Breast milk oxycodone concentrations in mothers given oxycodone for post-Caesarean delivery pain management.

AIMS: Both effective analgesia and early breastfeeding play an important role in maternal and neonatal well-being after Caesarean delivery. We studied controlled-release oxycodone tablet treatment for postoperative pain management and determined the excretion of oxycodone into breast milk. METHODS: Controlled-release oxycodone/naloxone 10/5-mg tablets (n = 21) or controlled-release oxycodone 10-mg tablets (n = 22) were administered to mothers twice a day for the first 3 days after elective Caesarean delivery as a part of multimodal analgesia. Maternal plasma and breast milk samples were collected daily. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed with ultra-performance liquid chromatography-mass spectrometry. Maternal pain intensity was recorded with an 11-point Numeric Rating Scale (0-10). Neonatal oxycodone exposure was estimated by simulating five different exposure scenarios, including the highest possible exposure through breast milk. RESULTS: The mean oxycodone and noroxycodone milk-to-maternal plasma ratios were 3.2 and 3.0, respectively. A strong correlation was found between plasma and breast milk oxycodone (R2 = 0.87) and noroxycodone concentrations (R2 = 0.91). In the simulated highest neonatal exposure scenario, the neonate's maximum plasma concentration was estimated to be 5.4 ng/mL and the estimated weight-adjusted infant oxycodone dose was less than 10% of the maternal dose. Pain intensities were similarly low between the two treatment groups. CONCLUSIONS: The oxycodone dose received from colostrum and breast milk during the first three postoperative days after Caesarean delivery is assumed safe for healthy, term neonates, but in extreme cases it is possible for the neonate to receive a dose through breast milk that may elicit opioid effects.

Electrophilic metabolites targeting the KEAP1/NRF2 partnership.

Numerous electrophilic metabolites are formed during cellular activity, particularly under conditions of oxidative, inflammatory and metabolic stress. Among them are lipid oxidation and nitration products, and compounds derived from amino acid and central carbon metabolism. Here we focus on one cellular target of electrophiles, the Kelch-like ECH associated protein 1 (KEAP1)/nuclear factor erythroid 2 p45-related factor 2 (NRF2) partnership. Many of these reactive compounds modify C151, C273 and/or C288 within KEAP1. Other types of modifications include S-lactoylation of C273, N-succinylation of K131, and formation of methylimidazole intermolecular crosslink between two KEAP1 monomers. Modified KEAP1 relays the initial signal to transcription factor NRF2 and its downstream targets, the ultimate effectors that provide means for detoxification, adaptation and survival. Thus, by non-enzymatically covalently modifying KEAP1, the electrophilic metabolites discussed here serve as chemical signals connecting metabolism with stress responses.

Buprenorphine plasma and cerebrospinal fluid concentrations in osteoarthritis patients during low-dose transdermal patch dosing.

METHODS: Fifty-six (56) patients scheduled for arthroplasty, received 7-day extended-release buprenorphine transdermal patches (5 µg/h) for five consecutive weeks, starting two weeks prior to the surgery. Simultaneous plasma and cerebrospinal fluid (CSF) samples were collected during spinal anesthesia. RESULTS: Median buprenorphine plasma and CSF concentrations at steady-state were 54 pg/mL (range 8.6 - 167 pg/mL) and 1.6 pg/mL (0.30 - 7.3 pg/mL), respectively. The median CSF/plasma -ratio was 3% (range 0.35 - 16%). Large between-subject variability was observed in the measured buprenorphine concentrations within the study population.

Central nervous system distribution of buprenorphine in pregnant sheep, fetuses and newborn lambs after continuous transdermal and single subcutaneous extended-release dosing.

