The analgesic efficacy and pharmacokinetics of epidural oxycodone after gynaecological laparotomy: a randomized, double‐blind, double‐dummy comparison with intravenous administration

Piirainen, Panu; Kokki, Hannu; Hautajärvi, Heidi; Ranta, Veli‐Pekka; Kokki, Merja

doi:10.1111/bcp.13643

Cited by 11 publications

(44 citation statements)

References 24 publications

(56 reference statements)

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“…Contrary to our second hypothesis, CSF oxycodone concentration did not predict the tissue concentrations. Since it is not ethical to measure actual drug concentrations in the human brain and spinal cord during treatment, CSF concentrations are used as surrogate markers of CNS exposure . However, in the present study, CSF oxycodone had a strong, positive correlation with oxycodone concentrations in the cortex and spinal cord, and a moderate correlation with oxycodone in the thalamus.…”

Section: Discussioncontrasting

confidence: 60%

“…One of the main limitations was that there was a lot of variance in the measured concentrations in both study groups, and this large variance was obtained both in the tissue concentrations and in the plasma and CSF concentrations. However, similar large between‐subjects variance has been shown also in human studies after epidural oxycodone administration . We do not have explanation for this large variance, and this warrants further studies.…”

Section: Discussionmentioning

confidence: 49%

“…Moreover, the spinal cord concentrations were between 15 and 4845 times higher compared to CSF oxycodone in the infusion group and between 0.5 and 3240 times higher in the repeated boluses group. In human beings, a single epidural bolus of oxycodone resulted in a 100‐350 times higher peak concentration of oxycodone in CSF compared to plasma . In the present study, CSF samples were collected from the cisterna magna and were mainly similar to plasma concentrations.…”

Section: Discussionmentioning

confidence: 90%

“…Oxycodone is metabolized to noroxycodone via CYP3A4, and thus, we assume that BBB and CNS tissue CYP3A4 expression may have contributed to noroxycodone tissue concentrations. In human beings, CSF noroxycodone concentrations have been modest after a single epidural oxycodone bolus …”

Section: Discussionmentioning

confidence: 99%

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

Kinnunen

Kokki

Hautajärvi

et al. 2019

Basic Clin Pharma Tox

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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.

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Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

Kinnunen

Kokki

Hautajärvi

et al. 2019

Basic Clin Pharma Tox

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“…morphine . Our recent data indicate that oxycodone could also be a feasible opioid in epidural analgesia . In our previous clinical trial, epidural oxycodone provided superior early postoperative analgesia to i.v.…”

Section: Introductionmentioning

confidence: 99%

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

Piirainen

Kokki

Anderson

et al. 2019

Brit J Clinical Pharma

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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.

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Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone

et al. 2019

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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. Mari Kinnunen and Panu Piirainen contributed equally to this work.

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The analgesic efficacy and pharmacokinetics of epidural oxycodone after gynaecological laparotomy: a randomized, double‐blind, double‐dummy comparison with intravenous administration

Abstract: The data support the superiority of epidural oxycodone compared with that of i.v. administration in pain management after laparotomy.

Cited by 11 publications

References 24 publications

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

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

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

Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone

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