BACKGROUND Results from studies with a combination of oral morphine and oxycodone in postsurgical patients demonstrate significant analgesia and a tolerability profile comparable to other pain medications at morphine-equivalent doses. However, an intravenous (IV) combination has not previously been studied. OBJECTIVE This study evaluated the efficacy and tolerability of IV morphine versus a combination of IV morphine and IV oxycodone in a 1:1 ratio. METHODS This was a 2-center, randomized, double-blind, active-controlled pilot trial of 40 patients who had undergone total hip replacement. After surgery, when pain levels reached ≥4 (on the 11-point Numerical Pain Rating Scale), patients were randomized to 1 of 2 treatment groups. In part 1 of the study, patients were dosed every 5 minutes for the first 65 minutes (up to 13 doses) with study drug, provided that vital signs criteria were met. After an initial loading dose of either morphine 1.5 mg coadministered with oxycodone 1.5 mg or morphine 3 mg alone, patients received IV morphine 1.5 mg or IV morphine 0.75 mg/IV oxycodone 0.75 mg every 5 minutes. If patients achieved a pain score of 2 or experienced intolerable adverse events to drug when stable, they were permitted to enter part 2. In part 2, patients received blinded study medication (IV morphine plus IV oxycodone [0.5 mg/0.5 mg] or 1 mg IV morphine alone) via patient-controlled analgesia (PCA) for 47 hours. RESULTS At baseline, treatment groups were comparable except for a higher proportion of females in the IV morphine group. Baseline pain intensity averaged 7 on the Numerical Pain Rating Scale of 0 to 10. One patient in the morphine group and 2 patients in the morphine/oxycodone group discontinued the study. The sum of the pain intensity differences from baseline to 65 minutes during the dose-titration phase was 1.8 for morphine alone versus 2.7 for morphine/oxycodone (P = 0.12); these values occurred at the same median number of doses (12) for each group. In part 2 (PCA dosing) of the study, similar levels of analgesia were achieved. During the study, 24% of the IV morphine/oxycodone group and 37% of the IV morphine group experienced nausea, and 10% of the IV morphine/oxycodone group and 16% of the IV morphine group had emesis. Two patients in the IV morphine/oxycodone group and 4 in the IV morphine alone group experienced oxygen desaturation. CONCLUSIONS The combination of IV morphine and oxycodone provided pain relief with an acceptable tolerability profile in these patients experiencing moderate to severe postoperative pain. However, as an explorative pilot study, the power was not adequate to demonstrate statistical significance for differences between IV morphine/oxycodone and IV morphine alone. European Clinical Trials Data Base registration code: EudraCT-No. 2008-008527-14.