Predicting Unacceptable Pain in Cardiac Surgery Patients Receiving Morphine Maintenance and Rescue Doses: A Model-Based Pharmacokinetic-Pharmacodynamic Analysis

Sebastiaan C. Goulooze, Elke H. Krekels, Mohammed A. Saleh, Sabine J. Ahlers, Pyry A. Välitalo, Eric P. Van Dongen, Ron H. Van Schaik, Thomas Hankemeier, Dick Tibboel, Catherijne A.J. Knibbe*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)


BACKGROUND: Optimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery. METHODS: The rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4). RESULTS: Patients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL-1(95% CI, 6.7-16). CONCLUSIONS: The pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed.

Original languageEnglish
Pages (from-to)726-734
Number of pages9
JournalAnesthesia and Analgesia
Issue number3
Publication statusPublished - 1 Mar 2021

Bibliographical note

Funding Information:
Management, St. Antonius Hospital, Nieuwegein, the Netherlands; ¶Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands; #Intensive Care and Department of Pediatric Surgery, Sophia’s Children’s Hospital, Rotterdam, the Netherlands; and **Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands. Accepted for publication September 2, 2020. Funding: C.A.J.K. was supported during this study by the Innovational Research Incentives Scheme (Vidi Grant, June 2013) of the Netherlands

Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.


Dive into the research topics of 'Predicting Unacceptable Pain in Cardiac Surgery Patients Receiving Morphine Maintenance and Rescue Doses: A Model-Based Pharmacokinetic-Pharmacodynamic Analysis'. Together they form a unique fingerprint.

Cite this