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Clinical Drug Investigation
Published in: Clinical Drug Investigation 3/2018

Open Access 01-03-2018 | Original Research Article

Pharmacokinetics of Oral and Intravenous Paracetamol (Acetaminophen) When Co-Administered with Intravenous Morphine in Healthy Adult Subjects

Authors: Robert B. Raffa, Jayne Pawasauskas, Joseph V. Pergolizzi Jr, Luke Lu, Yin Chen, Sutan Wu, Brant Jarrett, Randi Fain, Lawrence Hill, Krishna Devarakonda

Published in: Clinical Drug Investigation | Issue 3/2018

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Abstract

Background and Objective

Several features favor paracetamol (acetaminophen) administration by the intravenous rather than the oral route in the postoperative setting. This study compared the pharmacokinetics and bioavailability of oral and intravenous paracetamol when given with or without an opioid, morphine.

Methods

In this randomized, single-blind, parallel, repeat-dose study in healthy adults, subjects received four repeat doses of oral or intravenous 1000 mg paracetamol at 6-h intervals, and morphine infusions (0.125 mg/kg) at the 2nd and 3rd intervals. Comparisons of plasma pharmacokinetic profiles were conducted before, during, and after opioid co-administrations.

Results

Twenty-two subjects were included in the pharmacokinetic analysis. Observed paracetamol peak concentration (C max) and area under the plasma concentration-time curve over the dosing interval (AUC0–6) were reduced when oral paracetamol was co-administered with morphine (reduced from 11.6 to 7.25 µg/mL and from 31.00 to 25.51 µg·h/mL, respectively), followed by an abruptly increased C max and AUC0–6 upon discontinuation of morphine (to 13.5 µg/mL and 52.38 µg·h/mL, respectively). There was also a significantly prolonged mean time to peak plasma concentration (T max) after the 4th dose of oral paracetamol (2.84 h) compared to the 1st dose (1.48 h). However, pharmacokinetic parameters of paracetamol were not impacted when intravenous paracetamol was co-administered with morphine.

Conclusions

Morphine co-administration significantly impacted the pharmacokinetics of oral but not intravenous paracetamol. The abrupt release of accumulated paracetamol at the end of morphine-mediated gastrointestinal inhibition following oral but not intravenous administration of paracetamol suggests that intravenous paracetamol provides a better option for the management of postoperative pain.

ClinicalTrials.gov Identifier

NCT02848729.
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Metadata
Title
Pharmacokinetics of Oral and Intravenous Paracetamol (Acetaminophen) When Co-Administered with Intravenous Morphine in Healthy Adult Subjects
Authors
Robert B. Raffa
Jayne Pawasauskas
Joseph V. Pergolizzi Jr
Luke Lu
Yin Chen
Sutan Wu
Brant Jarrett
Randi Fain
Lawrence Hill
Krishna Devarakonda
Publication date
01-03-2018
Publisher
Springer International Publishing
Published in
Clinical Drug Investigation / Issue 3/2018
Print ISSN: 1173-2563
Electronic ISSN: 1179-1918
DOI
https://doi.org/10.1007/s40261-017-0610-4

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