A Randomized, Double-Blind, Active Controlled Study Comparing the Intravenous Dose of Morphine and Oxycodone Combined in a Ratio of 1:1 Versus Morphine Alone Required to Achieve Effective Pain Control After Total Hip Replacement and the Untoward Effects of Combined Morphine and Oxycodone vs. Morphine Alone

INTERVENTION: Trade Name: Oxygesic Injekt 10mg/1ml Product Name: Oxygesic injekt 10mg/1 ml Pharmaceutical Form: Injection* INN or Proposed INN: OXYCODONE HYDROCHLORIDE CAS Number: 124903 Concentration unit: % (W/V) percent weight/volume Concentration number: 10mg/‐1ml Trade Name: Morphin Merck 10 mg Product Name: Morphin Merck 10 mg Pharmaceutical Form: Injection* CAS Number: 52266 Other descriptive name: MORPHINE HYDROCHLORIDE Concentration unit: % (W/V) percent weight/volume Concentration number: 10mg/‐1ml CONDITION: To determine whether the intravenous coadministration of morphine and oxycodone has fewer opioid related adverse effects (AEs) than morphine alone at doses that result in effective and equi‐analgesic pain relief for acute post operative pain, and to determine the doses of morphine and oxycodone co‐administered versus morphine required to achieve effective pain relief. ; MedDRA version: 9.1 Level: LLT Classification code 10036276 Term: Postoperative analgesia ; MedDRA version: 9.1 Level: LLT Classification code 10054710 Term: Postoperative hip pain INCLUSION CRITERIA: To qualify for enrollment in this study, the patient must: ‐have voluntarily provided written informed consent and HIPAA authorization prior to any study‐related procedures are performed; ‐be male or female, at least 18 years of age, at the time of enrollment; ‐have undergone a primary unilateral total hip replacement performed under standardized general, spinal, or epidural anesthesia; ‐be scored I‐III on the American Society of Anesthesiologists (ASA) physical status classification system; ‐have developed moderate or severe pain on a 11‐point NPRS (> 4) scale within 6 hours post end of surgery (time of last stitch)on the day of surgery. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range PRIMARY OUTCOME: Main Objective: To compare the side effects with multiple dose intravenous coadministration of morphine and oxycodone vs. morphine alone at doses that result in effective relief of pain, defined as a score of 2 or less on the 11 point NPRS (Numeric Pain Rating Scale) Primary end point(s): Treatment Period – Part 1; 1. The number (%) of patients in the morphine/oxycodone and morphine treatment groups who achieve the target pain score defined as mild or no pain on the 4 point Likert scale or 2 or less on the 11 point NPRS (NCA responders). ; 2. The change in pain scores from baseline, as well as the percentage of patients categorized as Responders for the following time intervals: during the NCA period just prior to administration of study medication at Time 0 (Baseline) to 30 min and to 60 minutes and to the end of the NCA period (Part 1), and every 4 hours during the PCA (Part 2) period until hour 48 or time or early termination. Responders are defined as subjects with a decrease from baseline in NPRS score of at least 30%. Responder analysis will also be evaluated for decrease from baseline in NPRS score or 10%, 20%. 40%,and 50%. ; 3. The amount of study medication (measured in “mg”) required by patients in each treatment group for the Part 1 and Part 2 time intervals specific in item 2, above. ; 4. Patient Global Assessment of Effectiveness at approximately 8AM on the day following surgery (Day 2) and at hour 48 or at time of early termination.; 5. The amount of supplemental analgesia (measured in “mg”) required by patients in each treatment group on Day 1 (for each time interval and overall). ; 6. Time to first dose of PCA medication from the end of NCA, for NCA responders in each treatment group.; Treatment Period – Part 2; 1. SPID4H scores for the following time intervals: from the start of Part 2 on Day 1 to the end of the 48 hour evaluation period ; 2. Percent Reduction Responders from the start of Part 2 on Day 1 to the 8 AM on Day 2 and from 8 AM on Day 2 to Hour 48. Responders are defined as subjects with a decrease from baseline in NPRS score of at least 30%.. Responder analysis will also be evaluated for decrease from baseline in NPRS score or 10%, 205. 40%,and 50%. ; 3. The amount of study medication (measured in “mg”) required by patients in each treatment group for the following time intervals: from the start of Part 2 on to the end of the study. ; 4. Patient Global Assessment of Efficacy for the following time intervals: from the start of Part 2 on Day 1 to the end of the study. ; 5. The amount of supplemental analgesia (measured in “mg”) required by patients in each treatment group from the start of Part 2 to the end of the 48 hour evaluation period will also be determined.; For the efficacy endpoints, observations will be summarized by treatment group and by analysis populations. ; Secondary Objective: To compare the doses of opioid used and the analgesic efficacy provided by intravenous morphine plus oxycodone versus morphine alone in all study participants, including patients who do not achieve the target NPRS score (= 2) for comparison of equi‐analgesic effects.; ; To evaluate the safety and tolerability of intravenous co administration of morphine and oxycodone compared to morphine alone following repeat administration of study medication during the post operative period. ;