Population Kinetic Pharmacodynamic and Logistic Regression Analysis of Intravenous Morphine Titration in Immediate Postoperative Period
H. Abou hammoud(1), N. Simon(2), S. Urien(3), B. Riou(4), P. Lechat(1), F. Aubrun (5)
(1) Pharmacology Department, Pitié-Salpêtrière university hospital, Paris, France ; (2)Pharmacology Department, Timone university hospital, Marseille, France ; (3) INSERM & EA 3620, Tarnier hospital, Paris, France ; (4) Department of Emergency Medicine and Surgery, Pitié-Salpêtrière university hospital, Paris, France ;(5) Department of Anesthesiology and Critical Care, Pitié-Salpêtrière university hospital, Paris, France
Objectives: Intravenous morphine titration has currently become the gold standard for pain management. However, concerns over accurate morphine titration adapted to the patient’s need persist. The goal of this study was to develop a population kinetic pharmacodynamic (K-PD) model describing the morphine-induced analgesia during i.v. morphine titration in the immediate postoperative period and to evaluate sedation occurrence according to morphine dose in this setting.
Methods: Data was collected from patients undergoing major orthopedic surgery, who received titrated i.v. morphine during the immediate postoperative period 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 analyzed using a non-linear mixed-effect model NONMEM (version VI). 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.
Results: 1289 pain assessments from 228 patients were available for population modeling. The time course of the morphine-induced analgesia was best described by an indirect response model with an inhibitory function affecting pain onset (Kin) (1). Since model development depended solely on the assessed PD data where no PK data are available, a (K-PD) approach was employed (2), and the elimination half-life for morphine (t½) was fixed at 180 min (3). Mean PD parameters estimations were as follow: pain baseline (BASE) = 67 mm, morphine dose that produces 50% of the maximum analgesia (ED50) = 10.2 mg, first-order rate constant for the dissipation of pain (Kout) = 0.26 min-1 and sigmoidicity parameter (γ) = 1.9. The effects of (i) the delay between extubation and titration DEL, (ii) the intra-operative NSAIDs, and (iii) the initial VASi were significant on ED50. Logistic regression showed that a morphine dose of 20 mg was associated with a high likelihood of sedation occurrence.
Conclusions: The (K-PD) model developed supported the possibility of accurately modeling the time course of a complex response in the absence of PK data. The current data should lead to a more rational management of the immediate postoperative pain.
References:
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[2] Jacqmin P, Snoeck E, van Schaick EA, Gieschke R, Pillai P, Steimer JL, Girard P. Modelling Response Time Profiles in the Absence of Drug Concentrations: Definition and Performance Evaluation of the K-PD Model. J Pharmacokinet Pharmacodyn 2007;34(1):57-85.
[3] Lugo RA, Kern SE. Clinical pharmacokinetics of morphine. J Pain Palliat Care Pharmacother 2002;16(4):5-18.