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Enduring and well-tolerated analgesia for total knee arthroplasty postsurgical pain produced by a single, rapidly-eliminated, intraoperative instillation of 4975
Jeffrey C. Davis, MD1, Hayes T. Williams, MD1, Kenneth W. Bramlett, MD1, Thomas E. Powell, MD1, Abraham Schuster, MD1, Patricia T. Richards, MD, PhD2, K. Peony Yu, MD3, and Daniel Gennevois, MD3. (1) Capstone Clinical Trials, Inc., 2018 Brookwood Medical Center Drive, Suite 314, Birmingham, AL 35209, (2) JDS Pharmaceuticals, 405 Lexington Avenue, 59th Floor, New York, NY 10174, (3) Anesiva, Inc., 650 Gateway Boulevard, South San Francisco, CA 94080
4975 is a long-acting, non-opioid, TRPV1-specific analgesic for moderate-to-severe pain with demonstrated efficacy in postsurgical pain, osteoarthritis, intermetatarsal neuroma, and tendonitis. In this 12-week study, 50 patients undergoing unilateral total knee arthroplasty (TKA) were randomized to receive a single intra-operative instillation of 60mL 4975 (5mg; n=25) or placebo (n=25). Patients also received a preoperative femoral nerve block with ropivacaine (0.5%, 10–30mL); intra-operative bupivacaine (0.25%, up to 40mL via wound infiltration); pre-, intra-, and postoperative ketorolac (15–90mg, IV); and postoperative morphine (up to 10mg, IV bolus), IV PCA morphine (0.5–2mg bolus with 6-minute lockout [≤40mg every 4 hours]), and hydrocodone/acetaminophen (7.5mg/500mg). Notwithstanding this underlying multimodal analgesic protocol, patients receiving 4975 experienced less postsurgical pain than those receiving placebo. Average pain on first ambulation, as measured using an 11-point Numerical Rating Scale on days 1–14, was lower on days 1–2, 3–7, and 8–14 in the 4975 group; the difference was significant on day 1 (5.4±2.48 vs. 7.1±2.47; P=0.027). Moreover, at week 2, the 4975 group had significantly lower mean scores for “pain right now” (2.5±2.02 vs. 3.8±2.45; P=0.049) and “worst pain over the last 24 hours” (3.9±2.32 vs. 5.9±2.64; P=0.007) on the Brief Pain Inventory (assessed at 2, 6, and 12 weeks). Overall adverse event profiles and wound healing assessments were generally similar in the two treatment groups. At week 12, the two treatment groups displayed similar sensitivities to light touch, pain, and temperature at the procedural knee. 4975 exhibited low systemic distribution (CMAX=0.98±1.20ng/mL) and rapid turnover (tMAX=0.61±0.40hr; t˝=1.31±0.84hr). In conclusion, when added to a multimodal analgesic protocol, a single, rapidly-eliminated, intra-operative instillation of 4975 significantly reduced acute postsurgical pain from TKA for at least 2 weeks, without affecting overall safety, wound healing, or sensation.