Intravenous morphine titration in immediate postoperative pain management: Population kinetic-pharmacodynamic and logistic regression analysis

Morphine is widely used to treat moderate to severe postoperative pain. The goal of this study was to characterize the pharmacodynamics of morphine-induced analgesia during intravenous morphine titration in the immediate postoperative period and to evaluate sedation occurrence according to morphine dose in this setting. Two hundred and twenty-eight patients undergoing major orthopedic surgery were included. They received intravenous (iv) morphine titration in the post-anesthesia care unit as boluses of 2 or 3 mg, every 5 min until analgesia was established. Pain was assessed using visual analogue scale (VAS) scores. Morphine analgesia-time data were analysed via a kinetic-pharmacodynamic population approach using non-linear mixed-effect modeling NONMEM. Sedation was assessed by the Ramsay score with scores >2 representing clinically significant sedation. The relationship between sedation occurrence and morphine dose was modeled using logistic regression. Morphine pharmacodynamic was best described by an indirect response model with an inhibitory function affecting pain onset, and it showed that decreasing delay between extubation and titration, decreasing initial VAS and intra-operative non-steroidal anti-inflammatory drug resulted in increased morphine potency. Logistic regression showed that a morphine dose of 20 mg was associated with a high likelihood of sedation occurrence. Our study supported the possibility of modeling the time course of a complex response in the absence of pharmacokinetic data. The current data should lead to a more rational management of the immediate postoperative pain.