone were 9.0 and 14.2 ng·mL-1 after infusion and 0.4 and 1.1 ng·mL-1 after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentrations were 4-8 times higher and in the spinal cord 1310 times higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720 times higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia.

A prospective, randomized, open label, controlled study investigating the efficiency and safety of 3 different methods of rectus sheath block analgesia following midline laparotomy.

BACKGROUND: There is a controversy regarding the efficacy of rectus sheath block (RSB). The aim of the present study was to evaluate analgesic efficacy and safety of three different methods of RSB in postoperative pain management after midline laparotomy. METHODS: A prospective, randomized, controlled, open-label clinical trial with 4 parallel groups was conducted in a tertiary care hospital in Finland. A total of 57 patients undergoing midline laparotomy were randomized to the control group (n = 12) or to 1 of the 3 active RSB analgesia groups: single-dose (n = 16), repeated-doses (n = 12), or continuous infusion (n = 17). Opioid consumption with iv-patient-controlled analgesia pump was recorded, and pain scores and patients' satisfaction were surveyed on an 11-point numeric rating scale for the first 48 postoperative h. Plasma concentrations of oxycodone and levobupivacaine were analyzed. All adverse events during the hospital stay were recorded. RESULTS: Oxycodone consumption was less during the first 12 h in the repeated-doses and in the continuous infusion groups (P = .07) and in numerical values up to 48 h in the repeated-doses group. Plasma oxycodone concentrations were similar in all 4 groups. Pain scores were lower in the repeated-doses group when coughing during the first 4 h (P = .048 vs. control group), and at rest on the first postoperative morning (P = .034 vs. the other 3 groups) and at 24 h (P = .006 vs. the single-dose group). All plasma concentrations of levobupivacaine were safe. The patients' satisfaction was better in the repeated-doses group compared with the control group (P = .025). No serious or unexpected adverse events were reported. CONCLUSIONS: RSB analgesia with repeated-doses seems to have opioid sparing efficacy, and it may enhance pain relief and patients' satisfaction after midline laparotomy.

A Test of Canine Olfactory Capacity: Comparing Various Dog Breeds and Wolves in a Natural Detection Task.

Many dog breeds are bred specifically for increased performance in scent-based tasks. Whether dogs bred for this purpose have higher olfactory capacities than other dogs, or even wolves with whom they share a common ancestor, has not yet been studied. Indeed, there is no standard test for assessing canine olfactory ability. This study aimed to create a simple procedure that requires no pre-training and to use it to measure differences in olfactory capacity across four groups of canines: (1) dog breeds that have been selected for their scenting ability; (2) dog breeds that have been bred for other purposes; (3) dog breeds with exaggerated short-nosed features; and (4) hand-reared grey wolves. The procedure involved baiting a container with raw turkey meat and placing it under one of four identical ceramic pots. Subjects were led along the row of pots and were tasked with determining by olfaction alone which of them contained the bait. There were five levels of increasing difficulty determined by the number of holes on the container's lid. A subsample of both dogs and wolves was retested to assess reliability. The results showed that breeds selected for scent work were better than both short-nosed and non-scent breeds. In the most difficult level, wolves and scenting breeds performed better than chance, while non-scenting and short-nosed breeds did not. In the retested samples wolves improved their success; however, dogs showed no change in their performances indicating that a single test may be reliable enough to assess their capacity. Overall, we revealed measurable differences between dog breeds in their olfactory abilities and suggest that the Natural Detection Task is a good foundation for developing an efficient way of quantifying them.