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

Authors

Robert B. Raffa
Pawasauskas, University of Rhode IslandFollow
Joseph V. Pergolizzi Jr
Luke Lu
Yin Chen
Sutan Wu
Brant Jarrett
Randi Fain
Lawrence Hill
Krishna Devarakonda

Document Type

Article

Date of Original Version

12-6-2017

Department

Pharmacy Practice

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 (AUC_0–6) 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 AUC_0–6 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.

Citation/Publisher Attribution

Raffa, R.B., Pawasauskas, J., Pergolizzi, J.V. et al. Pharmacokinetics of Oral and Intravenous Paracetamol (Acetaminophen) When Co-Administered with Intravenous Morphine in Healthy Adult Subjects (2017) Clinical Drug Investigation 38(3): 259–268 https://doi.org/10.1007/s40261-017-0610-4

Available at: https://doi.org/10.1007/s40261-017-0610-4

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License