• - Relationships between morphine consumption, clinical events (efficacy or adverse effects) and morphine (and metabolites) blood concentrations. Immediate postoperative period (PACU) [ Time Frame: Immediate postoperative period (PACU) ] [ Designated as safety issue: No ]
• - Relationships between clinical events (pain relief, failure in pain relief, adverse effects) and genetic polymorphism. [ Time Frame: Immediate postoperative period (PACU) ] [ Designated as safety issue: No ]
• - Relationships between sub-acute clinical events and PK/PG profile. (on the wards at 24 hours after surgery) [ Time Frame: on the wards at 24 hours after surgery ] [ Designated as safety issue: No ]
• To better characterize the age- and sex-related differences which differ between acute and sub-acute periods. [ Time Frame: during the study ] [ Designated as safety issue: No ]

The main objective of this study is to improve our knowledge on the pharmacodynamic, pharmacokinetic, and pharmacogenetic relationships of morphine administered to relief severe postoperative pain. The analysis will encompass the efficacy (acute during titration and subacute during the first 24 hours) and adverse effects of morphine. Our purpose is also to better characterize the age- and sex-related differences which probably markedly differ between the two periods (acute vs sub acute).

No previous study attempted to characterize the pharmacodynamic, pharmacokinetic, and pharmacogenetic relationships of morphine in the early postoperative period, whereas it is the main clinical situation for severe pain and a unique model for its study (not possible in the healthy volunteer). Indeed, intravenous titration of morphine is the first step for pain control in the postanesthesia care unit. Administration of intravenous boluses of morphine enables to obtain complete pain relief in 98% of the patients. We intend to study the effects of morphine (intravenous titration then patient-controlled intravenous administration (PCA) for 24 hours), perform dosages of plasma concentration of morphine an its main metabolites, and also study gene polymorphisms coding for main proteins involved in the pharmacokinetic and pharmacodynamic profile of morphine (hepatic metabolism, distribution and elimination, interaction with morphine receptor). Five hundred patients scheduled for major orthopedic surgery will be included in this prospective study. The main objective of this study is to improve our knowledge on the pharmacodynamic, pharmacokinetic, and pharmacogenetic relationships of morphine administered to relief severe postoperative pain. The analysis will encompass the efficacy (acute during titration and subacute during the first 24 hours) and adverse effects of morphine. Our purpose is also to better characterize the age- and sex-related differences which probably markedly differ between the two periods (acute vs subacute). We consider that this knowledge is important to confirm or not several important concepts currently used to define the appropriate analgesic regimen to control severe pain in the postoperative period.

Inclusion criteria :

• scheduled major orthopedic surgery
• spine, hip or knee surgery
• Body weight between 50 and 100 kg
• Caucasians
• ASA status 1 to 3
• no cognitive dysfunction

Exclusion criteria :

• allergy or contraindication to morphine
• renal impairment (Cr Cl < 30 ml/min)
• severe hepatic impairment
• surgery performed under regional anaesthesia
• preoperative treatment including strong or weak opioids
• pregnancy, patients under 18 years, addiction