Buprenorphine is used during pregnancy for the treatment of opioid use disorder. Limited data exist on the central nervous system (CNS) permeation and distribution, and on the fetal exposure to buprenorphine. The aim of our study was to determine the extent of buprenorphine distribution to CNS in the pregnant sheep, and their fetus at steady-state, and their newborn lambs postdelivery, using three different dosing regimens. Twenty-eight pregnant ewes in late gestation received buprenorphine via 7-day transdermal patch releasing buprenorphine 20 µg/h (n=9) or 40 µg/h (n=11), or an extended-release 8 mg/week subcutaneous injection (n=8). Plasma, cerebrospinal fluid, and CNS tissue samples were collected at steady-state from ewes and fetuses, and from lambs 0.33 - 45 hours after delivery. High accumulation of buprenorphine was observed in all CNS tissues. The median CNS/plasma concentration -ratios of buprenorphine in different CNS areas ranged between 13 and 50 in the ewes, and between 26 and 198 in the fetuses. In the ewes the CNS/plasma -ratios were similar after the three dosing regimens, but higher in the fetuses in the 40 µg/h dosing group, medians 65 - 122, than in the 20 µg/h group, medians 26 - 54. The subcutaneous injection (theoretical release rate 47.6 µg/h) produced higher concentrations than observed after 40 µg/h transdermal patch dosing. The median fetal/maternal concentration -ratios in different dosing groups ranged between 0.21 and 0.54 in plasma, and between 0.38 and 1.3 in CNS tissues, respectively, with the highest ratios observed in the spinal cord. Buprenorphine concentrations in the cerebrospinal fluid were 8 - 13 % of the concurrent plasma concentration in the ewes and 28 % in the fetuses. Buprenorphine was quantifiable in the newborn lambs' plasma and CNS tissues two days postdelivery. Norbuprenorphine was analyzed from all plasma, cerebrospinal fluid, and CNS tissue samples but was nondetectable or below the LLOQ in most. The current study demonstrates that buprenorphine accumulates into CNS tissues at much higher concentrations than in plasma in pregnant sheep, fetuses, and their newborn lambs even 45 hours after delivery.

MATERNAL AND FETAL BUPRENORPHINE PHARMACOKINETICS IN PREGNANT SHEEP DURING TRANSDERMAL PATCH DOSING: Buprenorphine pharmacokinetics in pregnant sheep.

BACKGROUND: Buprenorphine is used in the opioid maintenance treatment for opioid dependent patients, including pregnant women. Despite the wide use, limited data exists on buprenorphine pharmacokinetics and fetal exposure during pregnancy. The aim of our study was to determine the buprenorphine pharmacokinetics during transdermal patch dosing to pregnant sheep and, to determine the extent of transplacental transfer of buprenorphine to the fetus. METHODS: Pregnant sheep in late gestation (n=50) received 20, 25 or 40 µg/h of buprenorphine as a 7-day extended-release transdermal patch. Plasma samples were collected from the ewe and the fetus on days 1 - 6, and buprenorphine and norbuprenorphine concentrations were determined. During the exposure period the sheep had a surgical procedure on the second day, a recovery phase, and an experimental procedure on the sixth day. In the experiment, hypoxia was induced under anesthesia for 18 sheep to investigate if decreased fetal pH would cause ion-trapping of buprenorphine in the fetus. The fetal/maternal plasma concentration ratio was determined on the second and on the sixth exposure day at baseline and during hypoxia. Maternal pharmacokinetics were modelled with a population pharmacokinetic method using the data from this study and our previous intravenous administration study. RESULTS: The transdermal patch provided an extended release of buprenorphine throughout the exposure period, but the release rate declined approximately 20 h after patch placement. The median fetal/maternal plasma concentration ratio was 13 - 27 % throughout the exposure period at baseline. A ratio over 100 % was observed for four sheep on the sixth exposure day (102 - 269 %). A minor increase was seen in the median fetal/maternal-ratios during maternal hypoxia. Norbuprenorphine was undetected in all plasma samples. CONCLUSIONS: The low transplacental passage of less than one fourth of the ewe's exposure supports buprenorphine as an alternative to methadone in opioid maintenance therapy during pregnancy.

Intranasal Fentanyl for Intervention-Associated Breakthrough Pain After Cardiac Surgery.

