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

Abstract

GLOSSARY AIC = Akaike information criterion; Chr.Analg = chronic use of analgesics; CI = confidence interval; EFF morphine = exponential effect of morphine concentration; ICU = intensive care unit; IQR = interquartile range; kbVHC = kernel-based visual hazard comparison; M3G = morphine-3-glucuronide; NRS = numerical rating scale; OPCIC = optimization of procedural pain control in intensive care unit patients; PK-PD = pharmacokinetic-pharmacodynamic; RSE = relative standard error; RTTE = repeated time-to-event; SNP = single nucleotide polymorphism; WDFY4 = WD repeat-and FYVE domain-containing protein 4 KEY POINTS• Question: Can morphine concentrations be related to the hazard of unacceptable pain following cardiac surgery using repeated time-to-event modeling? • Finding: A model was developed that predicts the hazard of unacceptable pain using the morphine concentration, time after surgery, and time of day. • Meaning: The low morphine concentrations that result from weaning may contribute to the high incidence of unacceptable pain following cardiac surgery.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.

Finding the right hazard function for time‐to‐event modeling: A tutorial and Shiny application

“…The Gompertz model reduces to the exponential model for γ = 0. Its application in pharmacometrics include the characterization of the time to recurrent venous thromboembolism, acute deep vein thrombosis, and pulmonary embolism 18 ; the time to analgesic remedication after surgery, 19–21 which can be expected to decrease with time after surgery; and the time to recurrent Clostridium difficile infection 22 …”