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Pharmacokinetics of Morphine and Morphine-6-Glucuronide During Postoperative Pain Therapy in Cardiac Surgery Patients

  • Original Research Article
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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Morphine is a standard analgesic drug for postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide (M6G) in cardiac surgery  patients during postoperative analgesia.

Methods

Twenty-five adult patients undergoing cardiac surgery received postoperative pain therapy by patient-controlled analgesia with intravenous bolus doses of morphine. Plasma concentrations of morphine and M6G were determined from arterial samples. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling.

Results

Data from twenty-one patients (aged 44–79 years) were analyzed. Pharmacokinetics were best described by a three-compartment model for morphine and a two-compartment model for M6G, linked by a transit compartment. Mean (±SD) population estimates for morphine were: clearance (CL) = 1.35±0.40 L/min, central volume of distribution (V1) = 8.1±2.2 L, steady-state volume of distribution (Vss) = 207±83 L, terminal elimination half-life (T1/2γ) = 177±50 min. Clearance of morphine was proportional to cardiac output. Mean (±SD) population estimates for M6G were: CL = 0.098±0.037 L/min, V1 = 5.5±0.8 L, Vss = 15.8±0.8 L, T1/2β = 227±74 min. The time to peak concentration of M6G after a bolus dose of morphine was 53±20 min. Clearance of M6G was proportional to estimated glomerular filtration rate.

Conclusions

The pharmacokinetics of morphine and M6G in pain therapy of cardiac surgery  patients could be well described by standard compartmental models. Cardiac output was identified as a significant covariate for morphine clearance, whereas renal function was identified as the most significant covariate for clearance of M6G. These effects should be particularly considered if morphine is administered as a continuous infusion. The developed pharmacokinetic model also enables patient-controlled target-controlled infusion for pain therapy with morphine.

Trial Registration

Clinical Trials NCT02483221 (June 26, 2015).

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Availability of Data and Material

Data are available on request from the authors

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Acknowledgements

The authors thank Rainer Knoll, Dipl. Bioingenieur (Department of Anesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany) for conducting the drug analysis, and Gabriele Göhring-Waldeck, Laboratory Technician (Department of Anesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany) for help in patient recruitment and study organization.

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Author notes

  1. Harald Ihmsen and Christian Jeleazcov contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Krankenhausstrasse 12, 91054, Erlangen, Germany

    Harald Ihmsen, Jürgen Schüttler & Christian Jeleazcov

Authors
  1. Harald Ihmsen
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  2. Jürgen Schüttler
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Contributions

Harald Ihmsen: Data acquisition, analysis and interpretation, drafting of the manuscript. Jürgen Schüttler: Analysis and interpretation of the data. Christian Jeleazcov: Study conception and design, acquisition, analysis and interpretation of the data. All authors revised and approved the final manuscript.

Corresponding author

Correspondence to Harald Ihmsen.

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Funding

This work was supported by a grant from the German Federal Ministry of Education and Research, Berlin, Germany (Bundesministerium für Bildung und Forschung, grant no: FKZ 13EX1015B).

Conflict of Interest

Harald Ihmsen, Jürgen Schüttler and Christian Jeleazcov declare that they have no conflict of interest.

Ethics Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Approval was obtained from the Institutional Ethical Committee (Ethikkommission der Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany).

Consent

Written informed consent was obtained from all individual participants included in the study.

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Ihmsen, H., Schüttler, J. & Jeleazcov, C. Pharmacokinetics of Morphine and Morphine-6-Glucuronide During Postoperative Pain Therapy in Cardiac Surgery Patients. Eur J Drug Metab Pharmacokinet 46, 249–263 (2021). https://doi.org/10.1007/s13318-020-00663-z

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  • DOI: https://doi.org/10.1007/s13318-020-00663-z

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