A Novel, Potent and Non-addictive Analgesic of Combinations for Knee Replacement Moderate to Severe Pain Management

Randomized, double-blind, parallel-group, 3-arm, oral Placebo A 650 mg + Naldebain 37.5 mg (0.5 mL oil solution) + Tween 20 and PEG 400 (1 capsule), oral SafeTynadol 650 mg + Placebo B (0.5 mL oil solution) + Tween 20 and PEG 400 (1 capsule), oral Naldebain 37.5 mg (0.5 mL oil solution) + SafeTynadol 650 mg + Tween 20 and PEG 400 (1 capsule), multiple doses for 3 days. Dosing at 0（2 ± 2 hour after surgery）, 6 ± 2, 14 ± 2, 22 ± 2, 34 ± 2, 46 ± 2, 58 ± 2 and 70 ± 2 hours after the first dose.

The complete evaluable 36 subjects (12 subjects in each group) will be analysis in this study. The experiment is divided into three groups of 12 people each. All subjects will be evaluated pharmacokinetics by drawing blood single point at 70.75 ± 2 hours after the first dose..

The population for this study in patients scheduled for knee replacement.

Each group of 12 subjects are administered group 1-3 from day 1-4 after surgery. Dosing at 0（2 ± 2 hour after surgery）, 6 ± 2, 14 ± 2, 22 ± 2, 34 ± 2, 46 ± 2, 58 ± 2 and 70 ± 2 hours after the first dose. Mode of administration of oral Naldebain 37.5 mg (0.5 mL oil solution) or Placebo B (0.5 mL oil solution) is withdrawing 0.5 mL of Naldebain 37.5 mg (0.5 mL oil solution) or Placebo B (0.5 mL oil solution) from the vial by a syringe, then is injected into the empty capsule and dispense within 10 minutes prior to dosing.

Screening (Days -30 to -1) (All Study Subjects)

The nature of the study as well as the potential risks and benefits associated with study participation will be fully explained to all potential subjects. The following will then be obtained:

1. Informed consent. 2. Demographic information, including height and weight. 3. Vital signs (temperature, respiratory rate, blood pressure and heart rate). 4. Medical history, including medication use. 5. Complete physical examination including 12-lead ECG. 6. Laboratory testing (blood 50 ± 5 mL) to include the following:

1. CBC with differential, platelets, White blood cell count (WBC), Red blood cell count (RBC), Hemoglobin, Hematocrit, Mean cell volume (MCV), Mean cell hemoglobin (MCH), Mean cell hemoglobin concentration (MCHC), Platelet count, Differential white cell count. 2. Blood chemistry screen (Glucose, AST, ALT, BUN, creatinine, K, Na, Antibody screening, ABO Grouping \& RH Type, Activated partial thromboplastin time, Prothrombin time). 3. Galactose single-point (GSP) test. 4. Urine pregnancy test (female only) (not applicable to female who has stopped menstruating for at least five years). 7. CHEST PA VIEW