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

Mari Kinnunen, Hannu Kokki, Heidi Hautajärvi, Juulia Lantto, Juha Rasanen, Hanna Marja Voipio, Merja Kokki

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalBasic and Clinical Pharmacology and Toxicology
DOIs
StatePublished - Jan 1 2019

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Oxycodone
Cerebrospinal fluid
Neurology
Cerebrospinal Fluid
Central Nervous System
Spinal Cord
Brain
Oxymorphone
Metabolites
Tissue
Thalamus
Plasmas
Cerebellum
Analgesia
Laparotomy
Analgesics
Sheep
Blood

Keywords

  • Analgesia
  • epidural
  • opioid
  • oxycodone
  • pharmacokinetics

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Oxycodone concentrations in the central nervous system and cerebrospinal fluid after epidural administration to the pregnant ewe. / Kinnunen, Mari; Kokki, Hannu; Hautajärvi, Heidi; Lantto, Juulia; Rasanen, Juha; Voipio, Hanna Marja; Kokki, Merja.

In: Basic and Clinical Pharmacology and Toxicology, 01.01.2019.

Research output: Contribution to journalArticle

Kinnunen, Mari ; Kokki, Hannu ; Hautajärvi, Heidi ; Lantto, Juulia ; Rasanen, Juha ; Voipio, Hanna Marja ; Kokki, Merja. / Oxycodone concentrations in the central nervous system and cerebrospinal fluid after epidural administration to the pregnant ewe. In: Basic and Clinical Pharmacology and Toxicology. 2019.
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AB - 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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