BACKGROUND: Cardiac bypass surgery patients have early postoperative interventions that elicit breakthrough pain. We evaluated the use of intranasal fentanyl for breakthrough pain management in these patients. METHODS: Multimodal analgesia (paracetamol 1 g three times a day, oxycodone 2-3 mg boluses with a patient-controlled intravenous pump) was used in 16 patients (age 49-70 years, weight 59-129 kg) after cardiac bypass surgery. Intranasal fentanyl 100 µg or 200 µg was used to manage breakthrough pain on the first and third postoperative mornings in a randomised order. Blood samples were collected for up to 3 h after fentanyl administration, pain was assessed with a numeric rating scale of 0-10. Plasma fentanyl concentration was assayed using liquid chromatography-mass spectrometry. Body composition was measured with a bioelectrical impedance device. RESULTS: Bioavailability of intranasal fentanyl was high (77%), absorption half-time short (< 2 min) and an analgesic plasma concentration ≥ 0.5 ng/mL was achieved in 31 of 32 administrations. Fentanyl exposure correlated inversely with skeletal muscle mass and total body water. Fentanyl analgesia was effective both on the first postoperative morning with chest pleural tube removal and during physiotherapy on the third postoperative morning. The median time of subsequent oxycodone administration was 1.1 h after intranasal fentanyl 100 µg and 2.1 h after intranasal fentanyl 200 µg, despite similar oxycodone concentrations (median 13.8, range 5.2-35 ng/mL) in both fentanyl dose groups. CONCLUSIONS: Intranasal fentanyl 100 µg provided rapid-onset analgesia within 10 min and is an appropriate starting dose for incidental breakthrough pain in the first 3 postoperative days after cardiac bypass surgery. CLINICAL TRIAL REGISTRATION: EudraCT Number: 2018-001280-22.

Pharmacokinetics of buprenorphine in pregnant sheep after intravenous injection.

Buprenorphine is a semi-synthetic opioid, widely used in the maintenance treatment for opioid-dependent pregnant women. Limited data exist on the pharmacokinetics of buprenorphine in pregnancy. We conducted a pharmacokinetic study to determine the pharmacokinetics of intravenous buprenorphine in pregnant sheep. Fourteen pregnant sheep in late gestation received 10 µg/kg of buprenorphine as an intravenous bolus injection. Plasma samples were collected up to 48 h after administration. Buprenorphine and its metabolite, norbuprenorphine, were quantified from plasma using a LC/MS/MS method, with lower limits of quantification of 0.01 µg/L and 0.04 µg/L for buprenorphine and norbuprenorphine, respectively. The pharmacokinetic parameters were calculated using noncompartmental analysis. The pharmacokinetic parameters, median (minimum-maximum), were Cmax 4.31 µg/L (1.93-15.5), AUCinf 2.89 h*µg/L (1.72-40.2), CL 3.39 L/h/kg (0.25-6.02), terminal t½ 1.75 h (1.07-31.0), Vss 8.04 L/kg (1.05-49.3). Norbuprenorphine was undetected in all plasma samples. The median clearance in pregnant sheep was higher than previously reported for nonpregnant sheep and human (male) subjects. Our sensitive analytical method was able to detect long terminal half-lives for six subjects, and a wide between-subject variability in the study population. Significance statement: Buprenorphine is widely used for the treatment of opioid use disorder in pregnancy. However, limited data exist on the pharmacokinetics of buprenorphine during pregnancy. As this type of study cannot be done in humans due to ethical reasons, we conducted a study in pregnant sheep. This study provides pharmacokinetic data on buprenorphine in pregnant sheep and helps us to understand the pharmacokinetics of the drug in humans.

Single dose epidural hydromorphone in labour pain: maternal pharmacokinetics and neonatal exposure.

INTRODUCTION: Epidural hydromorphone could be useful in obstetric analgesia as there is a need for a more water-soluble opioid than sufentanil or fentanyl with prolonged analgesic effect. To our knowledge, the pharmacokinetics of epidural hydromorphone has not been evaluated in parturients. MATERIALS AND METHODS: In this pilot study, seven healthy parturients were given a single epidural dose of hydromorphone for labour pain. One parturient received 1.5 mg, two 0.75 mg and four 0.5 mg of hydromorphone hydrochloride. Dose was decreased due to nausea and pruritus. Hydromorphone's effect, adverse effects and plasma concentrations were evaluated. Neonatal drug exposure was evaluated by umbilical vein and artery opioid concentration at birth. Neonatal outcomes were assessed using Apgar and the Neurologic Adaptive Capacity Score (NACS). RESULTS: All patients received additional levobupivacaine doses on parturients' requests. The first dose was requested at a median of 163 min (range 19-303 min) after hydromorphone administration. A total of 12 opioid related expected adverse events were reported by seven parturients. All newborn outcomes were uneventful. Hydromorphone's distribution and elimination after single epidural dose seem similar to that reported for non-pregnant subjects after intravenous hydromorphone administration, but further research is required to confirm this observation. CONCLUSIONS: The optimal dose of hydromorphone in labour pain warrants further evaluation.